MSAC Assessment Report Template
Immunoglobulin for acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT)August 2019MSAC Application no. 1565Assessment report? Commonwealth of Australia 2019ISSN (Online) 1443-7139Internet site work is copyright. You may download, display, print and reproduce this material in unaltered form only (retaining this notice) for your personal, non-commercial use or use within your organisation. Apart from any use as permitted under the Copyright Act 1968, all other rights are reserved. Requests and inquiries concerning reproduction and rights should be addressed to Commonwealth Copyright Administration, Attorney-General's Department, Robert Garran Offices, National Circuit, Barton ACT 2600 or posted at copies of the report can be obtained from the Medical Service Advisory Committee’s Internet site at about the content of the report should be emailed to hta@.au.The technical information in this document is used by the Medical Services Advisory Committee (MSAC) to inform its deliberations. MSAC is an independent committee which has been established to provide advice to the Minister for Health on the strength of evidence available on new and existing medical technologies and procedures in terms of their safety, effectiveness and cost effectiveness. This advice will help to inform government decisions about which medical services should attract funding under Medicare.MSAC’s advice does not necessarily reflect the views of all individuals who participated in the MSAC evaluation.This report was prepared by Allison Wyndham, Arlene Vogan, Skye Newton and Camille Schubert from Adelaide Health Technology Assessment (AHTA), the University of Adelaide. Clinical advice was provided by the Ig Review Reference Group. The report was commissioned by the Australian Government Department of Health. The suggested citation for this document is:Wyndham, A, Vogan, A, Newton, S, Schubert, C. (2019). Immunoglobulin for acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT). MSAC Application 1565, Assessment Report. Commonwealth of Australia, Canberra, ACT.Contents TOC \o "1-3" \h \z \u Contents PAGEREF _Toc16856262 \h iiiTables PAGEREF _Toc16856263 \h viiFigures PAGEREF _Toc16856264 \h xiExecutive Summary PAGEREF _Toc16856265 \h 1Immunoglobulin for acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT) PAGEREF _Toc16856266 \h 1Alignment with agreed PICO Confirmation PAGEREF _Toc16856267 \h 2Medical Service PAGEREF _Toc16856268 \h 2Public Funding PAGEREF _Toc16856269 \h 3Population PAGEREF _Toc16856270 \h 3Comparator Details PAGEREF _Toc16856271 \h 4Clinical management algorithm(s) PAGEREF _Toc16856272 \h 5Key Differences in the Delivery of the Proposed Medical Service and the Main Comparator PAGEREF _Toc16856273 \h 5Clinical Claim PAGEREF _Toc16856274 \h 5Approach Taken to the Evidence Assessment PAGEREF _Toc16856275 \h 5Characteristics of the Evidence Base PAGEREF _Toc16856276 \h 6Results PAGEREF _Toc16856277 \h 7Translation Issues PAGEREF _Toc16856278 \h 10Economic Evaluation PAGEREF _Toc16856279 \h 12Estimated Extent of Use and Financial Implications PAGEREF _Toc16856280 \h 14Consumer impact summary PAGEREF _Toc16856281 \h 15Acronyms and Abbreviations PAGEREF _Toc16856282 \h 16Section AContext PAGEREF _Toc16856283 \h 18A.1.Items in the agreed PICO Confirmation PAGEREF _Toc16856284 \h 18A.2.Medical Service Reviewed PAGEREF _Toc16856285 \h 19Current funding arrangements PAGEREF _Toc16856286 \h 19Marketing status of IgG products PAGEREF _Toc16856287 \h 20Current Clinical Practice PAGEREF _Toc16856288 \h 21Other Indications PAGEREF _Toc16856289 \h 23A.3.Public Funding PAGEREF _Toc16856290 \h 24A.4.Population PAGEREF _Toc16856291 \h 24A.parator Details PAGEREF _Toc16856292 \h 26A.6.Clinical management Algorithm(s) PAGEREF _Toc16856293 \h 27A.7.Key Differences in the Delivery of the Medical Service and the Main Comparator PAGEREF _Toc16856294 \h 29A.8.Clinical Claim PAGEREF _Toc16856295 \h 29A.9.Summary of the PICO PAGEREF _Toc16856296 \h 29A.10.Consumer impact statement PAGEREF _Toc16856297 \h 30Section BClinical Evaluation PAGEREF _Toc16856298 \h 32B.1.Literature Sources and Search Strategies PAGEREF _Toc16856299 \h 32B.2.Results of Literature Search PAGEREF _Toc16856300 \h 32Appraisal of the evidence PAGEREF _Toc16856301 \h 33B.3.Risk of Bias Assessment PAGEREF _Toc16856302 \h 33B.4.Characteristics of the Evidence Base PAGEREF _Toc16856303 \h 34B.5.Outcome Measures and Analysis PAGEREF _Toc16856304 \h 41B.6.Results of the Systematic Literature review PAGEREF _Toc16856305 \h 42Is it safe? PAGEREF _Toc16856306 \h 42Systemic and other AEs including infusion reactions PAGEREF _Toc16856307 \h 43Thromboembolic events (TEEs) PAGEREF _Toc16856308 \h 49Studies presenting no safety data PAGEREF _Toc16856309 \h 50Is it effective? PAGEREF _Toc16856310 \h 51Infections PAGEREF _Toc16856311 \h 58Resource Use Outcomes Presented as Infectious Complications PAGEREF _Toc16856312 \h 67Survival and/or Mortality PAGEREF _Toc16856313 \h 71Transplant-related outcomes PAGEREF _Toc16856314 \h 72Quality of Life PAGEREF _Toc16856315 \h 74B.7.Extended Assessment of Harms PAGEREF _Toc16856316 \h 75B.8.Interpretation of the Clinical Evidence PAGEREF _Toc16856317 \h 76Section CTranslation Issues PAGEREF _Toc16856318 \h 80C.1.Overview PAGEREF _Toc16856319 \h 80C.2.Applicability translation issues PAGEREF _Toc16856320 \h 80C.2.1. Patient demographics and settings PAGEREF _Toc16856321 \h 80C.2.2. Antibiotic use in the absence of Ig PAGEREF _Toc16856322 \h 82C.2.3. Dose of Ig PAGEREF _Toc16856323 \h 83C.2.4. Duration of Ig treatment PAGEREF _Toc16856324 \h 85C.3.Extrapolation translation issues PAGEREF _Toc16856325 \h 86C.3.1.What is the duration of the treatment effect of Ig in patients with acquired hypogammaglobulinaemia? PAGEREF _Toc16856326 \h 86C.3.2. What is the natural history of recurrent infections in patients with acquired hypogammaglobulinaemia? PAGEREF _Toc16856327 \h 87C.4.Transformation issues PAGEREF _Toc16856328 \h 88C.4.1. Transformation of outcomes into a common, patient-relevant outcome PAGEREF _Toc16856329 \h 88C.5.Relationship of each Pre-Modelling Study to the Economic Evaluation PAGEREF _Toc16856330 \h 91Section DEconomic Evaluation PAGEREF _Toc16856331 \h 93D.1.Overview PAGEREF _Toc16856332 \h 93D.2.Populations and settings PAGEREF _Toc16856333 \h 93D.3.Structure and rationale of the economic evaluation PAGEREF _Toc16856334 \h 95Literature review PAGEREF _Toc16856335 \h 95Structure of the economic evaluation PAGEREF _Toc16856336 \h 97D.4.Inputs to the economic evaluation PAGEREF _Toc16856337 \h 99D.4.1. Transition probabilities PAGEREF _Toc16856338 \h 99D.4.2. Resource use PAGEREF _Toc16856339 \h 104D.4.3. Utility weights PAGEREF _Toc16856340 \h 110D.5.Results of the economic evaluation PAGEREF _Toc16856341 \h 111D.5.1. Stepped economic evaluation PAGEREF _Toc16856342 \h 111D.5.2. Modelled base case analysis PAGEREF _Toc16856343 \h 112D.6.Sensitivity analyses PAGEREF _Toc16856344 \h 115D.6.1. Cost per gram of Ig PAGEREF _Toc16856345 \h 115D.6.2. Scenario based on the study which included antibiotic prophylaxis PAGEREF _Toc16856346 \h 115D.6.3. Scenarios based on the best estimates of analysis for specific indications PAGEREF _Toc16856347 \h 116D.6.4.Univariate sensitivity analyses PAGEREF _Toc16856348 \h 120Section EFinancial Implications PAGEREF _Toc16856349 \h 122E.1.Justification of the selection of sources of data PAGEREF _Toc16856350 \h 122E.2.Use and cost of Ig for acquired hypogammaglobulinaemia PAGEREF _Toc16856351 \h 123Estimated number of patients who receive Ig PAGEREF _Toc16856352 \h 123Estimated use and cost per patient who receives Ig PAGEREF _Toc16856353 \h 124E.3.Changes in use and cost of other medical services PAGEREF _Toc16856354 \h 127E.4.Financial implications for government health budgets PAGEREF _Toc16856355 \h 128E.5.Identification, estimation and reduction of uncertainty PAGEREF _Toc16856356 \h 129Appendix AClinical Experts and Assessment Group PAGEREF _Toc16856357 \h 131Assessment group PAGEREF _Toc16856358 \h 131Appendix BSearch strategies PAGEREF _Toc16856359 \h 132Bibliographic databases PAGEREF _Toc16856360 \h 132Appendix CStudies included in the Systematic Review PAGEREF _Toc16856361 \h 135Appendix DEvidence Profile Tables PAGEREF _Toc16856362 \h 138Appendix EExcluded Studies PAGEREF _Toc16856363 \h 153Appendix FSupporting clinical data PAGEREF _Toc16856364 \h 156Appendix GEconomic analysis appendices PAGEREF _Toc16856365 \h 168Overview PAGEREF _Toc16856366 \h 168Structure and rationale of the economic evaluation PAGEREF _Toc16856367 \h 168Inputs to the economic evaluation PAGEREF _Toc16856368 \h 170Resource use PAGEREF _Toc16856369 \h 170Sensitivity analyses PAGEREF _Toc16856370 \h 170Appendix HFinancial implications appendix PAGEREF _Toc16856371 \h 173Identification, estimation and reduction of uncertainty PAGEREF _Toc16856372 \h 173Attachment 1 PAGEREF _Toc16856373 \h 174References PAGEREF _Toc16856374 \h 179Tables TOC \h \z \c "Table" Table 1 Ig products funded for this indication PAGEREF _Toc16671599 \h 15Table 2 Relevant trimethoprim + sulfamethoxazole listings on the PBS PAGEREF _Toc16671600 \h 17Table 3 Population, Intervention and Comparator: Acquired Hypogammaglobulinaemia due to haematological conditions PAGEREF _Toc16671601 \h 17Table 4 Balance of clinical benefits and harms of IgG with antibiotics as required, relative to No IgG with antibiotics as required (GRADE assessment) PAGEREF _Toc16671602 \h 21Table 5 Summary of results of pre-modelling studies and their uses in the economic evaluation PAGEREF _Toc16671603 \h 22Table 6Summary of the economic evaluation PAGEREF _Toc16671604 \h 24Table 7 Results of the stepped economic analysis PAGEREF _Toc16671605 \h 25Table 8 Key sensitivity analyses PAGEREF _Toc16671606 \h 26Table 9 Net financial implications to government associated with Ig for acquired hypogammaglobulinaemia PAGEREF _Toc16671607 \h 27Table 10IgG products registered on the ARTG for use in Australia PAGEREF _Toc16671608 \h 32Table 11Ig products funded for this indication PAGEREF _Toc16671609 \h 32Table 12Numbers of patients receiving funded IgG for this indication (2017-18) PAGEREF _Toc16671610 \h 38Table 13Relevant trimethoprim + sulfamethoxazole listings on the PBS PAGEREF _Toc16671611 \h 38Table 14Population, Intervention and Comparator: Acquired Hypogammaglobulinaemia due to haematological conditions PAGEREF _Toc16671612 \h 42Table 15Key features of the included studies PAGEREF _Toc16671613 \h 48Table 16Comparative studies presenting systemic AE outcomes – IVIg vs No IVIg PAGEREF _Toc16671614 \h 55Table 17Comparative studies presenting systemic and other AE outcomes – SCIg vs No SCIg PAGEREF _Toc16671615 \h 57Table 18Studies presenting systemic and other AE outcomes for IgG case series PAGEREF _Toc16671616 \h 58Table 19Case series presenting systemic and other AE outcomes for more than one IgG group PAGEREF _Toc16671617 \h 60Table 20Studies presenting TEE outcomes – Ammann et al., 2016 PAGEREF _Toc16671618 \h 61Table 21Included studies presenting no AE data PAGEREF _Toc16671619 \h 62Table 22Baseline risk of infection in the included studies: serum IgG and history of infections PAGEREF _Toc16671620 \h 64Table 23Studies presenting resource use – comparative studies (RCTs and cohort studies) PAGEREF _Toc16671621 \h 79Table 24Studies presenting resource use – non-comparative studies PAGEREF _Toc16671622 \h 81Table 25Studies presenting survival and mortality PAGEREF _Toc16671623 \h 83Table 26Transplant-related outcomes – Sullivan et al., 1990 (IVIg vs No IVIg) PAGEREF _Toc16671624 \h 85Table 27Transplant-related outcomes – Sundin et al., 2012 (IVIg vs SCIg) PAGEREF _Toc16671625 \h 86Table 28Utility weights based on AQOL-6D survey PAGEREF _Toc16671626 \h 87Table 29Balance of clinical benefits and harms of IgG with antibiotics as required, relative to No IgG with antibiotics as required (GRADE assessment) PAGEREF _Toc16671627 \h 91Table 30A comparison of the demographics of the Australian population that receives Ig for acquired hypogammaglobulinaemia to those in the clinical evidence PAGEREF _Toc16671628 \h 94Table 31Analysis of prophylactic antibiotic use and infection outcomes from Duraisingham et al. (2014) PAGEREF _Toc16671629 \h 96Table 32A comparison of the doses dispensed in the Australian population that receives Ig for acquired hypogammaglobulinaemia to that used in the clinical evidence PAGEREF _Toc16671630 \h 97Table 33Utility weights used in the relevant economic literature PAGEREF _Toc16671631 \h 102Table 34Utility weights used in the economic evaluation PAGEREF _Toc16671632 \h 103Table 35Summary of results of pre-modelling studies and their uses in the economic evaluation PAGEREF _Toc16671633 \h 104Table 36Summary of the economic evaluation PAGEREF _Toc16671634 \h 108Table 37Transition probability matrix used in Windegger et al. (2019) PAGEREF _Toc16671635 \h 110Table 38Incidence of non-serious to serious infections PAGEREF _Toc16671636 \h 112Table 39Relative treatment effect of Ig PAGEREF _Toc16671637 \h 113Table 40Average duration of infection by model arm PAGEREF _Toc16671638 \h 113Table 41Per cycle probability of infection resolution in patients who had not died or developed bronchiectasis PAGEREF _Toc16671639 \h 113Table 42Remaining transition probabilities from the infection health state PAGEREF _Toc16671640 \h 114Table 43Adjusted transition probabilities of developing infections in bronchiectasis PAGEREF _Toc16671641 \h 115Table 44Transition probability matrix PAGEREF _Toc16671642 \h 117Table 45Cost per cycle of Ig PAGEREF _Toc16671643 \h 118Table 46Ongoing disease management costs included in the model PAGEREF _Toc16671644 \h 119Table 47Average cost to treat a serious infection PAGEREF _Toc16671645 \h 120Table 48Estimated cost of treating infections, by infection severity PAGEREF _Toc16671646 \h 120Table 49Average cost of treating infections by model arm PAGEREF _Toc16671647 \h 121Table 50Cost associated with the management of bronchiectasis PAGEREF _Toc16671648 \h 121Table 51Average cost of treating infections by model arm PAGEREF _Toc16671649 \h 122Table 52Cost per cycle in the chronic P. aeruginosa infection health state PAGEREF _Toc16671650 \h 122Table 53Health state costs per cycle PAGEREF _Toc16671651 \h 123Table 54Utility weights used in the economic evaluation PAGEREF _Toc16671652 \h 123Table 55Results of the stepped economic analysis PAGEREF _Toc16671653 \h 124Table 56Disaggregated costs PAGEREF _Toc16671654 \h 125Table 57Disaggregated LYs and QALYs PAGEREF _Toc16671655 \h 125Table 58Incremental cost-effectiveness ratios PAGEREF _Toc16671656 \h 128Table 59Scenario analyses regarding the cost of Ig PAGEREF _Toc16671657 \h 128Table 60Scenario analyses based on the study which included antibiotic prophylaxis PAGEREF _Toc16671658 \h 128Table 61Scenario analyses estimating indicative cost-effectiveness per indication PAGEREF _Toc16671659 \h 130Table 62Disaggregated events estimated for each of the per-indication analyses PAGEREF _Toc16671660 \h 132Table 63Key sensitivity analyses PAGEREF _Toc16671661 \h 133Table 64Number of patients who received Ig by indication, 2011-12 to 2017-18 PAGEREF _Toc16671662 \h 135Table 65Ig grams issued by indication, 2011-12 to 2017-18 PAGEREF _Toc16671663 \h 136Table 66Number of patients projected to receive Ig by indication, 2019-20 to 2023-24 PAGEREF _Toc16671664 \h 137Table 67Number of Ig grams issued by indication, 2019-20 to 2023-24 PAGEREF _Toc16671665 \h 138Table 68Average Ig use (g) per patient per year PAGEREF _Toc16671666 \h 138Table 69Cost of Ig for acquired hypogammaglobulinaemia, 2019-20 to 2023-24 PAGEREF _Toc16671667 \h 139Table 70Average number of treatment episodes per year PAGEREF _Toc16671668 \h 140Table 71Additional costs due to Ig administration PAGEREF _Toc16671669 \h 140Table 72Cost offsets associated with Ig use due to a reduction in infections PAGEREF _Toc16671670 \h 141Table 73Net financial implications to government associated with Ig for acquired hypogammaglobulinaemia PAGEREF _Toc16671671 \h 142Table 74Sensitivity analyses around the financial implication estimates PAGEREF _Toc16671672 \h 142Table 75Search terms for IgG replacement in patients with hypogammaglobulinaemia due to haematological malignancies (Pubmed) PAGEREF _Toc16671673 \h 146Table 76 Further searches for bone marrow transplantation (Pubmed example) PAGEREF _Toc16671674 \h 147Table 77List of the included studies PAGEREF _Toc16671675 \h 149Table 78List of the included studies as they apply to the NBA-funded conditions PAGEREF _Toc16671676 \h 150Table 79Included study profiles for safety and effectiveness – RCTs PAGEREF _Toc16671677 \h 152Table 80Included study profiles for safety and effectiveness – cohort studies PAGEREF _Toc16671678 \h 157Table 81Included study profiles for safety and effectiveness – case series PAGEREF _Toc16671679 \h 160Table 82List of the excluded systematic reviews or meta-analyses PAGEREF _Toc16671680 \h 167Table 83List of the excluded studies PAGEREF _Toc16671681 \h 167Table 84Antibiotic use and infection prophylaxis in the included studies PAGEREF _Toc16671682 \h 170Table 85Randomised studies presenting infections – IVIg vs no IVIg PAGEREF _Toc16671683 \h 172Table 86Randomised studies presenting infections – SCIg vs no SCIg PAGEREF _Toc16671684 \h 175Table 87Cohort studies presenting infections – IVIg vs no IVIg PAGEREF _Toc16671685 \h 175Table 88Studies presenting infections within sub-groups – Blombery et al., 2011 PAGEREF _Toc16671686 \h 176Table 89Case series presenting within-patient (before/after) infections outcomes – IVIg PAGEREF _Toc16671687 \h 176Table 90Non-comparative studies presenting within-patient (before/after) infections outcomes – SCIg PAGEREF _Toc16671688 \h 178Table 91IVIg+SCIg studies – infections outcomes as a single group PAGEREF _Toc16671689 \h 178Table 92Studies comparing infections outcomes between routes of administration – IVIg vs SCIg PAGEREF _Toc16671690 \h 180Table 93Supportive studies comparing infections outcomes between dose levels PAGEREF _Toc16671691 \h 181Table 94Decision algorithm for undertaking an economic evaluation in the setting of the Ig Review PAGEREF _Toc16671692 \h 182Table 95Economic literature search terms PAGEREF _Toc16671693 \h 182Table 96Estimation of Ig costs PAGEREF _Toc16671694 \h 184Table 97Sensitivity analyses PAGEREF _Toc16671695 \h 184Table 98Estimation of the average weighted cost per gram within the acquired hypogammaglobulinemia indictaion PAGEREF _Toc16671696 \h 187Figures TOC \h \z \c "Figure" Figure 1Treatment algorithm PAGEREF _Toc16671697 \h 40Figure 2 Summary of the process used to identify and select studies for the assessment PAGEREF _Toc16671698 \h 44Figure 3Randomised trials presenting serious infections – IgG vs No IgG groups PAGEREF _Toc16671699 \h 71Figure 4Randomised trials presenting other infections – IgG vs No IgG groups PAGEREF _Toc16671700 \h 71Figure 5Non-randomised trials presenting serious infections – before and after comparison of IgG PAGEREF _Toc16671701 \h 72Figure 6Non-randomised trials presenting total infections – before and after comparison of IgG PAGEREF _Toc16671702 \h 72Figure 7Quality of Life (SF-36) – Vacca et al., 2018 PAGEREF _Toc16671703 \h 86Figure 8State transition model used in Windegger et al. (2019) PAGEREF _Toc16671704 \h 109Figure 9Markov model structure PAGEREF _Toc16671705 \h 111Figure 10Markov model traces PAGEREF _Toc16671706 \h 127Figure 11Patient number projections PAGEREF _Toc16671707 \h 136Figure 12Ig use projections PAGEREF _Toc16671708 \h 137Executive SummaryImmunoglobulin for acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT) Main issues for MSAC considerationTrials were reported for patients with CLL, MM, and those who underwent HSCT. However, no adequate randomised trials were identified in patients with acute leukaemia, NHL, or ‘other haematological malignancies’. It was however considered plausible that similar outcomes would be observed in AL, NHL and ‘other’ haematological malignancies, assuming the patients satisfied the criteria for hypogammaglobulinaemia and history of infections. It was not possible to evaluate the claim that IgG with or without antibiotics is superior to No IgG with or without antibiotics. The clinical evidence in the included studies support a claim of superior efficacy but inferior safety for IgG compared to no IgG (with antibiotic use defined as part of supportive care). This evaluation could not address:Confirmation of a clinically active dose or frequency of dosing. Most studies included explored doses between 200 and 500 mg/kg. Definition of adequate treatment response: a qualitative reduction in infections rate was usually taken as evidence of a response. Timeframes for assessment were highly variable. Criteria for discontinuation. An initial patient response in terms of infections seemed to be adequate reason for ongoing IgG replacement which often lasted for some months or years. Frequency of serum IgG monitoring as a basis for response assessment or a decision to discontinue. Given the underlying uncertainty associated with the estimates of IgG treatment effectiveness, the use of these estimates in the economic model is therefore also associated with uncertainty.A main assumption in the economic model structure allows for the development of bronchiectasis. The inclusion of such health states was based on a recent economic evaluation in Australian patients comparing SCIg to IVIg for acquired hypogammaglobulinaemia ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019). A significant increase in the incremental cost-effectiveness ratio (ICER) is observed when transitions to bronchiectasis health states are not allowed. The resulting ICER from this sensitivity analysis is consistent with that observed in an older relevant economic model PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWVrczwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJl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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWVrczwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJl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 EN.CITE.DATA (Weeks, Tierney & Weinstein 1991) which did not model the development of bronchiectasis. The financial implications for government health budgets associated with Ig include cost offsets due to a reduction in infections. As these are indirect cost-offsets, and assume a relative treatment effect of Ig in reducing the incidence of infections, these are associated with uncertainty.This contracted assessment is part of a pilot process to review the evidence to support funding of immunoglobulin (IgG) for patients with acquired hypogammaglobulinaemia, under the national blood arrangements. This indication is one of several ‘diagnostic groups’ of conditions eligible for funded IgG treatment under the National Blood Authority’s Criteria for Immunoglobulin Use in Australia, Version 3 (the Criteria).Alignment with agreed PICO ConfirmationThis contracted assessment of IgG for acquired hypogammaglobulinaemia addresses all of the PICO elements that were pre-specified in the PICO Confirmation that was ratified by the Ig Review Reference Group. However, the Report needs to be interpreted in the context that there is a limited underlying scientific evidence base available to inform the assessment.Medical ServiceIgG replacement therapy (IgG-RT) is used to compensate for the low levels of serum IgG in patients with hypogammaglobulinaemia. It would be used in combination with standard care, which includes antibiotic use and treatment for the underlying conditions. IgG products are manufactured from pooled human donor plasma, and the IgG fraction formulated to contain the desired concentration of IgG as active substance. The IgG content represents a broad spectrum of human antibodies. Other immunoglobulins such as IgA, IgM and IgE may be present but are controlled as impurities. IgG products may be administered by intravenous (IV), subcutaneous (SC) or intramuscular infusion, although intramuscular administration is out of scope for this evaluation, as it is rarely used in Australia. There are currently 17 IgG products that are registered on the Australian Register of Therapeutic Goods (ARTG). For more information, see REF _Ref1645380 \h \* MERGEFORMAT Table 10, pg. PAGEREF _Ref10110574 \h 32. The recommended dose on BloodSTAR is 0.4 g/kg. The majority of documentation reviewed cites a maintenance dose for IVIg of 0.4 g/kg every four weeks, however, doses lower than 0.4 g/kg may be used during titration.Public FundingThis contracted assessment is to review the use of IgG for an indication which is currently funded under the National Blood Supply Arrangements. The products current funded are shown in REF _Ref10113234 \h \* MERGEFORMAT Table 1. Table SEQ Table \* ARABIC 1Ig products funded for this indicationProductSponsorRoute of Admin.StrengthNBA priceIntragam 10CSL BehringIV2.5g/25mL10g/100mL20g/200mL$146.23$584.93$1,169.86Privigen 10%CSL BehringIV5g/50mL10g/100mL20g/200mL40g/400mL$225.00$450.00$900.00$1,800.00HizentraCSL Behring SC1g/5mL2g/10mL4g/20mL10g/50mL$59.15$118.31$236.61$591.53Flebogamma 5%Grifols IV0.5g/10mL2.5g/50mL5g/100mL10g/200mL20g/400mL$22.50$112.50$225.00$450.00$900.00Flebogamma 10%Grifols IV5g/50mL10g/100mL20g/200mL$225.00$450.00$900.00EvogamCSL Behring SC16% 0.8g/5mL16%3.2g/20mL$46.79$187.18IV=intravenous; SC=subcutaneous Source: PICO Confirmation for MSAC 1565. PopulationAccording to the Criteria Version 3, the indication of acquired hypogammaglobulinaemia covers hypogammaglobulinaemia, when it occurs, secondary to the following specific conditions (or associated treatment):Acute leukaemiaChronic lymphocytic leukaemia (CLL)Multiple myeloma (MM)Non‐Hodgkin lymphoma (NHL)Other Haematological malignancy[Diagnosis of haematological malignancies should be according to the criteria of the current World Health Organization (WHO) classification. ]Memory B cell deficiency secondary to HSCT.The target population is identified by symptoms but covers different underlying haematological malignancies each characterised by low IgG levels. Patients with each condition will differ in clinical characteristics, treatments for underlying disease and prognosis. There are different baseline risks of infection (higher in acute leukaemia and post-HSCT patients) and consequently, a difference in infection treatments among the above conditions. In addition, the baseline risk of intensive care admission is greater for post-HSCT patients than for the other specific conditions. The way in which hypogammaglobulinaemia is diagnosed and treated (with or without access to IgG) is common across the patients in this indication. The Criteria Version 3 provide for IgG supply as follows:Patients with serum IgG less than 4 g/L regardless of episodes of infection or antibiotic use. Patients with serum IgG greater than 4 g/L, IF serum IgG is less than the lower limit of the age-related reference range, AND the patient has had either (1) at least one life-threatening infection in the last 12 months, or (2) two serious infections in the last six months requiring more than standard courses of antibiotics.[Serum IgG refers to values excluding paraprotein]The Ig Review Reference Group noted that a literature search should include a broad definition of the population not constrained by these criteria for access (limited to the haematological malignancies above). Comparator Details The comparator is defined in the ratified PICO Confirmation as ‘No IgG access; with or without antibiotics’. The Ig Review Reference Group advised oral trimethoprim + sulfamethoxazole (sometimes called co-trimoxazole) would be the first line antibiotic for prophylaxis against infections. This combination has a very broad TGA indication and is available on the Pharmaceutical Benefits Scheme (PBS) ( REF _Ref10225080 \h \* MERGEFORMAT Table 2). Table SEQ Table \* ARABIC 2Relevant trimethoprim + sulfamethoxazole listings on the PBSStrengthsBrandsDosage formPack sizeMax QtyRepeatsItem #PBS Benefit Typetrimethoprim 160mg + sulfamethoxazole 800mgResprim ForteSeptrin ForteBactrim DSTablets10 tablets1 pack12951HUnrestrictedtrimethoprim 40mg/5mL + sulfamethoxazole 200mg/5mLBactrimSeptrinOral liquid100mL1 bottle13103HUnrestrictedNote: the tablet brands are ‘a’ flagged as Schedule equivalent, but the oral liquids are not. Clinical management algorithm(s)The clinical management algorithms for the current use of IgG and for the comparator arm (No IgG) are shown in REF _Ref9797450 \h \* MERGEFORMAT Figure 1, pg. PAGEREF _Ref10113845 \h 40. Key Differences in the Delivery of the Proposed Medical Service and the Main Comparator In the absence of IVIg or SCIg, patients with acquired hypogammaglobulinaemia are expected to have a higher rate of infections, and therefore a higher need for antibiotics and hospitalisation due to infections. Clinical ClaimThe clinical claim in the PICO Confirmation was ‘IgG with antibiotics as required’ is superior to ‘no IgG with antibiotics as required’ for reducing infections in patients with acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-HSCT. Approach Taken to the Evidence AssessmentA systematic review of the published literature was undertaken. PubMed, and the Cochrane Library were searched for papers published between 1990 and March 2019. Relevant articles and reviews had their reference lists pearled for studies which may have potentially been missed through the searches. Studies were included if they met criteria determined a priori, as summarised in REF _Ref10114642 \h \* MERGEFORMAT Table 3. Table SEQ Table \* ARABIC 3Population, Intervention, Comparator and Outcomes: Acquired Hypogammaglobulinaemia due to haematological conditionsComponentDescriptionPatientsPatients with acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT) who are currently eligible for immunoglobulin (Ig) treatment in Australia according to version 3 of the Criteria for the clinical use of immunoglobulin in Australia.InterventionReplacement IgG therapy with or without antibiotics,including IgG by intravenous administration (IVIg) orby subcutaneous administration (SCIg)ComparatorNo IgG therapy with or without antibioticsOutcomesSafety Outcomes:Adverse events including development of disease or side effectsClinical effectiveness outcomes:Number of infectionsChange in quality of life, including anxietyMortality Healthcare system resources utilisationChanges in health system resource utilisation associated with the intervention, for exampleIg products, Infusion equipment,Administrative and clinician time (e.g. resources associated with requesting, and authorising, access to Ig), Nursing time (for initiation and monitoring if IVIg)Hospitalisation (including use of hospital resources)Management of adverse eventsTraining of patient or carer to provide infusions (SCIg only), Product dispensing and disposal of any unused productFollow-up and/or monitoring visits Change in health system resource utilisation associated with the comparators, for exampleComparator products Resources to deliver the comparatorHospitalisationManagement of adverse eventsFollow-up and/or monitoring visitsQuestions for evidence reviewIs IgG replacement therapy (with or without antibiotics) more safe, effective and cost-effective than no IgG (with or without antibiotics)? Two researchers independently reviewed the titles and abstracts, and the citations which looked relevant to either researcher were retrieved for evaluation of the full text article. Full text articles were assessed by one researcher. The included studies had their risk of bias evaluated according to checklists designed for their study designs. Randomised and non-randomised controlled trials and observational studies were assessed using the Scottish Intercollegiate Guidelines Network (SIGN) checklists, and case series were assessed using the Institute of Health Economics checklist. The overall body of evidence per outcome measure were evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process. Characteristics of the Evidence BaseA total of 24 studies were included in this contracted assessment. Given that IgG treatment is current clinical practice for patients with acquired hypogammaglobulinaemia, it was expected there would be a large volume of evidence. However, this was not the case. Overall, the studies included in the report were low level evidence consisting primarily of case series with a small number of randomised studies (several of which did not adequately report the primary efficacy outcome, infections). ResultsSafety In the included studies, safety data were limited to reports of systemic adverse events (AEs) directly related to the infusion, with the exception of a registry study reporting thromboembolic events (TEE) risk. Otherwise it was not feasible to consider long-term, rare or potentially unknown events. A number of the included studies reported no safety outcomes.Overall, the included studies show that IgG has inferior safety to No IgG, due to infusion-related AEs and a small risk of TEE events (note that safety relates to unintended adverse events - benefits and risks due to infections are considered as part of effectiveness). AEs associated with IgG infusion were frequent but generally mild (low grade) and were manageable with adjustments to infusion. Moderate AEs tended to be less frequent and were manageable with dose adjustment, cessation or corticosteroids. None of the included studies reported any AEs greater than Grade 3 severity, nor were there any deaths or anaphylaxis due to IgG. The ‘No IgG’ comparator was typically observation, thus safety of IgG was worse than the comparator, associated with injection site effects and systemic infusion reactions (and noting that differing rates of infection are part of effectiveness rather than safety). Occasionally recurrent infusion reactions lead to discontinuation of treatment. Some of the older studies employed a sham injection of solution such as albumin or saline – these were also associated with infusion-related AEs, but at a lower rate than IgG. A small number of studies compared IVIg and SCIg, which showed that SCIg is associated with different AEs (injection site reactions) but is generally more tolerable (fewer systemic infusion reactions). One study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012) reported that patients with a history of AEs due to IVIg products had fewer or more manageable AEs with SCIg. IgG products have been in use in this population for some decades, thus the safety profile is well understood, even as regards rare events. In lieu of adequate safety data from the included studies, the safety data contained within approved Product Information should provide a suitably comprehensive assessment of safety for IgG products. The most common AEs associated with IVIg infusion are chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain. Serious AEs such as thromboembolic reactions and myocardial infarctions, stroke, pulmonary embolisms, or deep vein thrombosis are very rare. Effectiveness The key effectiveness measure determined a priori during development of the PICO confirmation, was the rate of infections. Overall, there is reasonable evidence that IgG is effective at reducing the incidence of infections. The results are remarkably consistent despite the otherwise highly variable quality of the included studies.The randomised trial evidence showed that the rate of major infections/life-threatening infections/ septicaemia was significantly lower in patients with acquired hypogammaglobulinaemia, who received IVIg (k=5), or SCIg (k=1) than those who did not receive Ig (incident rate ratio/IRR=0.14, 95%CI 0.05, 0.43). Those receiving IgG only had one seventh the incidence of serious infections that those being managed without IgG had over the same time period, which is highly clinically important. The difference in non-serious infections was less marked, but still significant (k=6; IRR=0.61, 95%CI 0.51, 0.72). These trial data were supported by nine before and after case series, which compared the rate of infections within patients prior to receiving IgG, and while receiving IgG. The incidence of serious infections/sepsis or pneumonia or infections requiring hospitalisation was only a quarter of the incidence recorded prior to IgG initiation (IRR=0.25, 95%CI 0.15, 0.43). Similar to the randomised trials, the incidence of non-serious infections was also significantly reduced by the use of IgG (IRR=0.64, 95%CI 0.49, 0.84). The limitations of the evidence mean that the risk ratios reported in these meta-analyses are highly uncertain. Only one trial reported on the difference in mortality, which was not significantly different for the overall sample. However, in a subsample of patients aged over 20 who had undergone a bone marrow transplant (BMT) from HLA-identical donors, the cumulative incidence of non-relapse mortality was significantly higher in those who did not receive IVIg (46%) than those who did (30%, p=0.023) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1990). Quality of life on the SF-36 was reported to be statistically significantly higher in a sample of MM patients who were randomised to receive SCIg compared to no SCIg PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018). Vacca et al. (2018) performed a trial in MM patients, randomised to either SCIg or no SCIg. Patients who received SCIg had far fewer days of antibiotic use (28 vs 217) and hospitalisation (8 vs 121) than those who did not receive SCIg. These differences were considered both statistically significant and clinically important. The summary of evidence is shown in REF _Ref421184437 \h \* MERGEFORMAT Table 4. On the basis of the benefits and harms reported in the evidence base it is suggested that, relative to No IgG replacement with antibiotics as required, the use of IgG products with antibiotics as required has inferior safety and superior effectiveness (where safety is based on unintended adverse events and effectiveness is based on rates of infections).Table SEQ Table \* ARABIC 4Balance of clinical benefits and harms of IgG with antibiotics as required, relative to No IgG with antibiotics as required (GRADE assessment)Outcomes (units)Follow-upParticipants (studies)Quality of evidence (GRADE)Relative effectCommentsSafetyK=13 studies; N=1,342(2 RCTs reported AEs for both IgG and No IgG; N=125)????Low qualityIgG has worse safety than No IgGSafety data were limited and sometimes absent for the included studies, focusing on infusion-related events only (key RCTs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (Boughton et al. 1995; Chapel et al. 1994b)). No evidence was available for longer-term outcomes other than TEE risk. Adverse events reported were nevertheless consistent with the established safety profile for IgG products (discussed in Extended Assessment of Harms). TEE risk (arterial or venous)1 registry studyN=10,759????High quality% Risk difference (95% CI), 1 yr IgG tx:1.0 (-0.2, 2.7)Only 1 included study, but very large, recent registry study. Control and intervention groups were balanced for cardiovascular risk. Selection bias which limits use of this study for infections is unlikely to affect cardiovascular safety (the main endpoint of this study) – high confidence in risk of TEE due to IgG. InfectionsK=20 studies, N=1,930(15 in meta-analyses: 6 RCTs, 2 cohort, 7 case series; N=1,536)????Low qualityRate ratio (95% CI) 0.14 (0.05, 0.43) for reduction of serious infections with IgG compared to No IgGThe quality of evidence was poor overall and infections were both reported and defined in widely variable ways. Moderate confidence that IgG reduces serious infections in patients based on a meta-analysis, but effective dose range could not be identified with any confidence and evidence was absent or limited for some of the conditions such as HSCTs, AL and ‘Other haematological malignancies’. Transplant-related events1 RCT (N=369)1 supportive study (N=58)????Very low qualityNo conclusion drawn.Only two studies investigated transplant-related outcomes. One study from 1990 may not be replicable with current standard of care for HSCTs and management of GVHD risk. A second supportive study could not be used. Mortality4 included studies (1 RCT, 1 cohort study, 1 registry and 1 retrospective case series)N=11,674????Very low qualityNo conclusion drawn.Insufficient duration of follow-up and variability between patient disease stage and other clinical factors precluded any meaningful assessment.QoL1 RCT (N=46)1 case series with small amount of before and after data (N=307)????Low qualityIgG marginally improves QoL compared to No IgGOnly 2 of the 4 studies reported QoL for IgG versus no IgG. a GRADE Working Group grades of evidence PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXlhdHQ8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdXlhdHQ8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Guyatt et al. 2013)???? High quality: We are very confident that the true effect lies close to that of the estimate of effect. ???? Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. ???? Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.???? Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.Translation IssuesThe economic model presented is a cost-utility analysis, where Ig therapy is associated with a reduction in infection rates, but that is traded off against a reduced safety profile. Ig therapy is already in use in Australia and seven translation studies were conducted to address issues regarding the applicability, extrapolation and transformation of the evidence to the proposed setting. These are summarised in REF _Ref14097481 \h Table 5.Table SEQ Table \* ARABIC 5Summary of results of pre-modelling studies and their uses in the economic evaluationResults used in the economic analysisResults tested in sensitivity analysesApplicabilityPatient demographicsAverage patient ages and weights for patients who currently receive Ig for acquired hypogammaglobulinaemia were compared to those of patients enrolled in the randomised studies used to inform the economic analysis. Patient demographics were generally not well reported, though CLL patients in the studies tended to be older than those in current practice. The majority of the randomised evidence was published in the 1990s, however the treatment effect was observed to be reasonably consistent in the older and newer studies and across both randomised and non-randomised studies. Therefore the more recent Australian data from a mixed haematological malignancy population PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Paxton, Hawkins & Crispin 2016) will be used to approximate the baseline infection rate in the absence of Ig. The pooled risk reductions estimated in Section B will then be applied to the baseline infection rate to model the treatment effect of Ig.To explore the uncertainty around baseline infection rates modelled, infection rates from each of the included randomised studies were tested. To explore the uncertainty around the treatment effect of Ig, the 95% CI of the pooled estimates were tested, in addition to the pooled estimates derived from the non-randomised studies. Further, actual infection rates (with and without Ig) from each of the randomised studies were tested in scenario analyses.Antibiotic use in the absence of IgAntibiotic use in the ‘No Ig’ arms of the randomised studies were compared to what would happen in Australian clinical practice in the absence of Ig. Prophylactic use was generally not allowed or did not change with Ig in the included randomised studies. One non-randomised study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE.DATA (Duraisingham et al. 2014) did however report a slight decrease in prophylactic antibiotic use with Ig (from 80% to 67%). This study supported a benefit of similar magnitude for Ig irrespective of whether prophylactic antibiotics were used in the comparator, however due to the study design and small patient numbers, this was not conclusive and is currently being tested in an ongoing Australian trial.In the absence of alternative evidence to i) suggest that rates of antibiotic prophylaxis would increase in the absence of Ig; and ii) that this increase in antibiotic use would affect the relative treatment effect of Ig, the economic analysis will assume no difference in prophylactic antibiotic across model arms – and so the relative treatment effect observed in the randomised studies was assumed to apply to the current setting.A scenario analysis was presented based on the results of the Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE.DATA (2014) study. This analysis included the cost of antibiotic prophylaxis and modelled actual infection rates (before and after Ig initiation) observed when the proportion of patients who receive antibiotic prophylaxis decreased from 80% to 67%.Dose of IgThe Version 3 criteria suggest doses of 0.4?g/kg every 4 weeks or more frequently to achieve targeted IgG trough levels in patients with acquired hypogammaglobulinaemia. However it is also specified that the lowest dose possible that achieves the appropriate clinical outcome should be used. The weighted average doses observed in the BloodSTAR data ranged from 0.36 to 0.38?g/kg). The doses used in the randomised studies ranged from 0.3?g/kg to 0.8?g/kg every three to four weeks. Despite variations in the doses used in each of the studies, the relative treatment effect of Ig was observed to be reasonably consistent. Given the experience in use with Ig in current practice, it will be assumed that current dosing is appropriate to achieve the clinical outcome of preventing infections, and so the economic analysis will use actual doses from the BloodSTAR data under the assumption that this has no effect on the relative treatment effect of Ig as observed in the trials.A sensitivity analysis was presented increasing the dose to 0.4?g/kg. Trial-based scenario analyses were also presented that use the doses from the trials with the actual infection rates observed for each of the randomised studies.Duration of Ig treatmentNo data were available from BloodSTAR to inform average treatment durations in patients with acquired hypogammaglobulinaemia. The duration of Ig treatment in the studies included in Section B was reviewed. The randomised studies included most commonly reported an Ig treatment duration of 12 months which was generally fixed and not conditional on an assessment of treatment response. One non-randomised study was identified in Australian patients which reported a median treatment duration of 26 months. This source will be used in the base case analysis. The economic model in Section D will assume that while on Ig therapy, patients are at risk of infections, however after treatment cessation, it will be assumed that no new infections are modelled – in either model arm – after such time.Sensitivity analyses were presented assuming varying alternate treatment durations, ranging from 1 to the model time horizon of 10 years. ExtrapolationDuration of treatment effectBased on the continuing access criteria it is assumed that the direct treatment effect of Ig (reduced infection rate and severity) is maintained for the duration of treatment. No direct treatment effect occurs after this time, but there is a residual difference in survival and quality of life associated with the difference in the proportions of patients in the various health states at the end of the treatment period, between the treatment arms.This is not tested in sensitivity analyses.Natural history of recurrent infectionsThere is very little published information regarding the long term consequences of recurrent infections in patients with acquired hypogammaglobulinaemia. One narrative review ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2011</Year><RecNum>111</RecNum><DisplayText>(Brown, Baxendale & Floto 2011)</DisplayText><record><rec-number>111</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368134">111</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Brown, J. S.</author><author>Baxendale, H.</author><author>Floto, R. A.</author></authors><secondary-authors><author>Floto, R. A.</author><author>Haworth, C.S.</author></secondary-authors></contributors><titles><title>Immunodeficiencies associated with bronchiectasis</title><secondary-title>European Respiratory Society Monographs: Bronchiectasis</secondary-title></titles><pages>178-191</pages><dates><year>2011</year></dates><isbn>9781849840118
9781849840125</isbn><urls></urls><electronic-resource-num>10.1183/1025448x.10004210</electronic-resource-num></record></Cite></EndNote>(Brown, Baxendale & Floto 2011) was identified which described the association of secondary immune deficiencies with bronchiectasis. This study reported that patients with haematological malignancies (particularly MM and CLL) or post-HSCT were relatively commonly associated with bronchiectasis. This is consistent with a recent Australian economic evaluation in this population which modelled the development of bronchiectasis. Therefore, the model structure will include health states associated with bronchiectasis in the base case analysis.The inclusion of these health states are tested in a sensitivity analysis.TransformationUtilitiesUtility weights were sourced from the published literature. Utilities reported in a relevant Australian population using the AQoL-6D instrument will be preferentially used in the model presented in Section D. The utilities related to infections were based on an alternative source as the Australian data do not allow for differences in infection severity to be quantified. A disutility is applied per IV infusion, however no disutilities have been assumed due to infusion-related AEs (which were generally mild and manageable).Sensitivity analyses are presented using alternative assumptions regarding the utility weights used in the model.AE = adverse events; AQoL-6D = Assessment of Quality of Life, six dimension; CLL = chronic lymphocytic leukaemia; Ig = immunoglobulin; MM = multiple myeloma; post-HSCT = post- haemopoietic stem cell transplantation.Economic EvaluationThe clinical evaluation suggested that in patients with acquired hypogammaglobulinaemia secondary to haematological malignancies, relative to no Ig, Ig has inferior safety and superior effectiveness. On this basis, a modelled cost-utility analysis was presented.One economic analysis was presented across the acquired hypogammaglobulinaemia indications. This is consistent with contemporary clinical and economic modelling studies which generally included patients with mixed haematological malignancies. As the purpose of Ig in acquired hypogammaglobulinaemia is to reduce the risk of infection and as the treatment effect of Ig was observed to be consistent across indications with respect to this outcome, this is considered to be a reasonable approach. Scenario analyses have been presented determining the cost-effectiveness per indication assuming the best estimates available.Table SEQ Table \* ARABIC 6Summary of the economic evaluation PerspectiveAustralian healthcareComparatorNo IgType of economic evaluationCost-utility and cost-effectiveness analysesSources of evidenceSystematic review presented in Section BTime horizon10 yearsOutcomesQALYsInfections avoidedMethods used to generate resultsMarkov modelHealth statesInfection-freeInfectionBronchiectasisBronchiectasis, with infectionBronchiectasis, with chronic Pseudomonas aeruginosa infectionDeadCycle length1 weekDiscount rate5%Software packages usedMicrosoft Excel and TreeAge ProIg = immunoglobulin; QALY = quality-adjusted life year.Key structural assumptions of the model are:The risk of developing an infection varies depending on whether Ig is available and as such has been informed by the clinical evidence. Subsequent transitions were predominantly based on those reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019), though some were adjusted according to infection severity, and so varied by model arm.Once patients develop bronchiectasis, they are not able to transition back to the infection-free health state. This is consistent with a previously published economic evaluation conducted by Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019).The results of the stepped economic analysis are presented in REF _Ref14268960 \h Table 7. Table SEQ Table \* ARABIC 7 Results of the stepped economic analysisInc. costInc. QALYsICERStep 1 – Trial-based analysis.Applies the dose (0.4?g/kg), dose frequency (q4w), infection rates, time horizon (1 year) and Ig treatment duration (1 year) as per the Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b) study. This study was chosen on the basis that, of the randomised studies, this study had the most patient years of data and used a dose that was most consistent with those recommended in the Version 3 criteria.$22,734–0.0035DominatedStep 2 – Trial-based, extrapolated analysisApplies the dose, dose frequency and infection rates from the Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b) study, with the model time horizon extrapolated to 10 years, with the development of bronchiectasis to be modelled. Ig treatment duration is based on Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016) (26 months).$66,9220.2556$261,789Step 3 – Modelled economic evaluation (base case)Applies the pooled IRRs estimated in Section B.6 to the best available source of baseline infection rates in Australia (based on Paxton, Hawkins & Crispin 2016), while assuming the weighted average dose from BloodSTAR data (0.37?g/kg).$41,0110.4109$99,803Sensitivity analyses for the cost per gram of Ig (base case: $60.41)High cost of Ig, $140.18$117,3350.4109$285,543Low cost of Ig, $44.94$26,2090.4109$63,782Weighted average cost of Ig, $94.51$73,6340.4109$179,195ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; QALY = quality-adjusted life years; IRR = incidence rate ratio.In Step 1 of the analysis the ICER of Ig is observed to be dominated, with a net reduction in QALYs resulting from the inclusion of a disutility per IVIg infusion. In Step 2, the time horizon is extrapolated to 10 years and allows for the development of bronchiectasis which leads to a substantial improvement in the ICER. Further improvements in the ICER are observed when the best estimates of baseline infection rates, Ig treatment effect and dose are included in the modelling.In the base case analysis, the cost of Ig was the main driver of the incremental cost, with offsets related to a reduction in the number of infections and costs associated with managing chronic P. aeruginosa infections. Incremental QALYs were primarily accrued in the infection-free health state. As Ig was associated with fewer infections of lower severity, less time was spent in the infection health state with Ig and therefore, patients had a lower risk of progressing to subsequent health states.Key sensitivity analyses are presented in REF _Ref14270085 \h Table 8. The model is highly sensitive to the inclusion of the bronchiectasis health states. When these health states are excluded, the ICER significantly increases to $3 million per additional QALY gained. This result is consistent with that observed in Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991), which also did not model the development of bronchiectasis. The inclusion of these health states had been justified based on the model structure used in a contemporary economic evaluation ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019) and that this was most consistent with the natural history of recurrent infections ( REF _Ref14097481 \h Table 5). The modelled results were also sensitive to the selection of the time horizon, the relative treatment effect of Ig and baseline rates of infection. Table SEQ Table \* ARABIC 8Key sensitivity analysesInc. costInc. QALYsICER% changeBase case analysis$41,0110.4109$99,803-Baseline annual infection rates (base case: Paxton, Hawkins & Crispin 2016, serious 0.43, non-serious 1.05)Molica et al. (1996): serious 0.29, non-serious 1.73$50,1600.3819$131,32832%Chapel et al. (1994): serious 0.26, non-serious 1.75$51,3460.3653$140,55541%Sullivan et al. (1990): serious 1.79, non-serious 3.79$48,0620.7121$67,493–32%IRR of Ig treatment effect (base case: serious, 0.15; non-serious 0.61)Serious infections, 0.43$52,5260.3139$167,31568%Non-serious infections, 0.72$46,2360.3523$131,23331%Duration of Ig treatment (base case: 2.2 years)5 years$84,2610.5430$155,16855%10 years$125,0970.5457$229,233130%Exclude development of bronchiectasis$41,2130.0141$2,927,5252833%Time horizon (base case: 10 years)2.2 years (as per Ig treatment duration)$38,8690.0322$1,208,3431111%5 years$39,5520.1509$262,086163%Transition probabilities (base case: adjusted)Transitions from infection health state, unadjusted$45,3090.3087$146,79247%Transitions from infection and bronchiectasis, unadjusted$29,9270.2335$128,15428%Cost of hospitalisation of serious infections (base case: $12,775)$52,961, based on AR-DRG R01A$19,3490.4109$47,088–53%ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; IRR = incidence rate ratio; QALY = quality-adjusted life year. Estimated Extent of Use and Financial ImplicationsA market-based approach has been used to estimate the financial implications of Ig in acquired hypogammaglobulinaemia, based on current utilisation of Ig products in patients with acquired hypogammaglobulinaemia. As data available on utilisation were only available for use under the Version 2 Criteria, the impact of transitioning to the Version 3 Criteria were not able to be captured in the analysis. There is uncertainty as to whether trends observed in the past would continue to be observed.It is also acknowledged that rapid technological development is occurring in this therapeutic area and this may also change clinical demand and Ig use in the future. For example, demand may increase if patients using new therapies (such as monoclonal antibodies, CAR-T cell therapy and BTK inhibitors) live longer with suppressed immune systems.The financial implications associated with funding Ig for acquired hypogammaglobulinaemia are summarised in REF _Ref395200110 \h \* MERGEFORMAT Table 9.Table SEQ Table \* ARABIC 9Net financial implications to government associated with Ig for acquired hypogammaglobulinaemia2019-202020-212021-222022-232023-24Total cost of Ig$98,136,389$105,651,248$113,166,107$120,680,966$128,195,825Cost of Ig to the Commonwealth$61,825,925$66,560,286$71,294,647$76,029,008$80,763,370Cost of Ig to the States$36,310,464$39,090,962$41,871,460$44,651,957$47,432,455Cost of Ig administration to the States$15,427,172$16,394,813$17,362,453$18,330,093$19,297,734Total cost offsets due to a reduction in the number of infections–$18,180,716–$19,320,253–$20,459,790–$21,599,328–$22,738,865Offsets to the Commonwealth–$671,936–$714,051–$756,167–$798,283–$840,399Offsets to the States–$17,508,780–$18,606,202–$19,703,623–$20,801,045–$21,898,466Net cost$95,382,845$102,725,807$110,068,769$117,411,732$124,754,694Net cost to the Commonwealth$61,153,989$65,846,235$70,538,480$75,230,725$79,922,971Net cost to States$34,228,856$36,879,572$39,530,289$42,181,006$44,831,723Sensitivity analyses for the cost per gram of Ig (base case: $60.41)High cost of Ig $140.18$224,969,664$242,235,823$259,501,981$276,768,140$294,034,299Low cost of Ig, $44.94$70,251,742$75,670,273$81,088,805$86,507,336$91,925,867Weighted average cost of Ig, $94.51$150,773,057$162,357,562$173,942,066$185,526,570$197,111,075Ig = immunoglobulin.Consumer impact summaryPublic consultation responses received during the PICO confirmation development stage were positive regarding the availability of IgG replacement therapy for patients with acquired hypogammaglobulinaemia. The benefits seen to patients were the reduced risk of infections, including life-threatening infections, normalisation of IgG levels, reduced risk of Graft Versus Host Disease (GVHD) for HSCT patients, reduced use of antibiotics, and less anxiety/stress/worry about risk of infections. Benefits to carers/family were the reduction of anxiety/stress/worry about the risk of infections. The side-effects of IgG treatment were acknowledged (phlebitis at cannula insertion site, side effects of Ig, hospital acquired infection). Sponsor companies were also invited to provide submissions to the development of this contracted assessments and four responded with comments that have been considered in this report. Acronyms and Abbreviations AbbreviationMeaningAAaplastic anaemia (not a malignancy)AEadverse eventAIHWAustralian Institute of Health and WelfareALacute leukaemiaALLacute lymphoblastic leukaemia (a type of AL)AMLacute myeloid leukaemia (a type of AL)ARCBSAustralian Red Cross Blood ServiceARTGAustralian Register of Therapeutic GoodsBMTbone marrow transplant (a type of HSCT)CIconfidence intervalCLLchronic lymphocytic leukaemiaCMLchronic myeloid leukaemia (a type of ‘other haematological malignancy’)CMVcytomegalovirusCVIDcommon variable immunodeficiencyDLBCLdiffuse large B-cell lymphoma (a type of NHL)DVTdeep vein thrombosisEMAEuropean Medicines AgencyEUEuropean UnionFLfollicular lymphoma (a type of NHL)G-CSFgranulocyte colony stimulating factor (filgrastim)GIGastrointestinal (tract)GVHDgraft versus host diseaseHBVhepatitis B virusHCVhepatitis C virusHIVhuman immunodeficiency virusHLHodgkin lymphoma (a type of ‘other haematological malignancy’)HMhaematological malignancyHRhazard ratioHRQoLhealth-related quality of lifeHSAhuman serum albuminHSCThaemopoietic stem cell transplantationHSVHerpes simplex virusHTAhealth technology assessmenthypo-GGhypogammaglobulinaemiaICERincremental cost-effectiveness ratioICUintensive care unitIgAimmunoglobulin A (alpha)IgGimmunoglobulin G (gamma)IgG-RTIgG replacement therapyIgMimmunoglobulin M (mu)IRBinstitutional review board (USA)IRRincidence rate ratioIQRinterquartile rangeIMintramuscularITPidiopathic thrombocytopenic purpuraIVintravenousIVIgintravenous immunoglobulinJMMLjuvenile myelomonocytic leukaemia (a type of ‘other haematological malignancy’)LLNlower limit of normal (refers to laboratory reference range)LRTlower respiratory tractMBSMedicare Benefits ScheduleMCLmantle cell lymphoma (a type of NHL)MDmean differenceMDSmyelodysplastic syndrome, also ‘pre-leukaemia’ (a type of ‘other haematological malignancy’)MEPMmeropenem (carbapenem type antibiotic)MMmultiple myelomaMGUSmonoclonal gammopathy of undetermined significance (a precursor state but not a malignancy)MSACMedical Services Advisory CommitteeMZLmarginal zone lymphoma (a type of NHL)NATANational Association of Testing Authorities NBANational Blood AuthorityNHLnon‐Hodgkin lymphomaNHMRCNational Health and Medical Research CouncilNNHnumber needed to harmPAPSprimary antiphospholipid syndromePASCPICO Confirmation Advisory Sub-Committee of the MSACPEpulmonary embolismPICOPopulation, Intervention, Comparator, Outcome criteriaPIDprimary immunodeficiencyQALYquality adjusted life yearQoLquality of lifeRCTrandomised controlled trialRTreplacement therapySCsubcutaneoussdstandard deviationSCIgsubcutaneous immunoglobulinSEMstandard error of the meanSIDsecondary immunodeficiencySLLsmall lymphocytic lymphoma (similar to CLL)S+Tsulfamethoxazole+trimethoprimTEEthromboembolic eventTGATherapeutic Goods AdministrationtxtreatmentURTupper respiratory tractUTIurinary tract infectionWMWaldenstr?m macroglobulinaemia (a type of ‘other haematological malignancy’)Section AContextThis contracted assessment of human gamma immunoglobulin (IgG) for the treatment of acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT) is intended for the Medical Services Advisory Committee (MSAC). MSAC evaluates new and existing health technologies and procedures for which public funding is sought in terms of their safety, effectiveness and cost-effectiveness, while taking into account other issues such as access and equity. MSAC adopts an evidence-based approach to its assessments, based on reviews of the scientific literature and other information sources, including clinical expertise. IgG in this indication is presently funded under the national blood supply arrangements but cost-effectiveness of this use has not previously been established. The National Blood Agreement provides for MSAC to undertake evidence-based evaluation of blood products funded under the national blood supply arrangements at the request of the Jurisdictional Blood Committee. The Department of Health has convened an Ig Review Reference Group to provide advice for evaluation of IgG funded by the National Blood Authority (NBA). The PICO Confirmations for these products are being considered by the Ig Review Reference Group instead of the PICO Advisory Sub-committee (PASC). Otherwise the MSAC evaluation process remains the same as for applications for funding of items on the Medical Benefits Schedule (MBS). Adelaide Health Technology Assessment (AHTA) has been commissioned by the Australian Government Department of Health to conduct a systematic literature review and economic evaluation for MSAC referral application 1565. This assessment has been undertaken in order to inform MSAC’s consideration of the cost-effectiveness of IgG as it currently funded for treatment of acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT). The criteria for evaluation of IgG as it is currently funded for this indication in Australian clinical practice were outlined in a PICO Confirmation that was discussed at the IgG Review Reference Group (meeting of 7 February 2019) and ratified on 8th March 2019. Appendix A provides a list of the people involved in the development of this assessment report. Items in the agreed PICO ConfirmationThis contracted assessment addresses each of the PICO elements (that is, Population, Intervention, Comparator and Outcomes) in the ratified PICO confirmation (see summary in REF _Ref505165203 \h \* MERGEFORMAT Table 14, Section A.9). Medical Service ReviewedHypogammaglobulinaemia (that is, low levels of gamma immunoglobulin, or IgG antibodies) may occur due to many different underlying conditions, both primary (due to congenital immune deficiencies) and secondary (due to conditions such as haematological malignancies). Patients with sustained low levels of gamma immunoglobulin are at high risk of recurrent and severe infections. Hypogammaglobulinaemia affects the full spectrum of IgG antibodies. It is distinct from defects in IgA or IgM levels and also different to abnormal levels of specific IgG paraproteins, each of which can be clinical signs of haematological malignancies. Acquired hypogammaglobulinaemia in the context of MSAC application 1565 refers to a subset of patients where hypogammaglobulinaemia is due to haematological conditions. Defects in humoral immunity are due to the underlying disease (in CLL due to abnormal or malignant B cell activity) but may also be compounded by myelosuppressive chemotherapy or immunotherapy drugs used to treat the cancer. The most medically significant type of infections in these patients are respiratory, which can develop into pneumonia ADDIN EN.CITE <EndNote><Cite><Author>Wadhwa</Author><Year>2006</Year><RecNum>12</RecNum><DisplayText>(Wadhwa & Morrison 2006)</DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="r52pep2xqzzs95eap0gvsxxyapa2afa2vtpf" timestamp="1549419648">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wadhwa, P. D.</author><author>Morrison, V. A.</author></authors></contributors><auth-address>Section of Hematology/Oncology, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN 55417, USA. punit.wadhwa@med.</auth-address><titles><title>Infectious complications of chronic lymphocytic leukemia</title><secondary-title>Semin Oncol</secondary-title></titles><periodical><full-title>Semin Oncol</full-title></periodical><pages>240-9</pages><volume>33</volume><number>2</number><keywords><keyword>Antineoplastic Agents/adverse effects/therapeutic use</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Communicable Diseases/*etiology/*therapy</keyword><keyword>Humans</keyword><keyword>Leukemia, Lymphocytic, Chronic, B-Cell/*complications/drug therapy/immunology</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0093-7754 (Print)
0093-7754 (Linking)</isbn><accession-num>16616071</accession-num><urls><related-urls><url>;(Wadhwa & Morrison 2006). Repeated or severe pneumonia can lead to longer term complications such as scarring and bronchiectasis. In Australia, patients with a clinical finding of hypogammaglobulinaemia, accompanied by risk or incidence of severe infections, must meet specifications for access to funded IgG laid out in the NBA document Criteria for Immunoglobulin Use in Australia (the Criteria Version 3). The Criteria are periodically updated at which time eligibility criteria may be refined according to recommendations of the relevant NBA working group and subsequent approval by the Jurstictional Blood Committee. IgG is given as replacement therapy, which may or may not be in combination with antibiotics. Antibiotic use may be prophylactic or in response to symptoms of infection. This is considered standard of care in Australia. Current funding arrangementsIgG replacement therapy for certain haematological malignancies, has been funded since 2008 under the National Blood Arrangements as having an “Established Therapeutic Role”. The indication considered in this referral to MSAC is one of several ‘diagnostic groups’ of conditions eligible for funded IgG treatment under the Criteria Version 3. The specific coverage of malignancies has been updated to reflect clinical data with each version of the NBA’s Criteria. Marketing status of IgG productsAll IgG products that are registered on the Australian Register of Therapeutic Goods (ARTG), including the sponsor and route(s) of administration are listed in REF _Ref1645380 \h \* MERGEFORMAT Table 10. Available strengths, ARTG numbers and text of the registered indications are in REF _Ref10282068 \h \* MERGEFORMAT Attachment 1. Table SEQ Table \* ARABIC 10IgG products registered on the ARTG for use in AustraliaProductSponsorRoute of AdministrationNBA Funded*?Intragam 10CSL BehringIVYesPrivigen 10%CSL BehringIVYesHizentra CSL BehringSCYesGamunex 10%Grifols IV and SCNoFlebogamma 10%Grifols IVYesFlebogamma 5%Grifols IVYesIntragam PCSL BehringIVYes**EvogamCSL BehringSCNoPanzygaOctaphama IVNoHyqviaShireSCNoIntratectPfizer IVNoIntratect 5%Pfizer IVNoOctagamOctapharma IVNoKiovigShireIV and SCNoGammanormOctapharma SC (and IM)NoCuvitruShireSCNoCSL Normal Immunoglobulin VFCSL BehringIMOut of scope* Indicates that Ig is currently funded for the indication sought in this application. Tendering arrangements may change products funded in the future. **With the introduction of Intragram 10, Intragam P manufacturing ceased in 2017. Inventories of Intragam P were expected to be exhausted by between mid-March and mid-April 2017 and it is expected to be discontinued by the time this evaluation is completed. The Ig Review Reference Group has indicated it should be out of scope for this application.IV – intravenous; SC – subcutaneous; IM – intramuscular Source: Therapeutic Goods Administration (ebs..au), accessed January 2019Not all these products are funded under the National Blood Supply Arrangements. Those that are funded for this indication (for application 1565) are given in REF _Ref183488 \h \* MERGEFORMAT Table 11, including prices per pack strength (current as of July 2019).Table SEQ Table \* ARABIC 11Ig products funded for this indicationProductSponsorRoute of Admin.StrengthNBA priceIntragam 10CSL BehringIV2.5g/25mL10g/100mL20g/200mL$145.57$582.30$1,164.59Privigen 10%CSL BehringIV5g/50mL10g/100mL20g/200mL40g/400mL$225.00$450.00$900.00$1,800.00HizentraCSL Behring SC1g/5mL2g/10mL4g/20mL10g/50mL$59.15$118.31$236.61$591.53Flebogamma 5%Grifols IV0.5g/10mL2.5g/50mL5g/100mL10g/200mL20g/400mL$22.50$112.50$225.00$450.00$900.00Flebogamma 10%Grifols IV5g/50mL10g/100mL20g/200mL$225.00$450.00$900.00EvogamCSL Behring SC16% 0.8g/5mL16%3.2g/20mL$46.58 $186.33IV=intravenous; SC=subcutaneous; IM=intramuscular Source: Table 4, PICO Confirmation, updated from NBA price list July 2019IgG products are manufactured from pooled human donor plasma, and the IgG fraction formulated to contain the desired concentration of IgG as active substance. Source plasma is normal human immunoglobulin not hyperimmune plasma. The IgG content represents a broad spectrum of human antibodies. Other immunoglobulins such as IgA, IgM and IgE may be present but are controlled as impurities. IgG products may be administered by intravenous (IV) or subcutaneous (SC) infusion (IVIg and SCIg products respectively). IgG products for intramuscular (IM) administration are out of scope for this evaluation. Current Clinical PracticeProvider and treatment settingIn order to qualify for supply of IgG, a diagnosis must be made by an immunologist, haematologist, paediatrician, general medicine physician or an oncologist. Management and review of the patient and prescribing of continuing treatment should also be undertaken by one of these specialists. Applications for IgG are made through the BloodSTAR online portal and assessed against the Criteria Version 3. Assessment and processing of applications, and supply of IgG product is managed by the Australian Red Cross Blood Service under contract to the NBA. In terms of the level of information required and the opportunity for managing compliance with clinical eligibility criteria, the BloodSTAR process appears to be broadly similar to written applications for Section 100 Authority Required medicines on the Pharmaceutical Benefits Scheme.IVIg administration requires a hospital or clinic with IV infusion facilities. For access to SCIg (in addition to requirements applicable for access to IVIg), the patient must be being treated by a clinical specialist within a hospital based SCIg program, where the hospital provides access to all resources. The patient/carer must be trained in the procedure by a qualified nurse or technician to deliver SCIg in an out of hospital setting. Management of treatment and dosing is described below. The specific criteria for patient eligibility are presented in Section REF _Ref2782217 \w \h \* MERGEFORMAT A.4 REF _Ref2782224 \h \* MERGEFORMAT Proposed population.Initial treatmentAccording to the Criteria Version 3, treating specialists should report the following clinical parameters for review by the BloodSTAR assessment officer:?Serum IgG level (results of two readings at least an hour apart, one taken when the patient does not have active infection)?Serum IgM level (as a baseline for monitoring)?Serum IgA level (as a baseline for monitoring)?The number of acute episodes of bacterial infection requiring antibiotics in last 6 monthsMost severe infections (if any) in the last six months?Description of the bacterial infections and antibiotic or other treatment required These are the specific requirements according to the Criteria Version 3 but are subject to change in future versions which has not been taken into account in this evaluation. Continuing treatmentAccording to the Criteria Version 3, initial review is required within six months at which time only those patients showing ‘demonstrated clinical benefit’ should be considered for continuing treatment. Thereafter, review should be annual. The Criteria Version 3 do not define clinical benefit but the following factors ‘inform a decision to trial a cessation of therapy’ the reviewing medical officer:An increase in IgG levels (increase compared with baseline or stabilisation towards normal)An improvement in IgM levels (an indicator of humoral immune function)An improvement in IgA levels (an indicator of humoral immune function)An improvement in the number of acute episodes of bacterial infections followed by a sustained period with no infections in subsequent review periodsA trial cessation of IgG would be contraindicated on safety grounds (if the patient is receiving immunosuppressant medication or has neutropenia, active bronchiectasis, or suppurative lung disease) or if severe hypogammaglobulinaemia persists where no significant improvement has occurred in the underlying condition. Where bronchiectasis and/or suppurative lung disease is cited as the reason for continuing IgG treatment, the diagnosis must be consistent with the guideline of the Thoracic Society of Australia and New Zealand.DosingThe default dose in BloodSTAR is 0.4 g/kg. The majority of documentation reviewed cites a maintenance dose for IVIg of 0.4 g/kg every four weeks, however, doses lower than 0.4g/kg may be used during titration. A maximum IgG dose of up to 1 g/kg may be given. Dosing may be divided to give two or more infusions within the month. Dosing for SCIg is 0.1 g/kg per week (based on patient’s lean or ideal body weight). Modification of infusion rate and/or administration of divided doses may be required to manage infusion reactions which are relatively common with this type of product. The applicant states that the usual length of an authorisation for maintenance therapy is one year, though they can be as short as one month. Continuing therapy is allowed so treatment duration can exceed one year. The majority of patients have more than one authorisation. Specialists may prescribe an initial loading dose of 0.4 g/kg (on top of monthly maintenance supply) and a one-off dose of 2 g/kg is for disseminated enterovirus infection. The Ig Review Reference Group confirmed that disseminated enterovirus infection should be considered a separate indication.MonitoringCessation of Ig therapy should be considered at least after each twelve months of treatment. If serum IgM and IgA levels are trending upwards and near normal, this may suggest recovery of the immune system and a trial might be considered if the patient is well. Once the patient has normal IgA and IgM levels, the IgG is also likely to be normal and a trial off therapy may be undertaken. Monitoring of IgG trough levels enables dose adjustments as described above though no frequency is defined by the Criteria Version 3. Other IndicationsAccording to the Criteria, the indication sought is separate to a similar indication “Secondary hypogammaglobulinaemia unrelated to Haematological malignancy or HSCT” (including patients with low plasma IgG due to B cell depletion or immunosuppressant therapies, or underlying health conditions such as thymoma). The distinction between the terms ‘acquired’ versus ‘secondary’ hypogammaglobulinaemia is specific to these diagnostic groups in the Criteria Version 3. Elsewhere, and in the scientific literature ‘secondary hypogammaglobulinaemia’ often includes conditions covered by both indications. Other uses of IgG such as replacement therapy in patients with primary hypogammaglobulinaemia (due to Common Variable Immune Deficiency for example) and immune-modulatory uses (such as for myasthenia gravis) are funded separately under the National Blood Supply arrangements. Public FundingIgG replacement therapy for haematological conditions is already funded by the NBA and represents the standard of care in Australia. The proposal is to continue the current funding arrangements as administered by the NBA. PopulationThe NBA funds IgG replacement therapy for hypogammaglobulinaemia in patients with the following haematological conditions:Acute leukaemiaChronic lymphocytic leukaemia (CLL)Multiple myeloma (MM)Non‐Hodgkin lymphoma (NHL)Other haematological malignancyAlso; memory B cell deficiency secondary to HSCTEach of these conditions carries a different baseline risk of hypogammaglobulinaemia, infections, long-term prognosis, mortality and other factors. Of the conditions encompassed by this indication, hypogammaglobulinaemia is found in 25% of patients at diagnosis and will occur in up to 85% during the disease course ADDIN EN.CITE <EndNote><Cite><Author>Sanchez-Ramon</Author><Year>2016</Year><RecNum>24</RecNum><DisplayText>(Sanchez-Ramon, Dhalla & Chapel 2016)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sanchez-Ramon, S.</author><author>Dhalla, F.</author><author>Chapel, H.</author></authors></contributors><auth-address>Department of Clinical Immunology and IdISSC, Hospital Clinico San Carlos, Madrid, Spain; Department of Microbiology I, Complutense University School of Medicine, Madrid, Spain. Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Clinical Immunology, John Radcliffe Hospital, Headington, Oxford, UK.</auth-address><titles><title>Challenges in the Role of Gammaglobulin Replacement Therapy and Vaccination Strategies for Hematological Malignancy</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>317</pages><volume>7</volume><keywords><keyword>antibody production defect</keyword><keyword>chronic lymphocytic leukemia</keyword><keyword>hematological malignancy</keyword><keyword>hypogammaglobulinemia</keyword><keyword>multiple myeloma</keyword><keyword>replacement immunoglobulins</keyword><keyword>Hematologic Neoplasms</keyword><keyword>Immunotherapy, Active</keyword><keyword>Vaccination</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><isbn>1664-3224 (Print) 1664-3224 (Linking)</isbn><accession-num>27597852</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - background info</research-notes></record></Cite></EndNote>(Sanchez-Ramon, Dhalla & Chapel 2016). In CLL patients for example, hypogammaglobulinaemia is more pronounced with advanced disease stage and disease duration: 50% to 60% of CLL patients will die from infectious complications ADDIN EN.CITE <EndNote><Cite><Author>Wadhwa</Author><Year>2006</Year><RecNum>12</RecNum><DisplayText>(Wadhwa & Morrison 2006)</DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="r52pep2xqzzs95eap0gvsxxyapa2afa2vtpf" timestamp="1549419648">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wadhwa, P. D.</author><author>Morrison, V. A.</author></authors></contributors><auth-address>Section of Hematology/Oncology, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN 55417, USA. punit.wadhwa@med.</auth-address><titles><title>Infectious complications of chronic lymphocytic leukemia</title><secondary-title>Semin Oncol</secondary-title></titles><periodical><full-title>Semin Oncol</full-title></periodical><pages>240-9</pages><volume>33</volume><number>2</number><keywords><keyword>Antineoplastic Agents/adverse effects/therapeutic use</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Communicable Diseases/*etiology/*therapy</keyword><keyword>Humans</keyword><keyword>Leukemia, Lymphocytic, Chronic, B-Cell/*complications/drug therapy/immunology</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0093-7754 (Print)
0093-7754 (Linking)</isbn><accession-num>16616071</accession-num><urls><related-urls><url>;(Wadhwa & Morrison 2006). When hypogammaglobulinaemia does occur secondary to haematological conditions, the diagnosis and clinical management of it is common across these patients. The Criteria Version 3 provides for IgG supply as follows:Patients with serum IgG <4 g/L regardless of episodes of infection or antibiotic use. Patients with serum IgG >4 g/L, IF serum IgG is less than the lower limit of the age-related reference range, AND the patient has had either (1) at least one life-threatening infection in the last 12 months, or (2) two serious infections in the last six months requiring more than standard courses of antibiotics.[Serum IgG refers to values excluding paraprotein]These qualifying criteria have evolved with each version of the Criteria and may change in future versions. For the purposes of the literature search, the target population is considered to be patients with acquired hypogammaglobulinaemia (secondary to the above haematological conditions) accompanied by incidence or high risk of severe/recurrent infections. The Ig Review Reference Group advised that interpretation of age-related reference ranges for serum IgG would vary between pathology laboratories but would be acceptable if undertaken in a laboratory accredited by the National Association of Testing Authorities (NATA) for this testing.The applicant proposes that a positive recommendation by MSAC would support the application of the prevailing version of the Criteria for patients to gain access to IgG treatment. The Ig Review Reference Group advised that although treatment with IgG of disseminated enterovirus infection in these patients is currently permitted by the Criteria Version 3, it should be excluded from this evaluation.Some guidelines suggest IVIg doses of 0.4 g/kg every three weeks, consistent with trial evidence that studied this regimen. However, four-weekly/monthly dosing with monitoring of trough levels and upward dose adjustment targeting the lower limit of the age-related IgG reference range is the prevailing recommendation.For a 70 kg person, this represents a minimum the dose limits represent an annual dose of between 336 g and 840 g IgG. The applicant comments that the average grams per patient is much less than the maximum. Nevertheless, the average duration of Ig therapy for acquired hypogammaglobulinaemia is unknown and treatment duration is likely to vary between specific conditions due to varying mortality rates and varying remission and recovery rates following chemotherapy. Without information regarding the median and range of values for grams per patient and range of treatment durations it is not known what a typical dose is in a given month or year. As a summary of incident patient numbers, the table produced for the PICO Confirmation has been updated with the 2017-18 data provided for this evaluation by the NBA ( REF _Ref10218013 \h \* MERGEFORMAT Table 12). Prevalent patient numbers were not readily available. The utilisation data available from the NBA describes total treated patients judged eligible according to the NBA Criteria. Table SEQ Table \* ARABIC 12Numbers of patients receiving funded IgG for this indication (2017-18)Condition Patients diagnosed (2015)*Total NBA-funded patients (2017-18)**Mean episodes/ patient (2017-18)Mean dose/ episode (g)(2017-18)**CLL1,597163210.00.37 MM1,88514589.10.37 NHL5,031165110.10.36 Other Haem. MalignancyUnknown6257.80.38 Post-HSCTUnknown4437.60.37 Acute Leukaemia1431*[150-200 patients]**5.5**0.37***Notes for ACIM data: 2015 year data are the most recent in the ACIM books; ALL (n=389) and AML (n=1042) were used as a proxy for AL since this is not reported in the ACIM data as a group. Prevalent patients not calculated as data ACIM data do not include surviving+new patient statistics. **Notes for NBA data: the most recent full year NBA data are for 2017-18 and do not include AL patient numbers; part year data for 2018-19 (until December) indicate patient numbers between 35-45% of the previous year, suggesting a full year total of ~150–200 AL patients based on n=68 for the part year; episode and dose data for AL are from the 2018-19 part year.Abbreviations: ACIM=Australia Cancer Incidence and Mortality; AL=acute leukaemia; ALL=Acute Lymphoblastic Leukaemia; AML=Acute Myeloid Leukaemia; CLL=Chronic lymphocytic leukaemia; IgG=Immunoglobulin Gamma; MM=Multiple Myeloma; NHL=Non‐Hodgkin lymphoma; HSCT=haemopoietic stem cell transplantation; NBA=National Blood AuthorityComparator DetailsThe comparator is defined in the ratified PICO Confirmation as ‘No IgG access; with or without antibiotics’, given that the intervention is defined as ‘IgG access; with or without antibiotics’. The utilisation of antibiotics was expected to be higher in the comparator arm. The haematology expert on the Ig Review Reference Group advised oral trimethoprim + sulfamethoxazole would be the first line antibiotic. This has a broad TGA indication and is available on the Pharmaceutical Benefits Scheme (PBS) ( REF _Ref10217967 \h \* MERGEFORMAT Table 13). Table SEQ Table \* ARABIC 13Relevant trimethoprim + sulfamethoxazole listings on the PBSStrengthsBrandsDosage formPack sizeMax QtyRepeatsItem #PBS Benefit Typetrimethoprim 160mg + sulfamethoxazole 800mgResprim ForteSeptrin ForteBactrim DSTablets10 tablets1 pack12951HUnrestrictedtrimethoprim 40mg/5mL + sulfamethoxazole 200mg/5mLBactrimSeptrinOral liquid100mL1 bottle13103HUnrestrictedNote: the tablet brands are ‘a’ flagged as Schedule equivalent, but the oral liquids are not. Patients already on chemotherapy for MM or CLL would likely be offered prophylactic antibiotics, however those not receiving chemotherapy are unlikely to be offered prophylaxis. The patients may be treated with purine analogues and anti-CD20 monoclonal antibodies, both of which are associated with increased incidence of infections ADDIN EN.CITE <EndNote><Cite><Author>Sanchez-Ramon</Author><Year>2016</Year><RecNum>24</RecNum><DisplayText>(Sanchez-Ramon, Dhalla & Chapel 2016)</DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sanchez-Ramon, S.</author><author>Dhalla, F.</author><author>Chapel, H.</author></authors></contributors><auth-address>Department of Clinical Immunology and IdISSC, Hospital Clinico San Carlos, Madrid, Spain; Department of Microbiology I, Complutense University School of Medicine, Madrid, Spain. Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Clinical Immunology, John Radcliffe Hospital, Headington, Oxford, UK.</auth-address><titles><title>Challenges in the Role of Gammaglobulin Replacement Therapy and Vaccination Strategies for Hematological Malignancy</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>317</pages><volume>7</volume><keywords><keyword>antibody production defect</keyword><keyword>chronic lymphocytic leukemia</keyword><keyword>hematological malignancy</keyword><keyword>hypogammaglobulinemia</keyword><keyword>multiple myeloma</keyword><keyword>replacement immunoglobulins</keyword><keyword>Hematologic Neoplasms</keyword><keyword>Immunotherapy, Active</keyword><keyword>Vaccination</keyword></keywords><dates><year>2016</year><pub-dates><date>2016</date></pub-dates></dates><isbn>1664-3224 (Print) 1664-3224 (Linking)</isbn><accession-num>27597852</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - background info</research-notes></record></Cite></EndNote>(Sanchez-Ramon, Dhalla & Chapel 2016). The IgG Review Reference Group considered that around 10% of MM or CLL patients would receive antibiotic prophylaxis. The applicant advises that some patients with hypogammaglobulinaemia (likely less than 20%) are commenced on chemotherapy because the patient is getting infections. The clinical signs to commence chemotherapy are the same regardless of IgG access, but this is likely to be required more frequently without IgG replacement therapy. The IgG Review Reference Group considered that antibiotic use in the current treatment algorithm could be either prophylactic (based on high risk of infection) or prn (in response to clinical signs of infection). Chemotherapy was not considered to be a secondary comparator for the evaluation.None of the studies returned by the literature search had considered antibiotics as a comparator or intervention, thus this evaluation considered the intervention ‘IgG’ versus the comparator ‘No IgG’. Clinical management Algorithm(s) The current treatment algorithm from the PICO Confirmation is presented in REF _Ref9797450 \h \* MERGEFORMAT Figure 1. This algorithm represents treatment under the current NBA arrangements. As the purpose of this referral to MSAC is consider the cost-effectiveness of these arrangements, there is no ‘proposed’ treatment algorithm. Figure SEQ Figure \* ARABIC 1Treatment algorithm(A) Initial Access to IgG funded under the National Blood Arrangements(B) Monitoring response to IgG therapy(C) Treatment pathway when IgG is not an optionKey Differences in the Delivery of the Medical Service and the Main Comparator This evaluation was unable to compare the intervention and comparator as defined in the PICO Confirmation due to limitations of the clinical evidence, which did not include any studies reporting the safety or efficacy of antibiotics used with IgG either as part of intervention or comparator arms. For the purpose of this evaluation therefore, antibiotic prescribing was considered part of supportive care. This is highly variable, depending on (for example) the patient’s status (inpatient/outpatient), whether the infection required hospitalisation and if not whether infections would be managed in the community (by a GP for example in a patient in remission) or by the treating specialist at an outpatient clinic. HSCT patients would most likely be inpatients until engraftment/neutropenic recovery which could be some months. These factors would not differ between intervention and comparator, though rate of antibiotic prescribing and rate of hospitalisations (or duration of the same) could be expected to be higher in the comparator/‘No IgG’ patients.Clinical ClaimThe clinical claim in the PICO Confirmation was ‘IgG with antibiotics as required’ is superior to ‘no IgG with antibiotics as required’ for reducing infections in patients with acquired hypogammaglobulinaemia secondary to haematological malignancies, or HSCT. Summary of the PICOThe summary PICO from the PICO Confirmation is presented in REF _Ref505165203 \h \* MERGEFORMAT Table 14. Table SEQ Table \* ARABIC 14Population, Intervention and Comparator: Acquired Hypogammaglobulinaemia due to haematological conditionsComponentDescriptionPatientsPatients with acquired hypogammaglobulinaemia secondary to haematological malignancies, or post-haemopoietic stem cell transplantation (HSCT). InterventionReplacement IgG therapy with or without antibiotics.Subgroups: intravenous administration (IVIg), subcutaneous administration (SCIg).ComparatorNo IgG replacement therapy; with or without antibiotics.OutcomesPatient-relevant outcomesEffectivenessmortalityinfections, including severe and/or recurrent infections (or infections requiring hospitalisationantibiotic use (not including prophylaxis)hospitalisations (all cause), including duration of hospital stay or time to dischargeQuality of Life (QoL) including anxietyIgG trough levelsSafetyserious infusion reactions (including anaphylaxis)other serious adverse events ( such as thrombotic/veno-occlusive events, renal insufficiency, haemolytic anaemia, aseptic meningitis)venous damageantibiotic allergyantibiotic resistancedevelopment of bronchiectasis/lung diseasegraft versus host disease (GVHD). Healthcare system outcomescost, cost effectivenessfinancial implications (financial impact, healthcare resource use, etc.)Questions for evidence reviewIs IgG replacement therapy (with or without antibiotics) more safe, effective and cost-effective than no IgG (with or without antibiotics)? Several issues relevant to this PICO arose during this evaluation. Due limitations of the evidence, the intervention, comparator and some of the outcomes could not be evaluated as defined in the PICO Confirmation. This evaluation considered ‘IgG’ as intervention and ‘No IgG’ as comparator. This is discussed in Section B.4 Characteristics of the Evidence Base. Consumer impact statementPublic consultation responses received during the PICO confirmation development stage were positive regarding the availability of IgG replacement therapy for patients with acquired hypogammaglobulinaemia. The benefits seen to patients were the reduced risk of infections, including life-threatening infections, normalisation of IgG levels, reduced risk of Graft Versus Host Disease (GVHD) for HSCT patients, reduced use of antibiotics, and less anxiety/stress/worry about risk of infections. Benefits to carers/family were the reduction of anxiety/stress/worry about the risk of infections. Feedback from the public consultation process raised concern about whether measurement of IgA and IgM as a requirement of the current NBA Criteria. Only a few studies reviewed included monitoring of IgA and IgM. Nevertheless, it was evident that these provide a useful measure of immunoglobulin recovery in hypogammaglobulinaemic patients. In comparison, measuring serum IgG may only inform the treating physician whether dosing with IgG products is adequate as replacement therapy may mask endogenous IgG recovery. There was little evidence to support a threshold serum IgG<6g/L level, proposed by one respondent, in the absence of a documented history of infections. Most of the clinical evidence supported the approach of establishing a baseline risk of serious infections based on both medical history of recent infections and serum IgG below the lower limit of normal.Sponsor ConsultationOn 21 May 2019, sponsors of Ig were contacted and given an opportunity to provide input to the development of this contracted assessment, specifically information relevant to the utilisation, efficacy, safety and cost-effectiveness of Ig. Submissions received from four companies were provided to the contracted HTA group for consideration in the development of this report. The sponsor submission provided information and comments on:the PICOpatient benefits associated with new SCIg formulationsproducts that should be included/excluded from the assessment, and the interchangeability of productschanges to the criteria for Ig access for the treatment of acquired hypogammaglobulinaemiaestimating the prevalence of acquired hypogammaglobulinaemia, and estimating the utilisation of Ig for the treatment of acquired hypogammaglobulinaemiapublished data on effectivenessthe public health implications associated with antibiotic usethe likely impact of new oncology treatments on Ig demand and the impact that access changes may have on the value of immune-modulating oncology therapies.Sponsors also provided comments on management of the Ig supply and access to SCIg, and the process for the Ig Review. Sponsors did not provide any unpublished clinical trial data that would inform the contracted assessment.Section BClinical Evaluation Literature Sources and Search StrategiesThe medical literature was searched during March 2019 to identify relevant studies and systematic reviews published during the period 1990 onwards. Searches were conducted of databases and with search terms as described in REF _Ref14354544 \h Appendix B.Results of Literature SearchA PRISMA flowchart (Figure 2) shows the flow of the literature search results and application of the PICO criteria (above) in selecting the included studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2hlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2hlcjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl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 EN.CITE.DATA (Liberati et al. 2009; Moher et al. 2009). Studies were selected independently by two reviewers. Where study relevance was in doubt, the two reviewers discussed the merits of inclusion/exclusion to agree an outcome.Figure SEQ Figure \* ARABIC 2 Summary of the process used to identify and select studies for the assessment Studies that could not be retrieved or that met the inclusion criteria but contained insufficient or inadequate data for inclusion are listed as Excluded Studies in REF _Ref364237293 \h \* MERGEFORMAT Appendix E. All other studies that met the inclusion criteria are listed in REF _Ref364237249 \h \* MERGEFORMAT Appendix C.A profile of each included study is given in REF _Ref421017583 \h \* MERGEFORMAT Appendix D. This study profile describes the authors, publication year, study design and quality (level of evidence and risk of bias), geographic location, setting, length of follow-up, study population characteristics, description of the intervention, description of the comparator and the outcomes assessed. Study characteristics are also summarised in a shorter format in Section B.4. Appraisal of the evidenceAppraisal of the evidence was conducted in 3 stages:Stage 1: Appraisal of the risk of bias within individual studies included in the review. Stage 2: Extraction of the pre-specified outcomes for this assessment, synthesising (meta-analysing or a narrative synthesis) to determine an estimate of effect per outcome. A meta-analysis was undertaken for the primary efficacy outcome, infections, in spite of variability in how infections were defined and reported between the studies.Stage 3: Rating the overall quality of the evidence per outcome, across studies, based on the study limitations (risk of bias), imprecision, inconsistency of results, indirectness of evidence, and the likelihood of publication bias. This was done to provide an indication of the confidence in the estimate of effect in the context of Australian clinical practice (Evidence profile tables, REF _Ref421017583 \h \* MERGEFORMAT Appendix D). Stage 4: Integration of this evidence for conclusions about the net clinical benefit of the intervention in the context of Australian clinical practice. (Sections B.6-B.8)Risk of Bias AssessmentThree of the eight included RCTs were at moderate risk of bias due to the way events were pooled for reporting PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Boughton et al. 1995; Molica et al. 1996; Musto, Brugiatelli & Carotenuto 1995), and, for the former two, due to the open-label, three-stage crossover design. The other RCTs had a low risk of bias. For the remaining non-randomised studies with direct evidence (IgG versus No IgG), two retrospective cohort studies were at high risk of bias based on the marked difference in infection risk at baseline between intervention and comparator groups due to selection bias PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011; Paxton, Hawkins & Crispin 2016). The other cohort studies and case series were generally at moderate risk of bias, with the exception of one recent case study with low risk PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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==
ADDIN EN.CITE.DATA (Benbrahim et al. 2019) and not including the four supportive studies (that is, with no direct evidence) which could not be used for a comparison of IgG with No IgG. In addition to the individual studies, the overall body of evidence was assessed for the key outcomes using GRADE (Guyatt et al. 2011). Characteristics of the Evidence BaseAn overview of the included studies is provided in REF _Ref15306456 \h Table 15. More details are in REF _Ref364237249 \h \* MERGEFORMAT Appendix C ( REF _Ref10291240 \h \* MERGEFORMAT Table 77, full citations) and REF _Ref421017583 \h \* MERGEFORMAT Appendix D (study profiles). Also in REF _Ref364237249 \h \* MERGEFORMAT Appendix C is a breakdown of which of the included studies can be considered applicable to the NBA-funded conditions ( REF _Ref10291298 \h \* MERGEFORMAT Table 78). The search strategy returned 25 articles representing 24 studies (k=24). Six of the eight included RCTs dated from the early-to-mid 1990s. There were two recent RCTs; one from 2018 investigating SCIg (which was also the only RCT in the clinical evidence that studied SCIg)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018) and a second from 2014 investigating a carbapenem antibiotic with or without IVIg (the only study identified that explicitly studied an antibiotic with IgG)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE.DATA (Kobayashi et al. 2014). The recent literature is otherwise notable for the absence of eligible RCTs in this population. Four of the included studies were not applicable to any of the NBA indications due to insufficient patient numbers. Four other comparative studies comprised one large US registry study of over 10,000 CLL and MM patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016) and three cohort studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+
PFJlY051bT40NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQmxvbWJlcnkgZXQgYWwuIDIwMTE7IFBh
eHRvbiwgSGF3a2lucyAmYW1wOyBDcmlzcGluIDIwMTY7IFZhbiBXaW5rbGUgZXQgYWwuIDIwMTgp
PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ1PC9yZWMtbnVtYmVyPjxmb3JlaWdu
LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIy
cGQydGFkIiB0aW1lc3RhbXA9IjE1NTQyNTkwMzciPjQ1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl
Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+
PGF1dGhvcnM+PGF1dGhvcj5CbG9tYmVyeSwgUC48L2F1dGhvcj48YXV0aG9yPlByaW5jZSwgSC4g
TS48L2F1dGhvcj48YXV0aG9yPldvcnRoLCBMLiBKLjwvYXV0aG9yPjxhdXRob3I+TWFpbiwgSi48
L2F1dGhvcj48YXV0aG9yPllhbmcsIE0uPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBFLiBNLjwvYXV0
aG9yPjxhdXRob3I+V2VzdGVybWFuLCBELiBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1
dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIENhbmNlciBNZWRpY2luZSwgUGV0ZXIgTWFj
Q2FsbHVtIENhbmNlciBDZW50cmUsIEVhc3QgTWVsYm91cm5lLCBNZWxib3VybmUsIFZpY3Rvcmlh
LCBBdXN0cmFsaWEuIHBpZXJzLmJsb21iZXJ5QHBldGVybWFjLm9yZzwvYXV0aC1hZGRyZXNzPjx0
aXRsZXM+PHRpdGxlPlByb3BoeWxhY3RpYyBpbnRyYXZlbm91cyBpbW11bm9nbG9idWxpbiBkdXJp
bmcgYXV0b2xvZ291cyBoYWVtb3BvaWV0aWMgc3RlbSBjZWxsIHRyYW5zcGxhbnRhdGlvbiBmb3Ig
bXVsdGlwbGUgbXllbG9tYSBpcyBub3QgYXNzb2NpYXRlZCB3aXRoIHJlZHVjZWQgaW5mZWN0aW91
cyBjb21wbGljYXRpb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFubiBIZW1hdG9sPC9zZWNv
bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uIEhlbWF0b2w8
L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTY3LTcyPC9wYWdlcz48dm9sdW1lPjkw
PC92b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxlZGl0aW9uPjIwMTEvMDYvMTY8L2VkaXRpb24+
PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnYW1tYWdsb2J1bGlu
ZW1pYS9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkF1
c3RyYWxpYS9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+RWxlY3Ryb25pYyBIZWFsdGggUmVjb3Jkczwva2V5d29yZD48a2V5d29y
ZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGVtYXRvcG9pZXRpYyBTdGVtIENlbGwgVHJhbnNw
bGFudGF0aW9uLyBhZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SG9zcGl0YWxzLCBV
bml2ZXJzaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11
bm9nbG9idWxpbnMsIEludHJhdmVub3VzLyB0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv
cmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlk
ZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXVsdGlwbGUgTXllbG9tYS8gY29tcGxpY2F0aW9u
cy9pbW11bm9sb2d5L3BoeXNpb3BhdGhvbG9neS8gdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5P
cHBvcnR1bmlzdGljIEluZmVjdGlvbnMvZXBpZGVtaW9sb2d5LyBwcmV2ZW50aW9uICZhbXA7IGNv
bnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjxr
ZXl3b3JkPlN1cnZpdmFsIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlRyYW5zcGxhbnRhdGlv
biwgQXV0b2xvZ291czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFy
PjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQz
Mi0wNTg0IChFbGVjdHJvbmljKSYjeEQ7MDkzOS01NTU1IChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4yMTY3NDE0NDwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMt
cmVzb3VyY2UtbnVtPjEwLjEwMDcvczAwMjc3LTAxMS0xMjc1LTM8L2VsZWN0cm9uaWMtcmVzb3Vy
Y2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJv
dmlkZXI+PHJlc2VhcmNoLW5vdGVzPkhTQ1QgZm9yIE1NPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3Vh
Z2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1
dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNOdW0+NjY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt
YmVyPjY2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2
d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0aW1lc3RhbXA9IjE1NTQ0MzczMzki
PjY2PC9rZXk+PGtleSBhcHA9IkVOV2ViIiBkYi1pZD0iIj4wPC9rZXk+PC9mb3JlaWduLWtleXM+
PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv
cnM+PGF1dGhvcnM+PGF1dGhvcj5QYXh0b24sIEwuPC9hdXRob3I+PGF1dGhvcj5IYXdraW5zLCBD
LjwvYXV0aG9yPjxhdXRob3I+Q3Jpc3BpbiwgUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli
dXRvcnM+PGF1dGgtYWRkcmVzcz5BdXN0cmFsaWFuIE5hdGlvbmFsIFVuaXZlcnNpdHkgTWVkaWNh
bCBTY2hvb2wsIENhbmJlcnJhLCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50IG9mIEltbXVub2xv
Z3ksIENhbmJlcnJhIEhvc3BpdGFsLCBDYW5iZXJyYSwgQXVzdHJhbGlhLiYjeEQ7QXVzdHJhbGlh
biBOYXRpb25hbCBVbml2ZXJzaXR5IE1lZGljYWwgU2Nob29sLCBDYW5iZXJyYSwgQXVzdHJhbGlh
LiBwaGlsaXAuY3Jpc3BpbkBhY3QuZ292LmF1LiYjeEQ7RGVwYXJ0bWVudCBvZiBIYWVtYXRvbG9n
eSwgQ2FuYmVycmEgSG9zcGl0YWwsIENhbmJlcnJhLCBBdXN0cmFsaWEuIHBoaWxpcC5jcmlzcGlu
QGFjdC5nb3YuYXUuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+U2VsZWN0aW5nIGhhZW1h
dG9sb2dpY2FsIG1hbGlnbmFuY3kgcGF0aWVudHMgZm9yIGludHJhdmVub3VzIGltbXVub2dsb2J1
bGluPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkludGVybiBNZWQgSjwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkludGVybiBNZWQgSjwvZnVsbC10aXRs
ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEyMTYtMTIxODwvcGFnZXM+PHZvbHVtZT40Njwvdm9sdW1l
PjxudW1iZXI+MTA8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5
d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BdXN0cmFsaWE8L2tleXdv
cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkhlbWF0b2xvZ2ljIE5lb3BsYXNt
cy8qdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Kklt
bXVuaXphdGlvbiwgUGFzc2l2ZTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnMsIElu
dHJhdmVub3VzLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+
TGluZWFyIE1vZGVsczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1p
ZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29y
ZD48a2V5d29yZD5oYWVtYXRvbG9naWNhbCBtYWxpZ25hbmN5PC9rZXl3b3JkPjxrZXl3b3JkPmlu
ZmVjdGlvbjwva2V5d29yZD48a2V5d29yZD5pbnRyYXZlbm91cyBpbW11bm9nbG9idWxpbjwva2V5
d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+
T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ0NS01OTk0IChFbGVjdHJvbmlj
KSYjeEQ7MTQ0NC0wOTAzIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNzczNDYyMDwv
YWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVy
bGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmlo
Lmdvdi9wdWJtZWQvMjc3MzQ2MjA8L3N0eWxlPjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48
ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTExMS9pbWouMTMyMDU8L2VsZWN0cm9uaWMtcmVz
b3VyY2UtbnVtPjxyZXNlYXJjaC1ub3Rlcz5NaXhlZCBwb3AuIGJvdGggYmVmb3JlIGFuZCBhZnRl
ciBjYXNlIHNlcmllcyBhbmQgcmV0cm9zcGVjdGl2ZSBjb2hvcnQuIChmb3VuZCB0aHJvdWdoIGdv
b2dsaW5nKTwvcmVzZWFyY2gtbm90ZXM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+VmFu
IFdpbmtsZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJlY051bT4yNjwvUmVjTnVtPjxyZWNv
cmQ+PHJlYy1udW1iZXI+MjY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i
IGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0YWQiIHRpbWVzdGFtcD0i
MTU1MzgyNTA2MCI+MjY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h
bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlZh
biBXaW5rbGUsIFAuPC9hdXRob3I+PGF1dGhvcj5CdXJjaGV0dGUsIFIuPC9hdXRob3I+PGF1dGhv
cj5LaW0sIFIuPC9hdXRob3I+PGF1dGhvcj5SYWdodW5hdGhhbiwgUi48L2F1dGhvcj48YXV0aG9y
PlF1cmVzaGksIE4uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl
c3M+UGVkaWF0cmljIEhvc3BpdGFsaXN0IGF0IHRoZSBBbmFoZWltIE1lZGljYWwgQ2VudGVyIGlu
IENBLiBwYXRyaWNrLmoudmFud2lua2xlQGtwLm9yZy4gU3RhdGlzdGljaWFuIGZvciBLYWlzZXIg
UGVybWFuZW50ZSBTb3V0aGVybiBDYWxpZm9ybmlhIFJlc2VhcmNoIGFuZCBFdmFsdWF0aW9uIGlu
IFBhc2FkZW5hLiByYW91bC5qLmJ1cmNoZXR0ZUBrcC5vcmcuIFJlc2VhcmNoIEFzc2lzdGFudCBm
b3IgS2Fpc2VyIFBlcm1hbmVudGUgU291dGhlcm4gQ2FsaWZvcm5pYSBSZXNlYXJjaCBhbmQgRXZh
bHVhdGlvbiBpbiBQYXNhZGVuYS4gcndoa2ltQGdtYWlsLmNvbS4gUGVkaWF0cmljIE9uY29sb2dp
c3QgaW4gdGhlIERlcGFydG1lbnQgb2YgUGVkaWF0cmljIEhlbWF0b2xvZ3kgYW5kIE9uY29sb2d5
IGF0IHRoZSBBbmFoZWltIE1lZGljYWwgQ2VudGVyIGluIENBLiBydWttYW5pLnJhZ2h1bmF0aGFu
QGtwLm9yZy4gUGVkaWF0cmljIE9uY29sb2dpc3QgaW4gdGhlIERlcGFydG1lbnQgb2YgUGVkaWF0
cmljIEhlbWF0b2xvZ3kgYW5kIE9uY29sb2d5IGF0IHRoZSBBbmFoZWltIE1lZGljYWwgQ2VudGVy
IGluIENBLiBuYXZlZW4uYS5xdXJlc2hpQGtwLm9yZy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0
aXRsZT5QcmV2YWxlbmNlIGFuZCBTYWZldHkgb2YgSW50cmF2ZW5vdXMgSW1tdW5vZ2xvYnVsaW4g
QWRtaW5pc3RyYXRpb24gRHVyaW5nIE1haW50ZW5hbmNlIENoZW1vdGhlcmFweSBpbiBDaGlsZHJl
biB3aXRoIEFjdXRlIEx5bXBob2JsYXN0aWMgTGV1a2VtaWEgaW4gRmlyc3QgQ29tcGxldGUgUmVt
aXNzaW9uOiBBIEhlYWx0aCBNYWludGVuYW5jZSBPcmdhbml6YXRpb24gUGVyc3BlY3RpdmU8L3Rp
dGxlPjxzZWNvbmRhcnktdGl0bGU+UGVybSBKPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl
cmlvZGljYWw+PGZ1bGwtdGl0bGU+UGVybSBKPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn
ZXM+MTctMTQxPC9wYWdlcz48dm9sdW1lPjIyPC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPkFk
b2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdhbW1hZ2xvYnVsaW5lbWlhLyBjb21wbGljYXRp
b25zLyBkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyZW1pYS9jb21wbGljYXRp
b25zPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkLCBQcmVz
Y2hvb2w8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZ1bmdlbWlh
L2NvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk
PkltbXVub2dsb2J1bGlucywgSW50cmF2ZW5vdXMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl
LyB0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3
b3JkPk1haW50ZW5hbmNlIENoZW1vdGhlcmFweS9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1h
bGU8L2tleXdvcmQ+PGtleXdvcmQ+UHJlY3Vyc29yIENlbGwgTHltcGhvYmxhc3RpYyBMZXVrZW1p
YS1MeW1waG9tYS8gY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9r
ZXl3b3JkPjxrZXl3b3JkPlJlbWlzc2lvbiBJbmR1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+UmV0
cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPllvdW5nIEFkdWx0PC9rZXl3b3Jk
PjxrZXl3b3JkPkltbXVub2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxp
biBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5
d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBNPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2ds
b2J1bGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRTwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxODwvZGF0
ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1NTItNTc3NSAoRWxlY3Ryb25pYykgMTU1Mi01
NzY3IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTcwMjA1NDwvYWNjZXNzaW9uLW51
bT48dXJscz48L3VybHM+PGN1c3RvbTE+UkFZWUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVv
dDs9Jmd0OyZxdW90O0luY2x1ZGVkJnF1b3Q7fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+QUxM
IHJldHJvc3BlY3RpdmUgY29ob3J0IDwvcmVzZWFyY2gtbm90ZXM+PGxhbmd1YWdlPmVuZzwvbGFu
Z3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011; Paxton, Hawkins & Crispin 2016; Van Winkle et al. 2018) the former two of which were in Australian patients. The remainder of the evidence is case series or before/after time series. Overall, the studies included in the report were low level evidence consisting primarily of case series with a small number of randomised studies (several of which did not adequately report the primary efficacy outcome, infections). Four of the included studies were designed as comparative studies of different routes of IgG administration PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012; Windegger et al. 2019) or different dosing of IgG PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1994a; Stump et al. 2017). These four studies were included as case series of IgG, but offered no direct comparison of IgG with No IgG and can be considered supportive. Pearling indicated only a small number of studies published prior to 1990 that were excluded as prior to the search cut-off date, all in the more commonly studied indications, and which were considered unlikely to have changed the conclusions of this evaluation had they been included. Many studies returned by the search evaluated patients at risk of hypogammaglobulinaemia, but who did not have symptomatic hypogammaglobulinaemia, that is, documented low IgG levels accompanied by a history of infections. This was the main reason for excluding studies that investigated IgG in patients with haematological malignancies. Studies were excluded (see reasons for exclusion in REF _Ref364237293 \h \* MERGEFORMAT Appendix E) that presented neither the patient’s infections history nor the serum IgG levels at baseline, or where it was not known what proportion of patients had these clinical features.In some cases, baseline IgG levels showed patients in the excluded studies had normal or only moderately low IgG levels without any information regarding prior infections, or baseline data for these features was lacking altogether (see REF _Ref11931046 \h \* MERGEFORMAT Table 83, REF _Ref364237293 \h \* MERGEFORMAT Appendix E). This led to exclusion of a number of HSCT and paediatric studies (noting also for HSCTs that it was not clear whether the baseline serum IgG levels in HSCT recipients predicted post-transplant levels), so there is much less evidence to support use in these groups than might have been expected. The majority of studies identified in the searches were in patients with CLL, followed by MM, NHL and HSCT. HSCT from peripheral blood was not in routine use prior to 2000 or so – in earlier studies patients received bone marrow transplants (BMT). There were few data for patients with AL other than ALL. One RCT included children with ALL and a small number of AML patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE.DATA (Kobayashi et al. 2014). The most common approach was for a clinic or group of centres to recruit every patient indicated for IgG according to their institutional policy for IgG eligibility. Many studies had thus enrolled a mixed population of patients with different haematological malignancies, each at a different stages of disease course and treatment cycle. In these, patients were usually in single digits who had malignancies such as types of NHL (such as follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL)), AL, or other malignancies (myelodysplastic syndrome (MDS) or Hodgkin lymphoma (HL)).A search of clinical trials showed that a protocol has been registered for a head to head study of IgG and antibiotics. An Australian multi-centre head-to-head clinical trial of IgG versus S+T is underway in this population, funded by the NBA, and due to complete at the end of 2019. It is likely that this study is not powered to report a difference in efficacy between groups based on infection outcomes. The registered trial is described as a Phase II feasibility study, the primary endpoint for which is the proportion of patients remaining alive on assigned study treatment at the end of 12 months.The NBA advised that the purpose of this trial is to inform the sample size needed for a Phase III study powered to report infection as the primary outcome and adverse events of IgG compared with antibiotics in this population. Given that infections incidence was quite variable between studies, no conclusions could be drawn regarding different approaches to dose level, frequency or duration. These aspects of the evidence have not been discussed in detail with the results in B.6. Thus, details dosing and duration for each of the studies are included in the overview of the included studies in REF _Ref15306456 \h Table 15 for reference.Table SEQ Table \* ARABIC 15Key features of the included studiesStudyTypeRisk of BiasNPatientsDosingTx durationOutcomesFavours IgG?Randomised studies – IVIg vs No IVIgBoughton et al., 1995RCTRoB: moderate (SIGN)N=42CLL18g total IVIg3-weekly 12 months 12 month protocolInfections, serious infections, tx outcome (<3 infections [success] or ≥3 infections [failure])YesChapel et al., 1991RCT cross-overRoB: low (SIGN)N=12CLL, NHL (separate numbers not given)400 mg/kg IVIg3-week12 mo tx in 24 mo study12+12 mo crossoverIncidence of infections.YesChapel et al., 1994RCTRoB: low (SIGN)N=83MM400mg/kg IVIg4-weekly12 months12 month protocolIncidence and type of infections; adverse reactions including death; time to infection; infections in an immunised sub-setYesKobayashi et al., 2014RCTRoB: low (SIGN)N=61ALL(34); AML(12); other leukaemia(2); NHL(2); solid tumours(11)100 mg/kg per day (max 5g/day) for 72h72hTx success/failure; adverse events; infection-related deathUnclearMolica et al., 1996RCT cross-overRoB: moderate (SIGN)N=42CLL300mg/kg IVIg4-weekly6 months (+12+6 mo)6+12+6 mo crossoverInfections (incidence, type, severity)YesMusto et al., 1995RCT cross-overRoB: moderate (SIGN)N=25MM300mg/kg IVIg4-weekly6 months (+12+6 mo)6+12+6 mo crossoverMinor infections; serious infections.YesSullivan et al., 1990RCTRoB: low (SIGN)N=382 (369 evaluable)BMTIVIg 500mg/kg weekly (d-7 to d90); then monthly to d36012 months protocolAcute GVHD, systemic infections, local infections, interstitial pneumonia, actuarial survival, non-relapse mortality. YesRandomised studies – SCIg vs No SCIgVacca et al., 2018RCTRoB: low (SIGN)N=46MMSCIg: 0.4-0.8 g/kg/monthMean dose 80mg/kg/week6 mo initial txmean duration tx 18 mo (range 10–28)Annual rate of severe infections; days of hospitalisation due to severe infections; days of treatment with antibiotics; improvement of HRQoL (SF-36).AEs were reported though not defined as an endpoint.YesOther comparative studies – IVIg vs No IVIgPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016)Registry studyRoB: moderate (IHE)N= 10,759CLL (76%), MM (24%)Not reported (variable). Any Ig IVIg, SCIg or IMIg.Not reported (variable)TEEs; NNH, mortality, hospitalisations due to infection.NoPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011)Cohort studyRoB: high (SIGN)N=240MM+HSCT (autologous)400mg/kg IVIgsingle dose given to 123 of 130 patients (94.6%)Single dose studyInfections in 30 days HSCT (days of IV antimicrobial agents, number of febrile days); survival post-ASCTNoPaxton et al., 2016Cohort studyRoB: high (SIGN)N=92CLL (42); MM (18); NHL (27); other (5)IVIg. Dose not reported (variable).Median 26 mo (range 3-79)Rate of serious infections, defined as those requiring hospital admission. Hospitalisation compared before and after HSCT.NoVan Winkle et al., 2018Cohort studyRoB: moderate (SIGN)N=118ALL IVIg 400mg/kg monthlyMean 10.5 doses (range 1-31)Not reported (mean ~10.5 mo tx duration inferred from doses)Infectious complications before and during maintenance tx (including episodes of infection; hospitalisations and days of hospitalisation)NoNon-comparative studies – IVIg case seriesBesa, 1992Case series RoB: moderate (IHE)N=23CLL400mg/kg IVIg; 3-weekly; 12 months12 month protocol; 3 yrs maintenance reportedLymphocyte counts; leukaemic response. Infections not reported as outcome; but as a complication/ prognostic variableYesBrenner, 1996Time seriesRoB: moderate (IHE)N=54 (n=26 SID; n=28 PID)CLL(22), MM(4); ITP(20); PAPS(8)400mg/kg IVIg4-weekly~6 months~6 month protocolAdverse events; infections; infections requiring hospitalisationYesGünther & Dreger 2013Case seriesRoB: moderate (IHE)N=10CLL(5), FL(2), plasmacytoma; WM(1), MDS(1)0.35 g/kg IVIg3–4 weekly[no duration specified]Median 54 mo ( range 23–114) Incidence of bacterial infections; non-bacterial infections; antibiotic/anti-infective use; adverse events including death.YesJurlander et al., 1994Time seriesRoB: moderate (SIGN)N=15CLL10g total IVIg3-weekly[No duration specified]Median 19.5 infusions (or ~13 mo)Serum IgG levels; infection status; antibiotic use; hospital admission for infection; febrile episodesYesNon-comparative studies – SCIg case seriesDimou et al. 2018Before/after time seriesRoB: moderate (SIGN)N=33CLL(25); MM(3); NHL(3); HL(1)*0.4-0.8 g/kg/mo SCIg dose every 3-4 weeks. 12 month protocolIncidence of infections; adverse reactionsYesAny IgG (IVIg and SCIg) case seriesBenbrahim et al., 2018(preliminary report)Case series (prospective)RoB: low (IHE)N=231MM(64), CLL(84), NHL(71), AL(6); HL(6)385mg/k/mo IVIg99 mg/kg/wk SCIgReported in Benbrahim 2019Reported in Benbrahim 2019.―Benbrahim et al., 2019(Follow-up report)Case series (prospective)As above.N=160MM(54), CLL(54), aggressive NHL(19), indolent NHL(29), HL(4)IVIg dose 387±78mg/kg/mo 97±45mg/kg/wk SCIg (equals 388mg/kg/mo)12 month protocolMean exposure 8.4±4.0 mo (median 8.8 mo).Change in serum IgG from baseline; annual incidence of infections. Also infections requiring antibiotics, requiring IV antibiotics, and requiring hospitalisation. Incidence of WHO grade >2 infectionsYesDuraisingham et al., 2014Case series (PID vs SID)RoB: moderate (IHE)N=39 SID patients, of which 15 had HMCLL(1), MM(1), NHL(11); MDS(1); MGUS(1) Median IgG dose 0.53g/kg (range 0.35–1.03)4-weekly, 12 moSID patients had IVIg (n=13, 33%) or SCIg (n=26, 67%)12 month observation (median tx, 1 yr [range <1-9] – incl. existing patients)Patient demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, infection frequencyYesReiser et al., 2017Case seriesRoB: moderate (IHE)N=307CLL(130); MM(43); NHL(99); other(35)Variable. Median (IQR) 4-weekly dose:IVIg (n=287); 163mg/kg (116-258)SCIg (n=20); 330mg/kg (255-420)Duration of on-study treatment (mean, median or total months) not described.Infection rate; serious bacterial infections; IgG trough levels; side-effects; QoL; mortality; IgG utilisationYesNon-comparative studies – IVIg v SCIg case seriesSundin et al., 2012Case series (IVIg v SCIg cohort study design)RoB: moderateN=58, of which 26 had HMHSCTIVIg: 0.3–0.5 g/kg, every 2-4 weeks, ORSCIg: 0.1–0.2g/kg every 1-2 weeksSCIg: Median 9 (range 6-20 months)IVIg: Median 5 months (range 3-47 months)Rate of infections, IgG trough levels, GVHD; adverse eventsCompari-son not possibleWindegger et al. 2019Before/after time seriesRoB: moderate (IHE)N=13 (N=84 for QoL survey)Haem. malignancy (undefined)IVIg 4 weekly: mean: 29.46g/mofollowed bySCIg weekly: mean: 31.15g/mo12 months each IVIg then SCIg crossoverUtilities associated with disease and infectionsCompari-son not possibleOther (IVIg and SCIg) – dosing studiesChapel, Dicato et al. 1994Case seriesRoB: lowN=34CLL500mg/kg or 250 mg/kg12 month protocolIncidence of infections; adverse reactionsCompari-son not possibleStump et al., 2017Case seriesRoB: highN=79 (209 infusions)CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)Dose levels not reported. Comparison of actual vs ideal BW dosing.30 months or 2.5 years; median doses per patient 1 (range 1-18; mean 2.6) during this period Primary outcome was infection rate within 30 days of IVIg administration; Secondary outcomes incl. 60-day infection rate, IgG-level response (>400mg/dL), realised and potential IVIg pari-son not possibleRisk of Bias was assessed using the SIGN checklist for randomised trials (for RCTs only); the SIGN checklist for cohort studies, and the IHE checklist for case series. *Notes: Units conversion: 100mg/dL (units used in older studies) equals 1g/L; Benbrahim et al., 2018 – 23% of all patients had received auto-HSCT, mostly MM patients (31/64 MM patients had HSCT). See study profile for definition of aggressive vs indolent NHL. Dimou et al., 2018 – the dose units quoted in the paper should be ‘g/L’ not ‘mg/L’ – Maria Dimou (pers. comm., May 2019). Günther & Dreger 2013 – the plasmacytoma case was IgA-secreting which is most likely not included in the WHO definition of MM depending on other clinical features (if solitary or extramedullary), thus is an ‘other haematological malignancy’; FL is included in the WHO definition of NHL; the case of WM (described by authors as an IgM-secreting immunocytoma) is an ‘other haematological malignancy’; Paxton et al., 2016 – 5 patients with ‘other’ malignancies were AML(1), amyloidosis(1), T-cell NHL(3); Reiser et al., 2017 – NHL total was reported as 22 NHL patients and 77 indolent lymphoma (the latter is most likely FL, a type of NHL), ‘Other’: HIV(7), post-transplant(7), leukaemia (not CLL)(4), HL(2), 15 other malignant and non-malignant conditions (e.g. MGUS, MDS, AA, haemolytic anaemia, COPD); Sundin et al., 2012 – underlying diagnoses were ALL(11); AML(7); JMML(3); NHL(2); MDS(3); other 1° / 2° causes of hypo-GG. Abbreviations: AA=aplastic anaemia; AEs=adverse events; AML=acute myeloid leukaemia; BMT=bone marrow transplant; BW=body weight; CLL=chronic lymphocytic leukaemia; CML=chronic myeloid leukaemia; CMV=cytomegalovirus; COPD=chronic obstructive pulmonary disease; FL=follicular lymphoma; G-CSF=granulocyte colony stimulating factor (filgrastim); GVHD=graft versus host disease; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HM=haematological malignancy; HR=hazard ratio; HRQoL=health-related quality of life; HSCT=haematopoietic stem cell transplant; hypo-GG=hypogammaglobulinaemia; IgA=alpha immunoglobulin; IgG=gamma immunoglobulin; IgM=mu immunoglobulin; IMIg=intramuscular immunoglobulin; IQR=interquartile range; IRB=institutional review board (USA); ITP=idiopathic thrombocytopenic purpura; IVIg=intravenous immunoglobulin; JMML=juvenile myelomonocytic leukaemia; LLN=lower limit of normal (laboratory reference range); MDS=myelodysplastic syndrome; MGUS=monoclonal gammopathy of undetermined significance; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; NNH=number needed to harm; PAPS=primary antiphospholipid syndrome; QoL=quality of life; RCT=randomised controlled trial; SCIg=subcutaneous immunoglobulin; sd=standard deviation; SID=secondary immunodeficiency; S+T=sulfamethoxazole+ trimethoprim; tx=treatment; TEEs= thromboembolic events; URT=upper respiratory tract; WHO=World Health Organization; WM=Waldenstr?m macroglobulinaemia.Outcome Measures and AnalysisStudy profiles in REF _Ref421017583 \h \* MERGEFORMAT Appendix D include details on the outcomes measured in the included studies, along with the statistical methods used to analyse the results. The principal outcomes reported by the included studies were limited to incidence or rates of infections. Infections were assessed, defined, analysed and reported in a wide range of ways in the studies included. A large proportion of these studies also reported resource use (or infections outcomes that are relevant to resource use), for example, hospitalisations due to infection, infections requiring antibiotics, days of hospitalisation, or similar. Consideration of transplant related outcomes such as GVHD and virus reactivation was limited by the small number of eligible HSCT studies that could be included in the evaluation.Of those studies reporting IgG use, only a subset reported safety data, often limited to systemic AEs observed in the intervention arm, but not in the comparator. AEs were also typically reported immediately following the infusion and only in a few studies were longer term outcomes such as risks considered. Retrospective studies relied on the completeness of physician’s notes and medical records for adequacy of all outcomes data.As well as calculating infection rates per patient per month where possible, this evaluation undertook a meta-analysis of infection rates observed in the comparative studies (presented as a forest plot). This approach gave a relative risk of benefit in terms of infection with or without IgG. This provided a qualitative comparison of the included comparative studies given that each study defined and reported different types of infections and also evaluation of infections rates in each case suggests a wide variation in baseline risk of infection between studies.Results of the Systematic Literature reviewIs it safe? Summary – Is IgG replacement therapy more safe, effective and cost-effective than no IgG? AEs associated with IgG infusion were frequent but generally mild (low grade) and were manageable with adjustments to infusion. Moderate AEs tended to be less frequent and were manageable with dose adjustment, cessation or corticosteroids. None of the included studies reported AEs greater than Grade 3 severity, nor were there any deaths or anaphylaxis due to IgG. Safety data were limited to reports of systemic AEs directly related to the infusion, with the exception of a registry study reporting TEE risk. Otherwise it was not feasible to consider long-term, rare or potentially unknown events. A number of the included studies reported no safety outcomes ( REF _Ref9248035 \h \* MERGEFORMAT Table 21). The included studies did not adequately describe antibiotic use thus adverse events arising from antibiotic use could not be evaluated as specified in the PICO. Given that the ‘No IgG’ comparator was typically no intervention, safety of IgG was worse than the comparator, associated with injection site effects and systemic infusion reactions. Occasionally recurrent infusion reactions lead to discontinuation of treatment. Some of the older studies employed a sham injection of solution such as albumin or saline – these were also associated with AEs, but at a lower rate than IgG.A small number of studies compared IVIg and SCIg, which showed that SCIg is associated with different AEs (injection site reactions) but is generally more tolerable (fewer systemic infusion reactions). IgG products have been in use in this population for some decades, thus the safety profile is well understood, even as regards rare events. In lieu of adequate safety data from the included studies, the safety data contained within approved Product Information should provide a suitably comprehensive assessment of safety for IgG products. According to core safety text for IgGs in Europe, adverse reactions due to IgG are (in decreasing frequency):? chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain? reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion? (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration? (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequency unknown)? (very rarely) thromboembolic reactions such as myocardial infarction, stroke, PE, DVT? cases of reversible aseptic meningitis? cases of increased serum creatinine level and/or occurrence of acute renal failure? cases of Transfusion Related Acute Lung Injury (TRALI)Systemic and other AEs including infusion reactionsThe majority of included studies reported AEs either in the time immediately after infusion or limited to the study period. Two of the randomised studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1991; Molica et al. 1996) reported few or no AEs. One RCT of IVIg in combination with an antibiotic reported AEs specific to the antibiotic and none associated with IVIg. Only one cohort study presented AE data PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh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=
ADDIN EN.CITE.DATA (Van Winkle et al. 2018). Studies presenting no safety data are discussed further below (see REF _Ref9248035 \h \* MERGEFORMAT Table 21). A small number of studies monitored renal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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 EN.CITE.DATA (Benbrahim et al. 2019; Chapel et al. 1994b) and liver function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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ADDIN EN.CITE.DATA (Boughton et al. 1995; Brenner 1996; Sullivan et al. 1990), but each reported that there were no changes related to IgG treatment in these markers and presented few or no data. AEs reported in the included studies were typical of infusion reactions – fever, chills, headache/pains and nausea. These events, though mild in nature, often recurred and led to discontinuation in small numbers of patients. Systemic and other AEs – comparative studiesComparative studies presenting systemic AEs including infusion reactions and other general AEs are summarised in REF _Ref9247782 \h \* MERGEFORMAT Table 16 (IVIg) and REF _Ref10151744 \h \* MERGEFORMAT Table 17 (SCIg). Table SEQ Table \* ARABIC 16Comparative studies presenting systemic AE outcomes – IVIg vs No IVIgStudy, IndicationOutcomeInterventionComparator RCTsBoughton et al., 1995AEs (N=42)IVIg (n=24)No IVIg (albumin) (n=18)CLLPyrexia112Lethargy30Rigors21Sweating20Inflamed cannula10Hypothermia10Rigor10Headache01Total patients with AEs214*Chapel et al., 1994AEs and Discontinuations (N=83)IVIg (n=42)No IVIg (albumin) (n=41)MMEvaluable patients4241Patients completing 12 mo study3031Withdrawals and deaths12 (8)10 (5)recurrent infusion reactions20life threatening infections03 (1)disease progression9 (7)5 (3)other*1 (1)2 (1)Mild AEslethargy/malaise147shivers76headaches61felt cold95nausea/vomiting/diarrhoea31epigastric pain50drowsy30fever10blurred vision10tingling tongue10joint pain01Total mild AEs5021Moderate AEsRigors and vomiting21Hypotension10Total moderate AEs31*Total AEs (% of infusions)53 (12)23* (5)Kobayashi et al., 2014AEs (N=61; 146 episodes)MEPM+IVIg (n=62 episodes)MEPM alone (n=84 episodes)ALL, AML, othersPatients with liver dysfunction24Deaths due to invasive fungal infection02Molica et al., 1996Withdrawals due to AEs (N=42)IVIg therapy phase (N=21+21)Empirical phase (N=21+21)CLLPatient withdrawn due to AEs (chills, fever and back pain)20Sullivan et al., 1990AEs (N=369)IVIg (n=184)No IVIg (n=185)BMTTotal infusions22260Infusions with AEs, n (%)14 (0.6%)―Chills10-Fever1-Headache1-Pruritus1-Flushing1-Cohort studiesVan Winkle et al., 2018AEs (N=118)IVIg (n=36)No IVIg (n=82)ALLTotal infusions306―Infusions with no AEs296 (96.8%)n.r.Patients with AEs, n/N (%) (1 Grade 3 event; none >Grade 3)(AEs were fever, nausea/ vomiting, headache or chills).10/36 (27.8%)n.r.*Notes: Chapel et al., 1994 – placebo AE totals reported by the authors do not match mild and moderate AE totals. *Other patient withdrawals: IVIg - 1 cardiac amyloidosis death. Placebo - 1 unrelated cardiac death, 1 moved away. Kobayashi et al., 2014 – patient numbers not reported for the two groups, only episodes of febrile neutropenia; all instances of liver dysfunction were in patients receiving the higher 120mg/kg/day MEPM dose; liver dysfunction was Grade 2 in 5 patients and Grade 3 in 1 patient. Molica et al. 1996 – no AEs described other than representative AEs in these withdrawing patients. Sullivan et al., 1990 & Van Winkle et al., 2018 – in both studies, ‘No IVIg’ patients were untreated and received no placebo injection.AEs=adverse events; ALL=acute lymphoblastic leukaemia; AML=acute myeloid leukaemia; BMT=bone marrow transplant; CLL=chronic lymphocytic leukaemia; IVIg=intravenous immunoglobulin; MEPM=meropenem; MM=multiple myeloma; mo=month.Of the RCTS, only two reported AEs for both IgG and No IgG arms. Both investigated IVIg versus a sham injection. One, a 1995 study in 42 CLL patients in the UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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=
ADDIN EN.CITE.DATA (Boughton et al. 1995) reported that AEs were mostly mild, although one patient withdrew due to a ‘tolerance concern’ (infusion-related pyrexia). Three patients died in the study due to disease progression. AEs were higher in the IVIg group than the placebo which was an albumin sham injection (still associated with a low rate of AEs). No serious AEs were reported. The second study was in 83 MM patients also in the UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Chapel et al. 1994b). The albumin placebo recipients experienced 5% AEs compared to the IVIg group who had a 12% rate of AEs. AEs were generally mild though where patients experience reactions, these tended to recur. One IVIg patient had nine reactions in 13 infusions; similarly, one placebo patient had seven reactions in 13 infusions. Moderate reactions (in two patients with IVIg and one receiving albumin placebo) were managed with dose rate adjustment and hydrocortisone. Three IVIg patients in the study withdrew due to recurrent infusion reactions (although tabulated figures suggest it was only two patients). This did not include one further IVIg patient who did not complete the first infusion, due to a moderate reaction which led to their immediate withdrawal. Two patients in the Chapel et al study developed renal failure and were found on emergency unblinding to be in the IVIg group, resulting in the study being on clinical hold for 3 weeks. The study resumed after both cases of renal failure were considered to have been caused in one patient by light chain disease and, in the second, by septicaemia complicated by pre-existing (undetected) renal insufficiency. Serum creatinine was monitored prior to all remaining infusions (in addition to monitoring in patients with existing renal impairment), however found no change greater than 20?μmol/L during the study period (data not shown). The remaining RCTs reported variable amounts of safety data. One investigated IgG in combination with an antibiotic (meropenem) in Japanese children who had failed first line antibiotic prophylaxis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE.DATA (Kobayashi et al. 2014). AEs due to IVIg were not reported. The study reported liver AEs due to meropenem use, as this was the target organ of toxicity for this antibiotic. These AEs were not representative of the safety profile or event rate from other antibiotics used in combination with IgG as each class of molecules will have its own toxicological characteristics. The authors considered the liver toxicity observed with meropenem as marginally preferable to renal toxicity observed with vancomycin, a potential alternative in this line of treatment. An RCT of BMT recipients in the USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1990) recorded AEs occurred in 14 of 2226 (0.6%) IVIg infusions, noting only that ‘toxicity of IVIg was minimal’. A recent cohort study in US ALL patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh
cj48UmVjTnVtPjI2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihWYW4gV2lua2xlIGV0IGFsLiAyMDE4
KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNjwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJy
MnBkMnRhZCIgdGltZXN0YW1wPSIxNTUzODI1MDYwIj4yNjwva2V5PjwvZm9yZWlnbi1rZXlzPjxy
ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz
PjxhdXRob3JzPjxhdXRob3I+VmFuIFdpbmtsZSwgUC48L2F1dGhvcj48YXV0aG9yPkJ1cmNoZXR0
ZSwgUi48L2F1dGhvcj48YXV0aG9yPktpbSwgUi48L2F1dGhvcj48YXV0aG9yPlJhZ2h1bmF0aGFu
LCBSLjwvYXV0aG9yPjxhdXRob3I+UXVyZXNoaSwgTi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5QZWRpYXRyaWMgSG9zcGl0YWxpc3QgYXQgdGhlIEFuYWhl
aW0gTWVkaWNhbCBDZW50ZXIgaW4gQ0EuIHBhdHJpY2suai52YW53aW5rbGVAa3Aub3JnLiBTdGF0
aXN0aWNpYW4gZm9yIEthaXNlciBQZXJtYW5lbnRlIFNvdXRoZXJuIENhbGlmb3JuaWEgUmVzZWFy
Y2ggYW5kIEV2YWx1YXRpb24gaW4gUGFzYWRlbmEuIHJhb3VsLmouYnVyY2hldHRlQGtwLm9yZy4g
UmVzZWFyY2ggQXNzaXN0YW50IGZvciBLYWlzZXIgUGVybWFuZW50ZSBTb3V0aGVybiBDYWxpZm9y
bmlhIFJlc2VhcmNoIGFuZCBFdmFsdWF0aW9uIGluIFBhc2FkZW5hLiByd2hraW1AZ21haWwuY29t
LiBQZWRpYXRyaWMgT25jb2xvZ2lzdCBpbiB0aGUgRGVwYXJ0bWVudCBvZiBQZWRpYXRyaWMgSGVt
YXRvbG9neSBhbmQgT25jb2xvZ3kgYXQgdGhlIEFuYWhlaW0gTWVkaWNhbCBDZW50ZXIgaW4gQ0Eu
IHJ1a21hbmkucmFnaHVuYXRoYW5Aa3Aub3JnLiBQZWRpYXRyaWMgT25jb2xvZ2lzdCBpbiB0aGUg
RGVwYXJ0bWVudCBvZiBQZWRpYXRyaWMgSGVtYXRvbG9neSBhbmQgT25jb2xvZ3kgYXQgdGhlIEFu
YWhlaW0gTWVkaWNhbCBDZW50ZXIgaW4gQ0EuIG5hdmVlbi5hLnF1cmVzaGlAa3Aub3JnLjwvYXV0
aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlByZXZhbGVuY2UgYW5kIFNhZmV0eSBvZiBJbnRyYXZl
bm91cyBJbW11bm9nbG9idWxpbiBBZG1pbmlzdHJhdGlvbiBEdXJpbmcgTWFpbnRlbmFuY2UgQ2hl
bW90aGVyYXB5IGluIENoaWxkcmVuIHdpdGggQWN1dGUgTHltcGhvYmxhc3RpYyBMZXVrZW1pYSBp
biBGaXJzdCBDb21wbGV0ZSBSZW1pc3Npb246IEEgSGVhbHRoIE1haW50ZW5hbmNlIE9yZ2FuaXph
dGlvbiBQZXJzcGVjdGl2ZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QZXJtIEo8L3NlY29uZGFy
eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QZXJtIEo8L2Z1bGwtdGl0
bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNy0xNDE8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48
a2V5d29yZHM+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BZ2FtbWFnbG9i
dWxpbmVtaWEvIGNvbXBsaWNhdGlvbnMvIGRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5C
YWN0ZXJlbWlhL2NvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+
PGtleXdvcmQ+Q2hpbGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdv
cmQ+PGtleXdvcmQ+RnVuZ2VtaWEvY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5IdW1h
bnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLCBJbnRyYXZlbm91cy9hZG1pbmlz
dHJhdGlvbiAmYW1wOyBkb3NhZ2UvIHRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5J
bmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFpbnRlbmFuY2UgQ2hlbW90aGVyYXB5L21ldGhvZHM8
L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QcmVjdXJzb3IgQ2VsbCBM
eW1waG9ibGFzdGljIExldWtlbWlhLUx5bXBob21hLyBjb21wbGljYXRpb25zPC9rZXl3b3JkPjxr
ZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+UmVtaXNzaW9uIEluZHVjdGlvbjwv
a2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+
WW91bmcgQWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zPC9rZXl3b3JkPjxr
ZXl3b3JkPkltbXVub2dsb2J1bGluIFZhcmlhYmxlIFJlZ2lvbjwva2V5d29yZD48a2V5d29yZD5J
bW11bm9nbG9idWxpbiBEPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIE08L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9i
dWxpbiBFPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT4yMDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Nzc1
IChFbGVjdHJvbmljKSAxNTUyLTU3NjcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5
NzAyMDU0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVT
SU9OOiB7JnF1b3Q7U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20x
PjxyZXNlYXJjaC1ub3Rlcz5BTEwgcmV0cm9zcGVjdGl2ZSBjb2hvcnQgPC9yZXNlYXJjaC1ub3Rl
cz48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh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=
ADDIN EN.CITE.DATA (Van Winkle et al. 2018) concluded that IVIg was safe, based on no reactions in 98.6% of infusions with the remaining eight events either minor or (in one case) due to underlying causes. The authors further noted that no patients with reactions required corticosteroids or epinephrine. Table SEQ Table \* ARABIC 17Comparative studies presenting systemic and other AE outcomes – SCIg vs No SCIgStudy, IndicationOutcomeInterventionComparator Vacca et al., 2018Event, number of patients (%) (N=46)SCIg (n=24)SCIg (n=24)No SCIg (n=24)MMAEsGrade 3/4Grade 1/2―Allergic skin reaction1 (4)0-Oedema of the injection site015 (62)-Oedema and erythema08 (33)-Oedema and pain05 (21)-Oedema and pruritus03 (12)-Skin induration and pain 2 (8)3 (12)-Discontinuations due to AEs (%)3 (12.5)―*Note: Vacca et al., 2018 – AEs only reported for SCIg and not for control group. AEs=adverse events; MM=multiple myeloma; SCIg – subcutaneous immunoglobulin.One RCT compared SCIg to No SCIg in the clinical evidence PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
Y051bT4zMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oVmFjY2EgZXQgYWwuIDIwMTgpPC9EaXNwbGF5
VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl
eSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0
aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjMwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h
bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+
PGF1dGhvcj5WYWNjYSwgQS48L2F1dGhvcj48YXV0aG9yPk1lbGFjY2lvLCBBLjwvYXV0aG9yPjxh
dXRob3I+U3BvcnRlbGxpLCBBLjwvYXV0aG9yPjxhdXRob3I+U29saW08L2F1dGhvcj48YXV0aG9y
Pm8sIEEuIEcuPC9hdXRob3I+PGF1dGhvcj5EYW1tYWNjbywgRi48L2F1dGhvcj48YXV0aG9yPlJp
YSwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5SLiBS
aWEsIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUgYW5kIENsaW5pY2FsIE9uY29sb2d5
LCBVbml2ZXJzaXR5IG9mIEJhcmkg4oCcQWxkbyBNb3Jv4oCdIE1lZGljYWwgU2Nob29sLCBQb2xp
Y2xpbmljbyDigJMgUGlhenphIEdpdWxpbyBDZXNhcmUsIDExLCBCYXJpLCBJdGFseTwvYXV0aC1h
ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlN1YmN1dGFuZW91cyBpbW11bm9nbG9idWxpbnMgaW4gcGF0
aWVudHMgd2l0aCBtdWx0aXBsZSBteWVsb21hIGFuZCBzZWNvbmRhcnkgaHlwb2dhbW1hZ2xvYnVs
aW5lbWlhOiBhIHJhbmRvbWl6ZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2xpbmlj
YWwgSW1tdW5vbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs
LXRpdGxlPkNsaW5pY2FsIEltbXVub2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl
cz4xMTAtMTE1PC9wYWdlcz48dm9sdW1lPjE5MTwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5h
bnRpaGlzdGFtaW5pYyBhZ2VudDwva2V5d29yZD48a2V5d29yZD5pbW11bm9nbG9idWxpbjwva2V5
d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPmFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+YXJ0aWNsZTwva2V5d29yZD48a2V5d29yZD5j
bGluaWNhbCBhcnRpY2xlPC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2xsZWQgc3R1ZHk8L2tleXdv
cmQ+PGtleXdvcmQ+ZGlzZWFzZSBkdXJhdGlvbjwva2V5d29yZD48a2V5d29yZD5kaXNlYXNlIHNl
dmVyaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmZlbWFsZTwva2V5d29yZD48a2V5d29yZD5ob3NwaXRh
bGl6YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5v
Z2xvYnVsaW4gZGVmaWNpZW5jeTwva2V5d29yZD48a2V5d29yZD5pbmNpZGVuY2U8L2tleXdvcmQ+
PGtleXdvcmQ+aW5qZWN0aW9uIHNpdGUgaW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmlu
amVjdGlvbiBzaXRlIHBhaW48L2tleXdvcmQ+PGtleXdvcmQ+bWFsZTwva2V5d29yZD48a2V5d29y
ZD5tdWx0aXBsZSBteWVsb21hPC9rZXl3b3JkPjxrZXl3b3JkPnByaW9yaXR5IGpvdXJuYWw8L2tl
eXdvcmQ+PGtleXdvcmQ+cXVhbGl0eSBvZiBsaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJhbmRvbWl6
ZWQgY29udHJvbGxlZCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5za2luIGFsbGVyZ3k8L2tleXdv
cmQ+PGtleXdvcmQ+dHJlYXRtZW50IGR1cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2ds
b2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29yZD48a2V5
d29yZD5JbW11bm9nbG9idWxpbiBFPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEc8
L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5JbW11
bm9nbG9idWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVn
aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRl
cz48ZGF0ZT4yMDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMS03MDM1IDE1
MjEtNjYxNjwvaXNibj48YWNjZXNzaW9uLW51bT5yYXl5YW4tNDU4ODE2NzwvYWNjZXNzaW9uLW51
bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0i
ZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cDovL3d3dy5lbWJhc2UuY29tL3NlYXJjaC9yZXN1bHRz
P3N1YmFjdGlvbj12aWV3cmVjb3JkJmFtcDtmcm9tPWV4cG9ydCZhbXA7aWQ9TDYyMDgwOTY5MDwv
c3R5bGU+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+IDwv
c3R5bGU+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+
aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9qLmNsaW0uMjAxNy4xMS4wMTQ8L3N0eWxlPjwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVTSU9OOiB7JnF1b3Q7
U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20xPjxyZXNlYXJjaC1u
b3Rlcz5NTSAtIFNDSUcgdnMgY29udHJvbHM8L3Jlc2VhcmNoLW5vdGVzPjxsYW5ndWFnZT5Fbmds
aXNoPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018). The authors reported that three patients (3/24 [12.5%]) with Grade 3/4 events discontinued infusions and withdrew from the SCIg arm: two due to injection site reactions; one had an extensive allergic skin reaction after the second infusion that resolved with steroids and anti-histamines. Otherwise AEs due to SCIg were mild. Systemic and other AEs – case seriesCase series presenting safety data for IgG without a comparator group are summarised in REF _Ref9247850 \h \* MERGEFORMAT Table 18 (comparator indicated ‘N/A’ – these are studies that presented comparisons for efficacy outcomes based on untreated control patients or before/after data from IgG patients). Other case studies presenting AEs from two IgG intervention groups are in REF _Ref12276249 \h \* MERGEFORMAT Table 19.Table SEQ Table \* ARABIC 18Studies presenting systemic and other AE outcomes for IgG case seriesStudy, IndicationOutcomeInterventionComparator Non-comparative studies – IVIg case series*Brenner, 1996Total AEs (N=54)(SID=26; PID=28 patients)IVIg (N=54)N/ACLL(22), MM(4)No. of infusions with AEs (%) (N=301 infusions)41 (16%)―Infusions with mild AEs35 (65%)-Infusions with moderate AEs6 (11%)-Infusions with severe AEs0-Infusions with most common AE – fever12 (4%)-Infusions with AE – chills10 (3%)-Infusions with AE – nausean.r. (1.5%)-Infusions with AE – headachen.r. (1.5%)-Other AEs*<0.7%-Types of AEs reported66-AEs in CLL only (n=22 patients, 167 infusions)29 (17%)―AEs in MM only (n=4 patients, 18 infusions)1 (6%)―Günther & Dreger 2013Adverse Events (N=10)n events or n/N patientsN/A(various)*AEs related to IVIg (n patients)(none of these were judged serious AEs)8 (in 5/10 patients)―Patients with shivering and fever2/5-Patients with shivering and fever, concomitant pruritus1/5-Patients with shivering, headache and nausea1/5-Patients with arthralgia1/5 (on 3 occasions)-Patients with SAEs due to underlying disease (splenectomy[1]; renal failure[2]; death due to disease progression[5]; death during unrelated surgery[1])8 (in 6/10 patients)-Jurlander et al. 1994AEs (N=15 patients)During studyMedian 14mo(range 3-20)(N=14)N/ACLL (N=15)Total infusions225-Total n events (%)5 (2.2%)-Chills (in 3 patients), n (%)4 (1.8%)-Dizziness, headache and heat sensation (single episode), n (%)1 (<1%)-Discontinuations due to AE (n/N=15 patients)1/15 (7%)-12 months during study (median 14 mo, range 3-20) (n=14)-Non-comparative studies – SCIg case seriesDimou et al. 2018Adverse Events, patients with event n/N (%)During SCIg (N=33)N/ACLL(25), MM(3); NHL(3), HL(1)*Mild (grade 1) AEs (low grade fever and headache after the 1st and/or 2nd infusion)3/33 (9%)-**Other AE: recurrent unilateral scrotal oedema (transient, no severity described)1/33(3%)-Discontinued SCIg due to AE1/33 (3%)-**Late AEs (not attributed to SCIg)2/33 (6%)-*Notes: Brenner, 1996 – N=54 patients included CLL (22); MM (4); ITP (20) and PAPS (8). Other AEs: dizziness, weakness, back pain, excessive salivation, sleepiness, palmar erythema, itching, flushing, chest pain or pressure, mild hypotension and mild hypertension, palpitations, vomiting, cold sweats, and dry cough. Günther & Dreger 2013 – underlying disease types: CLL (5), FL (2), WM (1), IgA-plasmacytoma (1), MDS (1)]. Jurlander et al., 1994 – 1 of 15 patients discontinued after 4 infusions and is not included, thus N=14. Dimou et al., 2018 – the individual haematological malignancy totals do not add up to N=33. Scrotal oedema recurred in 1 patient after SCIg infusions (each time resolving within 24h) until timing changed to evening infusion; Discontinuation was due to rare rash, mucinosis, most likely irrelevant to SCIg; late AEs were 1 episode DVT after 1 yr of tx (patient was also receiving erythropoietin), and 1 maculopapular pruritic rash on abdomen + buttocks 3 days after 6th infusion. AEs=adverse events; CLL=chronic lymphocytic leukaemia; DVT=deep vein thrombosis; FL=follicular lymphoma; HL=Hodgkin lymphoma; ITP=idiopathic thrombocytopenic purpura; IVIg=intravenous immunoglobulin; MDS=myelodysplastic syndrome; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; n.r.=not reported; PAPS=primary antiphospholipid syndrome; PID=primary immunodeficiency; SAE=serious adverse event; SCIg=sub-cutaneous immunoglobulin; SID=secondary immunodeficiency; tx=treatment; WM=Waldenstr?m macroglobulinaemia. A sponsor-funded study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48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ADDIN EN.CITE.DATA (Brenner 1996) of the efficacy and safety of an IVIg product, Octagam (Octapharma) studied 54 patients in the USA with haematological malignancies (CLL and MM) or primary immunodeficiency. The author found that AEs were similar to other IVIg products, most commonly fever and chills, and that reactions were generally mild or manageable with dose adjustment and medication. A small sponsor-funded study in Germany of post-market experience with Alphaglobin/Flebogamma in 10 patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
PFJlY051bT4zNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR8O8bnRoZXIgJmFtcDsgRHJlZ2VyIDIw
MTMpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDll
MnIycGQydGFkIiB0aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjM0PC9rZXk+PC9mb3JlaWduLWtleXM+
PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv
cnM+PGF1dGhvcnM+PGF1dGhvcj5Hw7xudGhlciwgRy48L2F1dGhvcj48YXV0aG9yPkRyZWdlciwg
Qi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NZWRpY2Fs
IENhcmUgQ2VudGVyIGZvciBCbG9vZCBhbmQgQ2FuY2VyIERpc2Vhc2VzLCBQb3RzZGFtLCBHZXJt
YW55LiBkci5nZW9yZ19ndWVudGhlckB0LW9ubGluZS5kZTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+
PHRpdGxlPlBvc3QtbWFya2V0aW5nIG9ic2VydmF0aW9uYWwgc3R1ZHkgb24gNSUgaW50cmF2ZW5v
dXMgaW1tdW5vZ2xvYnVsaW4gdGhlcmFweSBpbiBwYXRpZW50cyB3aXRoIHNlY29uZGFyeSBpbW11
bm9kZWZpY2llbmN5IGFuZCByZWN1cnJlbnQgc2VyaW91cyBiYWN0ZXJpYWwgaW5mZWN0aW9uczwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5NaWNyb2Jpb2wgSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk1pY3JvYmlvbCBJbW11bm9sPC9mdWxs
LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTI3LTM1PC9wYWdlcz48dm9sdW1lPjU3PC92b2x1
bWU+PG51bWJlcj43PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIEluZmVjdGlvbnMvIHRoZXJh
cHk8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1
Zy1SZWxhdGVkIFNpZGUgRWZmZWN0cyBhbmQgQWR2ZXJzZSBSZWFjdGlvbnMvZXBpZGVtaW9sb2d5
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZW1hdG9sb2dpYyBO
ZW9wbGFzbXMvY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnMsIEludHJhdmVub3VzL2FkdmVyc2UgZWZmZWN0cy8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2xvZ2ljIERlZmljaWVuY3kgU3luZHJvbWVzLyBjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb2R1Y3Qg
U3VydmVpbGxhbmNlLCBQb3N0bWFya2V0aW5nPC9rZXl3b3JkPjxrZXl3b3JkPlNlY29uZGFyeSBQ
cmV2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxr
ZXl3b3JkPmNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWE8L2tleXdvcmQ+PGtleXdvcmQ+aW50
cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PGtleXdvcmQ+cmVjdXJyZW50IGluZmVj
dGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+c2Vjb25kYXJ5IGltbXVub2RlZmljaWVuY3k8L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5pemF0aW9uLCBQYXNzaXZlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdv
cmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBNPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v
Z2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxr
ZXl3b3JkPlJlY3VycmVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjEzNDgtMDQyMSAoRWxlY3Ryb25pYykgMDM4NS01NjAwIChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4yMzYwNzg2MzwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+UkFZ
WUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90O0luY2x1ZGVkJnF1b3Q7
fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+Q0xMLCBOSEwsIElnTS1zZWNyZXRpbmcgaW1tdW5v
Y3l0b21hLCBJZ0EgcGxhc21hIGN5dG9tYSwgTXllbG9keXNwbGFzdGljIHN5bmRyb21lL05ITC4g
QmVmb3JlIGFuZCBhZnRlciBjb21wYXJpc29uPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5n
PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Günther & Dreger 2013) reported 1.44% of infusions associated with at least one AE (8/556 infusions). None of the AEs related to the IVIg product was considered serious. A Danish study in 15 CLL patients ADDIN EN.CITE <EndNote><Cite><Author>Jurlander</Author><Year>1995</Year><RecNum>11</RecNum><DisplayText>(Jurlander, Geisler & Hansen 1995)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825059">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jurlander, J.</author><author>Geisler, C. H.</author><author>Hansen, M. M.</author></authors></contributors><auth-address>Department of Haematology, Rigshospitalet, State University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low-dose intravenous gammaglobulin</title><secondary-title>Eur J Haematol</secondary-title></titles><periodical><full-title>Eur J Haematol</full-title></periodical><pages>114-8</pages><volume>53</volume><number>2</number><keywords><keyword>Agammaglobulinemia/ complications/ drug therapy</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/blood</keyword><keyword>Immunoglobulins, Intravenous/ therapeutic use</keyword><keyword>Leukemia, Lymphocytic, Chronic, B-Cell/ blood/ complications</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1995</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0902-4441 (Print) 0902-4441 (Linking)</isbn><accession-num>8088382</accession-num><urls></urls><custom1>RAYYAN-INCLUSION: {"Skye"=>"Included"}</custom1><research-notes>CLL before and after case series</research-notes><language>eng</language></record></Cite></EndNote>(Jurlander, Geisler & Hansen 1995) reported 5 AEs in 15 patients who had received 225 IgG infusions; one patient discontinued due to AEs. A Greek study of 33 patients switching from IVIg to SCIg PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE.DATA (Dimou et al. 2018) reported four AEs during the study period, one of which led to discontinuation. The authors noted with interest that two patients who had had moderate AEs on IVIg (headache, chills, low grade fever after every infusion) tolerated SCIg without reactions. Table SEQ Table \* ARABIC 19Case series presenting systemic and other AE outcomes for more than one IgG groupStudy, IndicationOutcomeIntervention 1Intervention 2Non-comparative studies – Any IgG (IVIg and SCIg) case seriesBenbrahim et al., 2019Tolerability of IgG-RT (N=160)IVIg (n=50)SCIg (n=110)MM(54), CLL(54), NHL(48), HL(4)Serious AEs00Patients with other AEsPneumonia*1 (2%)0Itching/swelling/redness02 (1.8%)Blood pressure increase1 (2%)0Rash01 (0.9%)Cold sensation/asthenia01 (0.9%)Total patients with AEs2 (4%)4 (3.6%)Discontinuation due to tolerance concern n=1 (group not reported)n.r.n.r.Reiser et al., 2017On-study AEs (N=307)IVIg (n=287)SCIg (n=20)CLL(130); NHL(99); MM(43); other(35)*Total on-study AEs (all in IVIg patients)15―Serious AEs (leading to hospitalisation)4Non-serious AEs11Non-comparative studies – IVIg v SCIg case seriesSundin et al., 2012Side effects (N=58)IVIg (N=46)N with event/N(%)n=24 haem. malignancySCIg (N=12)N with event/N(%)n=2 haem. malignancyHSCTAllergic reaction6/46 (16.2%)0Headache 40/46 (54.1%)0Hypertonia 1/46 (2.7%)0Local infection/reaction 02/12 (16.7%)Other 1/46 (2.7%)0No. patients with any side effect31/46 (67.4%)2/12 (16.7%)Other (IVIg and SCIg) – dosing studiesChapel, Dicato et al. 1994AEs (N=34 patients; 378 infusions)High doseIVIg 500mg/kg (n=16)Low doseIVIg 250 mg/kg (n=18)CLLSerious AEs00Mild AEs (chills, fever, back pain) (events only; number of patients n.r.)28*Notes: Benbrahim et al., 2019 – the finding of pneumonia was reported as an AE rather than an infection; Reiser et al., 2017 – AEs specified as: allergic reactions (2), chill (5), back pain (1), thoracic pain (1), (severe) nausea (3), pleuritis (1), dizziness (1) and mild proctitis (1). Of these, the 4 AEs leading to hospitalisation were not identified. ‘Other’ underlying conditions were: HIV(7), post-transplant(7), leukaemia (not CLL)(4), HL(2), 15 other malignant and non-malignant conditions (e.g. MGUS, MDS, AA, haemolytic anaemia, COPD). AA=aplastic anaemia; AEs=adverse events; CLL=chronic lymphocytic leukaemia; COPD=chronic obstructive pulmonary disease; FL=follicular lymphoma; HIV=human immunodeficiency virus; HL=Hodgkin lymphoma; HSCT=haematopoietic stem cell transplant; IVIg=intravenous immunoglobulin; IgG-RT=immunoglobulin gamma replacement therapy; MDS=myelodysplastic syndrome; MGUS=monoclonal gammopathy of undetermined significance; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; n.r.=not reported; SAE=serious adverse event; SCIg=subcutaneous immunoglobulin; WM=Waldenstr?m macroglobulinaemia. A sponsor-funded study in 160 French patients published this year PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy
PjxSZWNOdW0+ODg8L1JlY051bT48RGlzcGxheVRleHQ+KEJlbmJyYWhpbSBldCBhbC4gMjAxOSk8
L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+ODg8L3JlYy1udW1iZXI+PGZvcmVpZ24t
a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJw
ZDJ0YWQiIHRpbWVzdGFtcD0iMTU1OTE4MzEwNiI+ODg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVm
LXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48
YXV0aG9ycz48YXV0aG9yPkJlbmJyYWhpbSwgTy48L2F1dGhvcj48YXV0aG9yPlZpYWxsYXJkLCBK
LiBGLjwvYXV0aG9yPjxhdXRob3I+Q2hvcXVldCwgUy48L2F1dGhvcj48YXV0aG9yPlJveWVyLCBC
LjwvYXV0aG9yPjxhdXRob3I+QmF1ZHVlciwgRi48L2F1dGhvcj48YXV0aG9yPkRlY2F1eCwgTy48
L2F1dGhvcj48YXV0aG9yPkNyYXZlLCBKLiBDLjwvYXV0aG9yPjxhdXRob3I+RmFyZGluaSwgWS48
L2F1dGhvcj48YXV0aG9yPkNsZXJzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5MZXZ5LCBWLjwvYXV0
aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPmEgSG9waXRhbCBkZSBM
YSBTb3VyY2UsIENlbnRyZSBIb3NwaXRhbGllciBSZWdpb25hbGUgT3JsZWFucyAsIE9ybGVhbnMg
LCBGcmFuY2UuJiN4RDtiIE1lZGVjaW5lIEludGVybmUgLCBIb3BpdGFsIEhhdXQgTGV2ZXF1ZSAs
IFBlc3NhYyAsIEZyYW5jZS4mI3hEO2MgSGVtYXRvbG9naWUsIEdIIFBpdGllIFNhbHBldHJpZXJl
ICwgQXNzaXN0YW5jZSBQdWJsaXF1ZS1Ib3BpdGF1eCBkZSBQYXJpcyAsIFBhcmlzICwgRnJhbmNl
LiYjeEQ7ZCBIZW1hdG9sb2dpZSBDbGluaXF1ZSAsIENIVSBBbWllbnMgLSBTdWQgLCBBbWllbnMg
LCBGcmFuY2UuJiN4RDtlIEhlbWF0b2xvZ2llICwgQ0ggQ290ZSBCYXNxdWUgLCBCYXlvbm5lICwg
RnJhbmNlLiYjeEQ7ZiBNZWRlY2luZSBJbnRlcm5lICwgQ0hVIFJlbm5lcyAtIFN1ZCAsIFJlbm5l
cyAsIEZyYW5jZS4mI3hEO2cgT2N0YXBoYXJtYSBGcmFuY2UgLCBCb3Vsb2duZSAsIEZyYW5jZS4m
I3hEO2ggU29sYWRpcyBDbGluaWNhbCBTdHVkaWVzICwgUm91YmFpeCAsIEZyYW5jZS4mI3hEO2kg
VVJDL0NSQyBHcm91cGUgSG9zcGl0YWxpZXIgUGFyaXMgU2VpbmUgU2FpbnQgRGVuaXMgLCBBUEhQ
ICwgSG9waXRhbCBBdmljZW5uZSAsIEZyYW5jZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs
ZT5UaGUgdXNlIG9mIG9jdGFnYW0gYW5kIGdhbW1hbm9ybSBpbiBpbW11bm9kZWZpY2llbmN5IGFz
c29jaWF0ZWQgd2l0aCBoZW1hdG9sb2dpY2FsIG1hbGlnbmFuY2llczogYSBwcm9zcGVjdGl2ZSBz
dHVkeSBmcm9tIDIxIEZyZW5jaCBoZW1hdG9sb2d5IGRlcGFydG1lbnRzPC90aXRsZT48c2Vjb25k
YXJ5LXRpdGxlPkhlbWF0b2xvZ3k8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh
bD48ZnVsbC10aXRsZT5IZW1hdG9sb2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+
MTczLTE4MjwvcGFnZXM+PHZvbHVtZT4yNDwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3
b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5
d29yZD5IZW1hdG9sb2dpYyBOZW9wbGFzbXMvYmxvb2QvKmRydWcgdGhlcmFweS9tb3J0YWxpdHk8
L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlu
cywgSW50cmF2ZW5vdXMvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5
d29yZD5JbW11bm9sb2dpYyBEZWZpY2llbmN5IFN5bmRyb21lcy9ibG9vZC8qZHJ1ZyB0aGVyYXB5
L2V0aW9sb2d5L21vcnRhbGl0eTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3
b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+TXVsdGlwbGUgbXllbG9tYTwva2V5d29yZD48a2V5d29yZD5jaHJvbmlj
IGx5bXBob2lkIGxldWtlbWlhPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVub2dsb2J1bGluczwva2V5
d29yZD48a2V5d29yZD5pbmZlY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPnNhdGlzZmFjdGlvbjwv
a2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE5PC95ZWFyPjxwdWItZGF0ZXM+PGRh
dGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTYwNy04NDU0IChFbGVjdHJv
bmljKSYjeEQ7MTAyNC01MzMyIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4zMDQ1ODY5
MDwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVu
ZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cHM6Ly93d3cubmNiaS5ubG0u
bmloLmdvdi9wdWJtZWQvMzA0NTg2OTA8L3N0eWxlPjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs
cz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA4MC8xMDI0NTMzMi4yMDE4LjE1MzgwMDE8
L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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==
ADDIN EN.CITE.DATA (Benbrahim et al. 2019) compared two of the company’s products, IVIg, Octagam, and SCIg, Gammanorm (both Octapharma). The authors reported that no serious AEs were observed and IgG was well-tolerated by both routes of administration. A German registry study of 307 patients with a range of haematological malignancies only reported those AEs that were recorded in patient records PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Reiser et al. 2017). Four patients experienced AEs that required hospitalisation (median follow-up was 10.8 months). The authors reported that “In view of the low drop-out rate in the study it can be assumed that IVIG and SCIG substitution therapies were overall well tolerated”. Actual numbers of discontinuations were not reported. One Swedish case series PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012) reported AEs for SCIg versus IVIg in 58 children who had received HSCTs. Similar to the Greek study above PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE.DATA (Dimou et al. 2018) the authors noted that three patients with a history of headaches due to IVIg infusions found these events resolved with the switch to SCIg. A UK study compared two doses of IgG in in 34 CLL patients ADDIN EN.CITE <EndNote><Cite><Author>Chapel</Author><Year>1994</Year><RecNum>47</RecNum><DisplayText>(Chapel et al. 1994a)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554259107">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Dicato, M.</author><author>Gamm, H.</author><author>Brennan, V.</author><author>Ries, F.</author><author>Bunch, C.</author><author>Lee, M.</author></authors></contributors><auth-address>Department of Immunology, John Radcliffe Hospital, Oxford.</auth-address><titles><title>Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes</title><secondary-title>Br J Haematol</secondary-title></titles><periodical><full-title>Br J Haematol</full-title></periodical><pages>209-12</pages><volume>88</volume><number>1</number><edition>1994/09/01</edition><keywords><keyword>Aged</keyword><keyword>Critical Illness</keyword><keyword>Dose-Response Relationship, Immunologic</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/administration & dosage/ therapeutic use</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Precursor Cell Lymphoblastic Leukemia-Lymphoma/ therapy</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1994</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0007-1048 (Print)
0007-1048 (Linking)</isbn><accession-num>7803248</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><research-notes>CLL dose comparison</research-notes><language>eng</language></record></Cite></EndNote>(Chapel et al. 1994a). No serious AEs were observed of 378 infusions, and of ten mild AEs that occurred, eight were in low dose patients and only two in the high dose IVIg group. Thromboembolic events (TEEs)A US registry study in over 10,000 patients with CLL or MM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016) investigated the risk of both arterial and venous thromboembolic events (TEEs) associated with IgG administration during 12 months of follow-up ( REF _Ref9248061 \h \* MERGEFORMAT Table 20).Table SEQ Table \* ARABIC 20Studies presenting TEE outcomes – Ammann et al., 2016Study, IndicationOutcomeResultsAmmann 2016Event rate differences (propensity matched data) – 12 mo of monthly IVIg% 1-yr incidence (cumulative) in unexposedHR, d0-30 after IgG (95% CI)% Risk difference (95% CI), 1 yr txNNH (95% CI), 1 yr txCLLMMArterial TEE (AMI or ischaemic stroke)1.81.38 (0.89, 2.14)0.7 (-0.2, 2.0)150 (50, ∞)Venous TEE (DVT or PE)1.11.27 (0.67, 2.41)0.3 (-0.4, 1.5)340 (66, ∞)Composite end point (arterial or venous TEE)2.91.36 (0.95, 1.96)1.0 (-0.2, 2.7)98 (37, ∞)Notes: Amman et al., 2016 – the study included patients receiving any of IVIg, SCIg and IMIg (proportions not reported).AMI=acute myocardial infarction; CI=confidence interval; d=day; DVT=deep vein thrombosis; HR=hazard ratio; IVIg=intravenous immunoglobulin; NNH=number needed to harm; PE=pulmonary embolism; TEE=thromboembolic event; tx=treatment; yr=year.Investigation of TEE risk was the primary objective of this study – risks due to TEE were considered in the context of a 30 day treatment cycle. The number needed to harm (NNH) for arterial and venous TEEs are given in REF _Ref9248061 \h \* MERGEFORMAT Table 20 above – the composite NNH for any TEE was 98 (37, ∞), noting that patients in the studied cohort were older and with a relatively high burden of risk factors for TEEs. The authors concluded: “For the primary endpoint, arterial TEE, we observed a transient increased risk of TEE during the day of an IVIg infusion and the day afterward (HR 3.40; 95% CI: 1.25-9.25); this risk declined over the remainder of the 30-day treatment cycle. When considered in terms of absolute risk averaged over a 1-year treatment period, the increase in risk attributable to IVIg was estimated to be 0.7% (95% CI: 0.2 – 2.0%) compared with a baseline risk of 1.8% for the arterial TEE end point.”The authors reported an overall increased risk of 1.0% (95% CI -0.2%, 2.7%) for a composite endpoint of arierial and venous TEE during 12 months’ IgG treatment. A recent study in Greece described above PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
Y051bT4yODwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oRGltb3UgZXQgYWwuIDIwMTgpPC9EaXNwbGF5
VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl
eSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0
aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjI4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h
bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+
PGF1dGhvcj5EaW1vdSwgTS48L2F1dGhvcj48YXV0aG9yPklsaWFraXMsIFQuPC9hdXRob3I+PGF1
dGhvcj5NYWx0ZXphcywgRC48L2F1dGhvcj48YXV0aG9yPkJpdHNhbmksIEEuPC9hdXRob3I+PGF1
dGhvcj5LYWx5dmEsIFMuPC9hdXRob3I+PGF1dGhvcj5Lb3Vkb3VuYSwgQS48L2F1dGhvcj48YXV0
aG9yPktvdHNhbnRpLCBTLjwvYXV0aG9yPjxhdXRob3I+UGV0c2EsIFAuPC9hdXRob3I+PGF1dGhv
cj5QYXBhaW9hbm5vdSwgUC48L2F1dGhvcj48YXV0aG9yPkt5cnRzb25pcywgTS4gQy48L2F1dGhv
cj48YXV0aG9yPlBhbmF5aW90aWRpcywgUC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv
cnM+PGF1dGgtYWRkcmVzcz4xc3QgUHJvcGFlZGV1dGljIENsaW5pYywgRGVwYXJ0bWVudCBvZiBJ
bnRlcm5hbCBNZWRpY2luZSwgTGFpa29uIEdlbmVyYWwgSG9zcGl0YWwsIE5hdGlvbmFsIGFuZCBL
YXBvZGlzdHJpYW4gVW5pdmVyc2l0eSBvZiBBdGhlbnMsIFNjaG9vbCBvZiBNZWRpY2luZSwgQXRo
ZW5zLCBHcmVlY2UgbXNkaW1vdUBnbWFpbC5jb20uIDFzdCBQcm9wYWVkZXV0aWMgQ2xpbmljLCBE
ZXBhcnRtZW50IG9mIEludGVybmFsIE1lZGljaW5lLCBMYWlrb24gR2VuZXJhbCBIb3NwaXRhbCwg
TmF0aW9uYWwgYW5kIEthcG9kaXN0cmlhbiBVbml2ZXJzaXR5IG9mIEF0aGVucywgU2Nob29sIG9m
IE1lZGljaW5lLCBBdGhlbnMsIEdyZWVjZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5F
ZmZpY2FjeS1zYWZldHkgb2YgRmFjaWxpdGF0ZWQgU3ViY3V0YW5lb3VzIEltbXVub2dsb2J1bGlu
IGluIEltbXVub2RlZmljaWVuY3kgRHVlIHRvIEhlbWF0b2xvZ2ljYWwgTWFsaWduYW5jaWVzLiBB
IFNpbmdsZS1DZW50ZXIgUmV0cm9zcGVjdGl2ZSBBbmFseXNpczwvdGl0bGU+PHNlY29uZGFyeS10
aXRsZT5BbnRpY2FuY2VyIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs
PjxmdWxsLXRpdGxlPkFudGljYW5jZXIgUmVzPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn
ZXM+NDE4Ny00MTkxPC9wYWdlcz48dm9sdW1lPjM4PC92b2x1bWU+PG51bWJlcj43PC9udW1iZXI+
PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+
PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3
b3JkPjxrZXl3b3JkPkhlbWF0b2xvZ2ljIE5lb3BsYXNtcy8gY29tcGxpY2F0aW9uczwva2V5d29y
ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy8gYWRt
aW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2xvZ2ljIERl
ZmljaWVuY3kgU3luZHJvbWVzLyBkcnVnIHRoZXJhcHkvIGV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3
b3JkPkluZnVzaW9ucywgU3ViY3V0YW5lb3VzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdv
cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBT
dHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkZhY2lsaXRhdGVkIHN1YmN1dGFuZW91cyBpbW11bm9n
bG9idWxpbjwva2V5d29yZD48a2V5d29yZD5oZW1hdG9sb2dpYyBtYWxpZ25hbmNpZXM8L2tleXdv
cmQ+PGtleXdvcmQ+c2Vjb25kYXJ5IGltbXVub2RlZmljaWVuY3k8L2tleXdvcmQ+PGtleXdvcmQ+
SGVtYXRvbG9naWMgTmVvcGxhc21zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEQ8
L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29yZD48a2V5d29yZD5JbW11
bm9nbG9idWxpbiBBPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEU8L2tleXdvcmQ+
PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRzwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxp
biBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zPC9rZXl3
b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5K
dWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNzkxLTc1MzAgKEVsZWN0cm9uaWMp
IDAyNTAtNzAwNSAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk5NzA1NDg8L2FjY2Vz
c2lvbi1udW0+PHVybHM+PC91cmxzPjxjdXN0b20xPlJBWVlBTi1JTkNMVVNJT046IHsmcXVvdDtT
a3llJnF1b3Q7PSZndDsmcXVvdDtJbmNsdWRlZCZxdW90O308L2N1c3RvbTE+PHJlc2VhcmNoLW5v
dGVzPkNMTCwgTU0sIE5ITCwgYW5kIEhvZGdraW4mYXBvcztzIEw8L3Jlc2VhcmNoLW5vdGVzPjxs
YW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA (Dimou et al. 2018) also reported one DVT ‘late’ adverse event after one year of SCIg in a CLL patient who was also receiving erythropoietin. DVT is more often associated with the latter product than IgG – only erythropoietin was discontinued. The patient received 3 months of low molecular weight heparin and continued SCIg, remaining event-free 15 months after the DVT occurred. The authors concluded this could not be attributed to SCIg.Studies presenting no safety dataThe studies in REF _Ref9248035 \h \* MERGEFORMAT Table 21 only considered the effect of IgG products on infections and reported few or no safety outcomes. A number of these were retrospective studies were limited by the information contained in patients records. Table SEQ Table \* ARABIC 21Included studies presenting no AE dataStudyIndicationNComments regarding on-study AEs including deathAmmann et al., 2016Various (undefined)N= 10,759TEE events reported only, no systemic AEs or other IgG-related outcomes.Benbrahim et al., 2018MM, NHL, CLL, HL231Preliminary report only – see Benbrahim et al., 2019 for AEs. Besa, 1992CLL23No mention of on-study AEs or infusion tolerability.Blombery et al., 2011MM+HSCT240No mention of on-study AEs or infusion tolerability.Chapel et al., 1991CLL, NHL12Paper presents data from two studies, but only presents AEs for a similar earlier study (Gale et al., 1988). No mention of on-study AEs or infusion tolerability.Duraisingham et al., 2014CLL(1), MM(1), NHL(11); MDS(1); MGUS(1)39 (SID group)No mention of on-study AEs, infusion tolerability, deaths or discontinuations.Musto et al., 1995MM25“No relevant adverse effect due to the infusion of IVIg was observed”. No discontinuations due to infusion were reported.Paxton et al., 2016CLL (42); MM (18); NHL (27); other (5)92No mention of on-study AEs or infusion tolerability.Stump et al., 2017CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)209 infusions(N=79 patients)“[O]f the 26 IVIG encounters excluded for death within 30 days [the observation period], 17 (65%) were for treatment of a pre-existing infection, and 9 (35%) were for infection prevention secondary to hypogammaglobulinemia.”Windegger et al. 2019(undefined HM)N=13“No serious adverse events requiring hospitalization due to [IgG] were reported in our cohort.”“No patient developed bronchiectasis or died within the 24 months [study] period.”AE=adverse event; AL=acute leukaemia; CLL=chronic lymphocytic leukaemia; CML=chronic myeloid leukaemia; HL=Hodgkin lymphoma; HM=haematological malignancy; HSCT=haematological stem cell transplant; IVIg=intravenous immunoglobulin; MM=multiple myeloma; NHL=non-Hodgkin lymphomaIs it effective? Summary – Is IgG replacement therapy more safe, effective and cost-effective than no IgG? Six randomised trials reported that patients with acquired hypogammaglobulinaemia who received IVIg (k=5) or SCIg (k=1) had fewer infections than those who did not have IgG therapy. These trials were in patients whose underlying conditions were CLL (k=3), MM (k=2); and those who underwent HSCT (k=1). Those patients who were randomised to receive IgG had significantly fewer infections than those who did not receive IgG. The difference in the number of severe/serious and life-threatening infections was large (weighted IRR=0.14; 95%CI 0.05, 0.43), whereas there was less difference in mild or moderate infections (weighted IRR=0.61; 95%CI 0.51, 0.72). These data were supported by before-and-after studies, where infection rates were available for patients prior to, and receiving IgG infusions (weighted IRR=0.64; 95%CI 0.49, 0.84). One randomised trial compared transplant-related outcomes in patients who had undergone HSCT, with or without IVIg. In those who received allografts, the rate of GVHD and interstitial pneumonia was significantly less in those who received IVIg than those who did not receive IVIg. One cohort study compared the rate of GVHD in patients who received IVIg versus those who received SCIg. The rate of acute and chronic GVHD was higher in the IVIg group, however, given the study design, selection bias may have influenced these results. IVIg did not appear to influence overall survival in a single trial and three observational studies identified. However, in the subgroup of patients randomised to IVIg, who were over 20 years old, and had HLA-identical bone marrow transplantation, the cumulative incidence of non-relapse mortality was significantly higher in those who did not receive IVIg (46%) than those who did (30%; p=0.023). Five observational studies reported that patients who received Ig therapy were also more likely to be hospitalised due to infections. The selection bias inherent in the study design mean that the influence of Ig on hospitalisation risk cannot be determined. One trial randomised MM patients with hypogammaglobulinaemia to receive SCIg or no SCIg. They graphically reported that quality of life on the SF-36 was significantly higher in those receiving SCIg for the domains of general health, physical functioning, role-physical, vitality, social functioning, role-emotional and mental health. The only domain which was not significant, was pain. Infection risk characteristics and definitions of infections for all included studies are summarised in REF _Ref9248112 \h \* MERGEFORMAT Table 22. Policies for antibiotic use in each study are described in REF _Ref11318489 \h \* MERGEFORMAT Table 84, REF _Ref10230975 \h \* MERGEFORMAT Appendix F.Table SEQ Table \* ARABIC 22Baseline risk of infection in the included studies: serum IgG and history of infections StudyIndicationDefinition of hypo-GGHypo-GG inclusion criterion?Infections inclusion criterion?Baseline IgG valuesIgG values during studyPrior infection historyInfections definitionsRandomised studies – IVIg vs No IVIgBoughton et al., 1995CLLHypo-GG: serum IgG <5.5g/LSevere hypo-GG: IgG <3.0g/L (normal range: 8-18g/L)Yes.Yes.Mean serum IgG±sd, g/L: IVIg: 3.5±0.7No IVIg: 3.6±0.6Measured 3-weekly for study duration. (all patients had history of infections)History of infections: ≥2 documented infections in the preceding 12 months.Life threatening infections such as septicaemias and pneumonias which required hospital admission for intravenous antibiotics, were classified as serious.Chapel et al., 1991CLL, NHLserum IgG <50% of LLN (LLN defined as 6.4g/L)Yes (OR 1 prior major infection).Yes (OR hypo-GG)Not reported. Measured but not reported. Recorded at baseline but not reported.“Major” infections were life-threatening (septicaemia or pneumonia). “Moderate” infections required oral antibiotics and (bronchitis, otitis media, UTIs etc). “Trivial” infections required symptomatic/topical tx.Chapel et al., 1994MMNot defined.No.No.Patients stratified at baseline according to serum Ig >LLN/<LLN:IVIg (n=42), n/n: 10/32Placebo (n=41), n/n: 15/26Not reported.Not reported.Serious infections: major or moderate.“Major”: Life-threatening infections (hospitalisation + IV antibiotics).“Moderate”: 2° bacterial infections (oral antibiotics), localised herpes zoster. “Minor” infections: not necessarily requiring antibiotics.Kobayashi et al., 2014 ALL(34); AML(12); other leukaemia(2); NHL(2); solid tumours(11)Not defined.NoYes (febrile neutropenia)Serum IgG, mg/dL, median (range):MEPM+IVIG: 673 (236–1344) MEPM: 667.5 (292–2047)(72h duration per episode)Patients with febrile neutropenia not responding to 1st line antibiotics. Febrile neutropenia at entry defined (i) fever, temperature ≥37.5°C for≥1 h or a single temperature >38°C; (ii) ANC <0.5×109/L. Tx success: at 120h fever disappearance, clinical improvement, infecting organism eradicated, maintenance of response ≥7d after tx discontinuation. Tx failure: persistent fever/ infecting organism, required modification of antibiotic tx, new infections, infection-related death.Molica et al., 1996CLLserum IgG <600mg/dLYes (OR history of infection).Yes (OR hypo-GG)IgG level mg/dL(%):<500: 16 (38)>500<650: 13 (30.9)>650: 13 (30.9)Serum IgG tested in 25/42 patients 2-5 times during tx, but only % increases not g/L values reported.Previous 6-mo. History of infections in 17/42 patients (40.4%)Infections graded as ‘severe or’ trivial’ (latter including those not requiring antibiotics). ‘Severe’ divided into major (usually IV antibiotics and hospitalisation needed; e.g. sepsis, pneumonia). ‘Minor’ (requiring no IV antibiotics, hospitalisation, e.g. bronchitis, otitis, lower UTIs)Musto et al., 1995MMserum IgG <LLNYes (OR history of infection).Yes (OR hypo-GG)Not reportedNot reportedInfection risk prior to and during study compared in results. Infections graded as serious or minor according to criteria in Chapel et al., 1994 (above)Sullivan et al., 1990Severe hypo-GG: serum IgG<4g/L IgG (5th %ile is ~6g/L)No.No.Pre-BMT levels recorded but presented as a figure (no values) suggesting pre-BMT values were low but within normal range. IgG d/L only dips below 5th %ile after BMT (as indicated by levels in no IVIg group). Measured d30, d60, d90 post-BMT, figure only no values reported. (IgG levels for ‘No IVIg’ group remain under 5th %ile until d90). Not reported. Incidence from d0-d100 or until discharge. Systemic infections culture-confirmed, as were local infections unless local site signs were adequate. Infections of URT, oral cavity or herpes simplex were not recorded. Bacteraemia: more than one positive blood culture with the same organism or positive blood culture+fever; Septicaemia: positive blood culture with hypotension, or positive blood culture with local infection both characterised by the same organism. Interstitial pneumonia based on pneumonitis with hypoxia + interstitial infiltrates on x-ray. CMV disease by viral culture or tissue evidence with clinical signs. Chest x-ray weekly until discharge. Randomised studies – SCIg vs No SCIgVacca et al., 2018MMSerum IgG <500mg/dLYesNo.IgG g/L, mean (range): All (N=46): 3.1 (1.3–5.2)SCIg (n=24): 3.2 (1.4–5.7)No SCIg (n=22): 3.2 (1.3–5.7)Measured monthly.Median IgG trough levels range g/LSCIg: 8.3-9.5No SCIg: 2.4-5.2Not reported.How infections were diagnosed or defined was not stated. Upper and lower respiratory tract infections were not defined. Infections were described variously as major or minor; mild/not serious vs serious; and severe. Other comparative studies – IVIg vs No IVIgAmmann, 2016CLL, MMNot stated. No.No.Not reported. The authors assume patients are hypo-GG, this seems to be based on dispensing for a ‘recognised indication’ (per PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcmFuZ2U8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcmFuZ2U8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (Orange et al. 2006) and according to FDA labelling) ― not clear how/if this was assessed.Not reported. Proportion reported with pneumonia, bronchitis, sepsis, UTI, influenza, other infections for prior 12mo.History of infections: Infections in 12 months prior to IVIg (influenza, pneumonia, chronic bronchitis, sepsis/septic shock, UTI, other). Extracted per patient records for study (ICD-9-CM codes) but not reported in article. Hospitalisation due to pneumonia and mortality during tx period compared.Blombery et al., 2011MM+HSCTCombined IgG/A/M <8g/L (excluding paraprotein).Yes.No.All had hypo-GGMedian total Ig, g/L (range) IVIg: 3 (0–8)No IVIg: 3 (1–7)Not available from patient records. Not reported for majority of patients (215/240 [90%]). History of infections in 25/240 subset (10%) already receiving IVIg as part of ongoing tx.History of infections: ≥2 previous bacterial infections (period not specified).Infection definitions were based on ADDIN EN.CITE <EndNote><Cite><Author>Carlisle</Author><Year>1993</Year><RecNum>101</RecNum><DisplayText>(Carlisle, Gucalp & Wiernik 1993)</DisplayText><record><rec-number>101</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1561969494">101</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carlisle, P. S.</author><author>Gucalp, R.</author><author>Wiernik, P. H.</author></authors></contributors><auth-address>Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York.</auth-address><titles><title>Nosocomial infections in neutropenic cancer patients</title><secondary-title>Infect Control Hosp Epidemiol</secondary-title></titles><periodical><full-title>Infect Control Hosp Epidemiol</full-title></periodical><pages>320-4</pages><volume>14</volume><number>6</number><keywords><keyword>Adult</keyword><keyword>Cross Infection/*epidemiology/etiology</keyword><keyword>Humans</keyword><keyword>Infection Control</keyword><keyword>Neoplasms/*complications</keyword><keyword>Neutropenia/*complications</keyword><keyword>New York City/epidemiology</keyword><keyword>Population Surveillance</keyword><keyword>Prospective Studies</keyword><keyword>Risk Factors</keyword></keywords><dates><year>1993</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0899-823X (Print)
0899-823X (Linking)</isbn><accession-num>8360462</accession-num><urls><related-urls><url>;(Carlisle, Gucalp & Wiernik 1993), included bloodstream infection, pneumonia, urinary tract infection and gastrointestinal infection.Paxton et al., 2016CLL (42); MM (18); NHL (27); other (5)Serum IgG <LLN(Severe hypo-GG serum IgG <4 g/L)Not for IVIg group; serum IgG <LLN only inclusion for ‘No IVIg’.No.Mean IgG g/L±sdIVIg: 2.8±1.6No IVIg: 4.0±1.6IgG stratification groups, n(%):<4g/L: 56 (61)≥4g/L: 36 (39)Not reported.29 patients had prior history of severe infections (requiring IV antibiotics or hospitalisation);41 had <3 infections in prior 24mo.No standard definitions. Infections prior to and during study period were per patient records.Van Winkle et al., 2018ALLPolicy: IVIg tx at doctor’s discretion if serum IgG<LLNLab LLN varied from 501-757mg/dLNo.No.24 of 31 patients tested [68%]) in the IVIg group (n=36) had hypo-GG at baseline.IgG levels tested an average 7 times (range 2-33) per patient.Mean IgG 474 mg/dL (range 89-785); 31 of 36 IVIg patients tested.21/36 (58%) patients in the IVIg group had a history of infections.Details compared for both IVIg and No IVIg groups.Infections reported as bacteraemia, fungaemia and hospitalisations per physician’s notes.Non-comparative studies – IVIg case seriesBesa, 1992CLLSerum IgG <700mg/dLNo.No.Serum IgG, mean (range):572 mg/dL (200–1720)18/23 patients (78%) had hypo-GG.Trough levels tested over 150 wks but values not reported. 13/23 patients (57%) had history of infections.Infection history (3 yr prior to IVIg) compared to infections during 3 yr IVIg tx.Infections: bacterial (sinusitis, cellulitis, pneumonia, sepsis) or viral (zoster). Brenner, 1996CLL, MMserum IgG <700mg/dLYes (OR history of infection).Yes (OR hypo-GG)Not reported.Values monitored but data not shown.CLL: 21 patients had a history of infections. MM: not reported (only 3 evaluable patients).History of infection: recurrent infections with at least 1 hospitalisation (period not stated).Infections reported as either those requiring hospitalisation; or as ‘treated ambulatory’. Infections during study compared to prior infections, adjusted to duration equivalent to study period. Günther & Dreger 2013CLL, FL and otherSecondary immune deficiency (definition not provided)YesYes (recurrent serial bacterial infections)Not reported. Most had normal IgG trough values (range: 600 – 1800 mg/dL)All 10 patients had experienced severe bacterial infections within 3 months before IVIg treatment (24 infections total).Bacterial infections (type, treatment and duration), and non-bacterial infections. No standard definitions. Jurlander et al., 1994CLLSerum IgG level below lower reference limitYesYes (history of recurrent infections)Mean: 12.5 micromoll/LMean: 28.5 micromol/LIn prior 168 months (total): 78 prior antibiotic prescriptions, 16 prior hospital admissions due to infections, 63 febrile episodes, 6 severe infectionsInfections requiring antibiotics, admission, febrile episodes or severe (no standard definition, but included septicaemia, pneumonia and meningitis)Non-comparative studies – SCIg case seriesDimou et al. 2018CLL, othersSerum Ig<LLNYes.Yes (≥2 severe episodes in last 12 months)Switching from IVIg to SCIg (n=13): Median pre-study trough level 532mg/dL (range 80-982)IVIg na?ve (n=18): Median pre-study trough level 403.5 mg/dL (range 102-632)Measured to permit tx goal trough of >600mg/dL. Values at 3,6,12,24 mo reported.26/33 patients had a history of severe recurrent infections.No standard definitions (infections listed in qualifying patients included LRT, URT; renal and soft tissue infections and Herpes zoster reactivation). Any IgG (IVIg and SCIg) case seriesBenbrahim et al., 2018MM, CLL, NHL, other (AL, HL)Serum IgG trough levels <5 g/LNo.No.In 195 of 231 patients tested:134/195 (68.7%) patients had hypo-GG (serum Ig< 5g/L)61/195 patients had Ig ≥5 g/L Of which, 59 had at least 1 infection within the previous 12 mo, 56 needed antibiotics. Reported in Benbrahim 2019.Mean 2.23±1.57 infections in 12 months before study.Reported in Benbrahim 2019.Benbrahim et al., 2019MM, CLL, NHL, HLSerum IgG trough levels <5 g/LNo.No.138/160 patients (86.3%) had Ig levels tested (median serum IgG levels 4.2 g/L). 91 patients were hypo-GG (65.9%) (IgG<5g/L).Mean serum IgG increase of 3.4±2.4 g/L from baseline to last visit. Reduction in patients with hypo-GG from 69.2% at baseline to 15.9% at last visit (p=0.14).Reported for larger group in Benbrahim 2018.Infections were classified according to the World Health Organization (WHO) grading with severe infections being WHO grade>2.Duraisingham et al., 2014(NHL, others)Serum IgG <5.5g/L (LLN), with or without low IgA or IgM.No.No.Serum IgG tested for 27 of 39 SID subjects; 21 SID patients (of 26; 80.8%) and 9 ‘probable SID’ patients (of 13; 69.2%) had hypo-GG.12mo median IgG trough levels (SID): 9.75 g/LIn 12mo preceding IgG-RT; (01/06/12 to 31/05/13) 6 of the 15 HM patients had suffered 1 or more serious infections.Based on patient records. ‘Serious infections’ defined as requiring hospitalisation and/or IV antibiotics. ‘Non-serious’ infections – any mild or moderate infection, with or without antibiotics.Reiser et al., 2017CLL(130); NHL(99); MM(43); other(35)Not defined.No.No.Median IgG level: 5.8g/L (mean 7.2±6.9 g/L). Measured every 6 mo for 2 years12mo infection history reported where available.The subgroup of serious bacterial infections comprised sepsis, osteomyelitis, and pneumonia. Other serious infections comprise e.g. Herpes zoster, otitis media or urinary tract infections. ‘General infections’ not defined, assumed to be same as those described as ‘non-serious’ or ‘other’ infections.Non-comparative studies – IVIg v SCIg case seriesSundin et al. 2012HSCT for 1° or 2° hypo-GGPlasma IgG <4g/LYes, for at least 3 months post-SCTNo.Not reported (although all patients had to be <4 g/L)IgG trough levels measured prior to each infusion and after cessation of IgG-RT (values not reported).64-96% reached IgG ≥4 g/LNot reported.Infections reported during IgG-RT (and are compared between SC and IV routes).Clinical infection defined as infectious symptoms requiring medical attention. Infections divided into bacterial, fungal, viral, and unidentified after microbiological testing.Windegger et al. 2019Haem. Malig. undefinedNot specified, but would have met NBA criteria from March 2013 to December 2016.YesYesNot reported. Mean serum IgG: IVIg phase: 7.1g/LSCIg phase: 8.4g/LNot reported. Number of infections (bacterial, viral and fungal), emergency department visits and hospitalisations from infection collected from medical charts and patient’s general practitioner. . Other (IVIg and SCIg) – dosing studiesChapel & Dicato et al., 1994CLLSerum IgG level <LLN (IgG ≤6.4g/L)Yes (OR history of infection)Yes (OR hypo-GG)High dose group: 5.1±2.9 (g/L)11 were ≤6.4; 6 were >6.4 g/LLow dose group: 5.7±5.212 were ≤6.4; 6 were >6.4Not reported. High dose group: ≥1: 11; none: 5Low dose group: ≥11; none: 7Infections were classified as major (usually requiring intravenous antibiotics and hospitalisation); moderate (requiring oral antibiotic therapy) and minor (requiring no antibiotic therapy). Serious infections were both ‘major’ and ‘moderate’ combined.Stump et al., 2017CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)Serum IgG <400mg/dLNo.No.Pre-infusion IgG levels (within 2 weeks prior to each dose, not baseline): tested prior to 133 of 238 infusions (56%) during study;Of which, hypo-GG (<400mg/dL):47/133 (35%);Of which, post-dose IgG values (within 2 weeks) were only taken after 14 infusions.Pre-infusion IgG values reported per infusion.Existing infections reported in 51.2% of patients receiving IBW doses and 33.6% of ABW doses. Note these are pre-infusion not per patient at baseline. Infections were reported for those patients who received a full dose, were alive at the end of the 30 day observation period and not lost to follow up, based on patient records.Existing infections recorded prior to dosing but not whether the recipient was IgG tx-na?ve (or if this was part of ongoing IgG replacement). AA=aplastic anaemia; AEs=adverse events; AML=acute myeloid leukaemia; BMT=bone marrow transplant CLL=chronic lymphocytic leukaemia; CMV=cytomegalovirus; FL=follicular lymphoma; G-CSF=granulocyte colony stimulating factor (filgrastim); GVHD=graft versus host disease; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HM=haematological malignancy; HR=hazard ratio; HRQoL=health-related quality of life; HSA=human serum albumin; HSCT=haematopoietic stem cell transplant; hypo-GG=hypogammaglobulinaemia; IgA=alpha immunoglobulin; IgG=gamma immunoglobulin; IgM=mu immunoglobulin; IMIg=intramuscular immunoglobulin; IQR=interquartile range; IRB=institutional review board (USA); ITP=idiopathic thrombocytopenic purpura; IVIg=intravenous immunoglobulin; JMML=juvenile myelomonocytic leukaemia) falls into ‘other’.; LLN=lower limit of normal (laboratory reference range); MDS=myelodysplastic syndrome; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; NNH=number needed to harm; PAPS=primary antiphospholipid syndrome; QoL=quality of life; RCT=randomised controlled trial; SCIg=subcutaneous immunoglobulin; sd=standard deviation; SID=secondary immunodeficiency; S+T=sulfamethoxazole+ trimethoprim; tx=treatment; TEEs= thromboembolic events; URT=upper respiratory tract; WM=Waldenstr?m macroglobulinaemia.InfectionsInfections – overview The way in which infections were defined and reported was variable across all the included studies (see definitions in REF _Ref9248112 \h \* MERGEFORMAT Table 22). Infections were usually grouped together either by severity or site of infection, but there was no approach common among the studies. Some studies excluded certain types of events – such as neutropenic episodes, localised infections, or infections not requiring IV antibiotics. Infections reporting also varied according to treatment setting; inpatient data were drawn from routine and relatively frequent observations by trained staff and were often supported by microbiological testing and imaging results, whereas outpatient clinics relied on patient diaries or patient recollection for event data. Nevertheless, serious/major/severe infections was either defined similarly across studies (or could be extracted for comparison), as requiring both antibiotics and hospitalisation or being systemic infections or infections of the lower respiratory tract (which would typically require IV antibiotics and hospitalisation). Studies that provided time periods and events for both arms had the infection incidence rates calculated. The infection incidence rates between groups were then compared using the incidence rate ratios (IRR), which were plotted using Stata/IC 14.1 with the metan plug-in. For the meta-analyses of serious infections (both randomised trials and non-randomised studies), the pooled estimates were estimated using a Poisson regression with random intervention effects, as zero events were observed in some study arms. Infections – randomised studies Results from the meta-analyses of the randomised studies were presented as forest plots for serious infections ( REF _Ref10205734 \h \* MERGEFORMAT Figure 3) and for non-serious infections reported in the same studies, where available ( REF _Ref12898265 \h \* MERGEFORMAT Figure 4). These plots compared IgG versus No IgG groups. Summary data used to derive these plots are in REF _Ref10230975 \h \* MERGEFORMAT Appendix F REF _Ref12611136 \h \* MERGEFORMAT Table 85 (IVIg versus No IVIg) and REF _Ref9898840 \h \* MERGEFORMAT Table 86 (SCIg versus No SCIg). The randomised trials had the least risk of bias due to their study design, having either low risk PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1991; Chapel et al. 1994b; Kobayashi et al. 2014; Sullivan et al. 1990; Vacca et al. 2018) or moderate risk PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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ADDIN EN.CITE.DATA (Boughton et al. 1995; Molica et al. 1996; Musto, Brugiatelli & Carotenuto 1995). Of these studies, the point estimates for major infections, serious infection and septicaemia all favoured the use of IgG ( REF _Ref10205734 \h \* MERGEFORMAT Figure 3). Outcomes including all infections or mild/less serious infections were not always reported and a relationship with IgG treatment was often less obvious. Figure SEQ Figure \* ARABIC 3Randomised trials presenting serious infections – IgG vs No IgG groupsFigure SEQ Figure \* ARABIC 4Randomised trials presenting other infections – IgG vs No IgG groupsTwo RCTs could not be included that reported infections according to number of episodes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE.DATA (Kobayashi et al. 2014) or reported pooled events according to a semi-quantitative measure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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=
ADDIN EN.CITE.DATA (Boughton et al. 1995) thus rates per patient could not be derived. Infections – non-randomised studies Forest plots for the non-randomised studies compared before and after IgG treatment (rather than IgG versus No IgG groups as for the RCT data). Plots are in REF _Ref12898205 \h \* MERGEFORMAT Figure 5 for serious infections and REF _Ref12898267 \h \* MERGEFORMAT Figure 6 for non-serious infections. Figure SEQ Figure \* ARABIC 5Non-randomised trials presenting serious infections – before and after comparison of IgGFigure SEQ Figure \* ARABIC 6Non-randomised trials presenting total infections – before and after comparison of IgGSummary data for infections from the non-randomised studies used to derive these plots are in REF _Ref10230975 \h \* MERGEFORMAT Appendix F as follows:Cohort studies: REF _Ref14101014 \h \* MERGEFORMAT Table 87 (data from a maintenance therapy sub-group PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011) in REF _Ref9453066 \h \* MERGEFORMAT Table 88).Case series including before/after time series: summary infections outcomes are in REF _Ref9900139 \h \* MERGEFORMAT Table 89 (IVIg) and REF _Ref15306522 \h Table 90 (SCIg). Case series of patients receiving IVIg and SCIg that reported results without differentiating between route of administration are summarised in REF _Ref9453302 \h \* MERGEFORMAT Table 91. Cohort studies were subject to selection bias, i.e. the patients with the highest risk of infections were most likely to receive IgG and this was evident in the difference in baseline incidence of infections PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Ammann et al. 2016; Blombery et al. 2011; Paxton, Hawkins & Crispin 2016; Van Winkle et al. 2018), and hence the studies showed misleading results. Data from these studies comparing IgG to No IgG was otherwise considered of limited value. Only the Blombery and Van Winkle studies reported infections as an outcome. Resource use due to infection was reported in the Paxton study and in the US registry study of CLL and MM patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016). Data from these cohort studies were only included in the forest plots where before/after results were available from the IgG group. Only patients who met certain criteria regarding infection rates were included in the pooling of results from before and after case series. Therefore, the results may be biased due to regression to the mean. Nevertheless a comparison of before and after IgG treatment was undertaken at the request of the Ig Review Reference Group. The overall / combined value for each meta-analysis has been included with each plot, noting that these values are uncertain due to the differences between the infections outcomes reported for each study. Tabulated results for infections outcomes for all studies are presented in REF _Ref10230975 \h \* MERGEFORMAT Appendix F supportive to the forest plots above. These are described further in the following sections according to indication. Evidence in patients with CLLRandomised studies – CLLAn RCT in 42 CLL patients in Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Molica et al. 1996) reported incidence of infections during the IVIg versus empirical treatment phases of a 24 month crossover study. Although patients were randomised into separate arms and received IVIg or observation according to a 6+12+6 months protocol, the authors pooled events for reporting into ‘IVIg’ or ‘empirical treatment’ and did not report which group they were originally randomised to nor how many patients completed the study. It was not clear whether a washout period was employed at crossover. Nevertheless, patients who were in an IVIg phase of the study experienced 35 serious infections (including 5 major) and 6 minor infections versus 51 serious infections (including 9 major) and 11 minor infections for patients in an empirical treatment phase. Ten of the IVIg phase patients remained infection free versus 22 patients during empirical treatment (p<0.02). These results favoured IVIg, but given the crossover design, the way events were reported, and moderate risk of bias for this study, this study’s conclusions should be interpreted with caution. One randomised study in 42 CLL patients in the United Kingdom PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VnaHRvbjwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+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=
ADDIN EN.CITE.DATA (Boughton et al. 1995) could not be included in the meta-analysis ( REF _Ref10205734 \h \* MERGEFORMAT Figure 3) as numbers of infections per group were not reported. Instead, infections were converted into a measure of treatment success (less than 3 infections) or failure (3 or more infections), although the infections threshold was not justified. The authors did not comment on the contribution of serious infections versus any infection to ‘success’ and ‘failure’ thus it was possible that a patient with three mild short-lived infections could be considered a failure whereas a patient with two severe refractory infections could be a success. Patients defined as failures in the Boughton study were switched, either to a higher dose if already on IVIg (7 patients at 5-9 months), or from placebo to IVIg (11 patients at 9-11 months). The article did not describe to which group events were attributed after switching. The authors did however report that serious infections, for example, septicaemia and pneumonia were less frequent in IVIg recipients than placebo patients (21% versus 56%; p=0.02). Also, in the placebo group, ten patients had severe hypogammaglobulinaemia (IgG <3 g/L) and seven of these experienced 80 (65%) of the total infections recorded in the study, noting that this was one of the few studies that required both history of infections and documented hypogammaglobulinaemia in all patients at recruitment. Only four infections coincided with neutropenic episodes. The study favoured use of IVIg in CLL patients, noting it was at moderate risk of bias. A small RCT in UK patients (N=12, mostly CLL) ADDIN EN.CITE <EndNote><Cite><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(Chapel et al. 1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(Chapel et al. 1991) employed a 24 months crossover protocol which only 5 patients completed, although it did favour IgG. The article was very brief, drawing its substance from discussion of an earlier study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxlPC9BdXRob3I+PFllYXI+MTk4ODwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxlPC9BdXRob3I+PFllYXI+MTk4ODwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Gale et al. 1988) on which the design of this later study was based. A supportive RCT that presented a dose comparison of IVIg in 34 CLL patients ADDIN EN.CITE <EndNote><Cite><Author>Chapel</Author><Year>1994</Year><RecNum>47</RecNum><DisplayText>(Chapel et al. 1994a)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554259107">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Dicato, M.</author><author>Gamm, H.</author><author>Brennan, V.</author><author>Ries, F.</author><author>Bunch, C.</author><author>Lee, M.</author></authors></contributors><auth-address>Department of Immunology, John Radcliffe Hospital, Oxford.</auth-address><titles><title>Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes</title><secondary-title>Br J Haematol</secondary-title></titles><periodical><full-title>Br J Haematol</full-title></periodical><pages>209-12</pages><volume>88</volume><number>1</number><edition>1994/09/01</edition><keywords><keyword>Aged</keyword><keyword>Critical Illness</keyword><keyword>Dose-Response Relationship, Immunologic</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/administration & dosage/ therapeutic use</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Precursor Cell Lymphoblastic Leukemia-Lymphoma/ therapy</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>1994</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0007-1048 (Print)
0007-1048 (Linking)</isbn><accession-num>7803248</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><research-notes>CLL dose comparison</research-notes><language>eng</language></record></Cite></EndNote>(Chapel et al. 1994a) reported that the infection rates in the 23 hypogammaglobulinaemic patients (IgG<6.4 g/L) (regardless of dose level) showed that those with previous infections had a slightly higher rate of any infection (0.19 infections/patient-month) than those without prior infections (0.06 infections/patient-month), though the numbers were too small for meaningful analysis. Non-randomised studies – CLLTwo case series reported infections in relatively large numbers of CLL patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Reiser et al. 2017)(130 CLL patients out of 307 in total) and PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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==
ADDIN EN.CITE.DATA (Benbrahim et al. 2019)(54 CLL patients out of 160). These recent studies were conducted in Germany and France, respectively. Both studies also included a mix of patients receiving IVIg and SCIg (Reiser: IVIg=287; SCIg=20; Benbrahim: IVIg n=50, SCIg n=110). The Reiser study was a retrospective analysis of German registry patients and was at moderate risk of bias with similar selection bias issues as the cohort studies (see overview). The Benbrahim case series had a low risk of bias and was conducted prospectively. Benbrahim et al. reported incidence of sepsis and of infections of higher than WHO Grade 2 (that is, severe or life-threatening but not including mild or moderate). Both events were reduced on initiation of IgG compared with that during the observation period prior to IgG. However, sepsis events were not included in the meta-analysis as the overall numbers were high compared to other events reported in the same study which was considered likely to be a definition issue. A retrospective German study reported infections for 307 patients (including 130 CLL patients) receiving either IVIg or SCIg prior to and during IgG treatment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Reiser et al. 2017). Although patients with infections were only reported as a proportion for most infection outcomes, before/after IgG numbers of infection events were reported for serious bacterial infections (77 before versus 11 during 24 months of IgG treatment). A similarly proportionate reduction in outcomes associated with IgG treatment was observed for other infections where only patient proportions were reported.Several other case series included CLL patients in only small or moderate numbers ADDIN EN.CITE <EndNote><Cite><Author>Jurlander</Author><Year>1995</Year><RecNum>11</RecNum><DisplayText>(Jurlander, Geisler & Hansen 1995)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825059">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jurlander, J.</author><author>Geisler, C. H.</author><author>Hansen, M. M.</author></authors></contributors><auth-address>Department of Haematology, Rigshospitalet, State University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low-dose intravenous gammaglobulin</title><secondary-title>Eur J Haematol</secondary-title></titles><periodical><full-title>Eur J Haematol</full-title></periodical><pages>114-8</pages><volume>53</volume><number>2</number><keywords><keyword>Agammaglobulinemia/ complications/ drug therapy</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/blood</keyword><keyword>Immunoglobulins, Intravenous/ therapeutic use</keyword><keyword>Leukemia, Lymphocytic, Chronic, B-Cell/ blood/ complications</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1995</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0902-4441 (Print) 0902-4441 (Linking)</isbn><accession-num>8088382</accession-num><urls></urls><custom1>RAYYAN-INCLUSION: {"Skye"=>"Included"}</custom1><research-notes>CLL before and after case series</research-notes><language>eng</language></record></Cite></EndNote>(Jurlander, Geisler & Hansen 1995)(15 CLL patients), PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXNhPC9BdXRob3I+PFllYXI+MTk5MjwvWWVhcj48UmVj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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXNhPC9BdXRob3I+PFllYXI+MTk5MjwvWWVhcj48UmVj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 EN.CITE.DATA (Besa 1992)(23), PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48
UmVjTnVtPjE1PC9SZWNOdW0+PERpc3BsYXlUZXh0PihCcmVubmVyIDE5OTYpPC9EaXNwbGF5VGV4
dD48cmVjb3JkPjxyZWMtbnVtYmVyPjE1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh
cHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0aW1l
c3RhbXA9IjE1NTM4MjUwNTkiPjE1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9
IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1
dGhvcj5CcmVubmVyLCBCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h
ZGRyZXNzPkIuIEJyZW5uZXIsIFRocm9tYm9zaXMgYW5kIEhlbW9zdGFzaXMgVW5pdCwgSW5zdGl0
dXRlIG9mIEhlbWF0b2xvZ3ksIFJhbWJhbSBNZWRpY2FsIENlbnRlciwgSGFpZmEgMzEwOTYsIElz
cmFlbDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsaW5pY2FsIGV4cGVyaWVuY2Ugd2l0
aCBPY3RhZ2FtLCBhIHNvbHZlbnQgZGV0ZXJnZW50IChTRCkgdmlydXMgaW5hY3RpdmF0ZWQgaW50
cmF2ZW5vdXMgZ2FtbWFnbG9idWxpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DbGluaWNhbCBh
bmQgRXhwZXJpbWVudGFsIFJoZXVtYXRvbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw
ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNsaW5pY2FsIGFuZCBFeHBlcmltZW50YWwgUmhldW1hdG9s
b2d5PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+UzExNS1TMTE5PC9wYWdlcz48dm9s
dW1lPjE0PC92b2x1bWU+PGtleXdvcmRzPjxrZXl3b3JkPmltbXVub2dsb2J1bGluIEc8L2tleXdv
cmQ+PGtleXdvcmQ+YWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5hZHVsdDwva2V5d29yZD48
a2V5d29yZD5hZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPmFudGlwaG9zcGhvbGlwaWQgc3luZHJvbWU8
L2tleXdvcmQ+PGtleXdvcmQ+Y2hyb25pYyBseW1waGF0aWMgbGV1a2VtaWE8L2tleXdvcmQ+PGtl
eXdvcmQ+Y2xpbmljYWwgdHJpYWw8L2tleXdvcmQ+PGtleXdvcmQ+Y29uZmVyZW5jZSBwYXBlcjwv
a2V5d29yZD48a2V5d29yZD5jb250cm9sbGVkIGNsaW5pY2FsIHRyaWFsPC9rZXl3b3JkPjxrZXl3
b3JkPmNvbnRyb2xsZWQgc3R1ZHk8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1ZyBlZmZpY2FjeTwva2V5
d29yZD48a2V5d29yZD5kcnVnIHNhZmV0eTwva2V5d29yZD48a2V5d29yZD5mZW1hbGU8L2tleXdv
cmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+bWFqb3IgY2xpbmljYWwgc3R1ZHk8
L2tleXdvcmQ+PGtleXdvcmQ+bWFsZTwva2V5d29yZD48a2V5d29yZD5tdWx0aXBsZSBteWVsb21h
PC9rZXl3b3JkPjxrZXl3b3JkPnByaW9yaXR5IGpvdXJuYWw8L2tleXdvcmQ+PGtleXdvcmQ+dGhy
b21ib2N5dG9wZW5pYyBwdXJwdXJhPC9rZXl3b3JkPjxrZXl3b3JkPnZpcnVzIGluYWN0aXZhdGlv
bjwva2V5d29yZD48a2V5d29yZD5vY3RhZ2FtPC9rZXl3b3JkPjxrZXl3b3JkPkRldGVyZ2VudHM8
L2tleXdvcmQ+PGtleXdvcmQ+U29sdmVudHM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll
YXI+MTk5NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjE5OTY8L2RhdGU+PC9wdWItZGF0ZXM+PC9k
YXRlcz48aXNibj4wMzkyLTg1Nlg8L2lzYm4+PGFjY2Vzc2lvbi1udW0+cmF5eWFuLTQ1ODc0NjI8
L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPjxzdHlsZSBmYWNlPSJ1bmRl
cmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPmh0dHA6Ly93d3cuZW1iYXNlLmNvbS9z
ZWFyY2gvcmVzdWx0cz9zdWJhY3Rpb249dmlld3JlY29yZCZhbXA7ZnJvbT1leHBvcnQmYW1wO2lk
PUwyNjI3MDU4ODwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20xPm9j
dGFnYW0oT2N0YXBoYXJtYSxBdXN0cmlhKSBSQVlZQU4tSU5DTFVTSU9OOiB7JnF1b3Q7U2t5ZSZx
dW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20xPjxyZXNlYXJjaC1ub3Rlcz5Y
IC0gdW5jbGVhciBob3cgbWFueSBoYWQgSHlwb0dHLiBCZWZvcmUgYW5kIGFmdGVyIGNhc2Ugc2Vy
aWVzPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3VhZ2U+RW5nbGlzaDwvbGFuZ3VhZ2U+PC9yZWNvcmQ+
PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA (Brenner 1996)(22) and PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE.DATA (Dimou et al. 2018)(25). These were each studies in only/mostly CLL patients. Each of these studies showed a reduction in serious infections during IgG treatment compared with a period of observation prior to IgG commencement. In each case, ‘serious infections’ comprised sepsis and pneumonia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXNhPC9BdXRob3I+PFllYXI+MTk5MjwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXNhPC9BdXRob3I+PFllYXI+MTk5MjwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Besa 1992; Brenner 1996), LRTIs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE.DATA (Dimou et al. 2018) or septicaemia, meningitis and pneumonia ADDIN EN.CITE <EndNote><Cite><Author>Jurlander</Author><Year>1995</Year><RecNum>11</RecNum><DisplayText>(Jurlander, Geisler & Hansen 1995)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825059">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jurlander, J.</author><author>Geisler, C. H.</author><author>Hansen, M. M.</author></authors></contributors><auth-address>Department of Haematology, Rigshospitalet, State University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low-dose intravenous gammaglobulin</title><secondary-title>Eur J Haematol</secondary-title></titles><periodical><full-title>Eur J Haematol</full-title></periodical><pages>114-8</pages><volume>53</volume><number>2</number><keywords><keyword>Agammaglobulinemia/ complications/ drug therapy</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/blood</keyword><keyword>Immunoglobulins, Intravenous/ therapeutic use</keyword><keyword>Leukemia, Lymphocytic, Chronic, B-Cell/ blood/ complications</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1995</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0902-4441 (Print) 0902-4441 (Linking)</isbn><accession-num>8088382</accession-num><urls></urls><custom1>RAYYAN-INCLUSION: {"Skye"=>"Included"}</custom1><research-notes>CLL before and after case series</research-notes><language>eng</language></record></Cite></EndNote>(Jurlander, Geisler & Hansen 1995). Further details are presented in the summary tables. Two cohort studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Paxton, Hawkins & Crispin 2016) and PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016) reported resource use due to infectious complications in CLL patients rather than infections incidence – discussed further in the section below. For the Paxton study, this outcome (hospitalisation due to infection) was used in the forest plot in the absence of infections. A United States dosing study in 79 patients included CLL patients (74 of 209 treatment episodes/infusions) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVtcDwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVtcDwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Stump et al. 2017) but included no control group or baseline values, thus no conclusion could be drawn in terms of infections reported compared with No IgG. Evidence in patients with MMA study in 83 MM patients from the UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Chapel et al. 1994b) recorded serious bacterial infections. The majority of patients in each arm had serum IgG below the lower limit of normal (LLN) (32/42 IVIg patients and 26/41 control patients). The authors reported a lower number of serious bacterial infections in the IVIg arm than the comparator (15 vs 29 respectively; p=0.05), including no cases of septicaemia or pneumonia, compared with 10 such instances in the comparator arm. Incidence of minor infections was not reported although it was noted “there was no protection against minor infections, which were mainly viral infections of the upper respiratory tract”. The authors concluded that IVIg protected against serious infections, serious bacterial infections and recurrent serious infections. The relationship between neutropenia and infections was not evaluated as only 15 patients (of 82 evaluable) had neutropenic episodes during the study. A small Italian study in 25 MM patients ADDIN EN.CITE <EndNote><Cite><Author>Musto</Author><Year>1995</Year><RecNum>60</RecNum><DisplayText>(Musto, Brugiatelli & Carotenuto 1995)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554267573">60</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Musto, P.</author><author>Brugiatelli, M.</author><author>Carotenuto, M.</author></authors></contributors><titles><title>Prophylaxis against infections with intravenous immunoglobulins in multiple myeloma</title><secondary-title>Br J Haematol</secondary-title></titles><periodical><full-title>Br J Haematol</full-title></periodical><dates><year>1995</year></dates><urls></urls><research-notes>MM (pearled) cross-over study IVIG vs no prophylaxis</research-notes></record></Cite></EndNote>(Musto, Brugiatelli & Carotenuto 1995) featured similar a 6+12+6 month crossover design and pooled reporting of infections as the Molica study in CLL patients above. The study reported 10 serious infections (without any life-threatening septicaemia or pneumonia) for patients in an IVIg phase versus 30 serious infections (including 10 life-threatening septicaemia/pneumonia infections) during observation. Minor infections were unaffected by treatment phases. The same caveats should be applied to these findings as for the Molica study in CLL patients. One randomised trial of SCIg was included PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
Y051bT4zMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oVmFjY2EgZXQgYWwuIDIwMTgpPC9EaXNwbGF5
VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl
eSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0
aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjMwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h
bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+
PGF1dGhvcj5WYWNjYSwgQS48L2F1dGhvcj48YXV0aG9yPk1lbGFjY2lvLCBBLjwvYXV0aG9yPjxh
dXRob3I+U3BvcnRlbGxpLCBBLjwvYXV0aG9yPjxhdXRob3I+U29saW08L2F1dGhvcj48YXV0aG9y
Pm8sIEEuIEcuPC9hdXRob3I+PGF1dGhvcj5EYW1tYWNjbywgRi48L2F1dGhvcj48YXV0aG9yPlJp
YSwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5SLiBS
aWEsIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUgYW5kIENsaW5pY2FsIE9uY29sb2d5
LCBVbml2ZXJzaXR5IG9mIEJhcmkg4oCcQWxkbyBNb3Jv4oCdIE1lZGljYWwgU2Nob29sLCBQb2xp
Y2xpbmljbyDigJMgUGlhenphIEdpdWxpbyBDZXNhcmUsIDExLCBCYXJpLCBJdGFseTwvYXV0aC1h
ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlN1YmN1dGFuZW91cyBpbW11bm9nbG9idWxpbnMgaW4gcGF0
aWVudHMgd2l0aCBtdWx0aXBsZSBteWVsb21hIGFuZCBzZWNvbmRhcnkgaHlwb2dhbW1hZ2xvYnVs
aW5lbWlhOiBhIHJhbmRvbWl6ZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2xpbmlj
YWwgSW1tdW5vbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs
LXRpdGxlPkNsaW5pY2FsIEltbXVub2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl
cz4xMTAtMTE1PC9wYWdlcz48dm9sdW1lPjE5MTwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5h
bnRpaGlzdGFtaW5pYyBhZ2VudDwva2V5d29yZD48a2V5d29yZD5pbW11bm9nbG9idWxpbjwva2V5
d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPmFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+YXJ0aWNsZTwva2V5d29yZD48a2V5d29yZD5j
bGluaWNhbCBhcnRpY2xlPC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2xsZWQgc3R1ZHk8L2tleXdv
cmQ+PGtleXdvcmQ+ZGlzZWFzZSBkdXJhdGlvbjwva2V5d29yZD48a2V5d29yZD5kaXNlYXNlIHNl
dmVyaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmZlbWFsZTwva2V5d29yZD48a2V5d29yZD5ob3NwaXRh
bGl6YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5v
Z2xvYnVsaW4gZGVmaWNpZW5jeTwva2V5d29yZD48a2V5d29yZD5pbmNpZGVuY2U8L2tleXdvcmQ+
PGtleXdvcmQ+aW5qZWN0aW9uIHNpdGUgaW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmlu
amVjdGlvbiBzaXRlIHBhaW48L2tleXdvcmQ+PGtleXdvcmQ+bWFsZTwva2V5d29yZD48a2V5d29y
ZD5tdWx0aXBsZSBteWVsb21hPC9rZXl3b3JkPjxrZXl3b3JkPnByaW9yaXR5IGpvdXJuYWw8L2tl
eXdvcmQ+PGtleXdvcmQ+cXVhbGl0eSBvZiBsaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJhbmRvbWl6
ZWQgY29udHJvbGxlZCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5za2luIGFsbGVyZ3k8L2tleXdv
cmQ+PGtleXdvcmQ+dHJlYXRtZW50IGR1cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2ds
b2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29yZD48a2V5
d29yZD5JbW11bm9nbG9idWxpbiBFPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEc8
L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5JbW11
bm9nbG9idWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVn
aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRl
cz48ZGF0ZT4yMDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMS03MDM1IDE1
MjEtNjYxNjwvaXNibj48YWNjZXNzaW9uLW51bT5yYXl5YW4tNDU4ODE2NzwvYWNjZXNzaW9uLW51
bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0i
ZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cDovL3d3dy5lbWJhc2UuY29tL3NlYXJjaC9yZXN1bHRz
P3N1YmFjdGlvbj12aWV3cmVjb3JkJmFtcDtmcm9tPWV4cG9ydCZhbXA7aWQ9TDYyMDgwOTY5MDwv
c3R5bGU+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+IDwv
c3R5bGU+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+
aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9qLmNsaW0uMjAxNy4xMS4wMTQ8L3N0eWxlPjwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVTSU9OOiB7JnF1b3Q7
U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20xPjxyZXNlYXJjaC1u
b3Rlcz5NTSAtIFNDSUcgdnMgY29udHJvbHM8L3Jlc2VhcmNoLW5vdGVzPjxsYW5ndWFnZT5Fbmds
aXNoPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018), which studied 46 patients with MM. Major infections occurred overwhelmingly in the No SCIg group (190, compared with only 16 in the SCIg group). A similar pattern was observed with upper respiratory tract infections as well as lower respiratory tract infections and minor infections. Days of infections were markedly different in each arm, with 62 days (range 26-87) in SCIg patients versus 135 (88-194) in the control arm (p<0.01). These were consistent with results for other outcomes in the study (days of hospitalisation and antibiotics). Serum IgG levels were measured monthly during the study – median values in the SCIg arm were 8.3-9.5 g/L compared with 2.4-5.2 g/L in the control arm patients (p<0.05), noting that mean values at enrolment had been consistently low across both arms (3.2?g/L (range 1.4–5.7) versus 3.2?g/L (1.3–5.7), respectively) although infection history had not been required as an entry criterion. Of the non-randomised trials, several cohort studies and case series described for CLL also included MM patients, and for whom the same observations regarding infections apply as for CLL PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016; Benbrahim et al. 2019; Paxton, Hawkins & Crispin 2016; Reiser et al. 2017; Stump et al. 2017). Evidence in HSCT patientsOnly one RCT of HSCT recipients was included, which studied 369 American patients receiving BMT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1990). Although neither hypogammaglobulinaemia nor history of infections were required at entry, serum IgG levels for the both IVIg and control groups were monitored every 30 days during the first 90 days post-transplant – the untreated group showed that patients remained under the 5th percentile without IVIg after BMT. Infections were reported for the first 100 days post-transplant or until discharge of the 12 month protocol. Two patients in the control group received IVIg during the first 100 days after developing recurrent infections. The authors reported an increased risk of septicaemia (relative risk 2.15 (p=0.0022)) and local infections (relative risk 1.36 (p=0.029)) but not bacteraemia in patients who received no IVIg compared with IVIg (note that infections were mostly culture confirmed). The authors also concluded that differences in infection rates were unrelated to rates of neutrophil recovery. This was the oldest study in the clinical evidence – patients were recruited between May 1986 and November 1987 and data cut-off was 1 May 1989. Since then, over 30 years have elapsed in which time numerous changes have occurred to standard of care for underlying disease, conditioning/ablation treatments, immunosupression and transplant methodology. In terms of non-randomised evidence, one Australian cohort study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011) investigated whether a single ‘pre-emptive’ peri-transplant dose was effective in reducing infections in HSCT recipients (IVIg received any time in a 30 day period peri-transplant) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011). This single dose study was not designed to investigate ongoing replacement therapy and reporting of infections was limited to the 30 day observation period. However, the study included a patient subset who received their single dose as part of NBA-funded IgG maintenance therapy ( REF _Ref9453066 \h \* MERGEFORMAT Table 88). The multi-dose sub-group shows an increased rate of pneumonia and GI infections compared to the single-dose recipients, however the authors noted these numbers were very small and that patients qualifying for replacement therapy likely had a higher baseline risk of infection. No further analysis was presented.In the Blombery study overall, the infections were reported in the 240 patients enrolled who had hypogammaglobulinaemia at baseline. An additional 19 patients with normal IgG levels were not included in the author’s primary analysis but infections were compared in those 19 subjects with those in the No IVIg group (i.e. who had hypogammaglobulinaemia) – there was no different in infections between the two untreated groups (data not shown). This may have been due either to the single dose nature of the study or the presence of a group of patients in this population who do well in spite of their hypogammaglobulinaemia. The Blombery authors also looked at a range of factors between the IVIg and No IVIg groups to consider whether these predisposed patients to infections (e.g. duration of neutropenia, pre-transplant serum IgG, CD34+ progenitor cell dose, intensity of conditioning), but the patients’ history of infections was not considered. A supportive study comparing IVIg versus SCIg in 58 HSCT patients (including 26 with haematological malignancies) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012) reported infections but included no control group or baseline values, thus no conclusion could be drawn for this evaluation. Evidence in patients with ALOne RCT of 61 children with ALL or AML in Japan explored IVIg in combination with a carpapenem antibiotic meropenem as second-line treatment of febrile neutropenia after first-line antibiotics PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2JheWFzaGk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy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ADDIN EN.CITE.DATA (Kobayashi et al. 2014). Patients received meropenem with or without IVIg for 72 hours for a given infection episode – the authors reported a range of 1-9 episodes per patient. The study reported no infections data nor episodes per patient – as such this RCT was not included in the meta-analysis. Treatment outcome was reported as ‘success’ or ‘failure’ per episode based on eradication or not of febrile neutropenia symptoms measured at 120 h and then maintained for at least a week. There was a trend for patients with serum IgG <500 mg/dL to do better if they received IVIg (81.3% treatment success) than those with MEPM only (62.5% treatment success) (p=0.238). The authors contended that although the difference was not statistically significant in the low IgG patients, this was due to the sample size and that results for this subset could have been significant in a larger study. Otherwise, the authors drew no conclusions about the efficacy of IVIg being mostly concerned with the value of meropenem as an alternative to other second line antibiotics for febrile neutropenia in this setting such as vancomycin. One cohort study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh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=
ADDIN EN.CITE.DATA (Van Winkle et al. 2018) in 118 children with ALL found no significant differences in infectious complications (as measured by bacteraemia or infections requiring antibiotics) in the IVIG versus non-IVIG groups. However, the infection rates in the IVIg arm prior to, and then during IVIg administration, shows that patients had considerably higher rates of infections before treatment than the control arm ― these infections nonetheless decreased on receipt of IVIg. As neither infection rates nor firm conclusions were available from the Japanese RCT above, this is the key trial for AL. The United States dosing study in 79 patients described above PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVtcDwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVtcDwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Stump et al. 2017) included AL patients (65 of 209 treatment episodes/infusions) but included no control group or baseline values, thus no conclusion could be drawn in terms of infections reported compared with No IgG. Evidence in patients with NHLNo RCTs were found for patients with NHL (see REF _Ref10291298 \h \* MERGEFORMAT Table 78 REF _Ref10230975 \h \* MERGEFORMAT Appendix F). Although one RCT appeared to include NHL patients ADDIN EN.CITE <EndNote><Cite><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(Chapel et al. 1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(Chapel et al. 1991), it was very small with only 12 patients (mostly CLL) and the proportion of NHL patients, though not reported, was likely to be less than 10% at study start (based on numbers from the preceding study on which this was based, PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxlPC9BdXRob3I+PFllYXI+MTk4ODwvWWVhcj48UmVj
TnVtPjQ8L1JlY051bT48RGlzcGxheVRleHQ+KEdhbGUgZXQgYWwuIDE5ODgpPC9EaXNwbGF5VGV4
dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw
cD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0YWQiIHRpbWVz
dGFtcD0iMTU1MzgyNTA1OSI+NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK
b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo
b3I+R2FsZSwgUi4gUC48L2F1dGhvcj48YXV0aG9yPkNoYXBlbCwgSC4gTS48L2F1dGhvcj48YXV0
aG9yPkJ1bmNoLCBDLjwvYXV0aG9yPjxhdXRob3I+UmFpLCBLLiBSLjwvYXV0aG9yPjxhdXRob3I+
Rm9vbiwgSy48L2F1dGhvcj48YXV0aG9yPkNvdXJ0ZXIsIFMuIEcuPC9hdXRob3I+PGF1dGhvcj5U
YWl0LCBELjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5J
bnRyYXZlbm91cyBpbW11bm9nbG9idWxpbiBmb3IgdGhlIHByZXZlbnRpb24gb2YgaW5mZWN0aW9u
IGluIGNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWEuIEEgcmFuZG9taXplZCwgY29udHJvbGxl
ZCBjbGluaWNhbCB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXcgRW5nbGFuZCBqb3Vy
bmFsIG9mIG1lZGljaW5lPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1
bGwtdGl0bGU+TmV3IEVuZ2xhbmQgam91cm5hbCBvZiBtZWRpY2luZTwvZnVsbC10aXRsZT48L3Bl
cmlvZGljYWw+PHBhZ2VzPjkwMuKAkDkwNzwvcGFnZXM+PHZvbHVtZT4zMTk8L3ZvbHVtZT48bnVt
YmVyPjE0PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3Jk
PkFnYW1tYWdsb2J1bGluZW1pYSBbZXRpb2xvZ3ksIHRoZXJhcHldPC9rZXl3b3JkPjxrZXl3b3Jk
PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIEluZmVjdGlvbnMgW2V0aW9sb2d5LCAq
cHJldmVudGlvbiAmYW1wOyBjb250cm9sXTwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCBUcmlh
bHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+RG91Ymxl4oCQQmxpbmQgTWV0aG9kPC9rZXl3
b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bml6YXRpb24sIFBhc3Np
dmU8L2tleXdvcmQ+PGtleXdvcmQ+SW5mdXNpb25zLCBJbnRyYXZlbm91czwva2V5d29yZD48a2V5
d29yZD5MZXVrZW1pYSwgTHltcGhvaWQgW2NvbXBsaWNhdGlvbnMsICp0aGVyYXB5XTwva2V5d29y
ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Qcm9iYWJpbGl0eTwva2V5
d29yZD48a2V5d29yZD5SYW5kb20gQWxsb2NhdGlvbjwva2V5d29yZD48a2V5d29yZD5SaXNrIEZh
Y3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48a2V5d29y
ZD5JbW11bm9nbG9idWxpbiBNPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEE8L2tl
eXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVnaW9u
PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlucywgSW50cmF2ZW5vdXM8L2tleXdvcmQ+
PGtleXdvcmQ+TGV1a2VtaWEsIEx5bXBob2lkPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1
bGluIEc8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk4ODwveWVhcj48cHViLWRh
dGVzPjxkYXRlPjE5ODg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48YWNjZXNzaW9uLW51bT5D
Ti0wMDA1NTcxNjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxl
IGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cHM6Ly93d3cu
Y29jaHJhbmVsaWJyYXJ5LmNvbS9jZW50cmFsL2RvaS8xMC4xMDAyL2NlbnRyYWwvQ04tMDAwNTU3
MTYvZnVsbDwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20xPlJBWVlB
Ti1JTkNMVVNJT046IHsmcXVvdDtTa3llJnF1b3Q7PSZndDsmcXVvdDtJbmNsdWRlZCZxdW90O30g
fCBSQVlZQU4tTEFCRUxTOiBDTEw8L2N1c3RvbTE+PHJlc2VhcmNoLW5vdGVzPlggLSB0b28gb2xk
PC9yZXNlYXJjaC1ub3Rlcz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxlPC9BdXRob3I+PFllYXI+MTk4ODwvWWVhcj48UmVj
TnVtPjQ8L1JlY051bT48RGlzcGxheVRleHQ+KEdhbGUgZXQgYWwuIDE5ODgpPC9EaXNwbGF5VGV4
dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw
cD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0YWQiIHRpbWVz
dGFtcD0iMTU1MzgyNTA1OSI+NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK
b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo
b3I+R2FsZSwgUi4gUC48L2F1dGhvcj48YXV0aG9yPkNoYXBlbCwgSC4gTS48L2F1dGhvcj48YXV0
aG9yPkJ1bmNoLCBDLjwvYXV0aG9yPjxhdXRob3I+UmFpLCBLLiBSLjwvYXV0aG9yPjxhdXRob3I+
Rm9vbiwgSy48L2F1dGhvcj48YXV0aG9yPkNvdXJ0ZXIsIFMuIEcuPC9hdXRob3I+PGF1dGhvcj5U
YWl0LCBELjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5J
bnRyYXZlbm91cyBpbW11bm9nbG9idWxpbiBmb3IgdGhlIHByZXZlbnRpb24gb2YgaW5mZWN0aW9u
IGluIGNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWEuIEEgcmFuZG9taXplZCwgY29udHJvbGxl
ZCBjbGluaWNhbCB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXcgRW5nbGFuZCBqb3Vy
bmFsIG9mIG1lZGljaW5lPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1
bGwtdGl0bGU+TmV3IEVuZ2xhbmQgam91cm5hbCBvZiBtZWRpY2luZTwvZnVsbC10aXRsZT48L3Bl
cmlvZGljYWw+PHBhZ2VzPjkwMuKAkDkwNzwvcGFnZXM+PHZvbHVtZT4zMTk8L3ZvbHVtZT48bnVt
YmVyPjE0PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3Jk
PkFnYW1tYWdsb2J1bGluZW1pYSBbZXRpb2xvZ3ksIHRoZXJhcHldPC9rZXl3b3JkPjxrZXl3b3Jk
PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIEluZmVjdGlvbnMgW2V0aW9sb2d5LCAq
cHJldmVudGlvbiAmYW1wOyBjb250cm9sXTwva2V5d29yZD48a2V5d29yZD5DbGluaWNhbCBUcmlh
bHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+RG91Ymxl4oCQQmxpbmQgTWV0aG9kPC9rZXl3
b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bml6YXRpb24sIFBhc3Np
dmU8L2tleXdvcmQ+PGtleXdvcmQ+SW5mdXNpb25zLCBJbnRyYXZlbm91czwva2V5d29yZD48a2V5
d29yZD5MZXVrZW1pYSwgTHltcGhvaWQgW2NvbXBsaWNhdGlvbnMsICp0aGVyYXB5XTwva2V5d29y
ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Qcm9iYWJpbGl0eTwva2V5
d29yZD48a2V5d29yZD5SYW5kb20gQWxsb2NhdGlvbjwva2V5d29yZD48a2V5d29yZD5SaXNrIEZh
Y3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48a2V5d29y
ZD5JbW11bm9nbG9idWxpbiBNPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEE8L2tl
eXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVnaW9u
PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlucywgSW50cmF2ZW5vdXM8L2tleXdvcmQ+
PGtleXdvcmQ+TGV1a2VtaWEsIEx5bXBob2lkPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1
bGluIEc8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk4ODwveWVhcj48cHViLWRh
dGVzPjxkYXRlPjE5ODg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48YWNjZXNzaW9uLW51bT5D
Ti0wMDA1NTcxNjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxl
IGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cHM6Ly93d3cu
Y29jaHJhbmVsaWJyYXJ5LmNvbS9jZW50cmFsL2RvaS8xMC4xMDAyL2NlbnRyYWwvQ04tMDAwNTU3
MTYvZnVsbDwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20xPlJBWVlB
Ti1JTkNMVVNJT046IHsmcXVvdDtTa3llJnF1b3Q7PSZndDsmcXVvdDtJbmNsdWRlZCZxdW90O30g
fCBSQVlZQU4tTEFCRUxTOiBDTEw8L2N1c3RvbTE+PHJlc2VhcmNoLW5vdGVzPlggLSB0b28gb2xk
PC9yZXNlYXJjaC1ub3Rlcz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Gale et al. 1988). As such, the three non-randomised studies that report infections for IgG versus No IgG PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Benbrahim et al. 2019; Paxton, Hawkins & Crispin 2016; Reiser et al. 2017) represent the key evidence for NHL. The same observations regarding infections in these studies apply to NHL patients as already described for CLL and MM.Evidence in patients with other haematological malignanciesNo studies of any kind were found that included more than a few patients with ‘other haematological malignancies’ (for example, Hodgkin lymphoma (HL), amyloidosis, Waldenstr?m macroglobulinaemia (WM), heavy chain disease, chronic myeloid leukaemia (CML), MDS and others). Resource Use Outcomes Presented as Infectious ComplicationsInfection-related resource use outcomes such as hospitalisation for infection or antibiotic use were informative outcomes for efficacy and were frequently presented as infectious complications. One RCT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018) and four cohort studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016; Blombery et al. 2011; Paxton, Hawkins & Crispin 2016; Van Winkle et al. 2018) reported these outcomes ( REF _Ref9451841 \h \* MERGEFORMAT Table 23). Case series reporting these outcomes are summarised in REF _Ref14270452 \h Table 24 including nine before and after time comparisons PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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ADDIN EN.CITE.DATA (Benbrahim et al. 2019; Brenner 1996; Duraisingham et al. 2014; Günther & Dreger 2013; Jurlander, Geisler & Hansen 1995) and one supportive study ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019). Table SEQ Table \* ARABIC 23Studies presenting resource use – comparative studies (RCTs and cohort studies)Study, IndicationOutcomeInterventionComparatorComparisonRCTsVacca et al., 2018Duration of resource usemean days per patient per yearSCIg (n=24)No SCIg (n=22)p-valueMMHospitalisations8121<0.001Days of antibiotic treatment28217<0.001Cohort studiesAmmann et al., 2016Hospitalisation for pneumonia (1-yr cumulative incidence)IgG users (n=2724)Non-users (n=8035)CLL, MMPropensity matched set15%12%Rate hospitalisations/ patient mo0.0130.010Hospitalisation for pneumoniaIgG users (n=2771)Non-users (n=8313)Randomly matched set15%6%Rate hospitalisations/ patient mo0.0130.005Blombery et al., 2011Duration of resource usemedian days [range]IVIg (n=130)No IVIg (n=110)p valueMM+HSCTIV antimicrobial agents7 [0–28]6 [0–33]p=0.046Hospital admission14 [6–38]13 [8–48]p=0.16Paxton et al., 2016Risk of hospitalisation for infection, /patient-years (95% CI)IVIg (n=35)No IVIg (n=57)Relative risk for IVIg pts Various*Prior to study0.43 (0.29–0.63)0.08 (0.05–0.13)5.5 (95% CI 3.0–10)Inferred mean # hospitalisations15.14.6During study0.14 (0.08–0.23)(unchanged)Inferred mean # hospitalisations4.94.6Rate / patient / month 0.0120.007Relative Risk of hospitalisation prior to IVIg3.1 (1.6–5.9)―Risk of hospitalisation for infection prior to study, per patient-year (range)IVIg (n=35)No IVIg (n=57)p-valueIgG <4 g/L0.51 (0.27–0.90)0.07 (0. 03–0.13)p<0.001Patients with IgG <4g/L2729Inferred mean # hospitalisations13.82.0Rate / patient / month 0.0430.006IgG ≥4 g/L0.40 (0.25–0.59)0.08 (0.04–0.15)Patients with IgG ≥4g/L828Inferred mean # hospitalisations3.22.2Crude rate per patient month 0.0330.007p-valuep>0.05p>0.05Van Winkle et al., 2018Infectious complications during maintenance chemo.±IVIg, All values mean (SEM)IVIg (N=36)No IVIg (N=82)p-valueALLHospitalisations prior to study(inferred total events)2.3 (0.4)82.3 1.9 (0.2) 155.8―Hospitalisations during study(inferred total events)1.9 (0.3)68.4 1.7 (0.2) 139.40.302Days of hospitalisation11.1 (2.3) 6.7 (0.9) 0.112*Notes: Ammann (2016) – The study included patients receiving IVIg, SCIg or IMIg but proportions of each were not reported. Paxton et al., 2016 – ‘various’ haematological malignancies were: CLL (42); MM (18); NHL (27); other (AML+allo-HSCT; amyloidosis; T-cell NHL). ALL=acute lymphoblastic leukaemia; AML=acute myeloid leukaemia; CI=confidence interval; CLL=chronic lymphocytic leukaemia; d=days; HSCT=haematopoietic stem cell transplant; IV=intravenous; IVIg=intravenous immunoglobulin; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; SCIg=subcutaneous immunoglobulin; SEM=standard error of the mean; yr=year. The one RCT reporting resource use PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
Y051bT4zMDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oVmFjY2EgZXQgYWwuIDIwMTgpPC9EaXNwbGF5
VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl
eSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0
aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjMwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h
bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+
PGF1dGhvcj5WYWNjYSwgQS48L2F1dGhvcj48YXV0aG9yPk1lbGFjY2lvLCBBLjwvYXV0aG9yPjxh
dXRob3I+U3BvcnRlbGxpLCBBLjwvYXV0aG9yPjxhdXRob3I+U29saW08L2F1dGhvcj48YXV0aG9y
Pm8sIEEuIEcuPC9hdXRob3I+PGF1dGhvcj5EYW1tYWNjbywgRi48L2F1dGhvcj48YXV0aG9yPlJp
YSwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5SLiBS
aWEsIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUgYW5kIENsaW5pY2FsIE9uY29sb2d5
LCBVbml2ZXJzaXR5IG9mIEJhcmkg4oCcQWxkbyBNb3Jv4oCdIE1lZGljYWwgU2Nob29sLCBQb2xp
Y2xpbmljbyDigJMgUGlhenphIEdpdWxpbyBDZXNhcmUsIDExLCBCYXJpLCBJdGFseTwvYXV0aC1h
ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlN1YmN1dGFuZW91cyBpbW11bm9nbG9idWxpbnMgaW4gcGF0
aWVudHMgd2l0aCBtdWx0aXBsZSBteWVsb21hIGFuZCBzZWNvbmRhcnkgaHlwb2dhbW1hZ2xvYnVs
aW5lbWlhOiBhIHJhbmRvbWl6ZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2xpbmlj
YWwgSW1tdW5vbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs
LXRpdGxlPkNsaW5pY2FsIEltbXVub2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl
cz4xMTAtMTE1PC9wYWdlcz48dm9sdW1lPjE5MTwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD5h
bnRpaGlzdGFtaW5pYyBhZ2VudDwva2V5d29yZD48a2V5d29yZD5pbW11bm9nbG9idWxpbjwva2V5
d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPmFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+YXJ0aWNsZTwva2V5d29yZD48a2V5d29yZD5j
bGluaWNhbCBhcnRpY2xlPC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2xsZWQgc3R1ZHk8L2tleXdv
cmQ+PGtleXdvcmQ+ZGlzZWFzZSBkdXJhdGlvbjwva2V5d29yZD48a2V5d29yZD5kaXNlYXNlIHNl
dmVyaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmZlbWFsZTwva2V5d29yZD48a2V5d29yZD5ob3NwaXRh
bGl6YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5v
Z2xvYnVsaW4gZGVmaWNpZW5jeTwva2V5d29yZD48a2V5d29yZD5pbmNpZGVuY2U8L2tleXdvcmQ+
PGtleXdvcmQ+aW5qZWN0aW9uIHNpdGUgaW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmlu
amVjdGlvbiBzaXRlIHBhaW48L2tleXdvcmQ+PGtleXdvcmQ+bWFsZTwva2V5d29yZD48a2V5d29y
ZD5tdWx0aXBsZSBteWVsb21hPC9rZXl3b3JkPjxrZXl3b3JkPnByaW9yaXR5IGpvdXJuYWw8L2tl
eXdvcmQ+PGtleXdvcmQ+cXVhbGl0eSBvZiBsaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJhbmRvbWl6
ZWQgY29udHJvbGxlZCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5za2luIGFsbGVyZ3k8L2tleXdv
cmQ+PGtleXdvcmQ+dHJlYXRtZW50IGR1cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2ds
b2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29yZD48a2V5
d29yZD5JbW11bm9nbG9idWxpbiBFPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEc8
L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5JbW11
bm9nbG9idWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVn
aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRl
cz48ZGF0ZT4yMDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMS03MDM1IDE1
MjEtNjYxNjwvaXNibj48YWNjZXNzaW9uLW51bT5yYXl5YW4tNDU4ODE2NzwvYWNjZXNzaW9uLW51
bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0i
ZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cDovL3d3dy5lbWJhc2UuY29tL3NlYXJjaC9yZXN1bHRz
P3N1YmFjdGlvbj12aWV3cmVjb3JkJmFtcDtmcm9tPWV4cG9ydCZhbXA7aWQ9TDYyMDgwOTY5MDwv
c3R5bGU+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+IDwv
c3R5bGU+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+
aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9qLmNsaW0uMjAxNy4xMS4wMTQ8L3N0eWxlPjwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVTSU9OOiB7JnF1b3Q7
U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20xPjxyZXNlYXJjaC1u
b3Rlcz5NTSAtIFNDSUcgdnMgY29udHJvbHM8L3Jlc2VhcmNoLW5vdGVzPjxsYW5ndWFnZT5Fbmds
aXNoPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018) studied patients with MM randomised to receive SCIg or No SCIg. Those in the control group received significantly more days of antibiotics (217 vs 28 days, p<0.001) than those on SCIg, and had more days of hospitalisation (121 vs 8 days, p<0.001). This large effect size was consistent with the difference between groups for other infectious complications described in the Infections outcomes above. One further RCT, a cross-over study in 42 CLL patients, measured antibiotic use without reporting data PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Molica et al. 1996). The authors noted only there was no apparent difference in the mean number of antibiotic prescriptions during the No IVIg phases of the study versus the IVIg therapy phases. Of the cohort studies, one Australian study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+
PFJlY051bT40NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQmxvbWJlcnkgZXQgYWwuIDIwMTEpPC9E
aXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjQ1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl
eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQy
dGFkIiB0aW1lc3RhbXA9IjE1NTQyNTkwMzciPjQ1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10
eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1
dGhvcnM+PGF1dGhvcj5CbG9tYmVyeSwgUC48L2F1dGhvcj48YXV0aG9yPlByaW5jZSwgSC4gTS48
L2F1dGhvcj48YXV0aG9yPldvcnRoLCBMLiBKLjwvYXV0aG9yPjxhdXRob3I+TWFpbiwgSi48L2F1
dGhvcj48YXV0aG9yPllhbmcsIE0uPC9hdXRob3I+PGF1dGhvcj5Xb29kLCBFLiBNLjwvYXV0aG9y
PjxhdXRob3I+V2VzdGVybWFuLCBELiBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y
cz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIENhbmNlciBNZWRpY2luZSwgUGV0ZXIgTWFjQ2Fs
bHVtIENhbmNlciBDZW50cmUsIEVhc3QgTWVsYm91cm5lLCBNZWxib3VybmUsIFZpY3RvcmlhLCBB
dXN0cmFsaWEuIHBpZXJzLmJsb21iZXJ5QHBldGVybWFjLm9yZzwvYXV0aC1hZGRyZXNzPjx0aXRs
ZXM+PHRpdGxlPlByb3BoeWxhY3RpYyBpbnRyYXZlbm91cyBpbW11bm9nbG9idWxpbiBkdXJpbmcg
YXV0b2xvZ291cyBoYWVtb3BvaWV0aWMgc3RlbSBjZWxsIHRyYW5zcGxhbnRhdGlvbiBmb3IgbXVs
dGlwbGUgbXllbG9tYSBpcyBub3QgYXNzb2NpYXRlZCB3aXRoIHJlZHVjZWQgaW5mZWN0aW91cyBj
b21wbGljYXRpb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFubiBIZW1hdG9sPC9zZWNvbmRh
cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uIEhlbWF0b2w8L2Z1
bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTY3LTcyPC9wYWdlcz48dm9sdW1lPjkwPC92
b2x1bWU+PG51bWJlcj4xMDwvbnVtYmVyPjxlZGl0aW9uPjIwMTEvMDYvMTY8L2VkaXRpb24+PGtl
eXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnYW1tYWdsb2J1bGluZW1p
YS9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkF1c3Ry
YWxpYS9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdv
cmQ+PGtleXdvcmQ+RWxlY3Ryb25pYyBIZWFsdGggUmVjb3Jkczwva2V5d29yZD48a2V5d29yZD5G
ZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGVtYXRvcG9pZXRpYyBTdGVtIENlbGwgVHJhbnNwbGFu
dGF0aW9uLyBhZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SG9zcGl0YWxzLCBVbml2
ZXJzaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnMsIEludHJhdmVub3VzLyB0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+
SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxl
IEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXVsdGlwbGUgTXllbG9tYS8gY29tcGxpY2F0aW9ucy9p
bW11bm9sb2d5L3BoeXNpb3BhdGhvbG9neS8gdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5PcHBv
cnR1bmlzdGljIEluZmVjdGlvbnMvZXBpZGVtaW9sb2d5LyBwcmV2ZW50aW9uICZhbXA7IGNvbnRy
b2w8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3
b3JkPlN1cnZpdmFsIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPlRyYW5zcGxhbnRhdGlvbiwg
QXV0b2xvZ291czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxw
dWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQzMi0w
NTg0IChFbGVjdHJvbmljKSYjeEQ7MDkzOS01NTU1IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u
LW51bT4yMTY3NDE0NDwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVz
b3VyY2UtbnVtPjEwLjEwMDcvczAwMjc3LTAxMS0xMjc1LTM8L2VsZWN0cm9uaWMtcmVzb3VyY2Ut
bnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlk
ZXI+PHJlc2VhcmNoLW5vdGVzPkhTQ1QgZm9yIE1NPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3VhZ2U+
ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011) investigated a single peri-transplant dose in HSCT recipients, thus it was not representative of current clinical practice as it applies to use IgG within the NBA arrangements. The study found no difference in days of hospital admissions between IVIg and No IVIg groups (p=0.16) and but higher days of IV antimicrobials in IVIg patients compared to No IVIg (p=0.046). This was likely due to higher risk of infection at baseline in the IVIg group. This study is discussed further in the section above on infections, which was the main outcome reported for this study. A second Australian cohort study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Paxton, Hawkins & Crispin 2016) was considered representative of recent clinical practice for use of IVIg in this population. Hospitalisation for infection was reported as the main outcome, rather than infections themselves. The authors of the article observed that, patients who went on to receive IVIg had a higher rate of hospitalisation for infections at baseline than those who never received IVIg, highlighting the selection bias which was a feature of essentially all the retrospective studies in the clinical evidence. Prior to IVIg, the treated patients had a relative risk of hospitalisation of 3.1 (95% CI 1.6-4.9) compared with after IVIg treatment. In contrast, prior to treatment these same patients had a relative risk of 5.5 (95% CI 3.0-10) compared with the never treated group. Thus the treated group was at higher risk of hospitalisation but this did improve with IVIg treatment, though not to the same level as the never treated patients. When the groups in the Paxton study were divided by serum IgG levels prior to the study period, never treated patients (regardless of serum IgG levels) had broadly similar rates of hospitalisation as the rates observed in treated patients whose serum IgG was above the 4 g/L threshold. In contrast, the patients who had serum IgG<4 g/L who also went on to receive IVIg had very high rates of hospitalisation at baseline. Although the treated and untreated patients had essentially the same risk of hospitalisation during the study, Paxton authors did not conclude a lack of efficacy of IVIg. Instead, the authors considered these results identified a population of hypogammaglobulinaemic patients who were unlikely to develop infections and that this supported withholding IVIg unless the patient had an infection history. One retrospective cohort study in children in the USA PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gV2lua2xlPC9BdXRob3I+PFllYXI+MjAxODwvWWVh
cj48UmVjTnVtPjI2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihWYW4gV2lua2xlIGV0IGFsLiAyMDE4
KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNjwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJy
MnBkMnRhZCIgdGltZXN0YW1wPSIxNTUzODI1MDYwIj4yNjwva2V5PjwvZm9yZWlnbi1rZXlzPjxy
ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz
PjxhdXRob3JzPjxhdXRob3I+VmFuIFdpbmtsZSwgUC48L2F1dGhvcj48YXV0aG9yPkJ1cmNoZXR0
ZSwgUi48L2F1dGhvcj48YXV0aG9yPktpbSwgUi48L2F1dGhvcj48YXV0aG9yPlJhZ2h1bmF0aGFu
LCBSLjwvYXV0aG9yPjxhdXRob3I+UXVyZXNoaSwgTi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5QZWRpYXRyaWMgSG9zcGl0YWxpc3QgYXQgdGhlIEFuYWhl
aW0gTWVkaWNhbCBDZW50ZXIgaW4gQ0EuIHBhdHJpY2suai52YW53aW5rbGVAa3Aub3JnLiBTdGF0
aXN0aWNpYW4gZm9yIEthaXNlciBQZXJtYW5lbnRlIFNvdXRoZXJuIENhbGlmb3JuaWEgUmVzZWFy
Y2ggYW5kIEV2YWx1YXRpb24gaW4gUGFzYWRlbmEuIHJhb3VsLmouYnVyY2hldHRlQGtwLm9yZy4g
UmVzZWFyY2ggQXNzaXN0YW50IGZvciBLYWlzZXIgUGVybWFuZW50ZSBTb3V0aGVybiBDYWxpZm9y
bmlhIFJlc2VhcmNoIGFuZCBFdmFsdWF0aW9uIGluIFBhc2FkZW5hLiByd2hraW1AZ21haWwuY29t
LiBQZWRpYXRyaWMgT25jb2xvZ2lzdCBpbiB0aGUgRGVwYXJ0bWVudCBvZiBQZWRpYXRyaWMgSGVt
YXRvbG9neSBhbmQgT25jb2xvZ3kgYXQgdGhlIEFuYWhlaW0gTWVkaWNhbCBDZW50ZXIgaW4gQ0Eu
IHJ1a21hbmkucmFnaHVuYXRoYW5Aa3Aub3JnLiBQZWRpYXRyaWMgT25jb2xvZ2lzdCBpbiB0aGUg
RGVwYXJ0bWVudCBvZiBQZWRpYXRyaWMgSGVtYXRvbG9neSBhbmQgT25jb2xvZ3kgYXQgdGhlIEFu
YWhlaW0gTWVkaWNhbCBDZW50ZXIgaW4gQ0EuIG5hdmVlbi5hLnF1cmVzaGlAa3Aub3JnLjwvYXV0
aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlByZXZhbGVuY2UgYW5kIFNhZmV0eSBvZiBJbnRyYXZl
bm91cyBJbW11bm9nbG9idWxpbiBBZG1pbmlzdHJhdGlvbiBEdXJpbmcgTWFpbnRlbmFuY2UgQ2hl
bW90aGVyYXB5IGluIENoaWxkcmVuIHdpdGggQWN1dGUgTHltcGhvYmxhc3RpYyBMZXVrZW1pYSBp
biBGaXJzdCBDb21wbGV0ZSBSZW1pc3Npb246IEEgSGVhbHRoIE1haW50ZW5hbmNlIE9yZ2FuaXph
dGlvbiBQZXJzcGVjdGl2ZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QZXJtIEo8L3NlY29uZGFy
eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QZXJtIEo8L2Z1bGwtdGl0
bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNy0xNDE8L3BhZ2VzPjx2b2x1bWU+MjI8L3ZvbHVtZT48
a2V5d29yZHM+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BZ2FtbWFnbG9i
dWxpbmVtaWEvIGNvbXBsaWNhdGlvbnMvIGRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5C
YWN0ZXJlbWlhL2NvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+
PGtleXdvcmQ+Q2hpbGQsIFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdv
cmQ+PGtleXdvcmQ+RnVuZ2VtaWEvY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5IdW1h
bnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLCBJbnRyYXZlbm91cy9hZG1pbmlz
dHJhdGlvbiAmYW1wOyBkb3NhZ2UvIHRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5J
bmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+TWFpbnRlbmFuY2UgQ2hlbW90aGVyYXB5L21ldGhvZHM8
L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5QcmVjdXJzb3IgQ2VsbCBM
eW1waG9ibGFzdGljIExldWtlbWlhLUx5bXBob21hLyBjb21wbGljYXRpb25zPC9rZXl3b3JkPjxr
ZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+UmVtaXNzaW9uIEluZHVjdGlvbjwv
a2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+
WW91bmcgQWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zPC9rZXl3b3JkPjxr
ZXl3b3JkPkltbXVub2dsb2J1bGluIFZhcmlhYmxlIFJlZ2lvbjwva2V5d29yZD48a2V5d29yZD5J
bW11bm9nbG9idWxpbiBEPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIE08L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9i
dWxpbiBFPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT4yMDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU1Mi01Nzc1
IChFbGVjdHJvbmljKSAxNTUyLTU3NjcgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5
NzAyMDU0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVT
SU9OOiB7JnF1b3Q7U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20x
PjxyZXNlYXJjaC1ub3Rlcz5BTEwgcmV0cm9zcGVjdGl2ZSBjb2hvcnQgPC9yZXNlYXJjaC1ub3Rl
cz48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Van Winkle et al. 2018) was one of the few included studies of patients with ALL. The authors reported incidence and days of hospitalisation as part of infectious complications outcomes, concluding that there was no difference between the IVIg and No IVIg groups. As with the Blombery study, this was likely due to higher risk of infection at baseline in the IVIg group. This study is discussed further in the section above on infections. A large registry study of CLL and MM patients aimed to evaluate TEE risks associated with IgG (any route of administration) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
ZWNOdW0+MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQW1tYW5uIGV0IGFsLiAyMDE2KTwvRGlzcGxh
eVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl
eSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0
aW1lc3RhbXA9IjE1NTM4MjUwNTkiPjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt
ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48
YXV0aG9yPkFtbWFubiwgRS4gTS48L2F1dGhvcj48YXV0aG9yPkpvbmVzLCBNLiBQLjwvYXV0aG9y
PjxhdXRob3I+TGluaywgQi4gSy48L2F1dGhvcj48YXV0aG9yPkNhcm5haGFuLCBSLiBNLjwvYXV0
aG9yPjxhdXRob3I+V2luaWVja2ksIFMuIEsuPC9hdXRob3I+PGF1dGhvcj5Ub3JuZXIsIEouIEMu
PC9hdXRob3I+PGF1dGhvcj5NY0Rvd2VsbCwgQi4gRC48L2F1dGhvcj48YXV0aG9yPkZpcmVtYW4s
IEIuIEguPC9hdXRob3I+PGF1dGhvcj5DaHJpc2NoaWxsZXMsIEUuIEEuPC9hdXRob3I+PC9hdXRo
b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBFcGlkZW1pb2xv
Z3kgYW5kLiBEZXBhcnRtZW50IG9mIEJpb3N0YXRpc3RpY3MsIENvbGxlZ2Ugb2YgUHVibGljIEhl
YWx0aCwgVW5pdmVyc2l0eSBvZiBJb3dhLCBJb3dhIENpdHksIElBOyBEaXZpc2lvbiBvZiBIZW1h
dG9sb2d5LCBPbmNvbG9neSBhbmQgQmxvb2QgJmFtcDsgTWFycm93IFRyYW5zcGxhbnRhdGlvbiwg
RGVwYXJ0bWVudCBvZiBJbnRlcm5hbCBNZWRpY2luZSwgQ2FydmVyIENvbGxlZ2Ugb2YgTWVkaWNp
bmUsIFVuaXZlcnNpdHkgb2YgSW93YSwgSW93YSBDaXR5LCBJQTsgT2ZmaWNlIG9mIEJpb3N0YXRp
c3RpY3MgYW5kIEVwaWRlbWlvbG9neSwgQ2VudGVyIGZvciBCaW9sb2dpY3MgRXZhbHVhdGlvbiAm
YW1wOyBSZXNlYXJjaCwgVVMgRm9vZCBhbmQgRHJ1ZyBBZG1pbmlzdHJhdGlvbiwgU2lsdmVyIFNw
cmluZywgTUQ7IFBvcHVsYXRpb24gUmVzZWFyY2ggQ29yZSwgSG9sZGVuIENvbXByZWhlbnNpdmUg
Q2FuY2VyIENlbnRlciwgVW5pdmVyc2l0eSBvZiBJb3dhIEhvc3BpdGFscyBhbmQgQ2xpbmljcywg
SW93YSBDaXR5LCBJQTsgYW5kLiBEaXZpc2lvbiBvZiBSZXNlYXJjaCwgS2Fpc2VyIFBlcm1hbmVu
dGUgTm9ydGhlcm4gQ2FsaWZvcm5pYSwgT2FrbGFuZCwgQ0EuIERlcGFydG1lbnQgb2YgRXBpZGVt
aW9sb2d5IGFuZCBQb3B1bGF0aW9uIFJlc2VhcmNoIENvcmUsIEhvbGRlbiBDb21wcmVoZW5zaXZl
IENhbmNlciBDZW50ZXIsIFVuaXZlcnNpdHkgb2YgSW93YSBIb3NwaXRhbHMgYW5kIENsaW5pY3Ms
IElvd2EgQ2l0eSwgSUE7IGFuZC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbnRyYXZl
bm91cyBpbW11bmUgZ2xvYnVsaW4gYW5kIHRocm9tYm9lbWJvbGljIGFkdmVyc2UgZXZlbnRzIGlu
IHBhdGllbnRzIHdpdGggaGVtYXRvbG9naWMgbWFsaWduYW5jeTwvdGl0bGU+PHNlY29uZGFyeS10
aXRsZT5CbG9vZDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp
dGxlPkJsb29kPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjAwLTc8L3BhZ2VzPjx2
b2x1bWU+MTI3PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFn
ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+
Q2FzZS1Db250cm9sIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr
ZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkhlbWF0b2xvZ2ljIE5l
b3BsYXNtcy9lcGlkZW1pb2xvZ3kvIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlucywgSW50cmF2ZW5vdXMvYWR2ZXJzZSBlZmZl
Y3RzLyB0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vdGhlcmFweS9hZHZl
cnNlIGVmZmVjdHMvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3
b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5TRUVSIFByb2dyYW08
L2tleXdvcmQ+PGtleXdvcmQ+VGhyb21ib2VtYm9saXNtLyBjaGVtaWNhbGx5IGluZHVjZWQvZXBp
ZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlVuaXRlZCBTdGF0ZXMvZXBpZGVtaW9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPkhlbWF0b2xvZ2ljIE5lb3BsYXNtczwva2V5d29yZD48a2V5d29yZD5U
aHJvbWJvZW1ib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLCBJbnRyYXZl
bm91czwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnM8L2tleXdvcmQ+PC9rZXl3b3Jk
cz48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbi0xNDwvZGF0ZT48
L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjgtMDAyMCAoRWxlY3Ryb25pYykgMDAwNi00OTcx
IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNjQ0MzYyMjwvYWNjZXNzaW9uLW51bT48
dXJscz48L3VybHM+PGN1c3RvbTE+UkFZWUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9
Jmd0OyZxdW90O0luY2x1ZGVkJnF1b3Q7fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+Q0xMIGFu
ZCBNTSAtIG91dGNvbWUgLSB0aHJvbWJvdGljIGV2ZW50czwvcmVzZWFyY2gtbm90ZXM+PGxhbmd1
YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016). Hospitalisation for pneumonia was the only infection-related parameter reported in the study, though as a covariate rather than an outcome. For the rates of hospitalisation for pneumonia there was essentially no difference between IgG and control groups. The propensity-matched set of patients had corresponding 12 month rates of prior infections (influenza, pneumonia, bronchitis, UTIs, sepsis and others), however there were no data regarding baseline levels of serum IgG and – as with other retrospective studies – the patients that received IgG likely had a higher risk of infection prior to treatment. Table SEQ Table \* ARABIC 24Studies presenting resource use – non-comparative studies Study, IndicationOutcomeComparator (prior IgG)Intervention (after IgG)ComparisonCase seriesBenbrahim et al., 2019Infectious episodesBaseline Total (N=160)(IVIg n=50, SCIg n=110)Last visit (N=160)(IVIg n=50, SCIg n=110)MM(54), CLL(54), NHL(48), HL(4)Patients with hypo-GG69.2%15.9%p=0.14Incidence of infectious episodes per patient*yearPrior to study(95% CI)During follow-up (95% CI)p-valueInfections requiring antibioticstotal events (12mo)rate /patient/month2.06 (1.82–2.33)3300.1721.28 (0.99–1.66)2050.107p<0.0001Infections requiring IV antibioticstotal events (12mo)rate /patient/month0.45 [0.36–0.57]720.0340.27 [0.19–0.39]430.023p=0.09Infections requiring hospitalisationtotal events (12mo)rate /patient/month0.58 [0.45–0.73]930.0480.31 [0.22–0.44]500.026p=0.04Brenner, 1996Infections in CLL patients (N=54)Patient historyEquivalent to study period (no IVIg)During studyperiod (~12mo)(+IVIg)CLL, MM*Evaluable patients, N212121Infections requiring hospitalisation322114Duraisingham et al., 2014Prophylactic antibiotics (SID group N=39; 15 of which HM)Antibiotics before IgG (1 yr)Antibiotics duringIgG (1 yr)Various*SID patients, n patients (%)27 (69.2%)23 (60.0%)Patients with HM+hypo-GG, n patients with event/N patients12/1511/15Günther & Dreger 2013Infections compared before/during IVIg (N=10)Prior to IVIg (3 mo) (N=10)During IVIg (mean tx 51.2±25.4 mo)(N=10)Various*Courses of antibioticsn.r.26Jurlander et al., 1994Infection-related outcomes (N=15)12 mo prior to study (N=14)12 mo during study (median 14 mo, range 3-20) (n=14)p-valueCLLPatient months168169Hospital admissions due to infections165p=0.047Antibiotic prescriptions7854p>0.05[Supportive] Case seriesWindegger et al., 2019Infection requiring hospitalisation/total annual (N=13)Initial 12 mo IVIgMean per patientSubsequent 12 mo SCIgMean per patient(undefined)Treatment sought for infection (hospital emergency or GP)3/24 1/30 LoS per infection without bronchiectasis, mean9/15 8/22LoS per infection with bronchiectasis, mean3.75 days2.67 daysRate of hospitalisation due to infection0.130.03Notes: Brenner, 1996 studied a population (N=54) of CLL(n=22), MM(n=4) and also ITP and PAPS patients. The CLL and MM patient results are reported separately where possible. For CLL, the total numbers of infections requiring hospitalisation did not correspond with the individual contributing infections but this was not explained by the authors. No further MM data were presented due to small patient numbers. Duraisingham et al., 2014 – only data from n=39 SID patients presented; figures for n=15 haematological malignancy subset in italics extracted from raw data in supplementary spreadsheet, note this includes one patient with MGUS and excludes another with WM. Günther & Dreger 2013 – underlying disease types: CLL(5), FL(2), WM(1), IgA-plasmacytoma (1), MDS(1)]. Sundin et al., 2012 – no observation period for events was reported thus infection rate per patient month could not be derived.CLL=chronic lymphocytic leukaemia; FL=follicular lymphoma; GP=general practitioner; IgG-RT=immunoglobulin gamma replacement therapy; IVIg=intravenous immunoglobulin; LoS = length of hospital stay; MDS=myelodysplastic syndrome; MM=multiple myeloma; mo=month; n.r.=not reported; n.s.=not statistically significant; n.r.=not reported; SAE=serious adverse event; SID=secondary immunodeficiency; tx=treatment; WM=Waldenstr?m macroglobulinaemia. The before/after time comparison studies tended to show an improvement in resource use as a measure of infectious complications after IgG compared with before treatment. This was true of two of the older studies in CLL patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48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ADDIN EN.CITE.DATA (Brenner 1996; Jurlander, Geisler & Hansen 1995), though numbers of patients and/or number of events were relatively small. A recent French study published in two parts PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy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ADDIN EN.CITE.DATA (Benbrahim et al. 2018, 2019) studied 160 patients, mostly with CLL, MM and NHL. The authors showed a consistent difference in antibiotic use, IV antibiotic use and hospitalisations for infection when comparing results before (at baseline) and after IgG therapy (last visit). This was one of the few case studies judged to be at low risk of bias. Although hypogammaglobulinaemia and infection history were not inclusion criteria, mean values at baseline for serum IgG and infection history (see REF _Ref9248112 \h \* MERGEFORMAT Table 22) suggested the majority of patients had symptomatic hypogammaglobulinaemia at entry. For three other recent studies, no conclusion could be drawn for IgG versus No IgG:A UK study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE.DATA (Duraisingham et al. 2014) reported only antibiotic prophylaxis not in response to infections. A very small study of 10 patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
PFJlY051bT4zNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR8O8bnRoZXIgJmFtcDsgRHJlZ2VyIDIw
MTMpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDll
MnIycGQydGFkIiB0aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjM0PC9rZXk+PC9mb3JlaWduLWtleXM+
PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv
cnM+PGF1dGhvcnM+PGF1dGhvcj5Hw7xudGhlciwgRy48L2F1dGhvcj48YXV0aG9yPkRyZWdlciwg
Qi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NZWRpY2Fs
IENhcmUgQ2VudGVyIGZvciBCbG9vZCBhbmQgQ2FuY2VyIERpc2Vhc2VzLCBQb3RzZGFtLCBHZXJt
YW55LiBkci5nZW9yZ19ndWVudGhlckB0LW9ubGluZS5kZTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+
PHRpdGxlPlBvc3QtbWFya2V0aW5nIG9ic2VydmF0aW9uYWwgc3R1ZHkgb24gNSUgaW50cmF2ZW5v
dXMgaW1tdW5vZ2xvYnVsaW4gdGhlcmFweSBpbiBwYXRpZW50cyB3aXRoIHNlY29uZGFyeSBpbW11
bm9kZWZpY2llbmN5IGFuZCByZWN1cnJlbnQgc2VyaW91cyBiYWN0ZXJpYWwgaW5mZWN0aW9uczwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5NaWNyb2Jpb2wgSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk1pY3JvYmlvbCBJbW11bm9sPC9mdWxs
LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTI3LTM1PC9wYWdlcz48dm9sdW1lPjU3PC92b2x1
bWU+PG51bWJlcj43PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIEluZmVjdGlvbnMvIHRoZXJh
cHk8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1
Zy1SZWxhdGVkIFNpZGUgRWZmZWN0cyBhbmQgQWR2ZXJzZSBSZWFjdGlvbnMvZXBpZGVtaW9sb2d5
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZW1hdG9sb2dpYyBO
ZW9wbGFzbXMvY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnMsIEludHJhdmVub3VzL2FkdmVyc2UgZWZmZWN0cy8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2xvZ2ljIERlZmljaWVuY3kgU3luZHJvbWVzLyBjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb2R1Y3Qg
U3VydmVpbGxhbmNlLCBQb3N0bWFya2V0aW5nPC9rZXl3b3JkPjxrZXl3b3JkPlNlY29uZGFyeSBQ
cmV2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxr
ZXl3b3JkPmNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWE8L2tleXdvcmQ+PGtleXdvcmQ+aW50
cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PGtleXdvcmQ+cmVjdXJyZW50IGluZmVj
dGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+c2Vjb25kYXJ5IGltbXVub2RlZmljaWVuY3k8L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5pemF0aW9uLCBQYXNzaXZlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdv
cmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBNPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v
Z2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxr
ZXl3b3JkPlJlY3VycmVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjEzNDgtMDQyMSAoRWxlY3Ryb25pYykgMDM4NS01NjAwIChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4yMzYwNzg2MzwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+UkFZ
WUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90O0luY2x1ZGVkJnF1b3Q7
fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+Q0xMLCBOSEwsIElnTS1zZWNyZXRpbmcgaW1tdW5v
Y3l0b21hLCBJZ0EgcGxhc21hIGN5dG9tYSwgTXllbG9keXNwbGFzdGljIHN5bmRyb21lL05ITC4g
QmVmb3JlIGFuZCBhZnRlciBjb21wYXJpc29uPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5n
PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE.DATA (Günther & Dreger 2013) reported on-study numbers of antibiotic prescriptions but no pre-study values. A supportive study ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019) compared IVIg to SCIg in 13 Australian patients but without an untreated group or values at baseline. Survival and/or MortalityA total of four studies reported survival or mortality in patients who received IgG ( REF _Ref11850104 \h \* MERGEFORMAT Table 25). Table SEQ Table \* ARABIC 25Studies presenting survival and mortalityStudy, IndicationOutcomeInterventionComparatorComparison Sullivan et al., 1990SurvivalIVIg (n=184)No IVIg (n=185)p-valueBMTSurvivors at follow-up6669Median duration of follow-up, yr, since randomisation1.92.0Actuarial survival, % after 2 years33±435±4p=0.79Cumulative incidence of non-relapse mortalityPatients <20 yoPatients ≥20 yo36%48%p=0.083Patients ≥20 yo, who received HLA-identical BMT30%(n=88)46%(n=89)p=0.023Blombery et al., 2011Survival post-HSCTIVIg (n=130)No IVIg (n=110)p-valueMM+HSCTMedian survival post-HSCT, mo [range] 45.0 [0.3–104.7]44.8 [0.6–118.4]p=0.75Ammann 2016All cause mortalityIgG users (n=2724)Non-users (n=8035)CLL, MMPropensity matched set (1-yr cumulative incidence)26%26%All cause mortalityIgG users (n=2771)Non-users (n=8313)Randomly matched set (1-yr cumulative incidence)26%14%Reiser et al., 2017Average follow-up – overall (N=307)20.5 monthsN/ACLL(130); NHL(99); MM(43); other(35)CLL21.4 monthsMM 21.6 monthsIndolent lymphoma22.3 monthsOther conditions (incl. other NHL)19.9 monthsMortality rate – overall 9.3%N/ACLL12.6% MM 14.0%Indolent lymphoma6.5%Other conditions (incl. other NHL)1.8%Mean survival from enrolment(no differences [p=0.104] between malignancies)23 monthsN/ANotes: Ammann (2016) – The study included patients receiving IVIg, SCIg or IMIg but proportions of each were not reported; BMT=bone marrow transplant; CLL=chronic lymphocytic leukaemia; HLA=human leukocyte antigen; HSCT=haematopoietic stem cell transplant; IVIg=intravenous immunoglobulin; MM=multiple myeloma; mo=months; NHL=non-Hodgkin lymphoma; yr=year.The highest level of evidence available was a single American RCT from 1990 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1990). The authors reported that survival at two years did not significantly differ between those who received IVIg and those who did not. In subgroup analyses, they reported that there was a higher rate of non-relapse mortality in patients older than 20 years old, who received HLA-identical bone marrow transplantation, in those who received IVIg (30%) than those did not receive IVIg (48%; p=0.023). Given that these results represent patients who received treatment in the late 1980s, it is uncertain whether this remains relevant to patients receiving present day standard of care for their underlying disease. The US registry study in over 10,000 CLL and MM patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016) found that after balancing the IgG and control groups for TEE risk factors, there was no difference in all-cause mortality between the two, removing the otherwise much higher rate of mortality from the IgG group in the unbalanced set (randomly matched) (noting a maximum of only 12 months follow-up). Likewise, one Australian cohort study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011) reported no significant difference (median survival post-HSCT of approximately 45 months in both arms). A retrospective case series in Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Reiser et al. 2017) did not have a control group, so no comparison could be made. Authors of several studies commented that survival analysis was not possible due to short study duration or follow-up duration PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1994b; Molica et al. 1996; Vacca et al. 2018). For example, the mean survival from enrolment of 23 months reported in the Reiser study above suggests several years at a minimum would be needed for a meaningful assessment of survival associated with IgG use. Transplant-related outcomesOne RCT from the US PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1990) and one supportive study from Sweden PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012) reported transplant-related outcomes in HSCT recipients. Table SEQ Table \* ARABIC 26Transplant-related outcomes – Sullivan et al., 1990 (IVIg vs No IVIg)Study, IndicationOutcomeInterventionComparatorComparisonSullivan et al., 1990Grade of acute GVHDIVIg (n=184)No IVIg (n=185)p-valueBMTTotal allo-BMT recipients166159Grade of acute GVHD; n/N patients (%)Grade 0 (none)79/166 (48%)60/159 (38%)Grade I (mild)17/166 (10%)16/159 (10%)Grade II (moderate)36/166 (22%)38/159 (24%)Grade III (severe)29/166 (17%)32/159 (20%)Grade IV (life-threatening)5/166 (3%)13/159 (8%)Relative risk, Grades II-IV GVHD――1.63 (0.0056)Acute GVHD, Grade II-IV, cumulative incidencePatients ≥20 yo34% (n=108)51% (n=110)p=0.0051Interstitial PneumoniaCMV seropositive patients, all (n=308)IVIg, CMV+ (n=154)No IVIg, CMV+ (n=154)Patients with interstitial pneumonia1934Types of pneumoniaCMVIdiopathicClinical (not culture confirmed)Parainfluenza virus1612023461Interstitial pneumonia, cumulative incidence13%22%p=0.021Relative risk of interstitial pneumonia (p-value)――1.70 (p=0.064)CMV+ patients <20 years oldn=65 patients8 patients (12%)n=57 patients7 patients (12%)n.s.CMV+ patients ≥20 years old n=119 patients11 patients (9%)n=128 patients27 patients (21%)p=0.0032Sullivan et al., 1990 – all CMV seropositive patients received prophylactic acyclovir from –d5 to d30 post-BMT. No CMV seronegative patients developed interstitial pneumonia, noting that these patients all received BMT from CMV- donors. BMT=bone marrow transplant; CMV=cytomegalovirus; GVHD=graft versus host disease; IVIg=intravenous immunoglobulinIn the Sullivan study ( REF _Ref9453080 \h \* MERGEFORMAT Table 26), patients who received IVIg were significant less likely to have a grade II to IV GVHD (RR=1.63, p=0.0056). Interstitial pneumonia (a risk of CMV reactivation) was evaluated only in CMV seropositive patients in the same study as a transplant-related outcome. Patients who were randomised to receive IVIg were significantly less likely to develop interstitial pneumonia than those who did not receive IVIg (cumulative incidence 13% vs 22%, p=0.021). It was however considered that management of HSCT transplants and GVHD risk in current clinical practice has changed radically compared with when this study was conducted in the late 1980s (new immunosuppressants and conditioning regimens, changes in HLA typing, use of mobilised stem cells) thus in the absence of other high quality studies reporting this outcome it was not clear whether this result for GVHD risk could be replicated in a similarly designed study in a modern population. The Swedish study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012) reported GVHD in terms of acute, chronic and graft rejection in 46 HSCT recipients receiving either IVIg or SCIg ( REF _Ref10295259 \h \* MERGEFORMAT Table 27). The authors concluded that IVIg recipients had a higher incidence than SCIg of acute GVHD but concluded that this was not significant (p-value not presented). Given the observational nature of the study, the difference in results may have been due to selection bias. The absence of a No IgG control group precludes any conclusion for the main purpose of this evaluation. Table SEQ Table \* ARABIC 27Transplant-related outcomes – Sundin et al., 2012 (IVIg vs SCIg)Study, IndicationOutcomeInterventionComparatorComparisonSundin et al., 2012GVHD, n (%)IVIg (N=46)n=24 haem. malignancy SCIg (N=12)n=2 haem. malignancy HSCTAcute GvHD30 (65.2%)5 (41.7%)Chronic GvHD9 (19.6%)1 (8.3%)Rejection1 (2.2%)1 (8.3%) GVHD=graft versus host disease; IVIg=intravenous immunoglobulin; SCIg=subcutaneous immunoglobulinQuality of LifeThree studies administered QoL questionnaires PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Reiser et al. 2017; Vacca et al. 2018; Windegger et al. 2019) and a fourth interviewed patients and families regarding acceptance of SCIg PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012). Figure SEQ Figure \* ARABIC 7Quality of Life (SF-36) – Vacca et al., 2018Arm A: patients receiving SCIg; Arm B: ‘No SCIg’ controls PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018). Asterisks indicate p-values *<0.05; **<0.01Note: this figure will need to be redacted prior to making this document publicly accessible.One RCT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018) used the SF-36 questionnaire to assess health-related quality of life in patients randomised to receive SCIg or no SCIg ( REF _Ref9901649 \h \* MERGEFORMAT Figure 7). SCIg patients scored better than the untreated control patients by all measures except pain. A study in Germany in 307 haematological malignancy patients receiving either IVIg or SCIg PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWlzZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Reiser et al. 2017) also used both EQ-5D and SF-36 tools to assess QoL. Patients commencing on IgG improved slightly during follow-up across all domains except psychological health. QoL values for patients entering the study on IgG maintenance did not change during follow-up.An Australian study ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019) surveyed 84 patients to ask whether SCIg was a cost-effective option for patients with secondary immunodeficiency disease compared to IVIg using the Assessment of Quality of Life (AQoL)-6D questionnaire ( REF _Ref10301224 \h \* MERGEFORMAT Table 28). The target population was patients with acquired hypogammaglobulinaemia secondary to malignancy or associated treatment – patients were surveyed who were receiving either IVIg or SCIg or picking up SCIg product from one of two different clinics in Queensland, to determine the utilities associated with different health states. The presence of infection and bronchiectasis (lung disease which allows mucus to pool in the damaged airways) reduced quality of life in these patients compared to no infection or bronchiectasis. In terms of cumulative QALYs, SCIg was dominant (3.51 QALY) compared to IVIg (3.07 QALY), given that costs for SCIg were lower (not shown) Table SEQ Table \* ARABIC 28Utility weights based on AQOL-6D survey Study IndicationRisk of biasPopulationHealth stateUtility score (95%CI)Windegger et al. (2019)(undefined)Moderate/ high84 patients with acquired hypogammaglobulinaemia secondary to haematological malignancy (192 responses)No infection0.71 (0.67, 0.75)With infection0.70 (0.63, 0.76)With bronchiectasis no infection0.64 0.55, 0.72)With bronchiectasis with infection0.63 (0.56, 0.70)A Swedish study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012) interviewed 10 SCIg and 22 IVIg paediatric HSCT recipients and their families about acceptability of the IgG treatment the child was receiving. All families interviewed were positive about IgG treatment regardless of route of administration. The authors noted that four families of IVIg recipients who had indicated acceptance of IVIg still wanted to switch or wanted their child to switch to SCIg based on the reduced burden of clinic visits or difficulties with venous access for IVIg. Two SCIg families had anxiety about administering injections to their own child at home and chose to come to the clinic for infusions but this did not appear to affect acceptability of SCIg. QoL data from a further study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS
ZWNOdW0+NTY8L1JlY051bT48RGlzcGxheVRleHQ+KENoYXBlbCBldCBhbC4gMTk5NGIpPC9EaXNw
bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+
PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFk
IiB0aW1lc3RhbXA9IjE1NTQyNjY2NjkiPjU2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl
IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv
cnM+PGF1dGhvcj5DaGFwZWwsIEguIE0uPC9hdXRob3I+PGF1dGhvcj5MZWUsIE0uPC9hdXRob3I+
PGF1dGhvcj5IYXJncmVhdmVzLCBSLjwvYXV0aG9yPjxhdXRob3I+UGFtcGhpbG9uLCBELiBILjwv
YXV0aG9yPjxhdXRob3I+UHJlbnRpY2UsIEEuIEcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJp
YnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBJbW11bm9sb2d5LCBKb2huIFJhZGNs
aWZmZSBIb3NwaXRhbCwgT3hmb3JkLCBVSy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5S
YW5kb21pc2VkIHRyaWFsIG9mIGludHJhdmVub3VzIGltbXVub2dsb2J1bGluIGFzIHByb3BoeWxh
eGlzIGFnYWluc3QgaW5mZWN0aW9uIGluIHBsYXRlYXUtcGhhc2UgbXVsdGlwbGUgbXllbG9tYS4g
VGhlIFVLIEdyb3VwIGZvciBJbW11bm9nbG9idWxpbiBSZXBsYWNlbWVudCBUaGVyYXB5IGluIE11
bHRpcGxlIE15ZWxvbWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0PC9zZWNvbmRhcnkt
dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0PC9mdWxsLXRpdGxl
PjwvcGVyaW9kaWNhbD48cGFnZXM+MTA1OS02MzwvcGFnZXM+PHZvbHVtZT4zNDM8L3ZvbHVtZT48
bnVtYmVyPjg5MDU8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5
d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9ucy8qcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3
b3JkPjxrZXl3b3JkPkJhY3RlcmlhbCBWYWNjaW5lczwva2V5d29yZD48a2V5d29yZD5Eb3VibGUt
QmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5I
dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLCBJbnRyYXZlbm91cy9hZHZl
cnNlIGVmZmVjdHMvKnRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbmZlY3Rpb24g
Q29udHJvbC9tZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+
TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TXVsdGlwbGUgTXllbG9tYS8qY29tcGxpY2F0
aW9uczwva2V5d29yZD48a2V5d29yZD5QbmV1bW9jb2NjYWwgSW5mZWN0aW9ucy9wcmV2ZW50aW9u
ICZhbXA7IGNvbnRyb2w8L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vY29jY2FsIFZhY2NpbmVzPC9r
ZXl3b3JkPjxrZXl3b3JkPlBuZXVtb25pYS9wcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tleXdv
cmQ+PGtleXdvcmQ+UHJlbWVkaWNhdGlvbjwva2V5d29yZD48a2V5d29yZD5Qcm9zcGVjdGl2ZSBT
dHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlJlY3VycmVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+U2Vw
c2lzL3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5TdHJlcHRvY29j
Y3VzIHBuZXVtb25pYWUvaW1tdW5vbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh
cj4xOTk0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByIDMwPC9kYXRlPjwvcHViLWRhdGVzPjwv
ZGF0ZXM+PGlzYm4+MDE0MC02NzM2IChQcmludCkmI3hEOzAxNDAtNjczNiAoTGlua2luZyk8L2lz
Ym4+PGFjY2Vzc2lvbi1udW0+NzkwOTA5OTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11
cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAw
JSI+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvNzkwOTA5OTwvc3R5bGU+PC91
cmw+PHVybD48c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJkZWZhdWx0IiBzaXplPSIxMDAl
Ij5odHRwczovL3d3dy5zY2llbmNlZGlyZWN0LmNvbS9zY2llbmNlL2FydGljbGUvcGlpL1MwMTQw
NjczNjk0OTAxODA1P3ZpYSUzRGlodWI8L3N0eWxlPjwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJs
cz48cmVzZWFyY2gtbm90ZXM+TU0gKHBlYXJsZWQpIG5vdCBjbGVhciBvbiBpZiBoYWQgaHlwb2dh
bW1hPC9yZXNlYXJjaC1ub3Rlcz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Chapel et al. 1994b) have been reported separately in a symposium presentation, but these data do not appear to have been published in the peer-reviewed literature. Extended Assessment of HarmsIgG has a long history of use for treatment of immunodeficiency dating back to the 1950s or earlier. IVIg has been used to manage hypogammaglobulinaemia infection risk in haematological malignancies since the late 1980s or so. In the European Union, the authorised product information for authorised products must include core text prescribed for both IVIg and SCIg presentations, reflecting the extent of safety information available for these products across these patient populations. The current approved Product Information for IgG products registered in Australia contain a corresponding extent of safety information, however the wording varies between products. Hence the EMA’s core text specifically relating to IgG safety profile (below) can be considered representative of IgG products registered in Australia. Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass:? chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain? reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion? (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration? (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequency unknown)? (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses? cases of reversible aseptic meningitis? cases of increased serum creatinine level and/or occurrence of acute renal failure? cases of Transfusion Related Acute Lung Injury (TRALI)In 2011, the EMA undertook a review of at least two immunoglobulin products (Octagam; Vivaglobin) which were associated with reports of increased TEEs and which led to a worldwide withdrawal of Octagam from the market. The EMA concluded that these events were due to residual impurities (clotting factors in the case of Octagam) which had caused the spike in events. Octagam remains authorised in both the EU, Australia and elsewhere following improvements to the manufacturing process to control for these impurities. The potential TEE risk is now highlighted in product information as described above. In the USA, TEE risks were added as a black box safety warning to IgG products. Relevant to this, a US registry study included in this evaluation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016) further investigated TEE risks associated with any IgG use in more than 10,000 matched subjects with CLL or MM.Interpretation of the Clinical EvidenceThe overall evidence shows that, in patients with hypogammaglobulinaemia secondary to any haematological malignancy, IgG replacement will significantly reduce the number of infections compared with ‘No IgG’. Studies were less likely to support this conclusion if they enrolled a high proportion of patients without documented risk factors (hypogammaglobulinaemia and a history of infections). Infections incidence appeared to be as variable between indications such as CLL or MM as they were within a single indication due to differences in disease severity, concomitant medications and other factors. The effectiveness of IgG in reducing infections incidence was confirmed in meta-analyses of randomised trials, as well as meta-analyses of before-and-after case series (within patient comparisons of infection rates before receiving IgG and while on IgG). The limitations of the evidence mean that the risk ratios reported in these meta-analyses are highly uncertain. The studies included in the report were low level evidence consisting primarily of case series with a small number of randomised studies (several of which did not adequately report the primary efficacy outcome, infections). An assessment of the quality of evidence for each outcome using GRADE is in REF _Ref399239890 \h \* MERGEFORMAT Table 29. The quality of evidence was low for efficacy (as measured by infections) and also low for safety (though not for TEE risk which had high quality evidence). Clinical evidence for IgG safety was limited to infusion reactions, with the exception of a registry study reporting TEE risk which showed a transient increase in TEE events following IgG initiation. It was considered that the safety profile described in approved Product Information (using the EMA core text as an example) provides a better and more comprehensive assessment of IgG safety for this population. This evaluation could not address:Confirmation of a clinically active dose or frequency of dosing. Most studies included explored doses between 200 and 500 mg/kg. Variability in patient characteristics and disease status, and the effect this had on infections, precluded any assessment of dose-response. Definition of adequate treatment response: a qualitative reduction in infections rate was usually taken as evidence of a response. Timeframes for assessment were highly variable. Criteria for discontinuation. An initial patient response in terms of infections seemed to be adequate reason for ongoing IgG replacement which often lasted for some months or years. The majority of the included studies did not describe criteria for treatment continuation or cessation – for those that did, it was typically the reasoning of the treating physician was reported. There was no prospective set of discontinuation criteria offered by any of the included studies. Frequency of serum IgG monitoring as a basis for response assessment or a decision to discontinue. Several studies monitored serum IgG levels, some as frequently as monthly or every 3 months. Others tested patients based on availability as representative of the whole cohort. Regarding the ‘other haematological malignancies’ category, use of IgG replacement in these patients is based on the principle that a history of infections and presence of hypogammaglobulinaemia is sufficient to warrant treatment. This is the basis of the current funding of IgG for this category of patients in Australia, but it still remains an assumption. On the other hand, the evidence reviewed does not suggest that response to IgG replacement therapy is any more variable in patients with the less-studied/infrequent malignancies compared with CLL and MM. A large registry study with adequate patients having ‘other’ conditions would be needed to address this. On the basis of the benefits and harms reported in the evidence base (summarised above), it is suggested that, relative to No IgG replacement with antibiotics as required, the use of IgG products with antibiotics as required has inferior safety and superior effectiveness.Table SEQ Table \* ARABIC 29Balance of clinical benefits and harms of IgG with antibiotics as required, relative to No IgG with antibiotics as required (GRADE assessment)Outcomes (units)Follow-upParticipants (studies)Quality of evidence (GRADE)Relative effectCommentsSafetyK=13 studies; N=1,342(2 RCTs reported AEs for both IgG and No IgG; N=125)????Low qualityIgG has worse safety than No IgGSafety data were limited and sometimes absent for the included studies, focusing on infusion-related events only (key RCTs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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==
ADDIN EN.CITE.DATA (Boughton et al. 1995; Chapel et al. 1994b)). No evidence was available for longer-term outcomes other than TEE risk. Adverse events reported were nevertheless consistent with the established safety profile for IgG products (discussed in Extended Assessment of Harms). TEE risk (arterial or venous)1 registry studyN=10,759????High quality% Risk difference (95% CI), 1 yr IgG tx:1.0 (-0.2, 2.7)Only 1 included study, but very large, recent registry study. Control and intervention groups were balanced for cardiovascular risk. Selection bias which limits use of this study for infections is unlikely to affect cardiovascular safety (the main endpoint of this study) – high confidence in risk of TEE due to IgG. InfectionsK=20 studies, N=1,930(15 in meta-analyses: 6 RCTs, 2 cohort, 7 case series; N=1,536)????Low qualityRate ratio (95% CI) 0.14 (0.05, 0.43) for reduction of serious infections with IgG compared to No IgGThe quality of evidence was poor overall and infections were both reported and defined in widely variable ways. Moderate confidence that IgG reduces serious infections in patients based on a meta-analysis, but effective dose range could not be identified with any confidence and evidence was absent or limited for some of the conditions such as HSCTs, AL and ‘Other haematological malignancies’. Transplant-related events1 RCT (N=369)1 supportive study (N=58)????Very low qualityNo conclusion drawn.Only two studies investigated transplant-related outcomes. One study from 1990 may not be replicable with current standard of care for HSCTs and management of GVHD risk. A second supportive study could not be used. Mortality4 included studies (1 RCT, 1 cohort study, 1 registry and 1 retrospective case series)N=11,674????Very low qualityNo conclusion drawn.Insufficient duration of follow-up and variability between patient disease stage and other clinical factors precluded any meaningful assessment.QoL1 RCT (N=46)1 case series with small amount of before and after data (N=307)????Low qualityIgG marginally improves QoL compared to No IgGOnly 2 of the 4 studies reported QoL for IgG versus no IgG. a GRADE Working Group grades of evidence (Guyatt et al., 2013)???? High quality: We are very confident that the true effect lies close to that of the estimate of effect. ???? Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. ???? Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.???? Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.Section CTranslation IssuesOverviewThe model presented in Section D is a cost-utility analysis, where Ig therapy is associated with an effective reduction in infection rates, but that is traded off against a reduced safety profile. Ig therapy is already in use in Australia and four applicability issues are considered:How do the patient demographics and settings in the clinical evidence compare to those that currently receive Ig therapy for acquired hypogammaglobulinaemia?How were antibiotics used in the absence of Ig in the clinical evidence, and is this reflective of what would happen in the absence of Ig in the contemporary setting?How do the doses used in the clinical evidence compare to those currently dispensed in the Australian population that receives Ig for acquired hypogammaglobulinaemia?What was the duration of Ig treatment in the clinical evidence, and how does this compare to use in the current Australian population?Extrapolation issues considered are:What is the expected duration of the treatment effect of Ig?What is the natural history of recurrent infections in patients with acquired hypogammaglobulinemia?Finally, one transformation issue is presented:How to transform the outcomes of the clinical evidence into a common patient-relevant outcome?Applicability translation issuesC.2.1.Patient demographics and settingsThe aim of this translation study is to determine how the patient demographics and settings in the clinical evidence compare to those of patients that currently receive Ig therapy for acquired hypogammaglobulinaemia in Australia. As per the Version 3 criteria, Ig is indicated for acquired hypogammaglobulinaemia secondary to haematological malignancies (including acute leukaemia, CLL, MM, NHL and others), or post-HSCT. BloodSTAR data are used to inform the average ages and weights of patients in Australia who currently receive Ig for this indication. These demographics will be compared to those of the patients enrolled in the primary clinical evidence used to inform the economic analysis.The demographics of patients in Australia who currently receive Ig for acquired hypogammaglobulinaemia are presented in REF _Ref10549632 \h Table 30. As the primary evidence that will inform the economic analysis will be the randomised studies identified in Section B PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1991; Chapel et al. 1994b; Molica et al. 1996; Musto, Brugiatelli & Carotenuto 1995; Sullivan et al. 1990; Vacca et al. 2018) (though noting that sensitivity analyses based on the before/after non-randomised studies will also be presented), this table presents a comparison of the demographics to those in the randomised studies. Table SEQ Table \* ARABIC 30A comparison of the demographics of the Australian population that receives Ig for acquired hypogammaglobulinaemia to those in the clinical evidenceAverage patient ageAverage patient weightBloodSTAR data aSection B studiesBloodSTAR data aSection B studiesCLL72.5Chapel et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(1991): NRMolica et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TW9saWNhPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TW9saWNhPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (1996): 64 ± 11.577.3Chapel et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(1991): NRMolica et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TW9saWNhPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TW9saWNhPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (1996): NRMM70.2Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll
YXI+MTk5NDwvWWVhcj48UmVjTnVtPjU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigxOTk0Yik8L0Rp
c3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5
cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0
YWQiIHRpbWVzdGFtcD0iMTU1NDI2NjY2OSI+NTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5
cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0
aG9ycz48YXV0aG9yPkNoYXBlbCwgSC4gTS48L2F1dGhvcj48YXV0aG9yPkxlZSwgTS48L2F1dGhv
cj48YXV0aG9yPkhhcmdyZWF2ZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5QYW1waGlsb24sIEQuIEgu
PC9hdXRob3I+PGF1dGhvcj5QcmVudGljZSwgQS4gRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIEpvaG4gUmFk
Y2xpZmZlIEhvc3BpdGFsLCBPeGZvcmQsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
PlJhbmRvbWlzZWQgdHJpYWwgb2YgaW50cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW4gYXMgcHJvcGh5
bGF4aXMgYWdhaW5zdCBpbmZlY3Rpb24gaW4gcGxhdGVhdS1waGFzZSBtdWx0aXBsZSBteWVsb21h
LiBUaGUgVUsgR3JvdXAgZm9yIEltbXVub2dsb2J1bGluIFJlcGxhY2VtZW50IFRoZXJhcHkgaW4g
TXVsdGlwbGUgTXllbG9tYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQ8L3NlY29uZGFy
eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQ8L2Z1bGwtdGl0
bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDU5LTYzPC9wYWdlcz48dm9sdW1lPjM0Mzwvdm9sdW1l
PjxudW1iZXI+ODkwNTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPkJhY3RlcmlhbCBJbmZlY3Rpb25zLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tl
eXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIFZhY2NpbmVzPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJs
ZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnMsIEludHJhdmVub3VzL2Fk
dmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlv
biBDb250cm9sL21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y
ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdWx0aXBsZSBNeWVsb21hLypjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlBuZXVtb2NvY2NhbCBJbmZlY3Rpb25zL3ByZXZlbnRp
b24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QbmV1bW9jb2NjYWwgVmFjY2luZXM8
L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmlhL3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5
d29yZD48a2V5d29yZD5QcmVtZWRpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZl
IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjdXJyZW5jZTwva2V5d29yZD48a2V5d29yZD5T
ZXBzaXMvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlN0cmVwdG9j
b2NjdXMgcG5ldW1vbmlhZS9pbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjE5OTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHIgMzA8L2RhdGU+PC9wdWItZGF0ZXM+
PC9kYXRlcz48aXNibj4wMTQwLTY3MzYgKFByaW50KSYjeEQ7MDE0MC02NzM2IChMaW5raW5nKTwv
aXNibj48YWNjZXNzaW9uLW51bT43OTA5MDk5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk
LXVybHM+PHVybD48c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC83OTA5MDk5PC9zdHlsZT48
L3VybD48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEw
MCUiPmh0dHBzOi8vd3d3LnNjaWVuY2VkaXJlY3QuY29tL3NjaWVuY2UvYXJ0aWNsZS9waWkvUzAx
NDA2NzM2OTQ5MDE4MDU/dmlhJTNEaWh1Yjwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxyZXNlYXJjaC1ub3Rlcz5NTSAocGVhcmxlZCkgbm90IGNsZWFyIG9uIGlmIGhhZCBoeXBv
Z2FtbWE8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b): 66Musto, Brugiatelli & Carotenuto ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Musto</Author><Year>1995</Year><RecNum>60</RecNum><DisplayText>(1995)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554267573">60</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Musto, P.</author><author>Brugiatelli, M.</author><author>Carotenuto, M.</author></authors></contributors><titles><title>Prophylaxis against infections with intravenous immunoglobulins in multiple myeloma</title><secondary-title>Br J Haematol</secondary-title></titles><periodical><full-title>Br J Haematol</full-title></periodical><dates><year>1995</year></dates><urls></urls><research-notes>MM (pearled) cross-over study IVIG vs no prophylaxis</research-notes></record></Cite></EndNote>(1995): NRVacca et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh
cj4yMDE4PC9ZZWFyPjxSZWNOdW0+MzA8L1JlY051bT48RGlzcGxheVRleHQ+KDIwMTgpPC9EaXNw
bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+
PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFk
IiB0aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjMwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl
IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv
cnM+PGF1dGhvcj5WYWNjYSwgQS48L2F1dGhvcj48YXV0aG9yPk1lbGFjY2lvLCBBLjwvYXV0aG9y
PjxhdXRob3I+U3BvcnRlbGxpLCBBLjwvYXV0aG9yPjxhdXRob3I+U29saW08L2F1dGhvcj48YXV0
aG9yPm8sIEEuIEcuPC9hdXRob3I+PGF1dGhvcj5EYW1tYWNjbywgRi48L2F1dGhvcj48YXV0aG9y
PlJpYSwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5S
LiBSaWEsIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUgYW5kIENsaW5pY2FsIE9uY29s
b2d5LCBVbml2ZXJzaXR5IG9mIEJhcmkg4oCcQWxkbyBNb3Jv4oCdIE1lZGljYWwgU2Nob29sLCBQ
b2xpY2xpbmljbyDigJMgUGlhenphIEdpdWxpbyBDZXNhcmUsIDExLCBCYXJpLCBJdGFseTwvYXV0
aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlN1YmN1dGFuZW91cyBpbW11bm9nbG9idWxpbnMgaW4g
cGF0aWVudHMgd2l0aCBtdWx0aXBsZSBteWVsb21hIGFuZCBzZWNvbmRhcnkgaHlwb2dhbW1hZ2xv
YnVsaW5lbWlhOiBhIHJhbmRvbWl6ZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2xp
bmljYWwgSW1tdW5vbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm
dWxsLXRpdGxlPkNsaW5pY2FsIEltbXVub2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw
YWdlcz4xMTAtMTE1PC9wYWdlcz48dm9sdW1lPjE5MTwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29y
ZD5hbnRpaGlzdGFtaW5pYyBhZ2VudDwva2V5d29yZD48a2V5d29yZD5pbW11bm9nbG9idWxpbjwv
a2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmFkdWx0PC9rZXl3b3Jk
PjxrZXl3b3JkPmFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+YXJ0aWNsZTwva2V5d29yZD48a2V5d29y
ZD5jbGluaWNhbCBhcnRpY2xlPC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2xsZWQgc3R1ZHk8L2tl
eXdvcmQ+PGtleXdvcmQ+ZGlzZWFzZSBkdXJhdGlvbjwva2V5d29yZD48a2V5d29yZD5kaXNlYXNl
IHNldmVyaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmZlbWFsZTwva2V5d29yZD48a2V5d29yZD5ob3Nw
aXRhbGl6YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+aW1t
dW5vZ2xvYnVsaW4gZGVmaWNpZW5jeTwva2V5d29yZD48a2V5d29yZD5pbmNpZGVuY2U8L2tleXdv
cmQ+PGtleXdvcmQ+aW5qZWN0aW9uIHNpdGUgaW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk
PmluamVjdGlvbiBzaXRlIHBhaW48L2tleXdvcmQ+PGtleXdvcmQ+bWFsZTwva2V5d29yZD48a2V5
d29yZD5tdWx0aXBsZSBteWVsb21hPC9rZXl3b3JkPjxrZXl3b3JkPnByaW9yaXR5IGpvdXJuYWw8
L2tleXdvcmQ+PGtleXdvcmQ+cXVhbGl0eSBvZiBsaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJhbmRv
bWl6ZWQgY29udHJvbGxlZCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5za2luIGFsbGVyZ3k8L2tl
eXdvcmQ+PGtleXdvcmQ+dHJlYXRtZW50IGR1cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29yZD48
a2V5d29yZD5JbW11bm9nbG9idWxpbiBFPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlu
IEc8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5J
bW11bm9nbG9idWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUg
UmVnaW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT4yMDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMS03MDM1
IDE1MjEtNjYxNjwvaXNibj48YWNjZXNzaW9uLW51bT5yYXl5YW4tNDU4ODE2NzwvYWNjZXNzaW9u
LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9u
dD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cDovL3d3dy5lbWJhc2UuY29tL3NlYXJjaC9yZXN1
bHRzP3N1YmFjdGlvbj12aWV3cmVjb3JkJmFtcDtmcm9tPWV4cG9ydCZhbXA7aWQ9TDYyMDgwOTY5
MDwvc3R5bGU+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+
IDwvc3R5bGU+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAw
JSI+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9qLmNsaW0uMjAxNy4xMS4wMTQ8L3N0eWxlPjwv
dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVTSU9OOiB7JnF1
b3Q7U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20xPjxyZXNlYXJj
aC1ub3Rlcz5NTSAtIFNDSUcgdnMgY29udHJvbHM8L3Jlc2VhcmNoLW5vdGVzPjxsYW5ndWFnZT5F
bmdsaXNoPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh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ADDIN EN.CITE.DATA (2018): 7177.8Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b): NRMusto, Brugiatelli & Carotenuto ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Musto</Author><Year>1995</Year><RecNum>60</RecNum><DisplayText>(1995)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554267573">60</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Musto, P.</author><author>Brugiatelli, M.</author><author>Carotenuto, M.</author></authors></contributors><titles><title>Prophylaxis against infections with intravenous immunoglobulins in multiple myeloma</title><secondary-title>Br J Haematol</secondary-title></titles><periodical><full-title>Br J Haematol</full-title></periodical><dates><year>1995</year></dates><urls></urls><research-notes>MM (pearled) cross-over study IVIG vs no prophylaxis</research-notes></record></Cite></EndNote>(1995): NRVacca et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh
cj4yMDE4PC9ZZWFyPjxSZWNOdW0+MzA8L1JlY051bT48RGlzcGxheVRleHQ+KDIwMTgpPC9EaXNw
bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjMwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+
PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFk
IiB0aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjMwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl
IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv
cnM+PGF1dGhvcj5WYWNjYSwgQS48L2F1dGhvcj48YXV0aG9yPk1lbGFjY2lvLCBBLjwvYXV0aG9y
PjxhdXRob3I+U3BvcnRlbGxpLCBBLjwvYXV0aG9yPjxhdXRob3I+U29saW08L2F1dGhvcj48YXV0
aG9yPm8sIEEuIEcuPC9hdXRob3I+PGF1dGhvcj5EYW1tYWNjbywgRi48L2F1dGhvcj48YXV0aG9y
PlJpYSwgUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5S
LiBSaWEsIERlcGFydG1lbnQgb2YgSW50ZXJuYWwgTWVkaWNpbmUgYW5kIENsaW5pY2FsIE9uY29s
b2d5LCBVbml2ZXJzaXR5IG9mIEJhcmkg4oCcQWxkbyBNb3Jv4oCdIE1lZGljYWwgU2Nob29sLCBQ
b2xpY2xpbmljbyDigJMgUGlhenphIEdpdWxpbyBDZXNhcmUsIDExLCBCYXJpLCBJdGFseTwvYXV0
aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlN1YmN1dGFuZW91cyBpbW11bm9nbG9idWxpbnMgaW4g
cGF0aWVudHMgd2l0aCBtdWx0aXBsZSBteWVsb21hIGFuZCBzZWNvbmRhcnkgaHlwb2dhbW1hZ2xv
YnVsaW5lbWlhOiBhIHJhbmRvbWl6ZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2xp
bmljYWwgSW1tdW5vbG9neTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm
dWxsLXRpdGxlPkNsaW5pY2FsIEltbXVub2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw
YWdlcz4xMTAtMTE1PC9wYWdlcz48dm9sdW1lPjE5MTwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29y
ZD5hbnRpaGlzdGFtaW5pYyBhZ2VudDwva2V5d29yZD48a2V5d29yZD5pbW11bm9nbG9idWxpbjwv
a2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPmFkdWx0PC9rZXl3b3Jk
PjxrZXl3b3JkPmFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+YXJ0aWNsZTwva2V5d29yZD48a2V5d29y
ZD5jbGluaWNhbCBhcnRpY2xlPC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2xsZWQgc3R1ZHk8L2tl
eXdvcmQ+PGtleXdvcmQ+ZGlzZWFzZSBkdXJhdGlvbjwva2V5d29yZD48a2V5d29yZD5kaXNlYXNl
IHNldmVyaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmZlbWFsZTwva2V5d29yZD48a2V5d29yZD5ob3Nw
aXRhbGl6YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+aW1t
dW5vZ2xvYnVsaW4gZGVmaWNpZW5jeTwva2V5d29yZD48a2V5d29yZD5pbmNpZGVuY2U8L2tleXdv
cmQ+PGtleXdvcmQ+aW5qZWN0aW9uIHNpdGUgaW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk
PmluamVjdGlvbiBzaXRlIHBhaW48L2tleXdvcmQ+PGtleXdvcmQ+bWFsZTwva2V5d29yZD48a2V5
d29yZD5tdWx0aXBsZSBteWVsb21hPC9rZXl3b3JkPjxrZXl3b3JkPnByaW9yaXR5IGpvdXJuYWw8
L2tleXdvcmQ+PGtleXdvcmQ+cXVhbGl0eSBvZiBsaWZlPC9rZXl3b3JkPjxrZXl3b3JkPnJhbmRv
bWl6ZWQgY29udHJvbGxlZCB0cmlhbDwva2V5d29yZD48a2V5d29yZD5za2luIGFsbGVyZ3k8L2tl
eXdvcmQ+PGtleXdvcmQ+dHJlYXRtZW50IGR1cmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29yZD48
a2V5d29yZD5JbW11bm9nbG9idWxpbiBFPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlu
IEc8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5J
bW11bm9nbG9idWxpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUg
UmVnaW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT4yMDE4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyMS03MDM1
IDE1MjEtNjYxNjwvaXNibj48YWNjZXNzaW9uLW51bT5yYXl5YW4tNDU4ODE2NzwvYWNjZXNzaW9u
LW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9u
dD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+aHR0cDovL3d3dy5lbWJhc2UuY29tL3NlYXJjaC9yZXN1
bHRzP3N1YmFjdGlvbj12aWV3cmVjb3JkJmFtcDtmcm9tPWV4cG9ydCZhbXA7aWQ9TDYyMDgwOTY5
MDwvc3R5bGU+PHN0eWxlIGZhY2U9Im5vcm1hbCIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+
IDwvc3R5bGU+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAw
JSI+aHR0cDovL2R4LmRvaS5vcmcvMTAuMTAxNi9qLmNsaW0uMjAxNy4xMS4wMTQ8L3N0eWxlPjwv
dXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVTSU9OOiB7JnF1
b3Q7U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20xPjxyZXNlYXJj
aC1ub3Rlcz5NTSAtIFNDSUcgdnMgY29udHJvbHM8L3Jlc2VhcmNoLW5vdGVzPjxsYW5ndWFnZT5F
bmdsaXNoPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
ADDIN EN.CITE.DATA (2018): NRNHL68.3Chapel et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(1991): NR76.3Chapel et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(1991): NROther HM54.7-67.1-Post-HSCT42.0Sullivan et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE.DATA (1990): NR63.6Sullivan et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE.DATA (1990): NROverall66.5-75.0-CLL = chronic lymphocytic leukaemia; HM = haematological malignancy; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin lymphoma.a Based on Version 2 data collected for the whole financial year, 2017-18 from the ‘HTA Data April2019.xlsx’ workbook provided by the NBA. Patient demographics in the studies were generally not well reported ( REF _Ref10549632 \h Table 30). Mean ages were only reported in three of the six studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1994b; Molica et al. 1996; Vacca et al. 2018), while mean weights were not reported in any of the randomised studies. While MM patients were generally consistent with the average ages of patients in Australia who currently receive Ig for acquired hypogammaglobulinaemia, CLL patients in the clinical evidence may have been slightly younger. Similar trends with respect to average ages were observed in the before/after non-randomised evidence identified in Section B (see REF _Ref14353333 \h Table 80 and REF _Ref14353338 \h Table 81, REF _Ref421017583 \h \* MERGEFORMAT Appendix D). One non-randomised study reported patient weights PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
PFJlY051bT4zNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR8O8bnRoZXIgJmFtcDsgRHJlZ2VyIDIw
MTMpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDll
MnIycGQydGFkIiB0aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjM0PC9rZXk+PC9mb3JlaWduLWtleXM+
PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv
cnM+PGF1dGhvcnM+PGF1dGhvcj5Hw7xudGhlciwgRy48L2F1dGhvcj48YXV0aG9yPkRyZWdlciwg
Qi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NZWRpY2Fs
IENhcmUgQ2VudGVyIGZvciBCbG9vZCBhbmQgQ2FuY2VyIERpc2Vhc2VzLCBQb3RzZGFtLCBHZXJt
YW55LiBkci5nZW9yZ19ndWVudGhlckB0LW9ubGluZS5kZTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+
PHRpdGxlPlBvc3QtbWFya2V0aW5nIG9ic2VydmF0aW9uYWwgc3R1ZHkgb24gNSUgaW50cmF2ZW5v
dXMgaW1tdW5vZ2xvYnVsaW4gdGhlcmFweSBpbiBwYXRpZW50cyB3aXRoIHNlY29uZGFyeSBpbW11
bm9kZWZpY2llbmN5IGFuZCByZWN1cnJlbnQgc2VyaW91cyBiYWN0ZXJpYWwgaW5mZWN0aW9uczwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5NaWNyb2Jpb2wgSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk1pY3JvYmlvbCBJbW11bm9sPC9mdWxs
LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTI3LTM1PC9wYWdlcz48dm9sdW1lPjU3PC92b2x1
bWU+PG51bWJlcj43PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIEluZmVjdGlvbnMvIHRoZXJh
cHk8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1
Zy1SZWxhdGVkIFNpZGUgRWZmZWN0cyBhbmQgQWR2ZXJzZSBSZWFjdGlvbnMvZXBpZGVtaW9sb2d5
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZW1hdG9sb2dpYyBO
ZW9wbGFzbXMvY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnMsIEludHJhdmVub3VzL2FkdmVyc2UgZWZmZWN0cy8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2xvZ2ljIERlZmljaWVuY3kgU3luZHJvbWVzLyBjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb2R1Y3Qg
U3VydmVpbGxhbmNlLCBQb3N0bWFya2V0aW5nPC9rZXl3b3JkPjxrZXl3b3JkPlNlY29uZGFyeSBQ
cmV2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxr
ZXl3b3JkPmNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWE8L2tleXdvcmQ+PGtleXdvcmQ+aW50
cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PGtleXdvcmQ+cmVjdXJyZW50IGluZmVj
dGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+c2Vjb25kYXJ5IGltbXVub2RlZmljaWVuY3k8L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5pemF0aW9uLCBQYXNzaXZlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdv
cmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBNPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v
Z2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxr
ZXl3b3JkPlJlY3VycmVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjEzNDgtMDQyMSAoRWxlY3Ryb25pYykgMDM4NS01NjAwIChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4yMzYwNzg2MzwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+UkFZ
WUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90O0luY2x1ZGVkJnF1b3Q7
fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+Q0xMLCBOSEwsIElnTS1zZWNyZXRpbmcgaW1tdW5v
Y3l0b21hLCBJZ0EgcGxhc21hIGN5dG9tYSwgTXllbG9keXNwbGFzdGljIHN5bmRyb21lL05ITC4g
QmVmb3JlIGFuZCBhZnRlciBjb21wYXJpc29uPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5n
PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
PFJlY051bT4zNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR8O8bnRoZXIgJmFtcDsgRHJlZ2VyIDIw
MTMpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDll
MnIycGQydGFkIiB0aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjM0PC9rZXk+PC9mb3JlaWduLWtleXM+
PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv
cnM+PGF1dGhvcnM+PGF1dGhvcj5Hw7xudGhlciwgRy48L2F1dGhvcj48YXV0aG9yPkRyZWdlciwg
Qi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NZWRpY2Fs
IENhcmUgQ2VudGVyIGZvciBCbG9vZCBhbmQgQ2FuY2VyIERpc2Vhc2VzLCBQb3RzZGFtLCBHZXJt
YW55LiBkci5nZW9yZ19ndWVudGhlckB0LW9ubGluZS5kZTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+
PHRpdGxlPlBvc3QtbWFya2V0aW5nIG9ic2VydmF0aW9uYWwgc3R1ZHkgb24gNSUgaW50cmF2ZW5v
dXMgaW1tdW5vZ2xvYnVsaW4gdGhlcmFweSBpbiBwYXRpZW50cyB3aXRoIHNlY29uZGFyeSBpbW11
bm9kZWZpY2llbmN5IGFuZCByZWN1cnJlbnQgc2VyaW91cyBiYWN0ZXJpYWwgaW5mZWN0aW9uczwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5NaWNyb2Jpb2wgSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk1pY3JvYmlvbCBJbW11bm9sPC9mdWxs
LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTI3LTM1PC9wYWdlcz48dm9sdW1lPjU3PC92b2x1
bWU+PG51bWJlcj43PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIEluZmVjdGlvbnMvIHRoZXJh
cHk8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1
Zy1SZWxhdGVkIFNpZGUgRWZmZWN0cyBhbmQgQWR2ZXJzZSBSZWFjdGlvbnMvZXBpZGVtaW9sb2d5
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZW1hdG9sb2dpYyBO
ZW9wbGFzbXMvY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnMsIEludHJhdmVub3VzL2FkdmVyc2UgZWZmZWN0cy8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2xvZ2ljIERlZmljaWVuY3kgU3luZHJvbWVzLyBjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb2R1Y3Qg
U3VydmVpbGxhbmNlLCBQb3N0bWFya2V0aW5nPC9rZXl3b3JkPjxrZXl3b3JkPlNlY29uZGFyeSBQ
cmV2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxr
ZXl3b3JkPmNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWE8L2tleXdvcmQ+PGtleXdvcmQ+aW50
cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PGtleXdvcmQ+cmVjdXJyZW50IGluZmVj
dGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+c2Vjb25kYXJ5IGltbXVub2RlZmljaWVuY3k8L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5pemF0aW9uLCBQYXNzaXZlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdv
cmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBNPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v
Z2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxr
ZXl3b3JkPlJlY3VycmVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjEzNDgtMDQyMSAoRWxlY3Ryb25pYykgMDM4NS01NjAwIChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4yMzYwNzg2MzwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+UkFZ
WUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90O0luY2x1ZGVkJnF1b3Q7
fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+Q0xMLCBOSEwsIElnTS1zZWNyZXRpbmcgaW1tdW5v
Y3l0b21hLCBJZ0EgcGxhc21hIGN5dG9tYSwgTXllbG9keXNwbGFzdGljIHN5bmRyb21lL05ITC4g
QmVmb3JlIGFuZCBhZnRlciBjb21wYXJpc29uPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5n
PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Günther & Dreger 2013) in a mixed, though predominantly CLL, population of 77?kg (which is consistent with the CLL patients in BloodSTAR). The randomised studies were all conducted in either the UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1991; Chapel et al. 1994b), Italy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xpY2E8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Molica et al. 1996; Musto, Brugiatelli & Carotenuto 1995; Vacca et al. 2018) or the US PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+
PFJlY051bT42NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oU3VsbGl2YW4gZXQgYWwuIDE5OTApPC9E
aXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjY3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl
eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQy
dGFkIiB0aW1lc3RhbXA9IjE1NTQ3ODgxNjAiPjY3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10
eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1
dGhvcnM+PGF1dGhvcj5TdWxsaXZhbiwgSy4gTS48L2F1dGhvcj48YXV0aG9yPktvcGVja3ksIEsu
IEouPC9hdXRob3I+PGF1dGhvcj5Kb2NvbSwgSi48L2F1dGhvcj48YXV0aG9yPkZpc2hlciwgTC48
L2F1dGhvcj48YXV0aG9yPkJ1Y2tuZXIsIEMuIEQuPC9hdXRob3I+PGF1dGhvcj5NZXllcnMsIEou
IEQuPC9hdXRob3I+PGF1dGhvcj5Db3VudHMsIEcuIFcuPC9hdXRob3I+PGF1dGhvcj5Cb3dkZW4s
IFIuIEEuPC9hdXRob3I+PGF1dGhvcj5QZXRlcnNvbiwgRi4gQi48L2F1dGhvcj48YXV0aG9yPldp
dGhlcnNwb29uLCBSLiBQLjwvYXV0aG9yPjxhdXRob3I+ZXQgYWwuLDwvYXV0aG9yPjwvYXV0aG9y
cz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyZWQgSHV0Y2hpbnNvbiBDYW5jZXIgUmVz
ZWFyY2ggQ2VudGVyLCBTZWF0dGxlLCBXQSA5ODEwNC48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0
aXRsZT5JbW11bm9tb2R1bGF0b3J5IGFuZCBhbnRpbWljcm9iaWFsIGVmZmljYWN5IG9mIGludHJh
dmVub3VzIGltbXVub2dsb2J1bGluIGluIGJvbmUgbWFycm93IHRyYW5zcGxhbnRhdGlvbjwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5OIEVuZ2wgSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl
cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJp
b2RpY2FsPjxwYWdlcz43MDUtMTI8L3BhZ2VzPjx2b2x1bWU+MzIzPC92b2x1bWU+PG51bWJlcj4x
MTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5Cb25l
IE1hcnJvdyBUcmFuc3BsYW50YXRpb24vKmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29y
ZD5DeXRvbWVnYWxvdmlydXMgSW5mZWN0aW9ucy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk
PkdyYWZ0IHZzIEhvc3QgRGlzZWFzZS8qcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3Jk
PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bml6YXRpb24sIFBhc3NpdmU8
L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLyphZG1pbmlzdHJhdGlvbiAmYW1wOyBk
b3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+KkluZmVjdGlvbiBDb250cm9sPC9rZXl3b3JkPjxrZXl3
b3JkPkluZnVzaW9ucywgSW50cmF2ZW5vdXM8L2tleXdvcmQ+PGtleXdvcmQ+TmVvcGxhc21zL3Ro
ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+UG9zdG9wZXJhdGl2ZSBDb21wbGljYXRpb25zL3ByZXZl
bnRpb24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QdWxtb25hcnkgRmlicm9zaXMv
cHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlJhbmRvbWl6ZWQgQ29u
dHJvbGxlZCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+U2Vwc2lzL3ByZXZlbnRp
b24gJmFtcDsgY29udHJvbDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTkwPC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDEzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlz
Ym4+MDAyOC00NzkzIChQcmludCkmI3hEOzAwMjgtNDc5MyAoTGlua2luZyk8L2lzYm4+PGFjY2Vz
c2lvbi1udW0+MjE2NzQ1MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+
aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjE2NzQ1MjwvdXJsPjwvcmVsYXRl
ZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNMTk5MDA5
MTMzMjMxMTAzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmRO
b3RlPn==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1990). However, only one of the studies had been conducted in the previous 20 years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYWNjYTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Vacca et al. 2018). One non-randomised study, Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll
YXI+MjAxNjwvWWVhcj48UmVjTnVtPjY2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigyMDE2KTwvRGlz
cGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj42NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz
PjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJyMnBkMnRh
ZCIgdGltZXN0YW1wPSIxNTU0NDM3MzM5Ij42Njwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9
IiI+MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi
PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGF4dG9uLCBMLjwv
YXV0aG9yPjxhdXRob3I+SGF3a2lucywgQy48L2F1dGhvcj48YXV0aG9yPkNyaXNwaW4sIFAuPC9h
dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QXVzdHJhbGlhbiBO
YXRpb25hbCBVbml2ZXJzaXR5IE1lZGljYWwgU2Nob29sLCBDYW5iZXJyYSwgQXVzdHJhbGlhLiYj
eEQ7RGVwYXJ0bWVudCBvZiBJbW11bm9sb2d5LCBDYW5iZXJyYSBIb3NwaXRhbCwgQ2FuYmVycmEs
IEF1c3RyYWxpYS4mI3hEO0F1c3RyYWxpYW4gTmF0aW9uYWwgVW5pdmVyc2l0eSBNZWRpY2FsIFNj
aG9vbCwgQ2FuYmVycmEsIEF1c3RyYWxpYS4gcGhpbGlwLmNyaXNwaW5AYWN0Lmdvdi5hdS4mI3hE
O0RlcGFydG1lbnQgb2YgSGFlbWF0b2xvZ3ksIENhbmJlcnJhIEhvc3BpdGFsLCBDYW5iZXJyYSwg
QXVzdHJhbGlhLiBwaGlsaXAuY3Jpc3BpbkBhY3QuZ292LmF1LjwvYXV0aC1hZGRyZXNzPjx0aXRs
ZXM+PHRpdGxlPlNlbGVjdGluZyBoYWVtYXRvbG9naWNhbCBtYWxpZ25hbmN5IHBhdGllbnRzIGZv
ciBpbnRyYXZlbm91cyBpbW11bm9nbG9idWxpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5JbnRl
cm4gTWVkIEo8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs
ZT5JbnRlcm4gTWVkIEo8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjE2LTEyMTg8
L3BhZ2VzPjx2b2x1bWU+NDY8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGtleXdvcmRzPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+
PGtleXdvcmQ+QXVzdHJhbGlhPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5
d29yZD5IZW1hdG9sb2dpYyBOZW9wbGFzbXMvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVt
YW5zPC9rZXl3b3JkPjxrZXl3b3JkPipJbW11bml6YXRpb24sIFBhc3NpdmU8L2tleXdvcmQ+PGtl
eXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLCBJbnRyYXZlbm91cy8qYWRtaW5pc3RyYXRpb24gJmFtcDsg
ZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkxpbmVhciBNb2RlbHM8L2tleXdvcmQ+PGtleXdvcmQ+
TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5SZXRy
b3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+aGFlbWF0b2xvZ2ljYWwgbWFsaWdu
YW5jeTwva2V5d29yZD48a2V5d29yZD5pbmZlY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+aW50cmF2
ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx
NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp
c2JuPjE0NDUtNTk5NCAoRWxlY3Ryb25pYykmI3hEOzE0NDQtMDkwMyAoTGlua2luZyk8L2lzYm4+
PGFjY2Vzc2lvbi1udW0+Mjc3MzQ2MjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs
cz48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUi
Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3NzM0NjIwPC9zdHlsZT48L3Vy
bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEv
aW1qLjEzMjA1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVzZWFyY2gtbm90ZXM+TWl4ZWQg
cG9wLiBib3RoIGJlZm9yZSBhbmQgYWZ0ZXIgY2FzZSBzZXJpZXMgYW5kIHJldHJvc3BlY3RpdmUg
Y29ob3J0LiAoZm91bmQgdGhyb3VnaCBnb29nbGluZyk8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3Jk
PjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016), was conducted in Australia, and another in the UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE.DATA (Duraisingham et al. 2014). Others were conducted in the US, Europe and Israel. More of the non-randomised studies were conducted in the contemporary setting PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZW5icmFoaW08L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy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ADDIN EN.CITE.DATA (Benbrahim et al. 2019; Dimou et al. 2018; Duraisingham et al. 2014; Günther & Dreger 2013; Paxton, Hawkins & Crispin 2016; Reiser et al. 2017; Van Winkle et al. 2018). Contemporary studies, which were predominantly non-randomised, tended to enrol patients with mixed haematological malignancies.It is unclear what impact these differences would have, if any, on baseline infection rates and the relative treatment effect of Ig. It is conceivable that changes in contemporary practice could decrease the absolute numbers of infections with or without Ig, which would likely increase the ICER. The implications of this on the relative treatment effect of Ig are unknown, however the treatment effect was observed to be reasonably consistent in the older and newer studies (both randomised and non-randomised before/after studies). Therefore the more recent Australian data from a mixed haematological malignancy population PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXh0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Paxton, Hawkins & Crispin 2016) will be used to approximate the baseline infection rate in the absence of Ig, and the pooled risk reductions estimated in Section B will be applied to the baseline infection rate in order to model the treatment effect of Ig. C.2.2.Antibiotic use in the absence of IgThe aim of this translation study is to determine how antibiotics were used in the absence of Ig in the clinical evidence, and whether this is reflective of what would happen in the absence of Ig in the contemporary setting. Antibiotic use in the ‘No Ig’ arms of the randomised evidence will be reviewed and compared to what would happen in Australian clinical practice in the absence of Ig.Prophylactic antibiotic use was generally not allowed in the randomised evidence presented in Section B PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1994b; Molica et al. 1996; Musto, Brugiatelli & Carotenuto 1995; Vacca et al. 2018). One study did not report whether antibiotic use was allowed ADDIN EN.CITE <EndNote><Cite><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(Chapel et al. 1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(Chapel et al. 1991), and the study in patients undergoing HSCT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTA8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1990) required prophylactic co-trimoxazole for the first 120 days post-transplant in both trial arms. One of the non-randomised studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE.DATA (Duraisingham et al. 2014) reported that prior to Ig initiation 12 of 15 (80%) patients with hypogammaglobulinaemia secondary to a haematological malignancy were on prophylactic antibiotics, whereas after the initiation of Ig replacement this reduced to 10 (67%) patients. A substantial decrease in the number of serious and non-serious infections was observed after Ig initiation ( REF _Ref10797453 \h Table 31). It is noted though that this study was conducted in the UK where guidelines require a trial of prophylactic antibiotics before considering Ig replacement, and that this is not a requirement in Australia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE.DATA (Wong et al. 2019). Table SEQ Table \* ARABIC 31Analysis of prophylactic antibiotic use and infection outcomes from Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE.DATA (2014)Before IgAfter IgProportion of patients on prophylactic antibiotics in HM subset12/15 (80%)10/15 (67%)No. serious infections in HM subset113Serious infection rate0.90.2No. non-serious infections in HM subset3721Non-serious infection rate3.11.4HM = haematological malignancy; Ig = immunoglobulin.Source: Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE.DATA (2014), supplemental dataIt is unclear what would occur in Australian clinical practice in the absence of Ig. A survey of Australian clinicians experienced in the care of patients with acquired hypogammaglobulinaemia indicated that only 3% of clinicians would routinely trial prophylactic antibiotics before initiating Ig replacement therapy, with a further 17% indicating that they would trial prophylactic antibiotics in certain situations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE.DATA (Wong et al. 2019). However this study was conducted in the setting where Ig is available, and rates of antibiotic prophylaxis may differ in the setting where Ig is not available, which may have implications for the relative treatment effect of Ig. While the results from the Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo
b3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PigyMDE0
KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJy
MnBkMnRhZCIgdGltZXN0YW1wPSIxNTUzODI1MDU5Ij4yMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxy
ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz
PjxhdXRob3JzPjxhdXRob3I+RHVyYWlzaW5naGFtLCBTLiBTLjwvYXV0aG9yPjxhdXRob3I+QnVj
a2w8L2F1dGhvcj48YXV0aG9yPiwgTS48L2F1dGhvcj48YXV0aG9yPkRlbXBzdGVyLCBKLjwvYXV0
aG9yPjxhdXRob3I+TG9yZW56bywgTC48L2F1dGhvcj48YXV0aG9yPkdyaWdvcmlhZG91LCBTLjwv
YXV0aG9yPjxhdXRob3I+TG9uZ2h1cnN0LCBILiBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy
aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkltbXVub2xvZ3kgRGVwYXJ0bWVudCwgQmFydHMgSGVhbHRo
IE5IUyBUcnVzdCwgTG9uZG9uLCBVbml0ZWQgS2luZ2RvbS48L2F1dGgtYWRkcmVzcz48dGl0bGVz
Pjx0aXRsZT5QcmltYXJ5IHZzLiBzZWNvbmRhcnkgYW50aWJvZHkgZGVmaWNpZW5jeTogY2xpbmlj
YWwgZmVhdHVyZXMgYW5kIGluZmVjdGlvbiBvdXRjb21lcyBvZiBpbW11bm9nbG9idWxpbiByZXBs
YWNlbWVudDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TIE9uZTwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRpdGxlPjwv
cGVyaW9kaWNhbD48cGFnZXM+ZTEwMDMyNDwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+PG51bWJl
cj42PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdv
cmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdhbW1hZ2xvYnVsaW5lbWlhL2NvbXBsaWNhdGlv
bnMvIGRpYWdub3Npcy8gZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48
a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpZWN0YXNp
cy9kaWFnbm9zaXMvZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+RGVsYXllZCBEaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxp
bnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1cHByZXNzaXZlIEFn
ZW50cy9hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mZWN0aW9uL2V0aW9sb2d5
L3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg
QWdlZDwva2V5d29yZD48a2V5d29yZD5QYXRpZW50IE91dGNvbWUgQXNzZXNzbWVudDwva2V5d29y
ZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5Zb3VuZyBBZHVs
dDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxrZXl3b3JkPklt
bXVub2dsb2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBBPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1
bGluIEU8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVnaW9uPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl
cz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxNDwvZGF0ZT48L3B1Yi1kYXRl
cz48L2RhdGVzPjxpc2JuPjE5MzItNjIwMyAoRWxlY3Ryb25pYykgMTkzMi02MjAzIChMaW5raW5n
KTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDk3MTY0NDwvYWNjZXNzaW9uLW51bT48dXJscz48L3Vy
bHM+PGN1c3RvbTE+UkFZWUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90
O0luY2x1ZGVkJnF1b3Q7fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+WCAtIG1vc3Qgb2YgdGhl
IHNlY29uZGFyeSBIeXBvR0cgZHVlIHRvIGNoZW1vIHdpdGggUlRYIC4gd3JvbmcgcG9wPC9yZXNl
YXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmRO
b3RlPgB=
ADDIN EN.CITE.DATA (2014) study are supportive of a benefit of similar magnitude for Ig irrespective of whether prophylactic antibiotics are used in the comparator, due to the inherent biases associated with the small patient numbers and study design, this is not conclusive. An Australian RCT comparing antibiotic prophylaxis to Ig in acquired hypogammaglobulinaemia (Australian New Zealand Clinical Trials Registry no. ACTRN12616001723471) is currently ongoing and aims to address this question. In the absence of alternative evidence to i) suggest that rates of antibiotic prophylaxis would increase in the absence of Ig (given that randomised trials, including one contemporary trial, did not allow antibiotic prophylaxis; or where allowed, use was equal irrespective of Ig use); and ii) that this increase in antibiotic use would affect the relative treatment effect of Ig (given that this comparison is currently being explored and the one non-randomised study identified showed a consistent effect despite prophylactic antibiotic use), the economic analysis will assume no increase in prophylactic antibiotic use relative to that in the Ig arm of the model – and so the relative treatment effect observed in the randomised studies is assumed to apply to the current setting. However a scenario analysis based on the results from the Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo
b3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PigyMDE0
KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJy
MnBkMnRhZCIgdGltZXN0YW1wPSIxNTUzODI1MDU5Ij4yMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxy
ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz
PjxhdXRob3JzPjxhdXRob3I+RHVyYWlzaW5naGFtLCBTLiBTLjwvYXV0aG9yPjxhdXRob3I+QnVj
a2w8L2F1dGhvcj48YXV0aG9yPiwgTS48L2F1dGhvcj48YXV0aG9yPkRlbXBzdGVyLCBKLjwvYXV0
aG9yPjxhdXRob3I+TG9yZW56bywgTC48L2F1dGhvcj48YXV0aG9yPkdyaWdvcmlhZG91LCBTLjwv
YXV0aG9yPjxhdXRob3I+TG9uZ2h1cnN0LCBILiBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy
aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkltbXVub2xvZ3kgRGVwYXJ0bWVudCwgQmFydHMgSGVhbHRo
IE5IUyBUcnVzdCwgTG9uZG9uLCBVbml0ZWQgS2luZ2RvbS48L2F1dGgtYWRkcmVzcz48dGl0bGVz
Pjx0aXRsZT5QcmltYXJ5IHZzLiBzZWNvbmRhcnkgYW50aWJvZHkgZGVmaWNpZW5jeTogY2xpbmlj
YWwgZmVhdHVyZXMgYW5kIGluZmVjdGlvbiBvdXRjb21lcyBvZiBpbW11bm9nbG9idWxpbiByZXBs
YWNlbWVudDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TIE9uZTwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRpdGxlPjwv
cGVyaW9kaWNhbD48cGFnZXM+ZTEwMDMyNDwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+PG51bWJl
cj42PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdv
cmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdhbW1hZ2xvYnVsaW5lbWlhL2NvbXBsaWNhdGlv
bnMvIGRpYWdub3Npcy8gZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48
a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpZWN0YXNp
cy9kaWFnbm9zaXMvZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+RGVsYXllZCBEaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxp
bnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1cHByZXNzaXZlIEFn
ZW50cy9hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mZWN0aW9uL2V0aW9sb2d5
L3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg
QWdlZDwva2V5d29yZD48a2V5d29yZD5QYXRpZW50IE91dGNvbWUgQXNzZXNzbWVudDwva2V5d29y
ZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5Zb3VuZyBBZHVs
dDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxrZXl3b3JkPklt
bXVub2dsb2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBBPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1
bGluIEU8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVnaW9uPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl
cz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxNDwvZGF0ZT48L3B1Yi1kYXRl
cz48L2RhdGVzPjxpc2JuPjE5MzItNjIwMyAoRWxlY3Ryb25pYykgMTkzMi02MjAzIChMaW5raW5n
KTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDk3MTY0NDwvYWNjZXNzaW9uLW51bT48dXJscz48L3Vy
bHM+PGN1c3RvbTE+UkFZWUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90
O0luY2x1ZGVkJnF1b3Q7fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+WCAtIG1vc3Qgb2YgdGhl
IHNlY29uZGFyeSBIeXBvR0cgZHVlIHRvIGNoZW1vIHdpdGggUlRYIC4gd3JvbmcgcG9wPC9yZXNl
YXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmRO
b3RlPgB=
ADDIN EN.CITE.DATA (2014) study, including the cost of prophylactic antibiotics and observed treatment effect, will be presented.C.2.3.Dose of IgThe third translation study presented aims to determine how the doses used in the clinical evidence compare to those currently dispensed in the Australian population that receives Ig for acquired hypogammaglobulinaemia. BloodSTAR data are used to inform the average dose in current practice, and will be compared to the doses reported in the clinical evidence. The Version 3 criteria suggest doses of 0.4?g/kg every 4 weeks or more frequently to achieve targeted IgG trough levels. However it is also specified that the lowest dose possible that achieves the appropriate clinical outcome should be used. A comparison of the average doses dispensed per episode of treatment as reported in the BloodSTAR data to the doses used in the clinical evidence are presented in REF _Ref10554693 \h Table 32. Table SEQ Table \* ARABIC 32A comparison of the doses dispensed in the Australian population that receives Ig for acquired hypogammaglobulinaemia to that used in the clinical evidenceIg doseBloodSTAR data aSection B studiesCLL0.37?g/kgChapel et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Chapel</Author><Year>1991</Year><RecNum>32</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chapel, H. M.</author><author>Griffiths, H.</author><author>Brennan, V.</author><author>Bunch, C.</author><author>Lea, J.</author><author>Lee, M.</author></authors></contributors><titles><title>Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy</title><secondary-title>Immunological investigations</secondary-title></titles><periodical><full-title>Immunological investigations</full-title></periodical><pages>187‐191</pages><volume>20</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications, *therapy]</keyword><keyword>Bacterial Infections [etiology, *prevention & control]</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G [therapeutic use]</keyword><keyword>Immunotherapy</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [complications]</keyword><keyword>Lymphoma, Non‐Hodgkin [complications]</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00077281</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>CLL and NHL IVIg vs saline</research-notes></record></Cite></EndNote>(1991): 0.4?g/kg q3wMolica et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TW9saWNhPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+TW9saWNhPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (1996): 0.3?g/kg q4wMM0.37?g/kgChapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b): 0.4?g/kg q4wMusto, Brugiatelli & Carotenuto ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Musto</Author><Year>1995</Year><RecNum>60</RecNum><DisplayText>(1995)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554267573">60</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Musto, P.</author><author>Brugiatelli, M.</author><author>Carotenuto, M.</author></authors></contributors><titles><title>Prophylaxis against infections with intravenous immunoglobulins in multiple myeloma</title><secondary-title>Br J Haematol</secondary-title></titles><periodical><full-title>Br J Haematol</full-title></periodical><dates><year>1995</year></dates><urls></urls><research-notes>MM (pearled) cross-over study IVIG vs no prophylaxis</research-notes></record></Cite></EndNote>(1995): 0.3?g/kg q4wVacca et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh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ADDIN EN.CITE.DATA (2018) (SCIg): 4 weekly infusions to give a total dose of 0.4–0.8?g/kg/monthNHL0.36?g/kg-Other HM0.38?g/kg-Post-HSCT0.37?g/kgSullivan et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE.DATA (1990): 0.5?g/kg/week for first three months, then monthlyWeighted average0.37?g/kg-CLL = chronic lymphocytic leukaemia; HM = haematological malignancy; HSCT = hematopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin lymphoma.a Based on Version 2 data collected for the whole financial year, 2017-18 from the ‘HTA Data April2019.xlsx’ workbook provided by the NBA. The doses used in the randomised evidence varied from 0.3?g/kg to 0.8?g/kg every three to four weeks, which was similar to the average doses observed in the BloodSTAR data (0.36?0.38?g/kg). The non-randomised before/after studies were also generally consistent with these doses and frequencies (see REF _Ref14353333 \h Table 80 and REF _Ref14353338 \h Table 81, REF _Ref421017583 \h \* MERGEFORMAT Appendix D). Despite variations in the doses used in each of the studies, the relative treatment effect of Ig was observed to be reasonably consistent (see Section B.6). Given the experience in use with Ig in current practice, it will be assumed that current dosing is appropriate to achieve the clinical outcome of preventing infections, and so the economic analysis will use actual doses from the BloodSTAR data under the assumption that this has no effect on the relative treatment effect of Ig as observed in the trials. This is further supported by the similar doses used in the studies compared to current practice and that consistency was observed in the treatment effect across the included studies, in spite of variations in dose. A sensitivity analysis is presented assuming the recommended dose of 0.4?g/kg every 4 weeks.C.2.4.Duration of Ig treatmentThe final applicability translation issue aims to determine what the duration of Ig treatment was in the clinical evidence, and how this compares to use in the current Australian population. Duration in the clinical evidence will be reviewed and compared against evidence to suggest what treatment durations are in current practice.The randomised evidence most commonly reported an Ig treatment duration of 12 months. This was generally fixed and not conditional on an assessment of treatment response. As a few of the studies had a randomised cross-over design PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1991; Molica et al. 1996; Musto, Brugiatelli & Carotenuto 1995), patients in these studies may have been considered at-risk of infections for two years, rather than just the one year while on Ig. The most recent of the studies, Vacca et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFjY2E8L0F1dGhvcj48WWVh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ADDIN EN.CITE.DATA (2018), specified no maximum treatment duration (or reasons for cessation of Ig other than side effects), and the average was observed to be 18 months. The non-randomised studies included in the clinical evidence reported varied treatment durations. Of the data presented in Australian patients with mixed haematological malignancies, Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016) reported that patients received Ig for a median of 26 months (range: 3?79), and the cohort of patients described in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) had received at least 12 months of IVIg prior to switching to 12 months of SCIg treatment. Treatment durations in other non-randomised studies are summarised below:The small Greek study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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==
ADDIN EN.CITE.DATA (Dimou et al. 2018) (n=13 mixed haematological malignancies) included patients who had been on IVIg for an average of 26.2 months prior to switching to SCIg.A small German study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hw7xudGhlcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
PFJlY051bT4zNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oR8O8bnRoZXIgJmFtcDsgRHJlZ2VyIDIw
MTMpPC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM0PC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDll
MnIycGQydGFkIiB0aW1lc3RhbXA9IjE1NTM4MjUwNjAiPjM0PC9rZXk+PC9mb3JlaWduLWtleXM+
PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRv
cnM+PGF1dGhvcnM+PGF1dGhvcj5Hw7xudGhlciwgRy48L2F1dGhvcj48YXV0aG9yPkRyZWdlciwg
Qi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5NZWRpY2Fs
IENhcmUgQ2VudGVyIGZvciBCbG9vZCBhbmQgQ2FuY2VyIERpc2Vhc2VzLCBQb3RzZGFtLCBHZXJt
YW55LiBkci5nZW9yZ19ndWVudGhlckB0LW9ubGluZS5kZTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+
PHRpdGxlPlBvc3QtbWFya2V0aW5nIG9ic2VydmF0aW9uYWwgc3R1ZHkgb24gNSUgaW50cmF2ZW5v
dXMgaW1tdW5vZ2xvYnVsaW4gdGhlcmFweSBpbiBwYXRpZW50cyB3aXRoIHNlY29uZGFyeSBpbW11
bm9kZWZpY2llbmN5IGFuZCByZWN1cnJlbnQgc2VyaW91cyBiYWN0ZXJpYWwgaW5mZWN0aW9uczwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5NaWNyb2Jpb2wgSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk1pY3JvYmlvbCBJbW11bm9sPC9mdWxs
LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTI3LTM1PC9wYWdlcz48dm9sdW1lPjU3PC92b2x1
bWU+PG51bWJlcj43PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIEluZmVjdGlvbnMvIHRoZXJh
cHk8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1
Zy1SZWxhdGVkIFNpZGUgRWZmZWN0cyBhbmQgQWR2ZXJzZSBSZWFjdGlvbnMvZXBpZGVtaW9sb2d5
PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IZW1hdG9sb2dpYyBO
ZW9wbGFzbXMvY29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+
PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy9ibG9vZDwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbnMsIEludHJhdmVub3VzL2FkdmVyc2UgZWZmZWN0cy8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2xvZ2ljIERlZmljaWVuY3kgU3luZHJvbWVzLyBjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5NYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb2R1Y3Qg
U3VydmVpbGxhbmNlLCBQb3N0bWFya2V0aW5nPC9rZXl3b3JkPjxrZXl3b3JkPlNlY29uZGFyeSBQ
cmV2ZW50aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxr
ZXl3b3JkPmNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWE8L2tleXdvcmQ+PGtleXdvcmQ+aW50
cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PGtleXdvcmQ+cmVjdXJyZW50IGluZmVj
dGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+c2Vjb25kYXJ5IGltbXVub2RlZmljaWVuY3k8L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5pemF0aW9uLCBQYXNzaXZlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdv
cmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBNPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v
Z2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxr
ZXl3b3JkPlJlY3VycmVuY2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjEzNDgtMDQyMSAoRWxlY3Ryb25pYykgMDM4NS01NjAwIChMaW5raW5nKTwvaXNibj48YWNjZXNz
aW9uLW51bT4yMzYwNzg2MzwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+UkFZ
WUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90O0luY2x1ZGVkJnF1b3Q7
fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+Q0xMLCBOSEwsIElnTS1zZWNyZXRpbmcgaW1tdW5v
Y3l0b21hLCBJZ0EgcGxhc21hIGN5dG9tYSwgTXllbG9keXNwbGFzdGljIHN5bmRyb21lL05ITC4g
QmVmb3JlIGFuZCBhZnRlciBjb21wYXJpc29uPC9yZXNlYXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5n
PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA (Günther & Dreger 2013) (n=10 mixed haematological malignancies) reported that patients received treatment on average for 4.5 years.Jurlander et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Jurlander</Author><Year>1995</Year><RecNum>11</RecNum><DisplayText>(1995)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825059">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jurlander, J.</author><author>Geisler, C. H.</author><author>Hansen, M. M.</author></authors></contributors><auth-address>Department of Haematology, Rigshospitalet, State University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low-dose intravenous gammaglobulin</title><secondary-title>Eur J Haematol</secondary-title></titles><periodical><full-title>Eur J Haematol</full-title></periodical><pages>114-8</pages><volume>53</volume><number>2</number><keywords><keyword>Agammaglobulinemia/ complications/ drug therapy</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/blood</keyword><keyword>Immunoglobulins, Intravenous/ therapeutic use</keyword><keyword>Leukemia, Lymphocytic, Chronic, B-Cell/ blood/ complications</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1995</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0902-4441 (Print) 0902-4441 (Linking)</isbn><accession-num>8088382</accession-num><urls></urls><custom1>RAYYAN-INCLUSION: {"Skye"=>"Included"}</custom1><research-notes>CLL before and after case series</research-notes><language>eng</language></record></Cite></EndNote>(1995) (n=15 CLL) reported that Danish patients received an average of 12 months of treatment.A Swedish study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdW5kaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Sundin et al. 2012) (n=26 post-HSCT) reported a median treatment duration of 9 months (range 6?20 months).Finally, a French study conducted by Benbrahim et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmVuYnJhaGltPC9BdXRob3I+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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmVuYnJhaGltPC9BdXRob3I+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=
ADDIN EN.CITE.DATA (2019) (n=160 mixed haematological malignancies) reported a mean exposure to Ig of 8.4 months, though the follow-up period was a maximum of 12 months.Thus the clinical evidence are highly variable with respect to the duration of Ig treatment, and may have limited applicability to the current Australian population that initiates Ig replacement therapy for acquired hypogammaglobulinaemia (as treatment duration across the population that initiates therapy is likely to follow some distribution with a long tail, and that some of these studies may be focussed on those with longer treatment durations, such as Windegger et al. 2019 which required 12 months on IVIg prior to switching to SCIg). The Version 3 criteria do not specify a maximum treatment duration for patients with acquired hypogammaglobulinaemia in Australia. Rather treatment is indicated if there is a demonstrated clinical benefit, and cessation should be considered at least after each 12 months of treatment. BloodSTAR data were not available to inform the average treatment durations of patients who currently receive Ig for acquired hypogammaglobulinaemia. The survey of Australian clinicians PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE.DATA (Wong et al. 2019) indicated quite variable results with regards to the duration of Ig treatment: 21% indicated that they would continue Ig until an AE, 24% indicated a fixed duration (mostly 6 or 12 months – 11% and 8% respectively), 15% indicated they would cease treatment when normal trough levels were achieved and the patient was infection-free, and 34% indicated that decisions were made on a case-by-case basis.The ongoing clinical trial conducted in Australia (ACTRN12616001723471) that compares prophylactic antibiotics to Ig in CLL, MM and NHL allows treatment for 12 months, or until the treating physician determines that the patient should come off the treatment. As patients enrolled in Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016) were not required to have received Ig for a minimum period of time, the treatment duration observed, 26 months, is considered to be most applicable to the current setting and will be assumed in the base case economic analysis. This is also not too dissimilar to the duration at-risk of infections in three of the randomised studies (i.e. those with the cross over design) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFwZWw8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Chapel et al. 1991; Molica et al. 1996; Musto, Brugiatelli & Carotenuto 1995). Extrapolation translation issuesC.3.1.What is the duration of the treatment effect of Ig in patients with acquired hypogammaglobulinaemia?The economic model in Section D will assume that while on Ig therapy, patients are at risk of infections, however after treatment cessation, it will be assumed that no new infections are modelled – in either model arm – after such time.As described in Section C.2.4 above, treatment durations in the randomised trials were generally fixed and not conditional on an assessment of treatment response. The Version 3 criteria do not specify a maximum treatment duration for patients with acquired hypogammaglobulinaemia in Australia, rather treatment is indicated if there is a demonstrated clinical benefit. As Section C.2.4 concluded that an average treatment duration of 26 months would be most applicable it is assumed this also represents the duration of clinical benefit or direct treatment effect of Ig, whereby a different risk of infection is modelled across the Ig treatment and no treatment arms of the model.Since this is beyond the duration of the randomised trial evidence presented in Section B (up to 18 months) this constitutes an extrapolation of treatment administration and benefit beyond the evidenciary time horizons (8?14 months). As there is no evidence to support an ongoing direct treatment effect once Ig treatment is ceased, it is appropriate for transition rates between all ‘off-treatment’ health states to be the same for each arm of the model.Therefore it is only the difference in health state allocation at the end of Ig treatment that results in long-term differences in overall survival and quality of life differences between the study arms.The long term transition probabilities, in the absence of other evidence, assume an ongoing constant per cycle risk, except for disease-adjusted age-specific mortality; these are fully detailed in Section D.4.1.C.3.2.What is the natural history of recurrent infections in patients with acquired hypogammaglobulinaemia?As described in Section C.3.1, while patients are on Ig treatment they are assumed to be at risk of infections, however once Ig treatment has ceased, no new infections are modelled. An extrapolation translation issue is presented to determine whether there are longterm sequelae related to recurrent infections.There is very little published information regarding the long term consequences of recurrent infections in patients with acquired hypogammaglobulinaemia. One narrative review ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2011</Year><RecNum>111</RecNum><DisplayText>(Brown, Baxendale & Floto 2011)</DisplayText><record><rec-number>111</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368134">111</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Brown, J. S.</author><author>Baxendale, H.</author><author>Floto, R. A.</author></authors><secondary-authors><author>Floto, R. A.</author><author>Haworth, C.S.</author></secondary-authors></contributors><titles><title>Immunodeficiencies associated with bronchiectasis</title><secondary-title>European Respiratory Society Monographs: Bronchiectasis</secondary-title></titles><pages>178-191</pages><dates><year>2011</year></dates><isbn>9781849840118
9781849840125</isbn><urls></urls><electronic-resource-num>10.1183/1025448x.10004210</electronic-resource-num></record></Cite></EndNote>(Brown, Baxendale & Floto 2011) was identified which described the association of secondary immune deficiencies with bronchiectasis. In haematological malignancies:“case reports or case series data have described bronchiectasis complicating chemotherapy, acute and chronic leukaemias, myeloma and lymphomas PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWFybmV5PC9BdXRob3I+PFllYXI+MTk3NzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWFybmV5PC9BdXRob3I+PFllYXI+MTk3NzwvWWVhcj48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ADDIN EN.CITE.DATA (Kearney, Kershaw & Stevenson 1977; Knowles, Stanhope & Green 1980; Li et al. 2005; Okada et al. 2004). In particular, due to the combination of prolonged survival and the high frequency of secondary hypogammaglobulinaemia, multiple myeloma and chronic lymphocytic leukaemia (CLL) seem to be relatively commonly associated with bronchiectasis, although the exact incidence has not been reported ADDIN EN.CITE <EndNote><Cite><Author>Knowles</Author><Year>1980</Year><RecNum>114</RecNum><DisplayText>(Knowles, Stanhope & Green 1980)</DisplayText><record><rec-number>114</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368567">114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Knowles, G. K.</author><author>Stanhope, R.</author><author>Green, M.</author></authors></contributors><titles><title>Bronchiectasis complicating chronic lymphatic leukaemia with hypogammaglobulinaemia</title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>217-8</pages><volume>35</volume><number>3</number><keywords><keyword>Agammaglobulinemia/*complications</keyword><keyword>Bronchiectasis/*etiology</keyword><keyword>Humans</keyword><keyword>Leukemia, Lymphoid/*complications</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1980</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0040-6376 (Print)
0040-6376 (Linking)</isbn><accession-num>7385094</accession-num><urls><related-urls><url>;(Knowles, Stanhope & Green 1980). CLL and myeloma patients with proven bronchiectasis and hypogammaglobulinaemia should be assessed for IVIG therapy. Bronchiectasis has also been reported to develop in association with more acute haematological malignancies, perhaps as a consequence of severe lung infections and/or due to the affects of leukaemia or chemotherapy on host immunity ADDIN EN.CITE <EndNote><Cite><Author>Kearney</Author><Year>1977</Year><RecNum>113</RecNum><DisplayText>(Kearney, Kershaw & Stevenson 1977)</DisplayText><record><rec-number>113</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368544">113</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kearney, P. J.</author><author>Kershaw, C. R.</author><author>Stevenson, P. A.</author></authors></contributors><titles><title>Bronchiectasis in acute leukaemia</title><secondary-title>Br Med J</secondary-title></titles><periodical><full-title>Br Med J</full-title></periodical><pages>857-9</pages><volume>2</volume><number>6091</number><keywords><keyword>Bronchiectasis/diagnosis/drug therapy/*etiology</keyword><keyword>Child, Preschool</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Leukemia, Lymphoid/*complications/drug therapy</keyword><keyword>Male</keyword><keyword>Remission, Spontaneous</keyword><keyword>Respiratory Tract Infections/*complications</keyword></keywords><dates><year>1977</year><pub-dates><date>Oct 1</date></pub-dates></dates><isbn>0007-1447 (Print)
0007-1447 (Linking)</isbn><accession-num>270386</accession-num><urls><related-urls><url>;(Kearney, Kershaw & Stevenson 1977). However, there are no precise data on the incidence and rate of progression of bronchiectasis in patients with haematological malignancies.” (Brown, Baxendale & Floto 2011, p185)In post-HSCT:“Haematopoietic stem cell transplantation (HSCT) is associated with an increased incidence of respiratory infections and potentially prolonged defects in cellular and humoral immunity in survivors ADDIN EN.CITE <EndNote><Cite><Author>Parkman</Author><Year>2008</Year><RecNum>116</RecNum><DisplayText>(Parkman 2008)</DisplayText><record><rec-number>116</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368767">116</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parkman, R.</author></authors></contributors><auth-address>Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA. rparkman@chla.usc.edu</auth-address><titles><title>Antigen-specific immunity following hematopoietic stem cell transplantation</title><secondary-title>Blood Cells Mol Dis</secondary-title></titles><periodical><full-title>Blood Cells Mol Dis</full-title></periodical><pages>91-3</pages><volume>40</volume><number>1</number><keywords><keyword>Antigens/*immunology</keyword><keyword>*Hematopoietic Stem Cell Transplantation/methods</keyword><keyword>Histocompatibility</keyword><keyword>Humans</keyword><keyword>Immune System/physiology</keyword><keyword>*Immunity, Cellular</keyword><keyword>Lymphocyte Depletion</keyword><keyword>T-Cell Antigen Receptor Specificity/*immunology</keyword><keyword>Thymus Gland</keyword><keyword>Tissue Donors</keyword></keywords><dates><year>2008</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>1079-9796 (Print)
1079-9796 (Linking)</isbn><accession-num>17870618</accession-num><urls><related-urls><url>;(Parkman 2008). These factors could predispose to bronchiectasis ADDIN EN.CITE <EndNote><Cite><Author>Morehead</Author><Year>1997</Year><RecNum>117</RecNum><DisplayText>(Morehead 1997)</DisplayText><record><rec-number>117</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368808">117</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morehead, R. S.</author></authors></contributors><auth-address>Division of Pulmonary Medicine, Veterans Affairs Medical Center, Lexington, Kentucky, USA.</auth-address><titles><title>Bronchiectasis in bone marrow transplantation</title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>392-3</pages><volume>52</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Bone Marrow Transplantation/*adverse effects</keyword><keyword>Bronchiectasis/*complications/diagnostic imaging/physiopathology</keyword><keyword>Female</keyword><keyword>Graft vs Host Disease/*complications</keyword><keyword>Hematologic Neoplasms/therapy</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Postoperative Complications</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>1997</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0040-6376 (Print)
0040-6376 (Linking)</isbn><accession-num>9196527</accession-num><urls><related-urls><url>;(Morehead 1997) and, in the authors’ experience, serial CT scans after allograft HSCT can demonstrate rapidly developing bronchiectasis over a period of weeks to months. In addition, up to 10% of HSCT allograft recipients will develop bronchiolitis obliterans (the main pulmonary manifestation of graft versus host disease) which precedes the appearance of diffuse bronchiectasis in ~40% of cases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW5uPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW5uPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Gunn et al. 2008; Tanawuttiwat & Harindhanavudhi 2009). Hence, although there are no precise prevalence data on bronchiectasis post-HSCT, it is probably a relatively common complication, especially in allograft recipients. Similarly, patients who develop bronchiolitis obliterans after lung transplantation may also have CT evidence of bronchiectasis ADDIN EN.CITE <EndNote><Cite><Author>de Jong</Author><Year>2006</Year><RecNum>120</RecNum><DisplayText>(de Jong et al. 2006)</DisplayText><record><rec-number>120</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368892">120</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Jong, P. A.</author><author>Dodd, J. D.</author><author>Coxson, H. O.</author><author>Storness-Bliss, C.</author><author>Pare, P. D.</author><author>Mayo, J. R.</author><author>Levy, R. D.</author></authors></contributors><auth-address>Department of Medicine, University of British Columbia, Vancouver, BC, Canada.</auth-address><titles><title>Bronchiolitis obliterans following lung transplantation: early detection using computed tomographic scanning</title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>799-804</pages><volume>61</volume><number>9</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Bronchiolitis Obliterans/*diagnostic imaging</keyword><keyword>Early Diagnosis</keyword><keyword>Humans</keyword><keyword>*Lung Transplantation</keyword><keyword>Middle Aged</keyword><keyword>Observer Variation</keyword><keyword>Postoperative Complications/*diagnostic imaging</keyword><keyword>Tomography, X-Ray Computed/*methods</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0040-6376 (Print)
0040-6376 (Linking)</isbn><accession-num>16670170</accession-num><urls><related-urls><url>;(de Jong et al. 2006), and there are case reports of bronchiectasis developing after transplantation of other solid organs ADDIN EN.CITE <EndNote><Cite><Author>Pijnenburg</Author><Year>2004</Year><RecNum>121</RecNum><DisplayText>(Pijnenburg et al. 2004)</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368912">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pijnenburg, M. W.</author><author>Cransberg, K.</author><author>Wolff, E.</author><author>Bouquet, J.</author><author>Merkus, P. J.</author></authors></contributors><auth-address>Department of Pediatrics, Division of Respiratory Medicine, Erasmus Medical Center/Sophia Children's Hospital, PO Box 2060, 3000 CB Rotterdam, The Netherlands. m.pijnenburg@erasmusmc.nl</auth-address><titles><title>Bronchiectasis in children after renal or liver transplantation: a report of five cases</title><secondary-title>Pediatr Transplant</secondary-title></titles><periodical><full-title>Pediatr Transplant</full-title></periodical><pages>71-4</pages><volume>8</volume><number>1</number><keywords><keyword>Adolescent</keyword><keyword>Bronchiectasis/*chemically induced/physiopathology</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/*adverse effects/therapeutic use</keyword><keyword>*Kidney Transplantation</keyword><keyword>*Liver Transplantation</keyword><keyword>Male</keyword><keyword>Respiratory Function Tests</keyword></keywords><dates><year>2004</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1397-3142 (Print)
1397-3142 (Linking)</isbn><accession-num>15009844</accession-num><urls><related-urls><url>;(Pijnenburg et al. 2004), presumably because of damage caused by intercurrent pneumonias and/or impaired pulmonary immunity due to prolonged immunosuppressive therapy.” (Brown, Baxendale & Floto 2011, p185)While these data cannot enable an estimate of the incidence of bronchiectasis in acquired hypogammaglobulinaemia, they support the premise that reducing recurrent infections due to the use of Ig may reduce the development of bronchiectasis. Furthermore, modelling the development of bronchiectasis is consistent with a recent Australian economic evaluation that compared SCIg to IVIg in this population ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019) (see also Section D.3). As described in Section D.3, the model structure will include health states associated with bronchiectasis in the base case analysis, however the inclusion of these health states are tested in a sensitivity analysis. Transformation issuesC.4.1.Transformation of outcomes into a common, patient-relevant outcomeA transformation pre-modelling study is conducted which aims to transform both the benefits (i.e. a reduction in infections) and any harms associated with Ig treatment into a common measure to allow these opposing effects to be traded-off in the economic evaluation. Quality-adjusted life years (QALYs) are considered to be an appropriate measure for transformation.A review of the economic literature was conducted (see Section D.3) and two relevant cost-utility analyses were identified PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWVrczwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWVrczwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Weeks, Tierney & Weinstein 1991; Windegger et al. 2019). The utility weights used in these studies are reported in REF _Ref14963754 \h Table 33.Table SEQ Table \* ARABIC 33Utility weights used in the relevant economic literatureHealth stateValueWindegger et al. (2019)Utility weight (95% CI)Utility of infection-free0.71 (0.67, 0.75)Utility of infection0.70 (0.63, 0.76)Utility of Bronchiectasis0.64 (0.55, 0.72)Utility of Bronchiectasis with infection0.63 (0.56, 0.70)Utility of Bronchiectasis with chronic P. aeruginosa infection0.63 (0.56, 0.70)Weeks, Tierney & Weinstein (1991)Utility weight (range)Utility of infection-free0.87 (0.50, 0.999)Utility of trivial infectiona0.86 (0.50, 0.999)Utility of moderate infectionb0.81 (0.50, 0.99)Utility of major infectionc0.46 (0.2, 0.90)IVIg infusion0.66 (0.20, 0.99)a Infections such as folliculitis or a paronychiab Infections such as bronchitis or otitis, requiring oral antibiotic therapyc Life-threatening infections, such as pneumonia or septicaemia, requiring parenteral anitbiotics, hospitalisation or both.Source: Table 2, Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) and Table 2, Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991)The utilities reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) were derived from a sample of 84 patients, and included patients who had only received one treatment mode (i.e. IVIg or SCIg), or who had not received 12 months of IVIg prior to switching to SCIg. Utilities were measured using the AQoL-6D instrument, whereas the utilities in Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) were derived from 10 oncologists experienced with the care of CLL. The utility weights as reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) will be preferentially used, as these were derived from an Australian population using a multi attribute utility instrument, rather than being based on clinicians’ assessment. Utilities were also reported for the selected health states used in the model (see Section D.3). However the disutility reported for the infection health state (a decrement of 0.01 relative to infection-free) seems small and on face-value may underestimate the disutility associated with infections, particularly severe infections. Further, as Ig also changes the distribution of infection severity, and reduces those infections that are most severe, the utilities modelled need to be able to capture this difference between the model arms. Therefore the model applies the decrements (relative to infection-free) in Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) for infection severity to the distribution of infection severity (see Section D.4.1), to determine a revised weighted disutility of infection.A utility decrement is also applied in the model to account for reduced quality-of-life associated with infusions. This has been derived from the difference in utility between infection-free and IVIg infusions as reported by Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) to determine a daily disutility associated with infusions. Over the course of a year, 13 infusion days have been estimated, leading to an estimated annual disutility of 0.0075 associated with IVIg infusions every four weeks. As the source data for baseline infection-free utility were based on patients on treatment, this disutility is implicit within the data, and so will be added to the infection-free utility in the No Ig arm of the model. A sensitivity analysis will be presented where this disutility is excluded.AEs in the clinical evidence associated with Ig were generally infusion-related. While AEs related to infusion were frequent, these were generally mild and manageable with adjustments to infusion. Moderate AEs tended to be less frequent and were manageable with dose adjustment, cessation or corticosteroids. None of the included studies reported any AEs greater than Grade 3 severity, nor were there any deaths or anaphylaxis due to Ig. On this basis, no quality-of-life adjustments have been made with respect to AEs related to IVIg infusion.The utility weights used in the model are presented in REF _Ref14963762 \h Table 34.Table SEQ Table \* ARABIC 34Utility weights used in the economic evaluationIgNo IgSourceUtility infection-free0.70730.7073Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Disutility per infusion day0.0006 aWeeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991)No. infusion days per year13 bAnnual disutility due to infusions0.0075Utility in infection-free, including IV infusions0.70730.7148 cDistribution of infection severitySection D.4.1 ? Serious infections, utility decrement 0.4119.1%29.0%Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) ? Non-serious infections, utility decrement 0.0680.9%71.0%Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991)Weighted utility decrement of infections0.12680.1616Utility with infection0.58050.5532Infection-free utility minus the weighted utility decrement of infectionsUtility of bronchiectasis0.63920.6392Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Distribution of infection severity with bronchiectasis d ? Serious infections, utility decrement 0.4112.5%12.5%Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) ? Non-serious infections, utility decrement 0.0687.5%87.5%Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991)Weighted utility decrement of infections0.10380.1038Utility of bronchiectasis with infection0.53550.5355Bronchiectasis utility minus the weighted utility decrement of infectionsUtility of Bronchiectasis with chronic Pseudomonas aeruginosa infection0.53550.5355As for Bronchiectasis with infectionIg = immunoglobulin; IV = intravenous.a (0.87 – 0.66)/365.25b weeks per year divided by infusion frequency (i.e. 52/4)c As source of baseline health state data were from patients on treatment, the disutility due to infusions has been assumed to be incorporated in the utility weightd In the absence of data to suggest a difference between model arms, the proportion of serious infections with bronchiectasis is assumed to be the same across both model arms and has been based on the proportion assumed in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019).Relationship of each Pre-Modelling Study to the Economic EvaluationA summary of the pre-modelling studies and their relationship to the model conducted in Section D is presented in REF _Ref10472782 \h Table 35.Table SEQ Table \* ARABIC 35Summary of results of pre-modelling studies and their uses in the economic evaluationSectionPre-modelling studyResults used in Section?DCross-referenceApplicabilityPatient demographicsPatient demographics in the included studies were generally not well reported. A comparison of the available information to the current population that receives Ig for acquired hypogammaglobulinaemia in Australia observed that CLL patients may be older than those studied. Further the majority of studies were conducted in the 1990s. However the treatment effect of Ig seemed relatively consistent across included studies (Section B.6).Contemporary Australian data will be used to inform baseline infection rates, and the pooled estimates for the treatment effect of Ig from randomised studies will be used in the base case analysis. These inputs will be tested in the sensitivity analyses.Section D.2Antibiotic use in the absence of IgIn the absence of alternative evidence to i) suggest that rates of antibiotic prophylaxis would increase in the absence of Ig; and ii) that this increase in antibiotic use would decrease the relative treatment effect of Ig, the economic analysis will assume no increase in prophylactic antibiotic use relative to that in the Ig arm of the model – and so the relative treatment effect observed in the randomised studies is assumed to apply to the current setting.Section D.3Dose of IgThe doses in the clinical evidence are consistent with doses used in current practice. Given the experience with Ig in the current setting, doses are assumed as per the real world data under the assumption that this has no effect on the relative treatment effect of Ig as observed in the trials. This is supported by the similarities in doses used in the studies compared to current practice and that consistency was observed in the treatment effect across the included studies, in spite of variations in dose.Section D.2 and D.4Duration of Ig treatmentDuration of Ig treatment in the included studies was variable. As patients in the Australian Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016) study were not required to have received Ig for a minimum period of time, the treatment duration observed, 26 months, is considered to be most applicable to the current setting and will be assumed in the base case analysis. The economic model in Section D will assume that while on Ig therapy, patients are at risk of infections, however after treatment cessation, it will be assumed that their risk of infections decreases to normal levels (and so no new infections are modelled after such time).Section D.2ExtrapolationDuration of treatment effectBased on the continuing access criteria it is assumed that the direct treatment effect of Ig (reduced infection rate and severity) is maintained for the duration of treatment. No direct treatment effect occurs after this time, but there is a residual difference in survival and quality of life associated with the difference in the proportions of patients in the various health states at the end of the treatment period, between the treatment arms. Section D.4.1Natural history of recurrent infectionsThere is very little published information regarding the long term consequences of recurrent infections in patients with acquired hypogammaglobulinaemia. One narrative review ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2011</Year><RecNum>111</RecNum><DisplayText>(Brown, Baxendale & Floto 2011)</DisplayText><record><rec-number>111</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1564368134">111</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Brown, J. S.</author><author>Baxendale, H.</author><author>Floto, R. A.</author></authors><secondary-authors><author>Floto, R. A.</author><author>Haworth, C.S.</author></secondary-authors></contributors><titles><title>Immunodeficiencies associated with bronchiectasis</title><secondary-title>European Respiratory Society Monographs: Bronchiectasis</secondary-title></titles><pages>178-191</pages><dates><year>2011</year></dates><isbn>9781849840118
9781849840125</isbn><urls></urls><electronic-resource-num>10.1183/1025448x.10004210</electronic-resource-num></record></Cite></EndNote>(Brown, Baxendale & Floto 2011) was identified which described the association of secondary immune deficiencies with bronchiectasis. This study reported that patients with haematological malignancies (particularly MM and CLL) or post-HSCT were relatively commonly associated with bronchiectasis. This is consistent with a recent Australian economic evaluation in this population which modelled the development of bronchiectasis. Therefore, the model structure will include health states associated with bronchiectasis in the base case analysis, however the inclusion of these health states are tested in a sensitivity analysis.Section D.3TransformationUtilitiesUtility weights were sourced from the published literature. Utilities reported in a relevant Australian population using the AQoL-6D instrument will be preferentially used in the model presented in Section D. The utilities related to infections were based on an alternative source as the Australian data do not allow for differences in infection severity to be quantified. A disutility is applied per IV infusion, however no disutilities have been assumed due to infusion-related AEs (which were generally mild and manageable).Section D.4.3AE = adverse events; AQoL-6D = Assessment of Quality of Life, six dimension; CLL = chronic lymphocytic leukaemia; Ig = immunoglobulin; MM = multiple myeloma; post-HSCT = post- haemopoietic stem cell transplantation.Section DEconomic EvaluationOverviewThe clinical evaluation suggested that in patients with acquired hypogammaglobulinaemia secondary to haematological malignancies, relative to no Ig, Ig has inferior safety and superior effectiveness based on the evidence profile given in REF _Ref399239890 \h Table 29. REF _Ref13559199 \h Table 94, REF _Ref13644183 \h Appendix G, presents the framework that was used to classify the clinical evidence in Section B so that a decision could be made about the type of economic analysis to present. On this basis, a modelled cost-utility analysis will be presented.The majority of higher quality evidence was identified in CLL and MM. Use in other haematological malignancies has been based on the principle that a history of infections and presence of hypogammaglobulinaemia is sufficient to warrant treatment. While no evidence was presented to support this use, the conclusion from Section B indicates that the evidence reviewed does not suggest that response to Ig is any more variable in patients with less-studied malignancies compared with CLL and MM. One economic analysis will be presented across the acquired hypogammaglobulinaemia indications. Given the heterogeneity within each indication, the studies presented in the clinical evidence are likely to be as applicable across the broader acquired hypogammaglobulinaemia indication as they are within each indication (see Section B.8). To further support this approach, contemporary clinical and economic modelling studies generally included patients with mixed haematological malignancies (see also Section D.3). As the purpose of Ig in acquired hypogammaglobulinaemia is to reduce the risk of infection and as the treatment effect of Ig was observed to be consistent across indications with respect to this outcome, this is considered to be a reasonable approach. Scenario analyses are presented determining the cost-effectiveness per indication assuming the best estimates available.Populations and settingsUnder the Version 3 criteria, Ig is indicated for acquired hypogammaglobulinaemia secondary to haematological malignancies (including acute leukaemia, CLL, MM, NHL and others), or post-HSCT. A comparison of the demographics of the patients in Australia who currently receive Ig across these indications to those in the randomised evidence was presented in Section C.2.1. Patient demographics were generally not well reported. CLL patients in the randomised clinical studies included were on average younger than those receiving Ig in the BloodSTAR database. Further, the majority of the randomised evidence was published in the 1990s. However the treatment effect of Ig seemed relatively consistent across included studies. Contemporary Australian data will be used to inform baseline infection rates, and the pooled estimates for the treatment effect of Ig from the randomised studies will be used in the base case analysis.As described in Section C.2.3, doses of Ig in the clinical evidence (0.3?g/kg to 0.8?g/kg) were generally consistent with those used in current Australian practice (0.36?0.38?g/kg). Given that currently there is substantial experience with Ig use, it will be assumed that current dosing is appropriate to achieve the clinical outcome of preventing infections, and so the economic analysis will use actual doses from the BloodSTAR data under the assumption that this has no effect on infection rates as observed in the trials. This is consistent with the Version 3 criteria which state that the aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for the patient.The majority of randomised studies allowed Ig treatment for a fixed period of time, rather than continuation based on an assessment of treatment response (as per the Version 3 criteria). BloodSTAR data were not available to inform the average treatment duration of patients who currently receive Ig for acquired hypogammaglobulinaemia. The translation study presented in Section C.2.4 concluded that as most patients would be managed on a case-by-case nature, the model will assume an average treatment duration of 26 months, based on Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016). This was the only study conducted in the Australian setting where patients were not required to have received Ig for a minimum period of time, and so is considered to be most applicable to the current setting.It is unclear what would occur in Australian clinical practice in the absence of Ig, given that it is currently available for acquired hypogammaglobulinaemia and is considered to be the standard of care: a recent survey of Australian clinicians experienced in the care of patients with acquired hypogammaglobulinaemia observed that 93% of clinicians surveyed use IVIg to prevent infections in this population, and 19% use SCIg. Pneumococcal vaccination and prophylactic antibiotics were used by 63% and 21% of clinicians respectively PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb25nPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj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==
ADDIN EN.CITE.DATA (Wong et al. 2019). As described in Section C.2.2, prophylactic antibiotics were either not allowed in the absence of Ig; or where allowed, use was equal irrespective of Ig use. One small (n?=?15) non-randomised before/after study conducted in the UK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE.DATA (Duraisingham et al. 2014) reported a decrease in the use of prophylactic antibiotics after initiation of Ig therapy (from 80% to 67%), with similar relative reductions in infection rates as the studies in which prophylactic antibiotic use was not allowed. This translation study concluded that while the results from the Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE.DATA (2014) study are supportive of a benefit of similar magnitude for Ig irrespective of whether prophylactic antibiotics are used in the comparator, due to the inherent biases associated with the small patient numbers and study design, this is not conclusive. The economic analysis therefore assumes no increase in prophylactic antibiotic use relative to that in the Ig arm of the model – and so infection rates reported in the randomised studies apply to the current setting. A scenario analysis based on the results of this study is presented.Structure and rationale of the economic evaluationA summary of the key characteristics of the economic evaluation is given in REF _Ref395196756 \h \* MERGEFORMAT Table 36.Table SEQ Table \* ARABIC 36Summary of the economic evaluation PerspectiveAustralian healthcareComparatorNo IgType of economic evaluationCost-utility and cost-effectiveness analysesSources of evidenceSystematic review presented in Section BTime horizon10 yearsOutcomesQALYsInfections avoidedMethods used to generate resultsMarkov modelHealth statesInfection-freeInfectionBronchiectasisBronchiectasis, with infectionBronchiectasis, with chronic Pseudomonas aeruginosa infectionDeadCycle length1 weekDiscount rate5%Software packages usedMicrosoft Excel and TreeAge ProIg = immunoglobulin; QALY = quality-adjusted life year.Literature reviewA search of the literature was conducted to identify published cost-effectiveness analyses of Ig in acquired hypogammaglobinaemia secondary to haematological malignancies. The terms and databases searched are presented in REF _Ref13559212 \h Table 95, REF _Ref13644183 \h Appendix G. The search retrieved 292 unique studies, of which one was identified that explored the cost-effectiveness of Ig use in CLL PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWVrczwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJl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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWVrczwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJl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 EN.CITE.DATA (Weeks, Tierney & Weinstein 1991). Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991)Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) published a cost-utility analysis, using a decision-analytic model based on the results of the randomised trial in CLL patients conducted by Gale et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2FsZTwvQXV0aG9yPjxZZWFy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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2FsZTwvQXV0aG9yPjxZZWFy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 EN.CITE.DATA (1988). The model compared Ig therapy (at 0.4?g/kg of IVIg every three weeks) for one year to no Ig therapy, with no prophylactic antibiotic use allowed. A lifetime time horizon was modelled, where a median life expectancy of 4.2 years was assumed. Gale et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2FsZTwvQXV0aG9yPjxZZWFy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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+R2FsZTwvQXV0aG9yPjxZZWFy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 EN.CITE.DATA (1988) reported that Ig use led to a reduction in the number of bacterial infections, but no survival benefit. Assumptions regarding rates of infection subsequent to Ig treatment cessation were not reported. Utilities were derived from 10 oncologists experienced with the care of CLL, and costs (in 1989 USD) related to Ig acquisition, preparation, administration and related to treating infections were included. The resulting ICER was observed to be $6 million per additional QALY gained (incremental cost of $13,984, for incremental QALY gain of 0.0023). The base case analysis did not include disutility due to Ig infusion – Ig treatment was observed to be dominated (i.e. more costly and less effective) if this inconvenience was included. Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)The search additionally identified a recently published cost-utility analysis conducted in the Australian setting that compared SCIg to IVIg in acquired hypogammaglobulinaemia secondary to malignancy or associated treatment ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019). While this study could not be used to answer the question of the cost-effectiveness of Ig relative to no Ig in population of interest, this study could be used to inform the model structure, and, given how recent and relevant the data are to the population of interest, other inputs, such as transition probabilities, costs and utility weights. The structure of the model and transition probability matrix are replicated below in REF _Ref10196689 \h Figure 8 and REF _Ref10196703 \h Table 37, respectively. A six-health state Markov model was used, which included health states for infection and the development of bronchiectasis and chronic P. aeruginosa infection. The model had a 10-year time horizon, with weekly cycles to account for weekly administrations of SCIg. Patients were assumed to remain on Ig treatment until death. The clinical data used to inform the transition probabilities and costs were derived from a cohort of Australian patients (n?=?13) who had received at least one year of IVIg followed by one year of SCIg, with limited baseline information provided. No patients died or developed bronchiectasis or P. aeruginosa infections during the two year observation period, however four patients had bronchiectasis at the beginning of the observation period. Transition probabilities that could not be informed by the clinical data were supplemented by the published literature. For each health state of interest, utility weights, using the AQoL-6D instrument, were derived from a wider cohort of patients (n?=?84), which additionally included those who had only experienced one form of treatment, or who switched to SCIg prior to having 12 months of IVIg. Figure SEQ Figure \* ARABIC 8State transition model used in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Source: Fig 1, Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019).Table SEQ Table \* ARABIC 37Transition probability matrix used in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Health states(1)(2)(3)(4)(5)(6) DeadIVIg(1) No infection0.9470.0530.00034(2) Infection0.5920.3130.0630.0310.00142(3) Bronchiectasis with no infection0.9170.050.030.00311(4) Bronchiectasis with infection0.30.6640.0330.00311(5)?Pseudomonas aeruginosa?infection0.1820.0910.7180.00916SCIg(1) No infection0.9560.0440.00034(2) Infection0.4630.4860.0240.0240.00142(3) Bronchiectasis with no infection0.9240.0540.0190.00311(4) Bronchiectasis with infection0.4330.50.0640.00311(5)?Pseudomonas aeruginosa?infection0.1820.0910.7180.009161 = No infection; 2 = Infection; 3 = Bronchiectasis with no infection; 4 = Bronchiectasis with infection; 5 = Bronchiectasis with chronic Pseudomonas aeruginosa infection; 6 = dead.IVIg = intravenous immunoglobulin; SCIg = subcutaneous Ig.Source: Table A1, Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Structure of the economic evaluationAs the studies identified in the search of the economic literature could not answer the question of the cost-effectiveness of Ig relative to no Ig in the contemporary Australian setting, an economic evaluation is presented. As Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) provides a model structure that captures the natural history of infections in acquired hypogammaglobulinaemia (see Section C.3.2) in an Australian population, a Markov model with a similar model structure will be used. The six health states modelled include: infection-free, infection, bronchiectasis, bronchiectasis with infection, bronchiectasis with chronic P. aeruginosa infection, and dead. The Markov model structure with allowable transitions between health states is depicted in REF _Ref377977732 \h \* MERGEFORMAT Figure 9. A sensitivity analysis is presented exploring the effect of reducing the number of health states in the model (such as excluding progression to bronchiectasis, which would reflect a similar approach as used in Weeks, Tierney & Weinstein 1991) (see Section D.6).Figure SEQ Figure \* ARABIC 9Markov model structurePatients with acquired hypogammaglobulinaemia with a history of infections enter the model in the infection-free health state. The model compares scenarios where Ig is available, to that where it is not available. As described in Section C.2.2 and Section D.2, in the model arm where Ig is not available, no prophylactic antibiotic use is assumed. The risk of developing an infection varies depending on whether Ig is available and as such has been informed by the clinical evidence presented in Section B (see also Section D.4). While subsequent transitions were predominantly based on those reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019), some were adjusted according to infection severity, and so varied by model arm (see Section D.4.1). As transitions in this study were reported for weekly cycles, a cycle length of one week has also been assumed up to the model time horizon of 10 years (also as per Windegger et al. 2019). The duration of the time horizon is tested in sensitivity analyses (see Section D.6).Inputs to the economic evaluationD.4.1.Transition probabilitiesInfection ratesBaseline infection rate (i.e. rate with no Ig)As described in Section C.2.1, infection rates in the absence of Ig modelled will be based on that reported in Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll
YXI+MjAxNjwvWWVhcj48UmVjTnVtPjY2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigyMDE2KTwvRGlz
cGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj42NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz
PjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJyMnBkMnRh
ZCIgdGltZXN0YW1wPSIxNTU0NDM3MzM5Ij42Njwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9
IiI+MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi
PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGF4dG9uLCBMLjwv
YXV0aG9yPjxhdXRob3I+SGF3a2lucywgQy48L2F1dGhvcj48YXV0aG9yPkNyaXNwaW4sIFAuPC9h
dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QXVzdHJhbGlhbiBO
YXRpb25hbCBVbml2ZXJzaXR5IE1lZGljYWwgU2Nob29sLCBDYW5iZXJyYSwgQXVzdHJhbGlhLiYj
eEQ7RGVwYXJ0bWVudCBvZiBJbW11bm9sb2d5LCBDYW5iZXJyYSBIb3NwaXRhbCwgQ2FuYmVycmEs
IEF1c3RyYWxpYS4mI3hEO0F1c3RyYWxpYW4gTmF0aW9uYWwgVW5pdmVyc2l0eSBNZWRpY2FsIFNj
aG9vbCwgQ2FuYmVycmEsIEF1c3RyYWxpYS4gcGhpbGlwLmNyaXNwaW5AYWN0Lmdvdi5hdS4mI3hE
O0RlcGFydG1lbnQgb2YgSGFlbWF0b2xvZ3ksIENhbmJlcnJhIEhvc3BpdGFsLCBDYW5iZXJyYSwg
QXVzdHJhbGlhLiBwaGlsaXAuY3Jpc3BpbkBhY3QuZ292LmF1LjwvYXV0aC1hZGRyZXNzPjx0aXRs
ZXM+PHRpdGxlPlNlbGVjdGluZyBoYWVtYXRvbG9naWNhbCBtYWxpZ25hbmN5IHBhdGllbnRzIGZv
ciBpbnRyYXZlbm91cyBpbW11bm9nbG9idWxpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5JbnRl
cm4gTWVkIEo8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs
ZT5JbnRlcm4gTWVkIEo8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjE2LTEyMTg8
L3BhZ2VzPjx2b2x1bWU+NDY8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGtleXdvcmRzPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+
PGtleXdvcmQ+QXVzdHJhbGlhPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5
d29yZD5IZW1hdG9sb2dpYyBOZW9wbGFzbXMvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVt
YW5zPC9rZXl3b3JkPjxrZXl3b3JkPipJbW11bml6YXRpb24sIFBhc3NpdmU8L2tleXdvcmQ+PGtl
eXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLCBJbnRyYXZlbm91cy8qYWRtaW5pc3RyYXRpb24gJmFtcDsg
ZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkxpbmVhciBNb2RlbHM8L2tleXdvcmQ+PGtleXdvcmQ+
TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5SZXRy
b3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+aGFlbWF0b2xvZ2ljYWwgbWFsaWdu
YW5jeTwva2V5d29yZD48a2V5d29yZD5pbmZlY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+aW50cmF2
ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx
NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp
c2JuPjE0NDUtNTk5NCAoRWxlY3Ryb25pYykmI3hEOzE0NDQtMDkwMyAoTGlua2luZyk8L2lzYm4+
PGFjY2Vzc2lvbi1udW0+Mjc3MzQ2MjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs
cz48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUi
Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3NzM0NjIwPC9zdHlsZT48L3Vy
bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEv
aW1qLjEzMjA1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVzZWFyY2gtbm90ZXM+TWl4ZWQg
cG9wLiBib3RoIGJlZm9yZSBhbmQgYWZ0ZXIgY2FzZSBzZXJpZXMgYW5kIHJldHJvc3BlY3RpdmUg
Y29ob3J0LiAoZm91bmQgdGhyb3VnaCBnb29nbGluZyk8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3Jk
PjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA (2016). This study reported that prior to initiation of Ig therapy, patients experienced 0.43 serious infections per year. However this study did not report the number of non-serious infections experienced. As Ig has been shown to reduce both serious and non-serious infections (see Section B.6), an estimate of the rate of non-serious infections is required.All of the randomised studies except Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll
YXI+MTk5NDwvWWVhcj48UmVjTnVtPjU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigxOTk0Yik8L0Rp
c3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5
cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0
YWQiIHRpbWVzdGFtcD0iMTU1NDI2NjY2OSI+NTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5
cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0
aG9ycz48YXV0aG9yPkNoYXBlbCwgSC4gTS48L2F1dGhvcj48YXV0aG9yPkxlZSwgTS48L2F1dGhv
cj48YXV0aG9yPkhhcmdyZWF2ZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5QYW1waGlsb24sIEQuIEgu
PC9hdXRob3I+PGF1dGhvcj5QcmVudGljZSwgQS4gRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIEpvaG4gUmFk
Y2xpZmZlIEhvc3BpdGFsLCBPeGZvcmQsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
PlJhbmRvbWlzZWQgdHJpYWwgb2YgaW50cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW4gYXMgcHJvcGh5
bGF4aXMgYWdhaW5zdCBpbmZlY3Rpb24gaW4gcGxhdGVhdS1waGFzZSBtdWx0aXBsZSBteWVsb21h
LiBUaGUgVUsgR3JvdXAgZm9yIEltbXVub2dsb2J1bGluIFJlcGxhY2VtZW50IFRoZXJhcHkgaW4g
TXVsdGlwbGUgTXllbG9tYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQ8L3NlY29uZGFy
eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQ8L2Z1bGwtdGl0
bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDU5LTYzPC9wYWdlcz48dm9sdW1lPjM0Mzwvdm9sdW1l
PjxudW1iZXI+ODkwNTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPkJhY3RlcmlhbCBJbmZlY3Rpb25zLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tl
eXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIFZhY2NpbmVzPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJs
ZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnMsIEludHJhdmVub3VzL2Fk
dmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlv
biBDb250cm9sL21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y
ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdWx0aXBsZSBNeWVsb21hLypjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlBuZXVtb2NvY2NhbCBJbmZlY3Rpb25zL3ByZXZlbnRp
b24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QbmV1bW9jb2NjYWwgVmFjY2luZXM8
L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmlhL3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5
d29yZD48a2V5d29yZD5QcmVtZWRpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZl
IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjdXJyZW5jZTwva2V5d29yZD48a2V5d29yZD5T
ZXBzaXMvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlN0cmVwdG9j
b2NjdXMgcG5ldW1vbmlhZS9pbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjE5OTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHIgMzA8L2RhdGU+PC9wdWItZGF0ZXM+
PC9kYXRlcz48aXNibj4wMTQwLTY3MzYgKFByaW50KSYjeEQ7MDE0MC02NzM2IChMaW5raW5nKTwv
aXNibj48YWNjZXNzaW9uLW51bT43OTA5MDk5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk
LXVybHM+PHVybD48c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC83OTA5MDk5PC9zdHlsZT48
L3VybD48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEw
MCUiPmh0dHBzOi8vd3d3LnNjaWVuY2VkaXJlY3QuY29tL3NjaWVuY2UvYXJ0aWNsZS9waWkvUzAx
NDA2NzM2OTQ5MDE4MDU/dmlhJTNEaWh1Yjwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxyZXNlYXJjaC1ub3Rlcz5NTSAocGVhcmxlZCkgbm90IGNsZWFyIG9uIGlmIGhhZCBoeXBv
Z2FtbWE8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b) reported the number of serious and non-serious infections. Only two of the non-randomised studies reported this information PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48
UmVjTnVtPjE1PC9SZWNOdW0+PERpc3BsYXlUZXh0PihCcmVubmVyIDE5OTY7IER1cmFpc2luZ2hh
bSBldCBhbC4gMjAxNCk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTU8L3JlYy1u
dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3
d3RzNXo5ZXVwOWUycjJwZDJ0YWQiIHRpbWVzdGFtcD0iMTU1MzgyNTA1OSI+MTU8L2tleT48L2Zv
cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+
PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJyZW5uZXIsIEIuPC9hdXRob3I+PC9hdXRo
b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+Qi4gQnJlbm5lciwgVGhyb21ib3NpcyBh
bmQgSGVtb3N0YXNpcyBVbml0LCBJbnN0aXR1dGUgb2YgSGVtYXRvbG9neSwgUmFtYmFtIE1lZGlj
YWwgQ2VudGVyLCBIYWlmYSAzMTA5NiwgSXNyYWVsPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0
bGU+Q2xpbmljYWwgZXhwZXJpZW5jZSB3aXRoIE9jdGFnYW0sIGEgc29sdmVudCBkZXRlcmdlbnQg
KFNEKSB2aXJ1cyBpbmFjdGl2YXRlZCBpbnRyYXZlbm91cyBnYW1tYWdsb2J1bGluPC90aXRsZT48
c2Vjb25kYXJ5LXRpdGxlPkNsaW5pY2FsIGFuZCBFeHBlcmltZW50YWwgUmhldW1hdG9sb2d5PC9z
ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2xpbmljYWwg
YW5kIEV4cGVyaW1lbnRhbCBSaGV1bWF0b2xvZ3k8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw
YWdlcz5TMTE1LVMxMTk8L3BhZ2VzPjx2b2x1bWU+MTQ8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdv
cmQ+aW1tdW5vZ2xvYnVsaW4gRzwva2V5d29yZD48a2V5d29yZD5hZG9sZXNjZW50PC9rZXl3b3Jk
PjxrZXl3b3JkPmFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPmFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+
YW50aXBob3NwaG9saXBpZCBzeW5kcm9tZTwva2V5d29yZD48a2V5d29yZD5jaHJvbmljIGx5bXBo
YXRpYyBsZXVrZW1pYTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbCB0cmlhbDwva2V5d29yZD48
a2V5d29yZD5jb25mZXJlbmNlIHBhcGVyPC9rZXl3b3JkPjxrZXl3b3JkPmNvbnRyb2xsZWQgY2xp
bmljYWwgdHJpYWw8L2tleXdvcmQ+PGtleXdvcmQ+Y29udHJvbGxlZCBzdHVkeTwva2V5d29yZD48
a2V5d29yZD5kcnVnIGVmZmljYWN5PC9rZXl3b3JkPjxrZXl3b3JkPmRydWcgc2FmZXR5PC9rZXl3
b3JkPjxrZXl3b3JkPmZlbWFsZTwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5
d29yZD5tYWpvciBjbGluaWNhbCBzdHVkeTwva2V5d29yZD48a2V5d29yZD5tYWxlPC9rZXl3b3Jk
PjxrZXl3b3JkPm11bHRpcGxlIG15ZWxvbWE8L2tleXdvcmQ+PGtleXdvcmQ+cHJpb3JpdHkgam91
cm5hbDwva2V5d29yZD48a2V5d29yZD50aHJvbWJvY3l0b3BlbmljIHB1cnB1cmE8L2tleXdvcmQ+
PGtleXdvcmQ+dmlydXMgaW5hY3RpdmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPm9jdGFnYW08L2tl
eXdvcmQ+PGtleXdvcmQ+RGV0ZXJnZW50czwva2V5d29yZD48a2V5d29yZD5Tb2x2ZW50czwva2V5
d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+
MTk5NjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAzOTItODU2WDwvaXNibj48YWNj
ZXNzaW9uLW51bT5yYXl5YW4tNDU4NzQ2MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11
cmxzPjx1cmw+PHN0eWxlIGZhY2U9InVuZGVybGluZSIgZm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAw
JSI+aHR0cDovL3d3dy5lbWJhc2UuY29tL3NlYXJjaC9yZXN1bHRzP3N1YmFjdGlvbj12aWV3cmVj
b3JkJmFtcDtmcm9tPWV4cG9ydCZhbXA7aWQ9TDI2MjcwNTg4PC9zdHlsZT48L3VybD48L3JlbGF0
ZWQtdXJscz48L3VybHM+PGN1c3RvbTE+b2N0YWdhbShPY3RhcGhhcm1hLEF1c3RyaWEpIFJBWVlB
Ti1JTkNMVVNJT046IHsmcXVvdDtTa3llJnF1b3Q7PSZndDsmcXVvdDtJbmNsdWRlZCZxdW90O308
L2N1c3RvbTE+PHJlc2VhcmNoLW5vdGVzPlggLSB1bmNsZWFyIGhvdyBtYW55IGhhZCBIeXBvR0cu
IEJlZm9yZSBhbmQgYWZ0ZXIgY2FzZSBzZXJpZXM8L3Jlc2VhcmNoLW5vdGVzPjxsYW5ndWFnZT5F
bmdsaXNoPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdo
YW08L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNOdW0+MjA8L1JlY051bT48cmVjb3JkPjxy
ZWMtbnVtYmVyPjIwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1p
ZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQydGFkIiB0aW1lc3RhbXA9IjE1NTM4
MjUwNTkiPjIwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0
aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5EdXJhaXNp
bmdoYW0sIFMuIFMuPC9hdXRob3I+PGF1dGhvcj5CdWNrbDwvYXV0aG9yPjxhdXRob3I+LCBNLjwv
YXV0aG9yPjxhdXRob3I+RGVtcHN0ZXIsIEouPC9hdXRob3I+PGF1dGhvcj5Mb3JlbnpvLCBMLjwv
YXV0aG9yPjxhdXRob3I+R3JpZ29yaWFkb3UsIFMuPC9hdXRob3I+PGF1dGhvcj5Mb25naHVyc3Qs
IEguIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW1t
dW5vbG9neSBEZXBhcnRtZW50LCBCYXJ0cyBIZWFsdGggTkhTIFRydXN0LCBMb25kb24sIFVuaXRl
ZCBLaW5nZG9tLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlByaW1hcnkgdnMuIHNlY29u
ZGFyeSBhbnRpYm9keSBkZWZpY2llbmN5OiBjbGluaWNhbCBmZWF0dXJlcyBhbmQgaW5mZWN0aW9u
IG91dGNvbWVzIG9mIGltbXVub2dsb2J1bGluIHJlcGxhY2VtZW50PC90aXRsZT48c2Vjb25kYXJ5
LXRpdGxlPlBMb1MgT25lPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1
bGwtdGl0bGU+UExvUyBPbmU8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5lMTAwMzI0
PC9wYWdlcz48dm9sdW1lPjk8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48a2V5d29yZHM+PGtl
eXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29y
ZD5BZ2FtbWFnbG9idWxpbmVtaWEvY29tcGxpY2F0aW9ucy8gZGlhZ25vc2lzLyBldGlvbG9neTwv
a2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVy
PC9rZXl3b3JkPjxrZXl3b3JkPkJyb25jaGllY3Rhc2lzL2RpYWdub3Npcy9ldGlvbG9neTwva2V5
d29yZD48a2V5d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5EZWxheWVkIERp
YWdub3Npczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z
PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlucy90aGVyYXBldXRpYyB1c2U8L2tleXdv
cmQ+PGtleXdvcmQ+SW1tdW5vc3VwcHJlc3NpdmUgQWdlbnRzL2FkdmVyc2UgZWZmZWN0czwva2V5
d29yZD48a2V5d29yZD5JbmZlY3Rpb24vZXRpb2xvZ3kvdGhlcmFweTwva2V5d29yZD48a2V5d29y
ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBh
dGllbnQgT3V0Y29tZSBBc3Nlc3NtZW50PC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRj
b21lPC9rZXl3b3JkPjxrZXl3b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu
b2dsb2J1bGluIEc8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRDwva2V5d29yZD48
a2V5d29yZD5JbW11bm9nbG9idWxpbiBNPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlu
IEE8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRTwva2V5d29yZD48a2V5d29yZD5J
bW11bm9nbG9idWxpbiBWYXJpYWJsZSBSZWdpb248L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xv
YnVsaW5zPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1Yi1k
YXRlcz48ZGF0ZT4yMDE0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTkzMi02MjAz
IChFbGVjdHJvbmljKSAxOTMyLTYyMDMgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI0
OTcxNjQ0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVT
SU9OOiB7JnF1b3Q7U2t5ZSZxdW90Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20x
PjxyZXNlYXJjaC1ub3Rlcz5YIC0gbW9zdCBvZiB0aGUgc2Vjb25kYXJ5IEh5cG9HRyBkdWUgdG8g
Y2hlbW8gd2l0aCBSVFggLiB3cm9uZyBwb3A8L3Jlc2VhcmNoLW5vdGVzPjxsYW5ndWFnZT5lbmc8
L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVubmVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48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ADDIN EN.CITE.DATA (Brenner 1996; Duraisingham et al. 2014). In the study arm where no Ig was used (or before Ig was used in the non-randomised evidence), non-serious infections were observed to occur from half as often to up to six-times more likely ( REF _Ref12883665 \h Table 38). The weighted average was estimated to be 2.45. Thus in the base case analysis, the rate of non-serious infections is estimated to be 1.05. Sensitivity analyses are presented to explore the uncertainty associated with this assumption (see Section D.6). Table SEQ Table \* ARABIC 38Incidence of non-serious to serious infectionsStudy [N patients]Number of infectionsRatio of non-serious to serious infectionsChapel et al. (1991) [N?=?12]10 serious, 35 non-serious3.5 timesMolica et al. (1996) [N?=?42]9 serious, 53 non-serious5.9 timesMusto, Brugiatelli & Carotenuto (1995) [N?=?25]9 serious, 48 non-serious5.3 timesVacca et al. (2018) [N?=?46]190 serious, 143 non-serious0.75 timesSullivan et al. (1990) [N?=?382]68 serious, 144 non-serious2.1 timesDuraisingham et al. (2014) [N?=?15]11 serious, 37 non-serious3.4 timesBrenner et al. (1996) [N?=?21]21 serious, 11 non-serious0.5 timesThe baseline rate of infection will assume to apply for the duration of Ig treatment, 26 months (see Section C.2.4). While it is possible that, in the absence of Ig, patients would be at risk of infections for a longer duration of time, no evidence was identified to enable this to be quantified. However it is noted that this is may be a conservative approach. Conversely, if patients are being treated with Ig for longer than they are at risk of infections, the ICER may be underestimated. Infection rate with IgTo estimate the rate of serious and non-serious infections with Ig, the IRRs estimated in Section B.6 are applied to the baseline rates of infection. The base case analysis will assume the IRRs estimated from the pooled randomised studies, with a sensitivity analysis presented using the IRRs based on the non-randomised studies (see Section D.6).Table SEQ Table \* ARABIC 39Relative treatment effect of IgIRR for serious infections (95% CI)IRR for non-serious infections (95% CI)Pooled randomised studies0.15 (0.05, 0.43)0.61 (0.51, 0.72)Pooled non-randomised studies0.25 (0.15, 0.43)0.46 (0.29, 0.74)Ig = immunoglobulin; IRR = incidence rate ratio.Applying these IRRs to the baseline rates of infection described above, the annual rate of serious and non-serious infections with Ig is estimated to be 0.06 and 0.64, respectively.Duration of infectionThe probability of infection resolution is estimated to vary by model arm, as recovery from an infection is likely to vary depending on the severity of the infection. The average duration of infection is estimated in REF _Ref12894613 \h Table 40.Table SEQ Table \* ARABIC 40Average duration of infection by model armIgNo IgProportion of serious infections0.06/0.70 (8.9%)0.43/1.48 (29.0%)Average duration of non-serious infections1 cycle1 cycleAverage duration of serious infections2 cycles2 cyclesAverage duration of infections1.1 cycles1.3 cyclesIg = immunoglobulin.A gamma distribution was then fitted to these data to estimate the per-cycle probability of infection resolution ( REF _Ref12894634 \h Table 41). A gamma distribution was chosen as it is constrained from zero to positive infinity.Table SEQ Table \* ARABIC 41Per cycle probability of infection resolution in patients who had not died or developed bronchiectasisProportion resolved aPer cycle probability of resolution bIgNo IgIgNo IgCycle 10.59380.509759.4%51.0%Cycle 20.84440.794861.7%58.2%Cycle 30.94120.917662.2%59.9%Cycle 40.97790.967662.4%60.7%Cycle 50.99170.987462.6%61.2%Cycle 60.99690.995262.7%61.5%Cycle 70.99890.998162.8%61.7%Cycle 80.99960.999362.8%61.9%Cycle 90.99980.999762.9%62.1%Cycle 100.99990.999962.9%62.2%Cycle 111.00001.000062.9%62.3%a Gamma distributions assuming the alpha parameter is equal to the average duration of infection, estimated in REF _Ref12894613 \h Table 40 above, and that the beta parameter equals 1.b Calculated as the proportion resolved at t minus the proportion resolved at t?1, divided by 1 minus the proportion resolved at t?1, e.g. in cycle 2 in the Ig model arm, (0.84 – 0.59)/(1 ? 0.59).Ig = immunoglobulin.In Section D.6, a sensitivity analysis is presented using the transition probability from the IVIg arm of Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) for both model arms (59.2%), however this is considered to underestimate the cost-effectiveness of Ig as infections tended to be less severe. Different per-cycle probabilities of infection resolution are considered to be more reasonable.Transitions from the infection health stateAside from infection resolution, other transitions from the infection health state include those to the bronchiectasis, bronchiectasis with infection and dead health states. As the per-cycle probabilities of resolution vary according to time in the health state ( REF _Ref12894634 \h Table 41), these other transitions have been adjusted to maintain the same relative proportions per cycle (see REF _Ref10196703 \h Table 37). The relative weight of these other transitions were assumed as per Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019): 76.6% for remaining in the infection state, 15.4% transitioning to the bronchiectasis health state, 7.6% to bronchiectasis with infection health state and 0.3% to dead.Table SEQ Table \* ARABIC 42Remaining transition probabilities from the infection health stateIgNo IgI_II_BI_BII_DI_II_BI_BII_D(76.6%)(15.4%)(7.6%)(0.3%)(76.6%)(15.4%)(7.6%)(0.3%)Cycle 131.1%6.3%3.1%0.1%37.6%7.6%3.7%0.2%Cycle 229.4%5.9%2.9%0.1%32.1%6.5%3.2%0.1%Cycle 329.0%5.8%2.9%0.1%30.8%6.2%3.0%0.1%Cycle 428.8%5.8%2.9%0.1%30.1%6.1%3.0%0.1%Cycle 528.7%5.8%2.8%0.1%29.8%6.0%2.9%0.1%Cycle 628.6%5.8%2.8%0.1%29.5%5.9%2.9%0.1%Cycle 728.5%5.7%2.8%0.1%29.3%5.9%2.9%0.1%Cycle 828.5%5.7%2.8%0.1%29.2%5.9%2.9%0.1%Cycle 928.5%5.7%2.8%0.1%29.1%5.9%2.9%0.1%Cycle 1028.4%5.7%2.8%0.1%29.0%5.8%2.9%0.1%Cycle 1128.4%5.7%2.8%0.1%28.9%5.8%2.9%0.1%Note: Transitions were calculated by applying the relative proportion by 1 minus the per cycle probability of resolution reported in REF _Ref12894634 \h Table 41.I_B = transition from infection to bronchiectasis health state; I_BI = transition from infection to bronchiectasis with infection health state; I_D = transition from infection to dead health state; Ig = immunoglobulin; I_I = proportion remaining in the infection health state.A sensitivity analysis is presented assuming no adjustment to the Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) transition probabilities, and so the same transitions would apply in both model arms (Section D.6). Transition probabilities related to bronchiectasisDeveloping infections in bronchiectasisPatients in the bronchiectasis health state are at-risk of developing infections, including chronic P. aeruginosa infections. The transition probabilities reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) for patients on IVIg treatment are assumed to apply to the model arm where Ig is available (as the majority of current use is by IV). However Ig treatment is assumed to continue to reduce the risk of such infections in patients with bronchiectasis. Though not well reported, some studies in Section B did include patients with bronchiectasis (e.g. 4/15 patients in Duraisingham et al. 2014 had bronchiectasis). In the absence of evidence to suggest that Ig would have a different treatment effect in patients with bronchiectasis, the IRRs presented in REF _Ref14254065 \h Table 39 are applied to adjust the transition probabilities reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) to the model arm where no Ig is available. Assuming that 12.5% of infections with bronchiectasis are serious (as per Windegger et al. 2019), the weighted risk reduction using the IRRs estimated from the meta-analyses presented in Section B is 0.552. The adjusted transitions are presented in REF _Ref13063825 \h Table 43.Table SEQ Table \* ARABIC 43Adjusted transition probabilities of developing infections in bronchiectasispB_BIpB_PProbability reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) (applicable to Ig model arm)5.0%3.0%Ig rate2.6671.584No Ig rate (i.e. Ig rate / weighted IRR, 0.552)4.8322.869No Ig adjusted transition probability8.9%5.4%Ig = immunoglobulin; pB_BI = probability of transitioning from the bronchiectasis to the bronchiectasis with infection health state; IRR = incidence rate ratio; pB_P = probability of transitioning from the bronchiectasis to the bronchiectasis with chronic P. aeruginosa infection health state.A sensitivity analysis will be presented assuming no adjustment to the Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) transition probabilities, and so the same transitions would apply in both model arms (Section D.6).Other transitions between non-dead health statesTransitions within the bronchiectasis health state with infection and with chronic P. aeruginosa infection health states are assumed as per Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019), and so have been assumed to be the same across model arms.MortalityThe sources of data to model increased risk of death in each of the health state are consistent with those applied in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019).In the infection-free health state, an increased mortality risk of 2.55 times that of the general Australian population has been applied. This was based on the increased risk of mortality in CLL patients, relative to the general Australian population, reported in Royle et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Um95bGU8L0F1dGhvcj48WWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Um95bGU8L0F1dGhvcj48WWVh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ADDIN EN.CITE.DATA (2011). Visentin et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmlzZW50aW48L0F1dGhvcj48
WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MjE8L1JlY051bT48RGlzcGxheVRleHQ+KDIwMTUpPC9E
aXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl
eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iejB2d3NlcGR3cHQyMHBld3d0czV6OWV1cDllMnIycGQy
dGFkIiB0aW1lc3RhbXA9IjE1NTM4MjUwNTkiPjIxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10
eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1
dGhvcnM+PGF1dGhvcj5WaXNlbnRpbiwgQS48L2F1dGhvcj48YXV0aG9yPkNvbXBhZ25vLCBOLjwv
YXV0aG9yPjxhdXRob3I+Q2luZXR0bywgRi48L2F1dGhvcj48YXV0aG9yPkltYmVyZ2FtbywgUy48
L2F1dGhvcj48YXV0aG9yPlphbWJlbGxvLCBSLjwvYXV0aG9yPjxhdXRob3I+UGlhenphLCBGLjwv
YXV0aG9yPjxhdXRob3I+U2VtZW56YXRvLCBHLjwvYXV0aG9yPjxhdXRob3I+VHJlbnRpbiwgTC48
L2F1dGhvcj48YXV0aG9yPkFnb3N0aW5pLCBDLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1
dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTWVkaWNpbmUsIEhlbWF0b2xvZ3kgYW5k
IENsaW5pY2FsIEltbXVub2xvZ3kgQnJhbmNoLCBQYWR1YSBVbml2ZXJzaXR5IFNjaG9vbCBvZiBN
ZWRpY2luZSwgSXRhbHkgVmVuZXRpYW4gSW5zdGl0dXRlIG9mIE1vbGVjdWxhciBNZWRpY2luZSwg
Q2VudHJvIGRpIEVjY2VsbGVuemEgcGVyIGxhIFJpY2VyY2EgQmlvbWVkaWNhIEF2YW56YXRhLCBJ
dGFseS4gRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgSGVtYXRvbG9neSBhbmQgQ2xpbmljYWwgSW1t
dW5vbG9neSBCcmFuY2gsIFBhZHVhIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBJdGFs
eS4gRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgSGVtYXRvbG9neSBhbmQgQ2xpbmljYWwgSW1tdW5v
bG9neSBCcmFuY2gsIFBhZHVhIFVuaXZlcnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBJdGFseSBW
ZW5ldGlhbiBJbnN0aXR1dGUgb2YgTW9sZWN1bGFyIE1lZGljaW5lLCBDZW50cm8gZGkgRWNjZWxs
ZW56YSBwZXIgbGEgUmljZXJjYSBCaW9tZWRpY2EgQXZhbnphdGEsIEl0YWx5IGNhcmxvLmFnb3N0
aW5pQHVuaXBkLml0IGxpdmlvLnRyZW50aW5AdW5pcGQuaXQuPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+Q2xpbmljYWwgcHJvZmlsZSBhc3NvY2lhdGVkIHdpdGggaW5mZWN0aW9ucyBpbiBw
YXRpZW50cyB3aXRoIGNocm9uaWMgbHltcGhvY3l0aWMgbGV1a2VtaWEuIFByb3RlY3RpdmUgcm9s
ZSBvZiBpbW11bm9nbG9idWxpbiByZXBsYWNlbWVudCB0aGVyYXB5PC90aXRsZT48c2Vjb25kYXJ5
LXRpdGxlPkhhZW1hdG9sb2dpY2E8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh
bD48ZnVsbC10aXRsZT5IYWVtYXRvbG9naWNhPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn
ZXM+ZTUxNS04PC9wYWdlcz48dm9sdW1lPjEwMDwvdm9sdW1lPjxudW1iZXI+MTI8L251bWJlcj48
a2V5d29yZHM+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zl
cjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3
b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGlucywgSW50cmF2ZW5vdXMvIGFkbWluaXN0cmF0aW9u
ICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5JbmZlY3Rpb24vIGRydWcgdGhlcmFweS9l
dGlvbG9neS9taWNyb2Jpb2xvZ3kvbW9ydGFsaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkxldWtlbWlh
LCBMeW1waG9jeXRpYywgQ2hyb25pYywgQi1DZWxsLyBkcnVnIHRoZXJhcHkvbWljcm9iaW9sb2d5
L21vcnRhbGl0eTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs
ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkNsbDwva2V5d29yZD48a2V5d29yZD5oeXBvZ2FtbWFn
bG9idWxpbmVtaWE8L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5vZ2xvYnVsaW4gcmVwbGFjZW1lbnQg
dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5pbmZlY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPnNl
Y29uZGFyeSBoeXBvZ2FtbWFnbG9idWxpbmVtaWE8L2tleXdvcmQ+PGtleXdvcmQ+TGV1a2VtaWEs
IEx5bXBob2lkPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluczwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRl
PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTU5Mi04NzIxIChFbGVjdHJvbmljKSAwMzkwLTYw
NzggKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2Mjk0NzM1PC9hY2Nlc3Npb24tbnVt
Pjx1cmxzPjwvdXJscz48Y3VzdG9tMT5SQVlZQU4tSU5DTFVTSU9OOiB7JnF1b3Q7U2t5ZSZxdW90
Oz0mZ3Q7JnF1b3Q7SW5jbHVkZWQmcXVvdDt9PC9jdXN0b20xPjxyZXNlYXJjaC1ub3Rlcz5DTEwg
Y2FzZSAoaW5mZWN0aW9ucykgY29udHJvbCAobm8gaW5mZWN0aW9ucyk8L3Jlc2VhcmNoLW5vdGVz
PjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmlzZW50aW48L0F1dGhvcj48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==
ADDIN EN.CITE.DATA (2015) did report that patients with a history of major infections had a 2.34 increased risk of death, however as increased mortality with infection health states has been modelled separately, this has not been included in the base case analysis as it may double-count mortality risk due to infections. The inclusion of this additional risk in the infection-free health state has been tested in a sensitivity analysis.In the bronchiectasis health state, a 2.20 increased risk of death has been applied to the mortality rates estimated for the infection-free health state, based on the increased risk reported in Quint et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UXVpbnQ8L0F1dGhvcj48WWVh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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UXVpbnQ8L0F1dGhvcj48WWVh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 EN.CITE.DATA (2016). With infections, a 4.18 increase in the risk of death has been assumed, which has been estimated from Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019), derived from the relative increase in death in the infection health state compared to the infection-free health state. The basis for this increased risk of death was not clear, and will be tested in sensitivity analyses.An increased risk of death with chronic P. aeruginosa infection will be assumed based on Finch et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RmluY2g8L0F1dGhvcj48WWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RmluY2g8L0F1dGhvcj48WWVh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ADDIN EN.CITE.DATA (2015), which reported increased odds of death with P. aeruginosa infection, relative to bronchiectasis without P. aeruginosa infection of 2.95. Using this OR and assuming a 12% mortality at five years, the RR is estimated to be 2.39.Summary matrix of transition probabilitiesA summary of the transition probabilities used in the model is depicted in REF _Ref13149508 \h Table 44.Table SEQ Table \* ARABIC 44Transition probability matrixFrom/ToIFIBBIPDeadIgIF#1.3% avaries bICycle 1: 59.4%…Cycle 11: 62.9%#Cycle 1: 6.3%…Cycle 11: 5.7%Cycle 1: 3.1%…Cycle 11: 2.8%Cycle 1: 0.1%…Cycle 11: 0.1%B#5.0%3.0%varies bBI30.0%#3.3%varies bP18.2%9.1%#varies bNo IgIF#2.8% avaries bICycle 1: 51.0%…Cycle 11: 62.3%#Cycle 1: 7.6%…Cycle 11: 5.8%Cycle 1: 3.7%…Cycle 11: 2.9%Cycle 1: 0.2%…Cycle 11: 0.1%B#8.9%5.4%varies bBI30.0%#3.3%varies bP18.2%9.1%#varies bNote: shaded cells depict transitions that are not allowed.B = bronchiectasis health state; BI = bronchiectasis with infection health state; I = infection health state; IF =infection-free health state; Ig = immunoglobulin; P = Bronchiectasis with chronic Pseudomonas aeruginosa infection health state # = the proportion that remain in that health state after considering all other allowable transitions.a risk of infection is modelled only for the duration that patients would have received Ig therapyb Transition probabilities vary by ageD.4.2.Resource useCost of IgThe cost per gram of Ig used in the base case analysis is $60.41. This cost was provided by the Applicant to inform the economic and financial analyses and had been estimated retrospectively based on the reported total domestic product cost in 2017/18 ($195 million) minus domestic SCIg product costs ($4 million) in that same year, divided by the number of IVIg domestic grams issued (3,161,673) as published in the National Report on the Issues and Use of Ig in 2017/18 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>National Blood Authority [NBA]</Author><Year>2019</Year><RecNum>109</RecNum><Prefix>NBA </Prefix><DisplayText>(NBA 2019b)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">109</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>National Blood Authority [NBA],</author></authors></contributors><titles><title>National Report on the Issue and Use of Immunoglobulin (Ig) Annual Report 2017-18</title></titles><dates><year>2019</year></dates><pub-location>Canberra</pub-location><publisher>National Blood Authority </publisher><urls><related-urls><url>;(NBA 2019b) (see also REF _Ref13214532 \h Table 96, REF _Ref13644183 \h Appendix G). Analyses will be presented assuming:The highest cost of Ig (i.e. domestic IVIg, including the cost of plasma fractionation), $140.18The lowest cost of Ig (i.e. imported IVIg), $44.94The weighted average cost of Ig across all indications, $94.51These costs were also provided by the Applicant and were derived from the 2017/18 National Report on the issue and use of Ig in Australia ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>National Blood Authority [NBA]</Author><Year>2019</Year><RecNum>109</RecNum><Prefix>NBA </Prefix><DisplayText>(NBA 2019b)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">109</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>National Blood Authority [NBA],</author></authors></contributors><titles><title>National Report on the Issue and Use of Immunoglobulin (Ig) Annual Report 2017-18</title></titles><dates><year>2019</year></dates><pub-location>Canberra</pub-location><publisher>National Blood Authority </publisher><urls><related-urls><url>;(NBA 2019b). While there are slight variations between the prices per gram used in the model to that published on the NBA website (e.g. domestic IVIg has a current published price per gram of $58.23 as of July 1 2019), as all costs (including that of plasma fractionation) could be sourced from the same year, for consistency the prices retrospectively estimated from the NBA report are used. A sensitivity analysis will be presented using the current published price of domestic IVIg.As dosing for Ig is weight based, an average patient weight of 75?kg has been assumed (based on REF _Ref10549632 \h Table 30, Section C.2.1) and the average dose assumed is 0.37?g/kg (as per Section C.2.3). The estimated Ig cost per IVIg infusion is therefore estimated to be $1,671. The dose frequency modelled is assumed to be every four weeks and so the average cost per cycle of Ig is $417.81.Other costs associated with Ig treatment include the cost of consumables (including syringes, needles, cannula, infusion lines and alcohol wipes) and ward costs (including the use of a treatment chair and nursing supervision during Ig infusion). Per infusion, the costs of consumables have been estimated to be $21.41 and the administration costs, $232.01. These have been derived from the weekly costs reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019), in which IV infusions were performed monthly. The total per-cycle costs related to Ig treatment and administration are presented in REF _Ref12975967 \h Table 45.Table SEQ Table \* ARABIC 45Cost per cycle of IgCostSourceCost of Ig$417.81Calculated aConsumables$5.35Windegger et al. (2019) bAdministration costs$58.00Windegger et al. (2019) bTotal cost of Ig per week$476.29Ig = immunoglobulin.a Calculated assuming patient is 75.0kg and receives a 0.37 g/kg dose every 4 weeks, at a cost of $60.41 per gram.b Costs reported in Windegger et al. (2019) have been adjusted for infusion frequency, as this study reported monthly infusions, compared to the base case analysis, which assumes infusions every four weeks.These costs are assumed to apply for up to 26 months based on the median treatment duration reported in Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016) (see Section C.2.4 for further information), whilst patients are in the infection-free or infection health states. However if patients develop bronchiectasis while on Ig therapy, as transition probabilities have been adjusted to account for Ig use (see Section D.4.1), the cost of Ig will continue to apply. This approach is somewhat different to Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) which assumed continued Ig use through the 10 year time horizon, in all health states including infection-free. A sensitivity analysis is presented excluding the cost of Ig from the bronchiectasis health states, and as such, assuming no benefit of Ig with regards to preventing infections in the bronchiectasis health state. Ongoing disease management costsOther costs associated with the management of patients with acquired hypogammaglobulinaemia who are at-risk of infections are reported in REF _Ref11228496 \h Table 46. These costs are assumed to apply equally to both model arms. Costs included two haematologist visits per year and a test to monitor IgG trough levels. These costs have been based on the relevant MBS item numbers (MBS items 110 and 71068, respectively) and are assumed to apply while patients are considered to be at-risk of infections (i.e. up to 26 months in the infection-free health state and ongoing if bronchiectasis had developed). The cost of professional attendances were slightly lower than modelled in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) ($6.84), while pathology test costs were substantially lower than in the published analysis, $6.00, which may have assumed more frequent monitoring of IgG trough levels and also included costs to screen for infections. As infection screening tests have been included in the cost of treating infections, and no guidelines were identified that supported routine infection screening, these costs have not been included in the disease management costs. A sensitivity analysis will be presented using the costs from Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019).Table SEQ Table \* ARABIC 46Ongoing disease management costs included in the modelCostSourceHaematologist consult fee (two per year)$5.98MBS item 110Monitoring of serum IgG trough levels$0.28MBS item 71068Cost per week$6.26Ig = immunoglobulinCosts associated with treating infectionsThe clinical studies included in Section B reported infections by severity – serious infections which generally required hospitalisation, and non-serious infections, which did not require hospitalisation. The cost of treating a serious infection in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) was $6,927. During the Assessment process, the Ig Review Group considered that this cost was likely an underestimate of the cost and resource use associated with treating the various types of serious infections that patients were vulnerable to. Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) reported resource utilisation by infection severity. Major infections required hospitalisation and a follow-up outpatient attendance. Thus the cost of treating a serious infection was estimated to be $12,775, based on the weighted average of treating a range of infection types of major complexity (see REF _Ref16153473 \h Table 47). The total cost of treating a serious infection, including a follow-up outpatient attendance, was estimated to be $12,852 ( REF _Ref13668862 \h Table 48). Alternate costs will be tested in sensitivity analyses.Table SEQ Table \* ARABIC 47Average cost to treat a serious infectionDRG?DRG Description?SeparationsTotal costNo.weightT60ASepticaemia, Major Complexity8,21813.8%$25,381R01ALymphoma and Leukaemia W Major GIs, Major Complexity4550.8%$52,961I64AOsteomyelitis, Major Complexity2,1263.6%$18,269I67ASeptic Arthritis, Major Complexity7091.2%$15,261E62ARespiratory Infections and Inflammations, Major Complexity48,07680.7%$9,961Weighted$12,775Source: National Hospital Cost Data Collection, Cost Weights for AR-DRG Version 9.0, Round 21 (2016-17) Public Sector - Estimated National ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Independent Hospital Pricing Authority [IHPA]</Author><Year>2019</Year><RecNum>107</RecNum><Prefix>IHPA </Prefix><DisplayText>(IHPA 2019)</DisplayText><record><rec-number>107</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">107</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Independent Hospital Pricing Authority [IHPA],</author></authors></contributors><titles><title>National Hospital Cost Data Collection Report, Public Sector, Round 21 (Financial year 2016-17)</title></titles><volume>2019</volume><number>5 July</number><dates><year>2019</year><pub-dates><date>12 March</date></pub-dates></dates><publisher>Independent Hospital Pricing Authority,</publisher><urls><related-urls><url>;(IHPA 2019).In Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991), moderate infections required two outpatient attendances, a 10-day treatment course of antibiotics and a range of tests including urinalysis, urine, blood and sputum culture, complete blood count and a chest x-ray, while trivial infections required one outpatient attendance. Outpatient attendances by GPs were assumed for moderate and trivial infections (as per Windegger et al. 2019). Using the applicable MBS and PBS items, the cost of treating a non-serious infection was estimated to be $184 ( REF _Ref13668862 \h Table 48) and assumed that approximately two-thirds of non-serious infections were of moderate severity, based on Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991). This was similar to the cost modelled in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) ($160). The alternate costs will be tested in a sensitivity analysis.Table SEQ Table \* ARABIC 48Estimated cost of treating infections, by infection severityCostSourceSerious infectionsHospitalisation$12,775Weighted average cost of T60A, R01A, I64A, I67A and E62A AR-DRGs ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Independent Hospital Pricing Authority [IHPA]</Author><Year>2019</Year><RecNum>107</RecNum><Prefix>IHPA </Prefix><DisplayText>(IHPA 2019)</DisplayText><record><rec-number>107</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">107</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Independent Hospital Pricing Authority [IHPA],</author></authors></contributors><titles><title>National Hospital Cost Data Collection Report, Public Sector, Round 21 (Financial year 2016-17)</title></titles><volume>2019</volume><number>5 July</number><dates><year>2019</year><pub-dates><date>12 March</date></pub-dates></dates><publisher>Independent Hospital Pricing Authority,</publisher><urls><related-urls><url>;(IHPA 2019) – see also REF _Ref16153473 \h Table 47.Follow-up outpatient attendance$76.65MBS item 116Total cost of treating serious infections$12,852Non-serious moderate infectionsTwo outpatient attendances$76.40MBS item 23Urinalysis$4.55MBS item 73805Urine culture$20.55MBS item 69333Blood culture$30.75MBS item 69354Sputum culture$33.75MBS item 69318Complete blood count$16.95MBS item 65070Chest x-ray$47.15MBS item 5850310-day antibiotic course$26.72PBS item 2951HTotal cost of treating moderate infections$412.67Cost of treating trivial infections$38.20MBS item 23Weighted cost of treating non-serious infections$183.95Based on weighting of infections as reported in Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991) (67% moderate)As infection severity varies with or without Ig so too will the overall cost of treating infections. Infection severity by model arm has previously been described in Section D.4.1, thus the overall cost of treating infections with Ig is estimated to be $1,313 and without Ig, $3,861 ( REF _Ref11229210 \h Table 49). This cost is applied on the transition from the infection-free to infection health state.Table SEQ Table \* ARABIC 49Average cost of treating infections by model armIgNo IgSourceProportion of serious infections8.9%29.0% REF _Ref12894613 \h Table 40Cost to treat a serious infection$12,852.05$12,852.05 REF _Ref13668862 \h Table 48Proportion of non-serious infections91.1%71.0%Cost to treat a non-serious infection$183.95$183.95 REF _Ref13668862 \h Table 48Average cost per infection$1,313.44$3,861.10Ig = immunoglobulinCosts associated with bronchiectasisCosts associated with the management of bronchiectasis are reported in REF _Ref11230493 \h Table 50, and were based on those reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019). These include additional attendances, respiratory function tests and imaging. Disease management costs for patients at-risk of infections have also been included in the cost per cycle of this health state.Table SEQ Table \* ARABIC 50Cost associated with the management of bronchiectasisCostSourceRespiratory consult fee$8.95Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Respiratory function test (including ward costs)$18.07Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Imaging tests$5.63Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Disease management costs$6.26 REF _Ref11228496 \h Table 46Cost per week of treating bronchiectasis$38.91Infections with bronchiectasisThe resource utilisation of treating infections with bronchiectasis has been estimated using a similar approach as for infections without bronchiectasis, and assumes the cost of hospitalisation (based on the weighted relevant AR-DRG costs) and a follow-up outpatient attendance. The estimated cost per serious infection is estimated to be $9,143. This is lightly lower than the cost modelled in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019), $9,580, and the alternate cost will be tested in a sensitivity analysis. No difference in resource utilisation, and so cost, has been assumed for the treatment of non-serious infections. The model presented will assume that the cost of treating infections in the bronchiectasis health state will be the same irrespective of model arm and that the proportion of serious infections is as reported in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) (i.e. 12.5%). Thus the average cost of treating an infection with bronchiectasis is estimated to be $1,360. This is applied on the transition between the bronchiectasis and the bronchiectasis with infection health states.Table SEQ Table \* ARABIC 51Average cost of treating infections by model armCost associated with treating infectionsCostSourceProportion of serious infections12.5%Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019)Cost to treat a serious infectionHospitalisation$9,066Average weighted cost per E77A and B AR-DRG ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Independent Hospital Pricing Authority [IHPA]</Author><Year>2019</Year><RecNum>107</RecNum><Prefix>IHPA </Prefix><DisplayText>(IHPA 2019)</DisplayText><record><rec-number>107</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">107</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Independent Hospital Pricing Authority [IHPA],</author></authors></contributors><titles><title>National Hospital Cost Data Collection Report, Public Sector, Round 21 (Financial year 2016-17)</title></titles><volume>2019</volume><number>5 July</number><dates><year>2019</year><pub-dates><date>12 March</date></pub-dates></dates><publisher>Independent Hospital Pricing Authority,</publisher><urls><related-urls><url>;(IHPA 2019)Follow-up outpatient attendance$77MBS item 116Total cost$9,143Cost to treat a non-serious infection$183.95 REF _Ref13668862 \h Table 48Average cost per infection with bronchiectasis$1,303.83Costs associated with chronic P. aeruginosa infectionThe model presented in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) did not quantify resource use with the chronic P. aeruginosa infection health state and assumed the same cost as for the bronchiectasis with infection. Blanchette et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE.DATA (2017) compared resource utilisation in a US population in patients with non-cystic fibrosis bronchiectasis 12-months before and after a diagnosis of P. aeruginosa infection. This study observed a significant increase in the number of hospitalisations (from 3.45 to 7.44), ER attendances (from 0.53 to 0.98) and outpatient physician attendances (from 16.33 to 27.11) in the year after P. aeruginosa diagnosis. Assuming annual resource utilisation as per this study and applying local costs, the estimated cost per cycle is estimated to be $1,322 ( REF _Ref14254783 \h Table 52). This is slightly lower than the cost modelled in Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) for this health state when the cost of Ig is excluded ($1,370). This alternate cost will be tested in a sensitivity analysis.Table SEQ Table \* ARABIC 52Cost per cycle in the chronic P. aeruginosa infection health stateAnnual resource use and costSourceHospital admissions7.44Blanchette et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE.DATA (2017)Cost per admission$9,066Average weighted cost per E77A and B AR-DRG ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Independent Hospital Pricing Authority [IHPA]</Author><Year>2019</Year><RecNum>107</RecNum><Prefix>IHPA </Prefix><DisplayText>(IHPA 2019)</DisplayText><record><rec-number>107</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">107</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Independent Hospital Pricing Authority [IHPA],</author></authors></contributors><titles><title>National Hospital Cost Data Collection Report, Public Sector, Round 21 (Financial year 2016-17)</title></titles><volume>2019</volume><number>5 July</number><dates><year>2019</year><pub-dates><date>12 March</date></pub-dates></dates><publisher>Independent Hospital Pricing Authority,</publisher><urls><related-urls><url>;(IHPA 2019)Cost of hospital admissions with chronic P. aeruginosa infection$67,454ED visits0.98Blanchette et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE.DATA (2017)Cost per ED visit$533Average cost per non-admitted ED presentation ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Independent Hospital Pricing Authority [IHPA]</Author><Year>2019</Year><RecNum>107</RecNum><Prefix>IHPA </Prefix><DisplayText>(IHPA 2019)</DisplayText><record><rec-number>107</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">107</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Independent Hospital Pricing Authority [IHPA],</author></authors></contributors><titles><title>National Hospital Cost Data Collection Report, Public Sector, Round 21 (Financial year 2016-17)</title></titles><volume>2019</volume><number>5 July</number><dates><year>2019</year><pub-dates><date>12 March</date></pub-dates></dates><publisher>Independent Hospital Pricing Authority,</publisher><urls><related-urls><url>;(IHPA 2019)Cost of ED visits with chronic P. aeruginosa infection$522Increase in annual outpatient physician attendances166%Blanchette et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+QmxhbmNoZXR0ZTwvQXV0aG9y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ADDIN EN.CITE.DATA (2017)Annual cost of physician attendances with bronchiectasis$465Annual cost of respiratory consultant (based on REF _Ref11230493 \h \* MERGEFORMAT Table 50)Cost of physician visits with chronic P. aeruginosa infection$773Total annual cost$68,749Total cost per week$1,322ED = emergency department; NHCDC = Nation Hospital Cost Data Collection.Summary of health state costsThe weekly cost per cycle in each model health state are summarised in REF _Ref11232151 \h Table 53. Table SEQ Table \* ARABIC 53Health state costs per cycleIgNo IgInfection-free$487.43$6.26Infection (applied only on transition to health state)$1,313.44$3,861.10Bronchiectasis$520.08$38.91Bronchiectasis with infection (applied only on transition to health state)$1,303.83$1,303.83Bronchiectasis with chronic P. aeruginosa infection$1,842.16$1,361.00Ig = immunoglobulin.D.4.3.Utility weightsA premodelling study was presented in Section C.4.1 to identify relevant utility weights for use in the economic model. A summary of the utility weights used is presented in REF _Ref11236166 \h Table 54.Table SEQ Table \* ARABIC 54Utility weights used in the economic evaluationIgNo IgUtility in infection-free, including IV infusions0.70730.7148Utility with infection0.58050.5532Utility of bronchiectasis0.63920.6392Utility of bronchiectasis with infection0.53550.5355Utility of Bronchiectasis with chronic Pseudomonas aeruginosa infection0.53550.5355Ig = immunoglobulin; IV = intravenous.Results of the economic evaluationD.5.1.Stepped economic evaluationA stepped economic evaluation will be presented. A summary of each of the steps is presented below:Step 1: Trial-based analysis. This step will apply the dose, dose frequency, relative infection rates, trial time horizon and Ig treatment duration from the Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b) trial. This study was selected on the basis that, of the randomised studies, this study had the most patient years of data and used a dose that was most consistent with those recommended in the Version 3 criteria. Step 2: Trial-based analysis, extrapolated. The second step of the model will continue to apply the trial doses, dose frequency and relative infection rates as reported in the Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll
YXI+MTk5NDwvWWVhcj48UmVjTnVtPjU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigxOTk0Yik8L0Rp
c3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5
cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0
YWQiIHRpbWVzdGFtcD0iMTU1NDI2NjY2OSI+NTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5
cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0
aG9ycz48YXV0aG9yPkNoYXBlbCwgSC4gTS48L2F1dGhvcj48YXV0aG9yPkxlZSwgTS48L2F1dGhv
cj48YXV0aG9yPkhhcmdyZWF2ZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5QYW1waGlsb24sIEQuIEgu
PC9hdXRob3I+PGF1dGhvcj5QcmVudGljZSwgQS4gRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIEpvaG4gUmFk
Y2xpZmZlIEhvc3BpdGFsLCBPeGZvcmQsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
PlJhbmRvbWlzZWQgdHJpYWwgb2YgaW50cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW4gYXMgcHJvcGh5
bGF4aXMgYWdhaW5zdCBpbmZlY3Rpb24gaW4gcGxhdGVhdS1waGFzZSBtdWx0aXBsZSBteWVsb21h
LiBUaGUgVUsgR3JvdXAgZm9yIEltbXVub2dsb2J1bGluIFJlcGxhY2VtZW50IFRoZXJhcHkgaW4g
TXVsdGlwbGUgTXllbG9tYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQ8L3NlY29uZGFy
eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQ8L2Z1bGwtdGl0
bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDU5LTYzPC9wYWdlcz48dm9sdW1lPjM0Mzwvdm9sdW1l
PjxudW1iZXI+ODkwNTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPkJhY3RlcmlhbCBJbmZlY3Rpb25zLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tl
eXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIFZhY2NpbmVzPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJs
ZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnMsIEludHJhdmVub3VzL2Fk
dmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlv
biBDb250cm9sL21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y
ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdWx0aXBsZSBNeWVsb21hLypjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlBuZXVtb2NvY2NhbCBJbmZlY3Rpb25zL3ByZXZlbnRp
b24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QbmV1bW9jb2NjYWwgVmFjY2luZXM8
L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmlhL3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5
d29yZD48a2V5d29yZD5QcmVtZWRpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZl
IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjdXJyZW5jZTwva2V5d29yZD48a2V5d29yZD5T
ZXBzaXMvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlN0cmVwdG9j
b2NjdXMgcG5ldW1vbmlhZS9pbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjE5OTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHIgMzA8L2RhdGU+PC9wdWItZGF0ZXM+
PC9kYXRlcz48aXNibj4wMTQwLTY3MzYgKFByaW50KSYjeEQ7MDE0MC02NzM2IChMaW5raW5nKTwv
aXNibj48YWNjZXNzaW9uLW51bT43OTA5MDk5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk
LXVybHM+PHVybD48c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC83OTA5MDk5PC9zdHlsZT48
L3VybD48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEw
MCUiPmh0dHBzOi8vd3d3LnNjaWVuY2VkaXJlY3QuY29tL3NjaWVuY2UvYXJ0aWNsZS9waWkvUzAx
NDA2NzM2OTQ5MDE4MDU/dmlhJTNEaWh1Yjwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxyZXNlYXJjaC1ub3Rlcz5NTSAocGVhcmxlZCkgbm90IGNsZWFyIG9uIGlmIGhhZCBoeXBv
Z2FtbWE8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b) trial. However the time horizon is extrapolated to 10 years and the model allows for the development of bronchiectasis. Ig treatment duration is estimated based on Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll
YXI+MjAxNjwvWWVhcj48UmVjTnVtPjY2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigyMDE2KTwvRGlz
cGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj42NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlz
PjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJyMnBkMnRh
ZCIgdGltZXN0YW1wPSIxNTU0NDM3MzM5Ij42Njwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9
IiI+MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi
PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGF4dG9uLCBMLjwv
YXV0aG9yPjxhdXRob3I+SGF3a2lucywgQy48L2F1dGhvcj48YXV0aG9yPkNyaXNwaW4sIFAuPC9h
dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+QXVzdHJhbGlhbiBO
YXRpb25hbCBVbml2ZXJzaXR5IE1lZGljYWwgU2Nob29sLCBDYW5iZXJyYSwgQXVzdHJhbGlhLiYj
eEQ7RGVwYXJ0bWVudCBvZiBJbW11bm9sb2d5LCBDYW5iZXJyYSBIb3NwaXRhbCwgQ2FuYmVycmEs
IEF1c3RyYWxpYS4mI3hEO0F1c3RyYWxpYW4gTmF0aW9uYWwgVW5pdmVyc2l0eSBNZWRpY2FsIFNj
aG9vbCwgQ2FuYmVycmEsIEF1c3RyYWxpYS4gcGhpbGlwLmNyaXNwaW5AYWN0Lmdvdi5hdS4mI3hE
O0RlcGFydG1lbnQgb2YgSGFlbWF0b2xvZ3ksIENhbmJlcnJhIEhvc3BpdGFsLCBDYW5iZXJyYSwg
QXVzdHJhbGlhLiBwaGlsaXAuY3Jpc3BpbkBhY3QuZ292LmF1LjwvYXV0aC1hZGRyZXNzPjx0aXRs
ZXM+PHRpdGxlPlNlbGVjdGluZyBoYWVtYXRvbG9naWNhbCBtYWxpZ25hbmN5IHBhdGllbnRzIGZv
ciBpbnRyYXZlbm91cyBpbW11bm9nbG9idWxpbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5JbnRl
cm4gTWVkIEo8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs
ZT5JbnRlcm4gTWVkIEo8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjE2LTEyMTg8
L3BhZ2VzPjx2b2x1bWU+NDY8L3ZvbHVtZT48bnVtYmVyPjEwPC9udW1iZXI+PGtleXdvcmRzPjxr
ZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+
PGtleXdvcmQ+QXVzdHJhbGlhPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5
d29yZD5IZW1hdG9sb2dpYyBOZW9wbGFzbXMvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+SHVt
YW5zPC9rZXl3b3JkPjxrZXl3b3JkPipJbW11bml6YXRpb24sIFBhc3NpdmU8L2tleXdvcmQ+PGtl
eXdvcmQ+SW1tdW5vZ2xvYnVsaW5zLCBJbnRyYXZlbm91cy8qYWRtaW5pc3RyYXRpb24gJmFtcDsg
ZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkxpbmVhciBNb2RlbHM8L2tleXdvcmQ+PGtleXdvcmQ+
TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5SZXRy
b3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+aGFlbWF0b2xvZ2ljYWwgbWFsaWdu
YW5jeTwva2V5d29yZD48a2V5d29yZD5pbmZlY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+aW50cmF2
ZW5vdXMgaW1tdW5vZ2xvYnVsaW48L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAx
NjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk9jdDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp
c2JuPjE0NDUtNTk5NCAoRWxlY3Ryb25pYykmI3hEOzE0NDQtMDkwMyAoTGlua2luZyk8L2lzYm4+
PGFjY2Vzc2lvbi1udW0+Mjc3MzQ2MjA8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJs
cz48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUi
Pmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzI3NzM0NjIwPC9zdHlsZT48L3Vy
bD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMTEv
aW1qLjEzMjA1PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVzZWFyY2gtbm90ZXM+TWl4ZWQg
cG9wLiBib3RoIGJlZm9yZSBhbmQgYWZ0ZXIgY2FzZSBzZXJpZXMgYW5kIHJldHJvc3BlY3RpdmUg
Y29ob3J0LiAoZm91bmQgdGhyb3VnaCBnb29nbGluZyk8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3Jk
PjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA (2016).Step 3: Modelled base case analysis. The final step of the analysis models the benefit of Ig relative to no Ig based on the pooled IRRs estimated in Section B.6, assuming baseline infection rates from Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016). The dose of Ig modelled is that of the weighted average dose estimated from 2017/18 BloodSTAR data, with a dose frequency of every four weeks assumed. The results of the stepped analysis is presented in REF _Ref13227870 \h Table 55.Table SEQ Table \* ARABIC 55Results of the stepped economic analysisInc. costInc. QALYsICERStep 1 – Trial-based analysis.Applies the dose (0.4?g/kg), dose frequency (q4w), infection rates, time horizon (1 year) and Ig treatment duration (1 year) as per the Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll
YXI+MTk5NDwvWWVhcj48UmVjTnVtPjU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigxOTk0Yik8L0Rp
c3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5
cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0
YWQiIHRpbWVzdGFtcD0iMTU1NDI2NjY2OSI+NTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5
cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0
aG9ycz48YXV0aG9yPkNoYXBlbCwgSC4gTS48L2F1dGhvcj48YXV0aG9yPkxlZSwgTS48L2F1dGhv
cj48YXV0aG9yPkhhcmdyZWF2ZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5QYW1waGlsb24sIEQuIEgu
PC9hdXRob3I+PGF1dGhvcj5QcmVudGljZSwgQS4gRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIEpvaG4gUmFk
Y2xpZmZlIEhvc3BpdGFsLCBPeGZvcmQsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
PlJhbmRvbWlzZWQgdHJpYWwgb2YgaW50cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW4gYXMgcHJvcGh5
bGF4aXMgYWdhaW5zdCBpbmZlY3Rpb24gaW4gcGxhdGVhdS1waGFzZSBtdWx0aXBsZSBteWVsb21h
LiBUaGUgVUsgR3JvdXAgZm9yIEltbXVub2dsb2J1bGluIFJlcGxhY2VtZW50IFRoZXJhcHkgaW4g
TXVsdGlwbGUgTXllbG9tYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQ8L3NlY29uZGFy
eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQ8L2Z1bGwtdGl0
bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDU5LTYzPC9wYWdlcz48dm9sdW1lPjM0Mzwvdm9sdW1l
PjxudW1iZXI+ODkwNTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPkJhY3RlcmlhbCBJbmZlY3Rpb25zLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tl
eXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIFZhY2NpbmVzPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJs
ZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnMsIEludHJhdmVub3VzL2Fk
dmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlv
biBDb250cm9sL21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y
ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdWx0aXBsZSBNeWVsb21hLypjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlBuZXVtb2NvY2NhbCBJbmZlY3Rpb25zL3ByZXZlbnRp
b24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QbmV1bW9jb2NjYWwgVmFjY2luZXM8
L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmlhL3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5
d29yZD48a2V5d29yZD5QcmVtZWRpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZl
IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjdXJyZW5jZTwva2V5d29yZD48a2V5d29yZD5T
ZXBzaXMvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlN0cmVwdG9j
b2NjdXMgcG5ldW1vbmlhZS9pbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjE5OTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHIgMzA8L2RhdGU+PC9wdWItZGF0ZXM+
PC9kYXRlcz48aXNibj4wMTQwLTY3MzYgKFByaW50KSYjeEQ7MDE0MC02NzM2IChMaW5raW5nKTwv
aXNibj48YWNjZXNzaW9uLW51bT43OTA5MDk5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk
LXVybHM+PHVybD48c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC83OTA5MDk5PC9zdHlsZT48
L3VybD48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEw
MCUiPmh0dHBzOi8vd3d3LnNjaWVuY2VkaXJlY3QuY29tL3NjaWVuY2UvYXJ0aWNsZS9waWkvUzAx
NDA2NzM2OTQ5MDE4MDU/dmlhJTNEaWh1Yjwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxyZXNlYXJjaC1ub3Rlcz5NTSAocGVhcmxlZCkgbm90IGNsZWFyIG9uIGlmIGhhZCBoeXBv
Z2FtbWE8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE.DATA (1994b) study.a$22,734–0.0035Dominated bStep 2 – Trial-based, extrapolated analysisApplies the dose, dose frequency and infection rates from the Chapel et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+Q2hhcGVsPC9BdXRob3I+PFll
YXI+MTk5NDwvWWVhcj48UmVjTnVtPjU2PC9SZWNOdW0+PERpc3BsYXlUZXh0PigxOTk0Yik8L0Rp
c3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5
cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVwOWUycjJwZDJ0
YWQiIHRpbWVzdGFtcD0iMTU1NDI2NjY2OSI+NTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5
cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0
aG9ycz48YXV0aG9yPkNoYXBlbCwgSC4gTS48L2F1dGhvcj48YXV0aG9yPkxlZSwgTS48L2F1dGhv
cj48YXV0aG9yPkhhcmdyZWF2ZXMsIFIuPC9hdXRob3I+PGF1dGhvcj5QYW1waGlsb24sIEQuIEgu
PC9hdXRob3I+PGF1dGhvcj5QcmVudGljZSwgQS4gRy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIEltbXVub2xvZ3ksIEpvaG4gUmFk
Y2xpZmZlIEhvc3BpdGFsLCBPeGZvcmQsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
PlJhbmRvbWlzZWQgdHJpYWwgb2YgaW50cmF2ZW5vdXMgaW1tdW5vZ2xvYnVsaW4gYXMgcHJvcGh5
bGF4aXMgYWdhaW5zdCBpbmZlY3Rpb24gaW4gcGxhdGVhdS1waGFzZSBtdWx0aXBsZSBteWVsb21h
LiBUaGUgVUsgR3JvdXAgZm9yIEltbXVub2dsb2J1bGluIFJlcGxhY2VtZW50IFRoZXJhcHkgaW4g
TXVsdGlwbGUgTXllbG9tYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQ8L3NlY29uZGFy
eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQ8L2Z1bGwtdGl0
bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMDU5LTYzPC9wYWdlcz48dm9sdW1lPjM0Mzwvdm9sdW1l
PjxudW1iZXI+ODkwNTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPkJhY3RlcmlhbCBJbmZlY3Rpb25zLypwcmV2ZW50aW9uICZhbXA7IGNvbnRyb2w8L2tl
eXdvcmQ+PGtleXdvcmQ+QmFjdGVyaWFsIFZhY2NpbmVzPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJs
ZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3Jk
Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnMsIEludHJhdmVub3VzL2Fk
dmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlv
biBDb250cm9sL21ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y
ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NdWx0aXBsZSBNeWVsb21hLypjb21wbGlj
YXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlBuZXVtb2NvY2NhbCBJbmZlY3Rpb25zL3ByZXZlbnRp
b24gJmFtcDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QbmV1bW9jb2NjYWwgVmFjY2luZXM8
L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmlhL3ByZXZlbnRpb24gJmFtcDsgY29udHJvbDwva2V5
d29yZD48a2V5d29yZD5QcmVtZWRpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZl
IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjdXJyZW5jZTwva2V5d29yZD48a2V5d29yZD5T
ZXBzaXMvcHJldmVudGlvbiAmYW1wOyBjb250cm9sPC9rZXl3b3JkPjxrZXl3b3JkPlN0cmVwdG9j
b2NjdXMgcG5ldW1vbmlhZS9pbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjE5OTQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BcHIgMzA8L2RhdGU+PC9wdWItZGF0ZXM+
PC9kYXRlcz48aXNibj4wMTQwLTY3MzYgKFByaW50KSYjeEQ7MDE0MC02NzM2IChMaW5raW5nKTwv
aXNibj48YWNjZXNzaW9uLW51bT43OTA5MDk5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVk
LXVybHM+PHVybD48c3R5bGUgZmFjZT0idW5kZXJsaW5lIiBmb250PSJkZWZhdWx0IiBzaXplPSIx
MDAlIj5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC83OTA5MDk5PC9zdHlsZT48
L3VybD48dXJsPjxzdHlsZSBmYWNlPSJ1bmRlcmxpbmUiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEw
MCUiPmh0dHBzOi8vd3d3LnNjaWVuY2VkaXJlY3QuY29tL3NjaWVuY2UvYXJ0aWNsZS9waWkvUzAx
NDA2NzM2OTQ5MDE4MDU/dmlhJTNEaWh1Yjwvc3R5bGU+PC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxyZXNlYXJjaC1ub3Rlcz5NTSAocGVhcmxlZCkgbm90IGNsZWFyIG9uIGlmIGhhZCBoeXBv
Z2FtbWE8L3Jlc2VhcmNoLW5vdGVzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA (1994b) study, with the model time horizon extrapolated to 10 years, with the development of bronchiectasis to be modelled. Ig treatment duration is based on Paxton, Hawkins & Crispin PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+UGF4dG9uPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA (2016) (26 months).$66,9220.2556$261,789Step 3 – Modelled economic evaluationApplies the pooled IRRs estimated in Section B.6 to the best available source of baseline infection rates in Australia (based on Paxton, Hawkins & Crispin 2016), while assuming the weighted average dose from BloodSTAR data (0.37?g/kg).$41,0110.4109$99,803ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; IRR = incidence rate ratio; QALY = quality-adjusted life years.a This study was chosen on the basis that, of the randomised studies, this study had the most patient years of data and used a dose that was most consistent with those recommended in the Version 3 criteria.b Ig is more costly and less effective than the comparator.In Step 1 of the analysis the ICER of Ig is observed to be dominated, with a net reduction in QALYs resulting from the inclusion of a disutility per IV infusion. In Step 2, the time horizon is extrapolated to 10 years and allows for the development of bronchiectasis which leads to a substantial improvement in the ICER. Further improvements in the ICER are observed when the best estimates of baseline infection rates, Ig treatment effect and dose are included in the modelling.D.5.2.Modelled base case analysisDisaggregated costs and outcomesThe costs and outcomes disaggregated for the base case analysis are presented in REF _Ref13228370 \h Table 56 and REF _Ref13228376 \h Table 57. Table SEQ Table \* ARABIC 56Disaggregated costsIgNo IgIncremental costIg$66,565$0$66,565Antibiotic prophylaxis$0$0$0Disease management$596$519$77Infections$1,659$8,668–$7,009Bronchiectasis$1,680$3,528–$1,848Infections in bronchiectasis$2,136$6,713–$4,577Bronchiectasis with chronic P. aeruginosa$5,638$17,835–$12,197Total cost$78,273$37,262$41,011Ig = immunoglobulin.The cost of Ig was the main driver of the incremental cost, with offsets related to a reduction in the number of infections and costs associated with managing chronic P. aeruginosa infections.Table SEQ Table \* ARABIC 57Disaggregated LYs and QALYsIgNo IgIncrementLife-years gainedInfection-free LYs5.89974.52971.3700Infection LYs0.03490.0668–0.0319Bronchiectasis LYs0.63031.1162–0.4859Bronchiectasis with infection LYs0.11770.3676–0.2500Bronchiectasis with chronic P. aeruginosa LYs0.08200.2594–0.1774Total LYs6.76466.33980.4248QALYs gainedInfection-free QALYs4.20353.23770.9658Infection QALYs0.02150.0369–0.0154Bronchiectasis QALYs0.40290.7135–0.3106Bronchiectasis with infection QALYs0.06300.1969–0.1338Bronchiectasis with chronic P. aeruginosa QALYs0.04390.1389–0.0950Total QALYs4.73494.32390.4109Number of infectionsNo. infections, without bronchiectasis1.262.24–0.98No. infections, with bronchiectasis1.645.15–3.51Number of infections2.907.39–4.49Development of chronic P. aeruginosa1.183.75–2.56Ig = immunoglobulin; LY = life years; QALY = quality-adjusted life years.The incremental QALYs were primarily accrued in the infection-free health state. As Ig was associated with fewer infections of lower severity, less time was spent in the infection health state with Ig and patients had a lower risk of developing bronchiectasis and subsequent health states. Markov traces depicting health state membership over time are presented in REF _Ref16607293 \h Figure 10. Figure SEQ Figure \* ARABIC 10Markov model tracesIg = immunoglobulin.Incremental cost-effectivenessThe ICERs per additional QALYs gained and per infection avoided are presented in REF _Ref13229107 \h Table 58.Table SEQ Table \* ARABIC 58Incremental cost-effectiveness ratiosIgNo IgIncrementTotal cost$78,273$37,262$41,011Total QALYs4.73494.32390.4109ICER per additional QALY gained$99,803Number of infections2.907.39–4.49ICER per infection avoided$9,128ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; QALY = quality-adjusted life years.Sensitivity analysesD.6.1.Cost per gram of IgSensitivity analyses ( REF _Ref14273310 \h Table 59) are presented applying differing assumptions regarding the cost of Ig modelled. Table SEQ Table \* ARABIC 59Scenario analyses regarding the cost of IgInc. costInc. QALYsICERBase case analysis ($60.41)$41,0110.4109$99,803High cost of Ig ($140.18)$117,3350.4109$285,543Low cost of Ig ($44.94)$26,2090.4109$63,782Weighted average cost of Ig ($94.51)$73,6340.4109$179,195ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; QALY = quality-adjusted life years.D.6.2.Scenario based on the study which included antibiotic prophylaxisAs described in Section C.2.2, it is uncertain whether rates of antibiotic prophylaxis would increase in the absence of Ig (given that randomised trials, including one contemporary trial, did not allow antibiotic prophylaxis in the absence of Ig). In the case that rates did increase in the absence of Ig, it is uncertain what effect this would have on the relative treatment effect of Ig, given that this comparison is currently being explored. One non-randomised study was identified that did observe a decrease in prophylactic antibiotic use after Ig initiation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EdXJhaXNpbmdoYW08L0F1dGhvcj48WWVhcj4yMDE0PC9Z
ZWFyPjxSZWNOdW0+MjA8L1JlY051bT48RGlzcGxheVRleHQ+KER1cmFpc2luZ2hhbSBldCBhbC4g
MjAxNCk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjA8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ6MHZ3c2VwZHdwdDIwcGV3d3RzNXo5ZXVw
OWUycjJwZDJ0YWQiIHRpbWVzdGFtcD0iMTU1MzgyNTA1OSI+MjA8L2tleT48L2ZvcmVpZ24ta2V5
cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1
dG9ycz48YXV0aG9ycz48YXV0aG9yPkR1cmFpc2luZ2hhbSwgUy4gUy48L2F1dGhvcj48YXV0aG9y
PkJ1Y2tsPC9hdXRob3I+PGF1dGhvcj4sIE0uPC9hdXRob3I+PGF1dGhvcj5EZW1wc3RlciwgSi48
L2F1dGhvcj48YXV0aG9yPkxvcmVuem8sIEwuPC9hdXRob3I+PGF1dGhvcj5Hcmlnb3JpYWRvdSwg
Uy48L2F1dGhvcj48YXV0aG9yPkxvbmdodXJzdCwgSC4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9j
b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbW11bm9sb2d5IERlcGFydG1lbnQsIEJhcnRzIEhl
YWx0aCBOSFMgVHJ1c3QsIExvbmRvbiwgVW5pdGVkIEtpbmdkb20uPC9hdXRoLWFkZHJlc3M+PHRp
dGxlcz48dGl0bGU+UHJpbWFyeSB2cy4gc2Vjb25kYXJ5IGFudGlib2R5IGRlZmljaWVuY3k6IGNs
aW5pY2FsIGZlYXR1cmVzIGFuZCBpbmZlY3Rpb24gb3V0Y29tZXMgb2YgaW1tdW5vZ2xvYnVsaW4g
cmVwbGFjZW1lbnQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBPbmU8L3NlY29uZGFyeS10
aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE9uZTwvZnVsbC10aXRs
ZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUxMDAzMjQ8L3BhZ2VzPjx2b2x1bWU+OTwvdm9sdW1lPjxu
dW1iZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxr
ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnYW1tYWdsb2J1bGluZW1pYS9jb21wbGlj
YXRpb25zLyBkaWFnbm9zaXMvIGV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdv
cmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QnJvbmNoaWVj
dGFzaXMvZGlhZ25vc2lzL2V0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVz
PC9rZXl3b3JkPjxrZXl3b3JkPkRlbGF5ZWQgRGlhZ25vc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkZl
bWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xv
YnVsaW5zL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbW11bm9zdXBwcmVzc2l2
ZSBBZ2VudHMvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlvbi9ldGlv
bG9neS90aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlk
ZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UGF0aWVudCBPdXRjb21lIEFzc2Vzc21lbnQ8L2tl
eXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PGtleXdvcmQ+WW91bmcg
QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRzwva2V5d29yZD48a2V5d29y
ZD5JbW11bm9nbG9idWxpbiBEPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIE08L2tl
eXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gQTwva2V5d29yZD48a2V5d29yZD5JbW11bm9n
bG9idWxpbiBFPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIFZhcmlhYmxlIFJlZ2lv
bjwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48
ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjIwMTQ8L2RhdGU+PC9wdWIt
ZGF0ZXM+PC9kYXRlcz48aXNibj4xOTMyLTYyMDMgKEVsZWN0cm9uaWMpIDE5MzItNjIwMyAoTGlu
a2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ5NzE2NDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+
PC91cmxzPjxjdXN0b20xPlJBWVlBTi1JTkNMVVNJT046IHsmcXVvdDtTa3llJnF1b3Q7PSZndDsm
cXVvdDtJbmNsdWRlZCZxdW90O308L2N1c3RvbTE+PHJlc2VhcmNoLW5vdGVzPlggLSBtb3N0IG9m
IHRoZSBzZWNvbmRhcnkgSHlwb0dHIGR1ZSB0byBjaGVtbyB3aXRoIFJUWCAuIHdyb25nIHBvcDwv
cmVzZWFyY2gtbm90ZXM+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwv
RW5kTm90ZT4A
ADDIN EN.CITE.DATA (Duraisingham et al. 2014), and so scenario analyses are presented based on the results of this study ( REF _Ref14273454 \h Table 60). Table SEQ Table \* ARABIC 60Scenario analyses based on the study which included antibiotic prophylaxisInc. costInc. QALYsICERBase case analysis$41,0110.4109$99,803Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE.DATA (2014) (trial based dose, 0.53 g/kg)$82,8430.5315$155,864Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo
b3I+PFllYXI+MjAxNDwvWWVhcj48UmVjTnVtPjIwPC9SZWNOdW0+PERpc3BsYXlUZXh0PigyMDE0
KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMDwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InowdndzZXBkd3B0MjBwZXd3dHM1ejlldXA5ZTJy
MnBkMnRhZCIgdGltZXN0YW1wPSIxNTUzODI1MDU5Ij4yMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxy
ZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3Jz
PjxhdXRob3JzPjxhdXRob3I+RHVyYWlzaW5naGFtLCBTLiBTLjwvYXV0aG9yPjxhdXRob3I+QnVj
a2w8L2F1dGhvcj48YXV0aG9yPiwgTS48L2F1dGhvcj48YXV0aG9yPkRlbXBzdGVyLCBKLjwvYXV0
aG9yPjxhdXRob3I+TG9yZW56bywgTC48L2F1dGhvcj48YXV0aG9yPkdyaWdvcmlhZG91LCBTLjwv
YXV0aG9yPjxhdXRob3I+TG9uZ2h1cnN0LCBILiBKLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy
aWJ1dG9ycz48YXV0aC1hZGRyZXNzPkltbXVub2xvZ3kgRGVwYXJ0bWVudCwgQmFydHMgSGVhbHRo
IE5IUyBUcnVzdCwgTG9uZG9uLCBVbml0ZWQgS2luZ2RvbS48L2F1dGgtYWRkcmVzcz48dGl0bGVz
Pjx0aXRsZT5QcmltYXJ5IHZzLiBzZWNvbmRhcnkgYW50aWJvZHkgZGVmaWNpZW5jeTogY2xpbmlj
YWwgZmVhdHVyZXMgYW5kIGluZmVjdGlvbiBvdXRjb21lcyBvZiBpbW11bm9nbG9idWxpbiByZXBs
YWNlbWVudDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TIE9uZTwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlBMb1MgT25lPC9mdWxsLXRpdGxlPjwv
cGVyaW9kaWNhbD48cGFnZXM+ZTEwMDMyNDwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+PG51bWJl
cj42PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdv
cmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdhbW1hZ2xvYnVsaW5lbWlhL2NvbXBsaWNhdGlv
bnMvIGRpYWdub3Npcy8gZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48
a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpZWN0YXNp
cy9kaWFnbm9zaXMvZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tl
eXdvcmQ+PGtleXdvcmQ+RGVsYXllZCBEaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxp
bnMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub3N1cHByZXNzaXZlIEFn
ZW50cy9hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mZWN0aW9uL2V0aW9sb2d5
L3RoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUg
QWdlZDwva2V5d29yZD48a2V5d29yZD5QYXRpZW50IE91dGNvbWUgQXNzZXNzbWVudDwva2V5d29y
ZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5Zb3VuZyBBZHVs
dDwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHPC9rZXl3b3JkPjxrZXl3b3JkPklt
bXVub2dsb2J1bGluIEQ8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gTTwva2V5d29y
ZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBBPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1
bGluIEU8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gVmFyaWFibGUgUmVnaW9uPC9r
ZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRl
cz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxNDwvZGF0ZT48L3B1Yi1kYXRl
cz48L2RhdGVzPjxpc2JuPjE5MzItNjIwMyAoRWxlY3Ryb25pYykgMTkzMi02MjAzIChMaW5raW5n
KTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDk3MTY0NDwvYWNjZXNzaW9uLW51bT48dXJscz48L3Vy
bHM+PGN1c3RvbTE+UkFZWUFOLUlOQ0xVU0lPTjogeyZxdW90O1NreWUmcXVvdDs9Jmd0OyZxdW90
O0luY2x1ZGVkJnF1b3Q7fTwvY3VzdG9tMT48cmVzZWFyY2gtbm90ZXM+WCAtIG1vc3Qgb2YgdGhl
IHNlY29uZGFyeSBIeXBvR0cgZHVlIHRvIGNoZW1vIHdpdGggUlRYIC4gd3JvbmcgcG9wPC9yZXNl
YXJjaC1ub3Rlcz48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmRO
b3RlPgB=
ADDIN EN.CITE.DATA (2014) (base case dose, 0.37 g/kg)$51,2210.5315$96,369ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; QALY = quality-adjusted life years.A substantial increase in the ICER is observed relative to the base case analysis. This is predominantly driven by a higher dose of Ig used (0.53?g/kg). When the dose is decreased to the weighted average (0.37?g/kg), a moderate reduction in the ICER relative to the base case analysis is observed ( REF _Ref14273454 \h Table 60).D.6.3.Scenarios based on the best estimates of analysis for specific indicationsScenario analyses are presented using the best estimates of model inputs specific to each indication ( REF _Ref16671931 \h Table 61). Disaggregated events (i.e. infections and development of chronic P. aeruginosa infections) are also depicted in REF _Ref16671937 \h Table 62. Given that there was not data to inform all model inputs specifically by indication, these are indicative results only, and should be interpreted with caution. No studies were available to enable an estimate for the ‘other haematological malignancies’ indication.Table SEQ Table \* ARABIC 61Scenario analyses estimating indicative cost-effectiveness per indicationCostLYsQALYsICER /QALY (Low – High cost)IgNo IgInc.IgNo IgInc.IgNo IgInc.Base case analysisAssumes the average patient demographics (age: 66, weight: 75.0?kg) and dose (0.37?g/kg) from BloodSTAR data for acquired hypogammaglobulinaemia patients overall. The treatment effect of Ig is based on the pooled IRRs (IRRS = 0.146, IRRNS = 0.61).$78,273$37,262$41,0116.766.340.424.734.320.41$99,803 ($63,782 ? $285,543)CLLAssumes the average patient demographics (age: 72, weight: 77.3?kg) and dose (0.37?g/kg) from BloodSTAR data for this indication. Baseline infection rates and mortality rates are unchanged from the base case analysis and the treatment effect of Ig is based on the pooled IRRs for CLL (IRRS = 0.38, IRRNS = 0.69).$81,220$28,345$52,8755.915.520.394.123.790.33$161,491 ($115,562 ? $398,319)MMAssumes the average patient demographics (age: 70, weight: 77.8?kg) and dose (0.37?g/kg) from BloodSTAR data for this indication. Baseline infection rates are unchanged from the base case analysis however a 100% increase in the infection-free mortality rate has been assumeda. The treatment effect of Ig is based on the pooled IRRs for MM (IRRS = 0.08, IRRNS = 0.55).$62,096$24,391$37,7055.334.690.653.763.230.52$71,951 ($48,060 ? $195,142)NHLAssumes the average patient demographics (age: 68, weight: 76.3?kg) and dose (0.36?g/kg) from BloodSTAR data for this indication. Baseline infection rates and mortality ratesb are unchanged from the base case analysis and the treatment effect of Ig is based on the Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE.DATA (2014) studyc (IRRS = 0.27, IRRNS = 0.57).$78,786$35,295$43,4916.536.080.454.574.160.41$106,290 ($70,579 ? $290,434)ALAssumes the average patient demographics (age: 37, weight: 57.1?kg) and dose (0.37?g/kg) from BloodSTAR data for this indication. Baseline infection rates and mortality ratesd are unchanged from the base case analysis and the treatment effect of Ig is based on the Van Winkle et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFuIFdpbmtsZTwvQXV0aG9y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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+VmFuIFdpbmtsZTwvQXV0aG9y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 EN.CITE.DATA (2018) study (IRRS = 0.32, IRRNS = 0.11).$64,623$82,737–$18,1137.797.640.155.485.080.40Dominante (Dominant ? $98,879)Post-HSCTAssumes the average patient demographics (age: 42, weight: 63.6?kg) and dose (0.37?g/kg) from BloodSTAR data for this indication. Baseline infection rates and mortality ratesf are unchanged from the base case analysis and the treatment effect of Ig is based on the Sullivan et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+U3VsbGl2YW48L0F1dGhvcj48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ADDIN EN.CITE.DATA (1990) study (IRRS = 0.59, IRRNS = 0.68).$104,842$46,594$58,2497.687.620.065.295.160.13$442,863 ($314,180 ? $1,106,408)AL = acute leukemia; CLL = chronic lymphocytic lymphoma; HSCT = haemopoietic stem cell transplantation; ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; IRRNS = incidence rate ratio for non-serious infections; IRRS = incidence rate ratio for serious infections; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma; QALY = quality-adjusted life years.a higher mortality rate has been assumed as Cancer Australia statistics indicate that five-year survival at MM diagnosis was approximately 49%, compared to five-year survival at diagnosis in CLL of 77%. The ICER is not sensitive to this change – assuming the same mortality risk as in the base case analysis increases the ICER slightly to $73,306.b No change in the mortality rate has been assumed relative to the CLL mortality rate used in the base case analysis as five-year survival estimates at diagnosis were similar between NHL (72%) and CLL (77%).c While the Duraisingham et al. PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiPjxBdXRob3I+RHVyYWlzaW5naGFtPC9BdXRo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ADDIN EN.CITE.DATA (2014) study included patients with mixed haematological malignancies, these were predominantly NHL.d No change in the mortality rate has been assumed relative to the CLL mortality rate used in the base case analysis as it is unclear what proportion of patients with AL and acquired hypogammaglobulinaemia have AML or ALL, which are associated with different five-year survival estimates at diagnosis (25% and 90%, respectively). One average, it is assumed that it would be approximately similar to CLL patients.e Ig is less costly and more effective than no treatment.f No change in the mortality rate has been assumed relative to the CLL mortality rate used in the base case analysis as no data could be identified to inform what the difference would be.Table SEQ Table \* ARABIC 62Disaggregated events estimated for each of the per-indication analysesNo. infections - no bronchiectasisNo. infections - with bronchiectasisDevelopment of chronic P. aeruginosaIgNo IgInc.IgNo IgInc.IgNo IgInc.Base case analysis1.262.24–0.981.645.15–3.511.183.75–2.56CLL1.502.21–0.711.683.51–1.841.212.55–1.34MM1.072.16–1.090.792.91–2.120.572.11–1.55NHL1.262.24–0.971.664.81–3.151.203.50–2.30AL0.492.28–1.801.3813.75–12.361.0010.48–9.48Post-HSCT1.652.28–0.633.566.70–3.142.584.87–2.29AL = acute leukemia; CLL = chronic lymphocytic lymphoma; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.In AL, Ig is observed to be both less costly and more effective (i.e. the ICER is dominant). This appears to be due to an assumed younger patient age, and therefore lower background mortality risk. AL patients therefore spend more time alive in the bronchiectasis health states which are associated with a higher cost. Further, the study in which this analysis was based on reported a substantial reduction in non-serious infections (and so preventing bronchiectasis with Ig). A substantial increase is observed in the ICER for post-HSCT. This is driven by higher IRRs modelled.D.6.4.Univariate sensitivity analysesAll other sensitivity analyses conducted around areas of uncertainty in the model are presented in REF _Ref13241082 \h Table 97, REF _Ref13644183 \h Appendix G. Key sensitivity analyses (i.e. those which changed the ICER by more than 10%) are presented in REF _Ref13241088 \h Table 63, below.Table SEQ Table \* ARABIC 63Key sensitivity analysesInc. costInc. QALYsICER% changeBase case analysis$41,0110.4109$99,803-Baseline annual infection rates (base case: Paxton, Hawkins & Crispin 2016, serious 0.43, non-serious 1.05)Molica et al. (1996): serious 0.29, non-serious 1.73$50,1600.3819$131,32832%Chapel et al. (1994): serious 0.26, non-serious 1.75$51,3460.3653$140,55541%Sullivan et al. (1990): serious 1.79, non-serious 3.79$48,0620.7121$67,493–32%IRR of Ig treatment effect (base case: serious, 0.15; non-serious 0.61)Serious infections, 0.43$52,5260.3139$167,31568%Non-serious infections, 0.72$46,2360.3523$131,23331%Duration of Ig treatment (base case: 2.2 years)5 years$84,2610.5430$155,16855%10 years$125,0970.5457$229,233130%Exclude development of bronchiectasis$41,2130.0141$2,927,5252833%Time horizon (base case: 10 years)2.2 years (as per Ig treatment duration)$38,8690.0322$1,208,3431111%5 years$39,5520.1509$262,086163%Transition probabilities (base case: adjusted)Transitions from infection health state, unadjusted$45,3090.3087$146,79247%Transitions from infection and bronchiectasis, unadjusted$29,9270.2335$128,15428%Cost of hospitalisation of serious infections (base case: $12,775)$52,961, based on AR-DRG R01A$19,3490.4109$47,088–53%ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; IRR = incidence rate ratio; QALY = quality-adjusted life year. The model is highly sensitive to the inclusion of the bronchiectasis health states. When these health states are excluded, the ICER significantly increases to $3 million per additional QALY gained. This result is consistent with that observed in Weeks, Tierney & Weinstein ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Weeks</Author><Year>1991</Year><RecNum>35</RecNum><DisplayText>(1991)</DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1553825060">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weeks, J. C.</author><author>Tierney, M. R.</author><author>Weinstein, M. C.</author></authors></contributors><titles><title>Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia</title><secondary-title>New England journal of medicine</secondary-title></titles><periodical><full-title>New England journal of medicine</full-title></periodical><pages>81‐86</pages><volume>325</volume><number>2</number><keywords><keyword>Agammaglobulinemia [complications]</keyword><keyword>Bacterial Infections [*prevention & control]</keyword><keyword>Cost‐Benefit Analysis</keyword><keyword>Humans</keyword><keyword>Immunization, Passive [*economics]</keyword><keyword>Immunoglobulins [*administration & dosage]</keyword><keyword>Infusions, Intravenous</keyword><keyword>Leukemia, Lymphocytic, Chronic, B‐Cell [*complications, economics]</keyword><keyword>Life Expectancy</keyword><keyword>Models, Theoretical</keyword><keyword>Quality of Life</keyword><keyword>United States</keyword><keyword>Cost-Benefit Analysis</keyword><keyword>Leukemia, Lymphoid</keyword><keyword>Immunoglobulins, Intravenous</keyword><keyword>Immunoglobulins</keyword></keywords><dates><year>1991</year><pub-dates><date>1991</date></pub-dates></dates><accession-num>CN-00076105</accession-num><urls><related-urls><url><style face="underline" font="default" size="100%">: {"Skye"=>"Included"}</custom1><research-notes>X - decision analytic study, no new clinical data</research-notes></record></Cite></EndNote>(1991), which also did not model the development of bronchiectasis. The inclusion of these health states had been justified based on the model structure used in a contemporary economic evaluation ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019).The model is also sensitive to the selection of the time horizon, the treatment effect of Ig, baseline infection rates and whether transition probabilities from Windegger et al. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(2019) have been adjusted for the comparison to no Ig.Section EFinancial ImplicationsA market-based approach has been used to estimate the financial implications of Ig in acquired hypogammaglobulinaemia, based on current utilisation of Ig products in patients with acquired hypogammaglobulinaemia. As data available on utilisation were only available for use under the Version 2 Criteria, the impact of transitioning to the Version 3 Criteria were not able to be captured in the analysis. There is uncertainty as to whether trends observed in the past would continue.It is also acknowledged that rapid technological development is occurring in this therapeutic area and this may also change clinical demand and Ig use in the future. For example, demand may increase if patients using new therapies (such as monoclonal antibodies, CAR-T cell therapy and BTK inhibitors) live longer with suppressed immune systems.Justification of the selection of sources of dataThe primary sources of data used in the estimates of the financial impact of Ig in acquired hypogammaglobulinaemia are:NBA ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>National Blood Authority [NBA]</Author><Year>2019</Year><RecNum>108</RecNum><DisplayText>(2019a)</DisplayText><record><rec-number>108</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">108</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>National Blood Authority [NBA],</author></authors></contributors><titles><title>Data Analysis and Reporting</title></titles><dates><year>2019</year></dates><pub-location>Canberra</pub-location><publisher>National Blood Authority </publisher><urls><related-urls><url>;(2019a) National reports on the issue and use of immunoglobulin (Ig), which report the number of patients and Ig use, by indication, from 2011-12 to 2015-16.The 'HTA Data April2019.xlsx' workbook provided by the NBA - which reports use, by indication, for the full financial year 2017-18 and for the 2018-19 partial year to December 31, 2018 (and so reports some use under the Version 3 criteria). The full year data available from these sources are summarised in REF _Ref9868003 \h Table 64 and REF _Ref12448325 \h Table 65. Table SEQ Table \* ARABIC 64Number of patients who received Ig by indication, 2011-12 to 2017-182011-122012-132013-142014-152015-162016-172017-18CLL1,0601,0801,1791,2831,380-1,632MM9019711,0121,1001,177-1,458NHL-9401,0601,2081,308-1,651Post HSCT---307345-443Other HM-510448428574-625CLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Source: NBA ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>National Blood Authority [NBA]</Author><Year>2019</Year><RecNum>108</RecNum><DisplayText>(2019a)</DisplayText><record><rec-number>108</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">108</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>National Blood Authority [NBA],</author></authors></contributors><titles><title>Data Analysis and Reporting</title></titles><dates><year>2019</year></dates><pub-location>Canberra</pub-location><publisher>National Blood Authority </publisher><urls><related-urls><url>;(2019a) National Reports on the issue and use of immunoglobulin (Ig), 2012-13, 2013-14, 20114-15 and 2015-16 and the 'HTA Data April2019.xlsx' workbook provided by the NBA.Table SEQ Table \* ARABIC 65Ig grams issued by indication, 2011-12 to 2017-182011-122012-132013-142014-152015-162016-172017-18CLL-253,763280,076315,205350,066435,193MM-208,997229,303255,962275,685354,158NHL-218,655245,436287,900332,148422,919Post HSCT---42,73848,26672,141Other HM-83,57180,80780,96994,004117,613CLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Source: NBA ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>National Blood Authority [NBA]</Author><Year>2019</Year><RecNum>108</RecNum><DisplayText>(2019a)</DisplayText><record><rec-number>108</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">108</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>National Blood Authority [NBA],</author></authors></contributors><titles><title>Data Analysis and Reporting</title></titles><dates><year>2019</year></dates><pub-location>Canberra</pub-location><publisher>National Blood Authority </publisher><urls><related-urls><url>;(2019a) National Reports on the issue and use of immunoglobulin (Ig), 2012-13, 2013-14, 20114-15 and 2015-16 and the 'HTA Data April2019.xlsx' workbook provided by the NBA.Use and cost of Ig for acquired hypogammaglobulinaemiaEstimated number of patients who receive IgPatient numbers were projected using linear extrapolations fitted to the observed data presented in REF _Ref9868003 \h Table 64 ( REF _Ref9868017 \h Figure 11). The projected estimated patient numbers for each indication are presented in REF _Ref10797587 \h Table 66. Figure SEQ Figure \* ARABIC 11Patient number projectionsCLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Note: Grey portion denotes estimates that have been projected.Source: ‘Estimated patient numbers’ worksheet in ‘1565 Financials.xlsx’ workbook.Prior to the Version 3 criteria, patients with acute leukaemia were counted under the ‘Other relevant haematological malignancies’ indication. Thus to project patient numbers with acute leukaemia, the partial 2018-19 Version 3 data have been used. During the observation period, 68 patients with acute leukaemia received Ig, while 86 patients received Ig for other haematological malignancies. Therefore patients with acute leukaemia are estimated to account for 44.2% of other haematological malignancies.Table SEQ Table \* ARABIC 66Number of patients projected to receive Ig by indication, 2019-20 to 2023-242019-202020-212021-222022-232023-24CLL1,7941,8921,9902,0892,187MM1,5831,6731,7631,8531,943NHL1,9102,0512,1932,3342,475Post HSCT533579625670716Other HM (Version 2)667699730762793 Acute leukaemia (44.2%)295309322336350 Other HM (Version 3)373390408425443Total6,4886,8947,3017,7078,114CLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Source: ‘Estimated patient numbers’ worksheet in ‘1565 Financials.xlsx’ workbook.Estimated use and cost per patient who receives IgAverage grams per patient per yearA similar approach is used to estimate Ig use over the projected period, as patient weights and dose may change over time. The projected estimated grams for each indication are presented in REF _Ref12448852 \h Table 67. Figure SEQ Figure \* ARABIC 12Ig use projectionsCLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Note: Grey portion denotes estimates that have been projected.Source: ‘Estimated grams issued’ worksheet in ‘1565 Financials.xlsx’ workbook.The proportion of Ig use attributable to acute leukaemia was also estimated using a similar approach, with 6,700 grams issued during the observed period under the Version 3 criteria for acute leukaemia, compared to 13,407 for other haematological malignancies. Thus the proportion attributable to acute leukaemia was estimated to be 33.3%.Table SEQ Table \* ARABIC 67Number of Ig grams issued by indication, 2019-20 to 2023-242019-202020-212021-222022-232023-24CLL502,376538,942575,508612,074648,640MM403,000431,787460,574489,361518,148NHL501,437543,109584,781626,453668,125Post HSCT91,434101,543111,652121,761131,870Other HM (Version 2)126,258133,522140,786148,049155,313 Acute leukaemia (33.3%)42,07344,49446,91449,33551,755 Other HM (Version 3)84,18589,02893,87198,714103,558Total1,624,5061,748,9031,873,3011,997,6982,122,096CLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Source: ‘Estimated grams issued’ worksheet in ‘1565 Financials.xlsx’ workbook.Using the projected number of grams issued and the projected patient numbers, the average number of grams of Ig issued per patient is estimated to increase over the projected period ( REF _Ref9933803 \h Table 68). Table SEQ Table \* ARABIC 68Average Ig use (g) per patient per year2017-18[observed]2019-202020-212021-222022-232023-24CLL267280285289293297MM243255258261264267NHL256262265267268270Post HSCT163172175179182184Acute leukaemia133143144146147148Other HM232226228230232234CLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Source: ‘Section E tables’ worksheet in ‘1565 Financials.xlsx’ workbook.Average cost per gram of IgThe base case financial estimates will assume the cost per gram of Ig of $60.41 (see Section D.4.2). As per Section D, sensitivity analyses will be conducted assuming:The highest cost of Ig (i.e. domestic Ig including plasma, $140.18)The lowest cost of Ig (i.e. imported IVIg, $44.94)Average cost of Ig, weighted across all indications, $94.51Prices per gram are assumed to remain constant over the projected period.Estimated cost of IgProjected costs across the acquired hypogammaglobulinaemia indications are presented in REF _Ref9939196 \h Table 69.Table SEQ Table \* ARABIC 69Cost of Ig for acquired hypogammaglobulinaemia, 2019-20 to 2023-242019-202020-212021-222022-232023-24Cost per gram of Ig$60.41No. CLL patients1,7941,8921,9902,0892,187Ig grams issued for CLL502,376538,942575,508612,074648,640Cost of Ig for CLL$30,348,534$32,557,486$34,766,438$36,975,390$39,184,342No. MM patients1,5831,6731,7631,8531,943Ig grams issued for MM403,000431,787460,574489,361518,148Cost of Ig for MM$24,345,230$26,084,253$27,823,275$29,562,298$31,301,321No. NHL patients1,9102,0512,1932,3342,475Ig grams issued for NHL501,437543,109584,781626,453668,125Cost of Ig for NHL$30,291,809$32,809,215$35,326,620$37,844,026$40,361,431No. post-HSCT patients533579625670716Ig grams issued for post-HSCT91,434101,543111,652121,761131,870Cost of Ig for post-HSCT$5,523,545$6,134,230$6,744,915$7,355,600$7,966,284No. AL patients295309322336350Ig grams issued for AL42,07344,49446,91449,33551,755Cost of Ig for AL$2,541,652$2,687,872$2,834,093$2,980,313$3,126,533No. other HM patients373390408425443Ig grams issued for other HM84,18589,02893,87198,714103,558Cost of Ig for other HM$5,085,618$5,378,192$5,670,765$5,963,339$6,255,913Total number of patients6,4886,8947,3017,7078,114Total number of Ig grams issued1,624,5061,748,9031,873,3011,997,6982,122,096Total cost of Ig$98,136,389$105,651,248$113,166,107$120,680,966$128,195,825Proportion Commonwealth funded63.0%Cost of Ig to the Commonwealth$61,825,925$66,560,286$71,294,647$76,029,008$80,763,370Cost of Ig to the States$36,310,464$39,090,962$41,871,460$44,651,957$47,432,455CLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.a Under the National Blood Agreement, products are funded 63% by the Commonwealth and 37% by the states and territories.Changes in use and cost of other medical services Additional costs due to Ig administrationThe majority of patients who currently receive Ig for acquired hypogammaglobulinaemia do so by intravenous infusion. The average number of treatment episodes per year has been derived from data provided by the NBA ( REF _Ref14263806 \h Table 70). These have been used to approximate the average number of IV infusions per year to estimate the additional cost associated with Ig administration. Table SEQ Table \* ARABIC 70Average number of treatment episodes per yearAverage number of treatment episodes per yearCLL10.0MM9.1NHL10.1Post HSCT7.6Acute leukaemia7.1Other HM8.4CLL = chronic lymphocytic lymphoma; HM = haematological malignancies; HSCT = haemopoietic stem cell transplantation; Ig = immunoglobulin; MM = multiple myeloma; NHL = non-Hodgkin’s lymphoma.Source: ‘Ig use’ worksheet in ‘1565 Financials.xlsx’ workbook.The total number of administrations per year are estimated within each indication by multiplying the number of patients per year by the average number of treatment episodes per patient. The estimated cost per infusion is $253.42, as per Section D.4.2. The estimated additional costs due to administration increase from $15.4 million in 2019-20 to $19.3 million in 2023-24. Administration costs are all assumed to be incurred by the States.Table SEQ Table \* ARABIC 71Additional costs due to Ig administration2019-202020-212021-222022-232023-24Number of infusions per year60,87664,69468,51372,33176,149Cost per administration$253.42Cost associated with Ig due to infusion administration$15,427,172$16,394,813$17,362,453$18,330,093$19,297,734Ig = immunoglobulin.Changes in costs associated with Ig due to a reduction in infectionsIt is unclear whether in the absence of Ig, use of prophylactic antibiotics would increase (see Section C.2.2), and so no direct cost offsets have been assumed. However the clinical evidence did support that Ig would lead to a reduction in antibiotic use and hospitalisations, due to a reduction in infections. While these are indirect cost offsets, these have been quantified in REF _Ref13666595 \h Table 72 and an estimate of the net financial implications to different government budgets is presented. As per Section D.4.2, each serious infection is associated with one hospitalisation (assumed to be attributable to State budgets) and one follow-up outpatient attendance (attributable to the Commonwealth), while non-serious infections were associated with outpatient attendance(s), and depending on the severity of infection, oral antibiotics and pathology and imaging tests (all assumed to be attributable to the Commonwealth).Table SEQ Table \* ARABIC 72Cost offsets associated with Ig use due to a reduction in infections2019-202020-212021-222022-232023-24Change in the number of serious infections per patient per year–0.37Total change in serious infections–2,382–2,532–2,681–2,830–2,980Cost of hospitalisation for serious infection$7,349Cost of follow-up outpatient attendance for serious infection$77Change in hospitalisation costs due to reduction in serious infections–$17,508,780–$18,606,202–$19,703,623–$20,801,045–$21,898,466Change in outpatient attendance costs due to reduction in serious infections–$182,608–$194,053–$205,499–$216,944–$228,390Change in the number of non-serious infections per patient per year–0.41Total change in non-serious infections–2,660–2,827–2,994–3,160–3,327Cost per non-serious infection (attributable to the MBS or PBS)$184Change in costs due to reduction in non-serious infections–$489,328–$519,998–$550,668–$581,339–$612,009Total cost offsets due to a reduction in the number of infections–$18,180,716–$19,320,253–$20,459,790–$21,599,328–$22,738,865Offsets attributable to the Commonwealth–$671,936–$714,051–$756,167–$798,283–$840,399Offsets attributable to the States–$17,508,780–$18,606,202–$19,703,623–$20,801,045–$21,898,466Ig = immunoglobulin.Financial implications for government health budgets The net financial implications for government budgets associated with the funding of Ig for acquired hypogammaglobulinaemia are presented in REF _Ref13664229 \h Table 73. However, there is uncertainty associated with the estimated cost offsets as these are indirect in nature and rely on assumptions regarding the treatment effect of Ig. Table SEQ Table \* ARABIC 73Net financial implications to government associated with Ig for acquired hypogammaglobulinaemia2019-202020-212021-222022-232023-24Total cost of Ig$98,136,389$105,651,248$113,166,107$120,680,966$128,195,825Cost of Ig to the Commonwealth$61,825,925$66,560,286$71,294,647$76,029,008$80,763,370Cost of Ig to the States$36,310,464$39,090,962$41,871,460$44,651,957$47,432,455Cost of Ig administration to the States$15,427,172$16,394,813$17,362,453$18,330,093$19,297,734Total cost offsets due to a reduction in the number of infections–$18,180,716–$19,320,253–$20,459,790–$21,599,328–$22,738,865Offsets to the Commonwealth–$671,936–$714,051–$756,167–$798,283–$840,399Offsets to the States–$17,508,780–$18,606,202–$19,703,623–$20,801,045–$21,898,466Net cost$95,382,845$102,725,807$110,068,769$117,411,732$124,754,694Net cost to the Commonwealth$61,153,989$65,846,235$70,538,480$75,230,725$79,922,971Net cost to States$34,228,856$36,879,572$39,530,289$42,181,006$44,831,723Ig = immunoglobulin.Identification, estimation and reduction of uncertaintySensitivity analyses exploring uncertainty in the assumptions used to determine the financial implications are presented in REF _Ref13667009 \h Table 74.Table SEQ Table \* ARABIC 74Sensitivity analyses around the financial implication estimates2019-202020-212021-222022-232023-24Base financial implications$95,382,845$102,725,807$110,068,769$117,411,732$124,754,694Cost of Ig (base case: $60.41 per gram)High cost of Ig, $140.18$224,969,664$242,235,823$259,501,981$276,768,140$294,034,299Low cost of Ig, $44.94$70,251,742$75,670,273$81,088,805$86,507,336$91,925,867Weighted average of Ig across all indications, $94.51$150,773,057$162,357,562$173,942,066$185,526,570$197,111,075Weighted average across the acquired hypogammaglobulinemia indication, $129.66 a$207,881,199$223,838,797$239,796,396$255,753,994$271,711,592Current published price, $58.23$91,841,423$98,913,198$105,984,973$113,056,749$120,128,524Change in infections per patient per year (base case: ?0.37 serious, ?0.41 non-serious)Using lower bounds of the 95% CIs: ?0.41 serious, ?0.52 non-serious$93,268,649$100,479,097$107,689,545$114,899,992$122,110,440Using the upper bounds of the 95% CIs: ?0.25 serious, ?0.29 non-serious$101,404,179$109,124,549$116,844,918$124,565,288$132,285,657Using the pooled IRRs based on the non-randomised studies: ?0.32 serious, ?0.57 non-serious$97,349,097$104,815,300$112,281,504$119,747,708$127,213,911Growth rate of Ig use (base case: average 7.2%)5%$90,624,094$95,121,079$99,851,508$104,827,053$110,059,9716%$92,411,185$97,949,172$103,829,752$110,073,480$116,702,1468%$96,036,185$103,767,467$112,131,003$121,177,373$130,961,205a For estimation of the average weighted price per gram within the acquired hypogammaglobulinemia see REF _Ref16607859 \h Table 98, Appendix H.Ig = immunoglobulin; IRR = incidence rate ratios.Appendix SEQ Appendix \* ALPHABETIC AClinical Experts and Assessment GroupAssessment group Adelaide Health Technology AssessmentNamePositionAllison WyndhamSenior research officerArlene VoganHealth economistSkye NewtonTeam leaderCamille SchubertTeam leader - Health economicsNoted conflicts of interestThere were no conflicts of interest.Appendix SEQ Appendix \* ALPHABETIC BSearch strategiesIgG replacement therapy has been in use since the 1940s for primary immunodeficiencies, mostly as IM injections. IV presentations were developed in the late 1970s and early 80s at the same time as use of IgG in other indications began to be explored. Authorisation of commercial IVIg products for secondary immunodeficiencies did not occur until 1990 or so at which time consensus was reached that IgG could be used in certain haematological malignancies ADDIN EN.CITE <EndNote><Cite><Author>Eibl</Author><Year>2008</Year><RecNum>95</RecNum><DisplayText>(Eibl 2008)</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1559299453">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eibl, M. M.</author></authors></contributors><auth-address>Medical University of Vienna, Center for Physiology, Pathophysiology and Immunology, Institute of Immunology, Borschkegasse 8a, 1090 Vienna, Austria. martha.eibl@meduniwien.ac.at</auth-address><titles><title>History of immunoglobulin replacement</title><secondary-title>Immunol Allergy Clin North Am</secondary-title></titles><periodical><full-title>Immunol Allergy Clin North Am</full-title></periodical><pages>737-64, viii</pages><volume>28</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Antibodies, Monoclonal/therapeutic use</keyword><keyword>Consensus Development Conferences, NIH as Topic</keyword><keyword>History, 19th Century</keyword><keyword>History, 20th Century</keyword><keyword>History, 21st Century</keyword><keyword>Humans</keyword><keyword>Immunization, Passive/*history</keyword><keyword>Immunoglobulins, Intravenous/*administration & dosage/*adverse</keyword><keyword>effects/chemistry/immunology</keyword><keyword>Immunologic Deficiency Syndromes/history/*therapy</keyword><keyword>National Institutes of Health (U.S.)/history</keyword><keyword>United States</keyword></keywords><dates><year>2008</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0889-8561 (Print)
0889-8561 (Linking)</isbn><accession-num>18940572</accession-num><urls><related-urls><url>;(Eibl 2008). The literature search terms were kept broad to capture the range of terminology used for ‘immunoglobulin’ and ‘hypogammaglobulinaemia’ as well as the range of malignancies relevant to this evaluation. It was not possible to narrow the search string to exclude studies of patients with malignancy having immunoglobulin investigations but no IVIg given, or studies in patients with solid tumours or those with primary immunodeficiencies. Hence there were a very large number of results from initial searches. There is a body of experimental literature from the 1980s investigating IVIg in patients with haematological malignancies, however the search strategy for this evaluation only included results from 1990 onwards in order to keep the number of search results manageable and the low likelihood of relevant trials conducted prior to 1990. Results from Embase were further limited using the ‘evidence-based medicine’ function to focus results with the highest level of evidence. The search relied on pearling of the included and ‘near miss’ excluded studies, especially systematic reviews, to identify results not returned by the search strings. Bibliographic databasesElectronic databaseTime period searchedEmbaseFrom 1990 onwardsMedlineFrom 1990 onwardsThe Cochrane Library (CDSR, Central, DARE, HTA, HEED)From 1990 onwardsThe bibliographic databases above were searched for relevant studies using the representative search string in REF _Ref9247600 \h \* MERGEFORMAT Table 75. During the process of the review, it was apparent that studies with patients who have received bone marrow transplantation (BMT, as opposed to HSCT with mobilised stem cells collected by apheresis) may not have been identified with the search terms used. An additional search was therefore performed ( REF _Ref10106675 \h \* MERGEFORMAT Table 76). IgG product brand names were included in both search strings but results indicated that these identified only a small number of results – they are included here for completeness. As well as the terms in the search strings, pre-specified criteria for excluding studies included: no studies published prior to 1990, no grey literature, no non-peer reviewed articles, no non-English language articles, no conference abstracts or conference presentations. Culling against PICO criteria could not be done against the title and abstract in some cases, thus many of the search results were downloaded and read in part particularly to determine whether the population and intervention were appropriate (articles read in part were not included in the PRISMA flowchart in REF _Ref16673975 \h Figure 2). Table SEQ Table \* ARABIC 75Search terms for IgG replacement in patients with hypogammaglobulinaemia due to haematological malignancies (Pubmed)ElementPubmed search termsPopulation(Hypogammaglobulinemia OR Hypogammaglobulinaemia OR hypogamma* OR “low immunoglobulin” OR “immunoglobulin deficiency” [mh]) AND(leukaemia* OR leukemia* OR “Leukemia, Lymphoid”[mh] OR “Leukemia, Mast-Cell”[mh] OR “Leukemia, Myeloid”[mh] OR “Leukemia, plasma cell”[mh] OR “Leukemia, Radiation-Induced”[mh] OR “Multiple myeloma”[mh] OR “multiple myeloma”OR“Lymphoma”[mh] OR lymphoma OR lymphoproliferative OR “non-hodgkin”OR ((B-cell OR haematological OR hematological) AND (malignancy OR malignancies OR neoplasm[mh]) OR “Hematologic Neoplasms”[mh])OR“Hematopoietic Stem Cell Transplantation”[mh] OR HSCT OR ((“stem cell” OR “progenitor cell”) AND (transplantation OR transplant OR transplants)))InterventionAND (”Immunoglobulin G”[mh] OR immunoglob* OR “immune globulin” immunoglobulin OR “gamma globulin” OR gammaglobulin OR IVIg OR SCIg OR IgG OR IgOR Intragam OR Privigen OR Hizentra OR Gamunex OR Flebogamma OR Intragam OR Evogam OR Panzyga OR Hyqvia OR Intratect OR Octagam OR Kiovig OR Gammanorm OR Cuvitru OR GammaSTAN OR BayGam OR Polygam OR GAMMAGARD OR Sandoglobulin OR Panglobulin OR Carimune OR GAMMAKED OR Iveegam OR Bivigam OR Gammaplex OR Intratect OR IQYMUNE OR SUBCUVIA OR Subgam OR Vigam OR CUTAQUIG OR GAMASTAN OR GAMIMUNE OR IGIVNEX OR RESPIGAM OR VIVAGLOBINORGammaQuin OR NanogamORCLAIRYG OR ENDOBULINE OR SANDOGLOBULINE OR TECTASIM OR TEGELINEOR“Kenketu Glovenin”)Comparator (if applicable)?Outcomes (if applicable)?Limits?mh = Medical Subject Heading, based on a PubMed platformTable SEQ Table \* ARABIC 76Further searches for bone marrow transplantation (Pubmed example)Pubmed search termsPopulation(Hypogammaglobulinemia OR Hypogammaglobulinaemia OR hypogamma* OR “low immunoglobulin” OR “immunoglobulin deficiency”[mh] OR "low Ig" OR "low IgG" OR "immunoglobulin deficiency" OR "immunoglobulin deficient" OR "Ig deficiency" OR "IgG deficiency" OR immunoparesis) AND (“bone marrow transplant”[mh] OR (bone AND marrow AND transplant*))InterventionAND (”Immunoglobulin G”[mh] OR immunoglob* OR “immune globulin” immunoglobulin OR “gamma globulin” OR gammaglobulin OR IVIg OR SCIg OR IgG OR IgOR Intragam OR Privigen OR Hizentra OR Gamunex OR Flebogamma OR Intragam OR Evogam OR Panzyga OR Hyqvia OR Intratect OR Octagam OR Kiovig OR Gammanorm OR Cuvitru OR GammaSTAN OR BayGam OR Polygam OR GAMMAGARD OR Sandoglobulin OR Panglobulin OR Carimune OR GAMMAKED OR Iveegam OR Bivigam OR Gammaplex OR Intratect OR IQYMUNE OR SUBCUVIA OR Subgam OR Vigam OR CUTAQUIG OR GAMASTAN OR GAMIMUNE OR IGIVNEX OR RESPIGAM OR VIVAGLOBINORGammaQuin OR NanogamORCLAIRYG OR ENDOBULINE OR SANDOGLOBULINE OR TECTASIM OR TEGELINEOR“Kenketu Glovenin”)mh = Medical Subject Heading, based on a PubMed platformAppendix SEQ Appendix \* ALPHABETIC CStudies included in the Systematic ReviewTable SEQ Table \* ARABIC 77List of the included studiesStudy IDTitleCitationRandomised studies – IVIg vs No IVIgBoughton et al., 1995Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemiaClin Lab Haematol 17(1): 75-80.Chapel et al., 1991Hypogammaglobulinaemia in low grade B cell tumours; significance and therapyImmunol Invest 20(2): 187-191.Chapel et al., 1994Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma.Lancet 343(8905): 1059-1063.Kobayashi et al., 2014Effect of meropenem with or without immunoglobulin as second-line therapy for pediatric febrile neutropenia.Pediatrics International 56(4): 526-529.Molica et al., 1996Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover studyHaematologica 81(2): 121-126.Musto et al., 1995Prophylaxis against infections with intravenous immunoglobulins in multiple myeloma. Br J Haematol. 1995;89(4):945–6.Sullivan et al., 1990Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation." N Engl J Med 323(11): 705-712.Randomised studies – SCIg vs No SCIgVacca et al., 2018Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trialClinical Immunology 191: 110-115.Other comparative studies – IVIg vs No IVIgAmmann et al., 2016Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancyBlood 127(2): 200-207.Blombery et al., 2011Prophylactic intravenous immunoglobulin during autologous haemopoietic stem cell transplantation for multiple myeloma is not associated with reduced infectious complicationsAnn Hematol 90(10): 1167-1172.Paxton et al., 2016Selecting haematological malignancy patients for intravenous immunoglobulinIntern Med J 46(10): 1216-1218.Van Winkle et al., 2018Prevalence and Safety of Intravenous Immunoglobulin Administration During Maintenance Chemotherapy in Children with Acute Lymphoblastic Leukemia in First Complete Remission: A Health Maintenance Organization Perspective.Perm J 22: 17-141.Non-comparative studies – IVIg case seriesBesa, 1992Recent advances in the treatment of chronic lymphocytic leukemia: defining the role of intravenous immunoglobulin.Semin Hematol 29(3): 14-23.Brenner, 1996Clinical experience with Octagam, a solvent detergent (SD) virus inactivated intravenous gammaglobulinClin Exp Rheumatol 14 Suppl 15: S115-119.Günther & Dreger 2013Post-marketing observational study on 5% intravenous immunoglobulin therapy in patients with secondary immunodeficiency and recurrent serious bacterial infectionsMicrobiol Immunol 57(7): 527-535.Jurlander et al., 1994Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low-dose intravenous gammaglobulinEur J Haematol 53(2): 114-118.Non-comparative studies – SCIg case seriesDimou et al., 2018Efficacy-safety of Facilitated Subcutaneous Immunoglobulin in Immunodeficiency Due to Hematological Malignancies. A Single-Center Retrospective AnalysisAnticancer Res 38(7): 4187-4191.Any IgG (IVIg and SCIg) case seriesBenbrahim et al., 2018A French observational study describing the use of human polyvalent immunoglobulins in hematological malignancy-associated secondary immunodeficiency Eur J Haematol 101(1): 48-56.Benbrahim et al., 2019The use of octagam and gammanorm in immunodeficiency associated with hematological malignancies: a prospective study from 21 French hematology departmentsHematology 24(1): 173-182.Duraisingham et al., 2014Primary vs. secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement.PLoS One 9(6): e100324.Reiser et al., 2017Management of patients with malignancies and secondary immunodeficiencies treated with immunoglobulins in clinical practice: Long-term data of the SIGNS studyEur J Haematol 99(2): 169-177.[Supportive] Non-comparative studies – IVIg v SCIg case seriesSundin et al., 2012Subcutaneous IgG replacement after pediatric SCTPediatric Transplantation 16(8): 866-871.Windegger et al. 2019Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency.Vox Sang. 2019 Apr;114(3):237-246.[Supportive] Other (IVIg or SCIg) – dosing studiesChapel, Dicato et al. 1994Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimesBr J Haematol 88(1): 209-212.Stump et al., 2017Comparison of Weight-Based Dosing Strategies for Intravenous Immunoglobulin in Patients with Hematologic MalignanciesPharmacotherapy 37(12): 1530-1536.Table SEQ Table \* ARABIC 78List of the included studies as they apply to the NBA-funded conditionsStudy Study typeRisk of biasNStudied indication(s)Acute LeukaemiaKobayashi et al., 2014RCTLow (SIGN)N=61[ALL(34); AML(12); other leukaemia(2); NHL(2); solid tumours(11)Of whom 22 received HSCT (which ones not specified)Van Winkle et al., 2018Cohort studyModerate (SIGN)N=118ALL Stump et al., 2017Case seriesRoB: high (IHE)N=79 (n=209 infusions)CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)CLLBoughton et al., 1995RCTRoB: moderate (SIGN)N=42CLLChapel et al., 1991RCT cross-overRoB: low (SIGN)N=12CLL, NHL (breakdown not given; NHL likely v small)Molica et al., 1996RCT cross-overRoB: moderate (SIGN)N=42CLLPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016)Registry studyRoB: moderate (IHE)N= 10,759CLL(76%), MM(24%)Paxton et al., 2016Cohort studyRoB: high (SIGN)N=92CLL (42); MM (18); NHL (27); other (5)Besa, 1992Case series RoB: high (IHE)N=23CLLBrenner, 1996Time seriesRoB: moderate (IHE)N=54 (26 patients SID)CLL(22), MM(4)Dimou et al. 2018Before/after time seriesRoB: moderate (SIGN)N=33CLL(25); MM(3); NHL(3); HL(1)Jurlander et al., 1994Time seriesRoB: moderate (SIGN)N=15CLLReiser et al., 2017Case seriesRoB: moderate (IHE)N=307CLL(130); indolent lymphoma(77); MM(43); NHL(22); other(35)Benbrahim et al., 2019(Follow-up report)Case series (prospective)RoB: low (IHE)N=160MM(54), CLL(54), aggressive NHL(19), indolent NHL(29), HL(4)Chapel, Dicato et al. 1994Case seriesRoB: lowN=34CLLStump et al., 2017Case seriesRoB: high (IHE)N=79 (n=209 infusions)CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)MMChapel et al., 1994RCTRoB: low (SIGN)N=83MMMusto et al., 1995RCT cross-overRoB: low (SIGN)N=25MMVacca et al., 2018RCTRoB: low (SIGN)N=46MMPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbW1hbm48L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Ammann et al. 2016)Registry studyRoB: moderate (IHE)N= 10,759CLL(76%), MM(24%)Paxton et al., 2016Cohort studyRoB: high (SIGN)N=92CLL (42); MM (18); NHL (27); other (5)Benbrahim et al., 2019(Follow-up report)Case series (prospective)RoB: low (IHE)N=160MM(54), CLL(54), aggressive NHL(19), indolent NHL(29), HL(4)Reiser et al., 2017Case seriesRoB: moderate (IHE)N=307CLL(130); indolent lymphoma(77); MM(43); NHL(22); other(35)Stump et al., 2017Case seriesRoB: high (IHE)N=79 (n=209 infusions)CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)NHLPaxton et al., 2016Cohort studyRoB: high (SIGN)N=92CLL (42); MM (18); NHL (27); other (5)Benbrahim et al., 2019(Follow-up report)Case series (prospective)RoB: low (IHE)N=160MM(54), CLL(54), aggressive NHL(19), indolent NHL(29), HL(4)Reiser et al., 2017Case seriesRoB: moderate (IHE)N=307CLL(130); indolent lymphoma(77); MM(43); NHL(22); other(35)Stump et al., 2017Case seriesRoB: high (IHE)N=79 (n=209 infusions)CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)HSCTSullivan et al., 1990RCTRoB: low (SIGN)N=369BMTPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyeTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+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ADDIN EN.CITE.DATA (Blombery et al. 2011)Cohort studyRoB: high (SIGN)N=240MM+HSCT (autologous)Sundin et al., 2012Case seriesRoB: moderateN=58 (26 had HM)HSCTOther haematological malignanciesNone identified.Included studies that could not be used for any of the NBA-funded conditions Günther & Dreger 2013Case seriesRoB: moderate (IHE)N=10CLL(5), FL(2), plasmacytoma; WM(1), MDS(1)Benbrahim et al., 2018(preliminary report)Case series (prospective)RoB: low (IHE)N=231MM(64), CLL(84), NHL(71), AL(6); HL(6)Duraisingham et al., 2014Case series (PID vs SID)RoB: moderate (IHE)N=39 SID patients, of which 15 had HMCLL(1), MM(1), NHL(11); MDS(1); MGUS(1) Windegger et al. 2019Before/after time seriesRoB: moderate (IHE)N=13 (N=84 for QoL survey)Haem. malignancy (unspecified)Abbreviations are the same as those for REF _Ref15306456 \h \* MERGEFORMAT Table 15. Orange shading indicates RCTs; grey is supportive only. . Appendix SEQ Appendix \* ALPHABETIC DEvidence Profile Tables Table SEQ Table \* ARABIC 79Included study profiles for safety and effectiveness – RCTsAuthor, YearCountryStudy design Risk of bias (RoB)Population characteristics (at baseline unless specified)Eligibility criteria ObjectivesInterventionComparatorOutcomes assessedStatistical AnalysesDuration of follow-upCommentsRandomised studies – IVIg vs No IVIgBoughton et al., 1995UKMulti-centre(20 sites)RCT, double-blindRoB: moderate (SIGN)N=42 (CLL)Sex, ♀/♂: 16/26Mean age±sd, yr IVIg/placebo: 61±7/63±7Mean weight±sd, kg IVIg/placebo: 66±11/72±14Disease stage, A/B/C: 20/7/15Mean serum IgG±sd, g/L: IVIg: 3.5±0.7No IVIg: 3.6±0.6Inclusion: CLL patient with serum IgG levels <5.5 g/L (excluding paraprotein) and a history of 2+ recent infectionsExclusion: if prophylactic antibiotics in prior 2 weeks; if severe infection at trial entry; if any IVIg or human plasma in 3 months prior to trial entry; prior severe reactions to IV blood products.Objectives: investigation of IVIg in preventing infections in CLL and to identify high risk patients for whom IVIg prophylaxis may be cost effective.IVIg (n=24): 18g every 3 weeks for 12 months (Sandoglobulin, Sandoz). If 3 infections, classified as tx failure and weekly dose increased to 24g.7 patients failed tx after 9-11 mo; were switched to higher dose 24g IVIg. Placebo (n=18): 0.6g albumin for 12 months. If 3 infections, classified as tx failure and switched to IVIg. 11 placebo patients failed tx; were switched to IVlg after 5-9 mo.Outcomes: infections, serious infections, tx outcome (success or failure); liver function (for viral safety, not presented)Analyses: statistical comparisons used Fisher’s Exact test or Wilcoxon Rank Sum, and statistical correlation was calculated by least squaresFollow-up: Not stated. Fig 1 suggests 1 mo after 12-mo tx period. 1 IVIg patient withdrew due to infusion-related pyrexia; 3 patients died due to disease progression. No patients lost to follow-up.Ethics: Local hospital ethical committee permission was obtained at each siteFunding: Authors supported by the Leukaemia Research Fund; Sandoz provided logistical and analytical support (study coordination; biostatistician) and Sandoglobulin study drug. Outcomes pooled in 6mo or 12mo groups, no info on which /how many completed 24mo protocol; when did discontinuations occur; nor if any wash-out period.Chapel et al., 1991UKSingle centreComparative, double-blind, crossover.Not stated if randomised allocation used.RoB: low (SIGN)N=12 (CLL or NHL)No serum IgG or other parameters described. Numbers of CLL or NHL patients not given. Inclusion: Patients with CLL or low-grade NHL and had either IgG <50% of LLN or a previous major infection.Exclusion: Not described.Objectives: investigation of IVIg on infections in CLL and NHL patients based on crossover design. IVIg 400mg/kg 3-weeklyAs for Gale, 1988. Crossover at 12 months for a further year’s tx (24 mo total).No IVIg (equivalent infusion volume of saline)As for Gale, 1988. Crossover at 12 months for a further year’s tx (24 mo total).Outcomes: Incidence of infections.Analyses and follow-up not described.Only 5 patients remained at 24 mo (3 died, 1 discontinued due to futility, 2 moved away in the 2nd yr, 1 refused cross-over)Funding: grant received from Baxter (manufacturer of Gammagard used in this study)Study heavily based on earlier trial by same authors in Gale et al., 1988 New England journal of medicine 319(14): 902‐907. (excluded as pre-1990)Chapel et al., 1994UKmulti-centre (9 sites)RCT, double-blindRoB: low (SIGN)N=83 (MM)(analysis set N=82 due to patient withdrawal after 1 dose)Mean age±sd, yr: IVIg: 65.6± 6.6Placebo: 66.3±9.2Sex ♀/♂:IVIg, n/n: 17/25Placebo, n/n: 24/17Total Ig >LLN/<LLN:IVIg, n/n: 10/32Placebo, n/n: 15/26Disease, n (%)Stage I: 23 (28)Stage II: 35 (42)Stage III: 25 (30)Inclusion: plateau phase MM; expected to survive 6+ months; well enough for infusions and travel to clinic.Exclusion: Any prior IgG therapy during the month before entry; Prior anaphylaxis to a blood product; Total selective deficiency of serum IgA.Patients stratified by serum Ig (below or above non-paraprotein Ig LLN).Objectives: investigation of IVIg as prophylaxis against infection in MM patients in plateau phase.IVIg (n=42*): 0.4g/kg, every 4 weeks for 12 months (Gammagard, Baxter).No prophylactic antibiotics permitted.*n=42 includes a patient that withdrew after 1 dose (analysis set n=41).12 patients did not complete the IVIg therapy and 10 did not complete the placebo treatmentPlacebo (n=41): 0.4% HSA, every 4 weeks for 12 months.No prophylactic antibiotics permitted.12 patients did not complete the IVIg therapy and 10 did not complete the placebo treatmentOutcomes: Incidence and type of infections; adverse reactions including death; time to infection; infections in an immunised sub-set (n=54; immunised prior to study start). Analyses: Chi-square test was used to compare qualitative data and two-sample t-test (2-tailed p value) for quantitative data; time to first infection was determined by Kaplan-Meier plots and distributions compared by Cox-Mantel.See paper for further analyses.Follow-up not described.Same trial as described in Chapel & Lee 1994. One author (M Lee) an employee of Baxter (IVIg manufacturer)Ethics: protocol approved by each hospital ethics committee; formal written consent obtained from all participants.Funding: The authors thank Baxter for a financial grant for this study. [Baxter manufactures Gammagard, IVIg used in this study]Kobayashi et al., 2014JapanSingle centreRCT, open-label, sub-study [August 2008 ― April 2012]RoB: low (SIGN)N=61 patients with 146 (range 1-9) febrile neutropenic episodes. [ALL(34); AML(12); other leukaemia(2); NHL(2); solid tumours(11)]In 22 tx episodes patients had received HSCT, but not clear which ones.Age, median (range): 6.0 years (0–22).Sex ♀/♂: 29/32Serum IgG, mg/dL, median (range):MEPM+IVIG: 673 (236–1344) MEPM: 667.5 (292–2047)Inclusion: paediatric chemo or HSCT patients with febrile neutropenia who failed 1st line antibiotics. Exclusion: none describedObjectives: meropenem (MEPM) ± IVIG as 2nd line tx for paediatric oncology patients with febrile neutropeniaMEPM + IVIG (62 episodes): 100 mg/kg/d (max 5g/day) for 3 days (Venoglobulin IH 5% Mitsubishi Tanabe/ Benesis). MEPM as described for MEPM only arm.G-CSF permitted.MEPM without IVIG (84 episodes): MEPM only for 3 days as follows:Aug2008-Apr2010;:60 mg/kg/d (max 1.5g/d) Apr2010-Apr2012:120mg/kg/d (max: 3g/d)G-CSF permitted.Outcomes: tx success vs failure evaluated 120h after the start of therapy (failure defined as defined as persistence of fever or infecting organism, any required modification of antibiotic tx, new infections, or infection-related death)Analyses: Differences between groups were analysed using Fisher’s exact test and the Mann–Whitney U-test.Follow-up: not stated. 2 deaths were due to invasive fungal infection in MEPM only group.Ethics: research was approved by the hospital IRB. Written informed consent was obtained from all patients or parents of patients.Funding: no funding sources were declared nor competing interests statement provided. 17/74 MEPM episodes had received HSCT compared with 5/62 MEPM + IVIg episodes. Molica et al., 1996ItalyMulti-centre (5 sites)RCT (crossover study with random allocation); open-labelRoB: moderate (SIGN)N=42 (CLL)♀/♂: 12/30Age mean±sd: 64±11.5Rai stage, n(%) 0: 2 (4.7%)I–II: 14 (33.3%)III-IV: 36 (61.9%)IgG level mg/dL(%):<500: 16 (38)>500<650: 13 (30.9)>650: 13 (30.9)Inclusion: serum IgG <600mg/dL or a history of at least one serious infection in 6-months prior to study31% of patients had IgG>650mg/dL at entry and 40% had a history of infections.Exclusion: Not described.Objectives: to investigate effect on infections of low-dose IVIg given to CLL patients in a cross-over setting. IVIg: 300 mg/kg every 4 weeks for 6 months (Ig-Vena N, Sclavo).Then crossover to observation for 12 months; finally crossover to IVIg for further 6 months.Prophylactic antibiotics not allowed.No IVIg: observation (empirical treatment) for 6 months.Then crossover to IVIg for 12 months; finally crossover to observation for further 6 months.Prophylactic antibiotics not allowed.Outcomes: infections (incidence, type, severity)Analyses: The number of infections occurring during the treatment or observation period were compared by the chi-square test and also by the McNemar test for non-parametric data corrected for continuity.Follow-up duration not described. 2 withdrawals due to IVIg toxicity; 2 patients lost to follow-up (2 and 18 mo). 13 deaths were due to disease progression (5), second neoplasm (2); surgical sequelae (1); infections (5; of which 4 occurred during observation).All patients gave informed consent. No mention of ethics committee approval.Funding: this work was supported by a grant from Sclavo (Siena, Italy) which sells immunoglobulins in Italy.Musto et al., 1995ItalySingle centreRCT, open-label, crossoverRoB: moderate (SIGN)N=25 (MM)22 patients had extended (stage III) disease, of which 3 had moderate renal failure (serum creatinine 1.8-2.5mg/dL).No baseline data reported. Inclusion: serum IgG <LLN or a recent history of recurrent infections.Exclusion: Not described.Objectives: to investigate IVIg efficacy in preventing infections in MM patients selected for hypo-GG and history of infections. IVIg (0.3g/kg every 4 weeks) for 6 months. Crossover to no IVIg for further 12 months.Crossover back to IVIg for final 6 months.No antibiotic prophylaxis permittedNo IVIg (observation) for 6 months.Crossover to IVIg for further 12 months.Crossover back to no IVIg for final 6 months.No antibiotic prophylaxis permittedOutcomes: minor infections; serious infections.Analyses and follow-up not described.9 patients did not complete the study; due to disease progression (4) or lethal infections (5, all during the observation period).No mention of research ethics approval.No description of funding source or conflict of interest declaration. Sullivan et al., 1990USASingle centre.RCT, open-labelRoB: low (SIGN)N=382 eligible; 369 received tx in line with criteria.AA(13)/MDS(20); AL(207), CML(77), lymphoma(43), other(13), no BMT(9)Age<20yo: 124(32%)>20yo: 258(68%)BMT source:?Allo: 342(90%)?Auto: 40(10%)Sex, serum IgG not reported.Inclusion: undergoing BMT for haematological malignancy; either CMV seropositive or, if CMV seronegative receiving BMT from CMV+ donor (May 1986 – Nov 1987)Exclusion: none describedObjectives: Investigation of the effect of IVIg on acute GVHD, severe infections and survival in haematological malignancy patients. IVIg (n=191, of which 184 evaluable): 500mg/kg weekly from d-7 to d90; then monthly to d360 post BMT (Gamimune, Cutter Biologicals), plus supportive care. All patients received S+T prophylaxis until d120 for Pneumocystis spp. Acyclovir prophylaxis for baseline CMV+ patients.No IVIg (n=191, of which 185 evaluable): supportive care.All patients received S+T prophylaxis until d120 for Pneumocystis spp.Acyclovir prophylaxis for baseline CMV+ patients.2 patients developed severe hypo-GG [IgG<4g/L] and recurrent bacterial infections – were given IVIg.Outcomes: acute GVHD, infection**, interstitial pneumonia, death.**Infections of oral cavity, URT or infection with herpes simplex not recorded. Analyses: survival (censored at last contact) and mortality (censored at relapse) analyses included all 382 eligible patients. Analyses of infection and interstitial pneumonia included only 359 evaluable patients. Log-rank test (2-sided p) used to compare times to: death; relapse; acute GVHD; interstitial pneumonia. More details in paper. Follow-up: median duration of follow-up since randomisation:?Surviving IVIg (n=66): 1.9 yr?Surviving no IVIg (n=69): 2 yr(no ranges given)Ethics: consent forms were approved by the IRB. Funding: grants disclosed from NIH, Cutter Biological Inc (manufacturer of Gamimune, the IVIg product used in this study) and NIAID.Cutter Biological is now part of Grifols. 1st 6 patients recruited inadvertently received antibiotic prophylaxis. A continuation study for this cohort is described in PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWxsaXZhbjwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+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ADDIN EN.CITE.DATA (Sullivan et al. 1996) alongside a 2nd cohort of patients recruited at the same time as this group of BMT recipients, but was excluded as neither tx group had hypo-GG by that stage.Randomised studies – SCIg vs No SCIgVacca et al., 2018ItalySingle-centreRCT, open-labelRoB: low (SIGN)N=46 (MM)Sex ♀/♂: 21/25Age, mean (range): 71 (56–85)Stage, n (%):IIA: 3 (6.5)IIIA: 39 (84.8)IIIB: 4 (8.7)[Durie & Salmon]IgG g/L, mean (range): 3.1 (1.3–5.2)Inclusion: adult (<18 yo); serum IgG <500mg/dL; life expectancy >1 year; self or carer able to administer SCIg at homeExclusion: other cause of immunodeficiency; active HCV/ HBV/HIV infection; unable to administer SCIg at home. All patients were free of infection at trial entry, and none were inpatients.Objectives: evaluation of effect of SCIg tx on rate of severe infections in MM patients. SCIg (n=24): 4 weekly infusions to give a total dose of 0.4–0.8g/kg/ month (Hizentra, CSL Behring). Dosing was adjusted according to normal IgG monthly trough levels. Mean administered dose was 80mg/kg/week. Tx until discontinuation or withdrawal of consent (mean duration 18 mo [range 10–28]). No patient received antibiotic prophylaxis or G-CSF.At the end of the first 6mo tx, 21 of 24 SCIg patients accepted to continue, whereas 3 patients withdrew from the study due to side effects.Controls (n=22): No SCIgNo patient received antibiotic prophylaxis or G-CSF.Monthly serum IgG levels measured as for active arm. Outcomes: annual rate of severe infections; days of hospitalisation due to severe infections; days of treatment with antibiotics; improvement of HRQoL (SF-36).AEs were reported though not defined as an endpoint.Analyses: Continuous variables, including rate of infections, were assessed as mean, median, sd, and range. Groups were compared by Student-Fisher t-test, and Chi-square test. The Wilcoxon correlation and Mann-Whitney U test assessed the correlation by rate of infection and other variables. Follow-up: patients followed for mean 18mo duration of tx (10-28 mo range). Ethics: study was approved by the local Ethical Committee. A signed patient informed consent was an inclusion criterion. Funding: Hizentra’s manufacturer had no role in support of the study. None of the authors has received honoraria or consulting fees from [CSL Behring] and none of them has conflicts of interest with any other commercial entity.[funding sources declared derive from Italian non-profit organisations and from EU Framework 7]Units conversion: 100mg/dL (units used in older studies) equals 1g/LRisk of Bias was assessed using the SIGN checklist for controlled trials (for RCTs only); the SIGN checklist for cohort studies, and the IHE checklist for case series. AA=aplastic anaemia (underlying disease not specified); AEs=adverse events; AL=acute leukaemia (AML+ALL); ALL=acute lymphoblastic leukaemia; AML=acute myeloid leukaemia; ARCBS=Australian Red Cross Blood Service; BMT=bone marrow transplant; CLL=chronic lymphocytic leukaemia; CMV=cytomegalovirus; DLBCL=diffuse large B-cell lymphoma (Richter’s syndrome); ECOG-PS=Eastern Cooperative Oncology Group – Performance Status; FL=follicular lymphoma; GCSF=granulocyte colony stimulating factor (filgrastim); GVHD=graft versus host disease; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HL=Hodgkin lymphoma; HM=haematological malignancy; HR=hazard ratio; HRQoL=health-related quality of life; HSA=human serum albumin; HSCT=haematopoietic stem cell transplant; hypo-GG=hypogammaglobulinaemia; IgA=alpha immunoglobulin; IgG=gamma immunoglobulin; IgM=immunoglobulin M; IMIg=intramuscular immunoglobulin; IQR=interquartile range; IRB=institutional review board (USA); ITP=idiopathic thrombocytopenic purpura; IVIg=intravenous immunoglobulin; LLN=lower limit of normal (laboratory reference range); MAb=monoclonal antibody; MCL=mantle cell lymphoma; MDS=myelodysplastic syndrome; MEPM=meropenem; MGUS=monoclonal gammopathy of undetermined significance; MM=multiple myeloma; MZL=marginal zone lymphoma; NHL=non-Hodgkin lymphoma; NNH=number needed to harm; OS=overall survival; PAPS=primary antiphospholipid syndrome; PID=primary immunodeficiency; RCT=randomised controlled trial; RT=replacement therapy; SCIg=subcutaneous immunoglobulin; sd=standard deviation; SCID=severe combined immunodeficiency; SID=secondary immunodeficiency; SLL=small lymphocytic lymphoma; S+T=sulfamethoxazole+trimethoprim; tx=treatment; TEEs= thromboembolic events; URT=upper respiratory tract; WM=Waldenstr?m macroglobulinaemia.Table SEQ Table \* ARABIC 80Included study profiles for safety and effectiveness – cohort studiesAuthor, YearCountryStudy design Risk of bias (RoB)Population characteristics (at baseline unless specified)Eligibility criteria ObjectivesInterventionComparatorOutcomes assessedStatistical AnalysesDuration of follow-upCommentsOther comparative studies – IVIg vs No IVIgAmmann et al., 2016USASEER national cancer registryCancer registry retrospective cohort [1992-2010]RoB: moderate (IHE)N=10,759CLL/MM: 76%/24%Mean age±sd IgG/non-users: 75.8±6.4/75.9±6.6♀/♂ IgG, %: 41/59♀/♂ non-users, %: 42/58Neutropenia, %, IgG/nonusers: 27/26No baseline serum IgG described.Not clear how hypo-GG status assessed.Inclusion: IgG users and non-user controls who were ≥66years old, diagnosed with CLL within 16 years or MM within 8 years, with evidence of US healthcare utilisationExclusion: hospice care within the previous year; prevalent users (defined as patients who already on IgG prior to reaching eligible age for US Medicare coverage and thus study inclusion)Objectives: to assess rates of clinically serious TEEs in new users of IVIg versus a propensity-matched control group of non-users.IgG (n=2724 [25%]): one year of monthly infusions; includes IVIg, SCIg, IMIgNo further dose information described; only days since last IVIg per TEE event.Non-user controls (no IgG) (n=8035 [75%]):IgG and non-user individuals matched by cancer type (CLL or MM) and utilization status and using time-dependent propensity scores derived from Cox regression models to yield a cohort of patients balanced for factors including disease stage, TEE risk and treatment start date.Outcomes: TEEs; NNH.Infections not reported as outcomes but as disease covariates.Analyses: Cox regression used to assess hazards of arterial and venous TEEs (IgG vs nonusers).1-year cumulative incidence difference and NNH for each TEE type, representing the estimated absolute risk attributable to IgG.Estimates were based on the Kaplan-Meier cumulative TEEs observed in the unexposed patients and the model-based HR in IgG at follow-up.Follow-up: one year.Funding: University of Iowa Holden Comprehensive Cancer Center Population Research Core, supported by a National Institutes of Health National Cancer Institute grant. Financial interests declared relate to US government funding only. Ethics: approved by the University of Iowa Institutional Review Board.Blombery et al., 2011Australia (Peter MacCallum)Single centreRetrospective cohort [1 Jan 2000 – 31 Dec 2009]RoB: high (SIGN)N=240 (MM; auto-HSCT)Median age (range) IVIg/noIVIg: 58(34–74)/60(31–79)Median total Ig, g/L (range) IVIg/no IVIg: 3(0–8)/3(1–7)Median days of neutropenia ANC <0.5x109/L (range):IVIg: 5 (3–24) No IVIg: 5 (3–18)Inclusion: MM patients receiving auto-HSCT; pre-transplant hypo-GG (defined as combined IgG/A/M <8g/L excluding paraprotein).Exclusion: none described.Objectives: does peri-transplant IVIg (0.4g/kg) reduce infectious complications in MM patients after HSCT? IVIg (n=130): one 0.4g/kg IVIg dose (123 patients (94.6%) received this dose)Single dose given peri-transplant (d?30 to d+30)(104 patients, [80%] received IVIG between days ?2 to +2).>95% received Intragam P, (CSL).25 patients (19.2%) received IVIg as part of ongoing (multi-dose) replacement tx for MM.Management of febrile neutropenia same as for control group.No IVIg (n=110): auto-HSCT patients receiving no IVIg in peritransplant period (days ?30 to +30)Cefepime (until 2004) or piperacillin–tazobactam (2004–2009) given to patients with febrile neutropenia. Management of febrile neutropenia and use of G-CSF was according to institutional guidelines.Outcomes: infections within 30 days post-transplant (days of intravenous antimicrobial agents number of febrile days); survival post-ASCTAnalyses: Association of categorical variables tested using Fisher's exact test; quantitative variables using Student's t test and Mann–Whitney rank-sum test. Survival data analysed by log-rank test.Follow-up: 30 days (not including survival outcomes culled from patient records.Ethics: study approved by the institutional ethics committee.Funding: none (one author employed by ARCBS).IVIg tx is physician’s preference – no formal unit policy for IVIg in HSCT.Patients typically received antifungal prophylaxis (fluconazole 200mg daily) and antiviral prophylaxis (valacyclovir 500mg daily) whilst neutropenic.Paxton et al., 2016Australia (Canberra Hospital)Single centreRetrospective cohort [2009-2013]RoB: high (SIGN)N=92 [CLL(42); MM(18); B-cell NHL(27); other(5) (AML, T-cell NHL, amyloidosis, post-HSCT)]Sex ♀/♂: 42/50Age, mean±sd yrs IVIg/NoIVIg: 68.2±12/66.7±11Mean IgG g/L±sdIVIg: 2.8±1.6No IVIg: 4.0±1.6Low IgG, n(%):<4g/L: 56 (61)≥4g/L: 36 (39)Inclusion: haematological malignancy patients who either (1) received IVIg for infection prophylaxis or (2) untreated controls with at least 1 serum IgG value <LLN. Exclusion: IVIg for indications other than infection prophylaxis.Objectives: a retrospective study to determine the absence of a history of recurrent or severe infections affects efficacy and safety of IVIg in patients with haematological malignancy and hypo-GG.IVIg, n (%)=35 (38)Antibiotics are not routine practice for hypo-GG but co-trimoxazole and fluconazole are given [routinely] with chemotherapy involving high-dose steroids, purine analogues or transplantation. Penicillin prophylaxis in 1 patient after allo-HSCT.No further details given – tx according to hospital practice.No IVIg, n (%)=57 (62)Antibiotics/anti-infective prophylaxis as for IVIg.No further details given – tx according to hospital practice.Outcomes: rate of serious infections, defined as those requiring hospital admission. Hospitalisation compared before and after HSCT. Analyses: Group characteristics compared using Fisher’s exact test for categorical variables or Student’s t-tests; event rates expressed as rate ratios with estimated variance to determine 95% confidence limits.Patients stratified by IgG level±4g/L, diagnosis, age, sex.Follow-up not described.Funding: None.Ethics: approval was received from the ACT Health Human Research Ethics Committee. The untreated group had fewer cases with severe hypogammaglobulinaemia (51% vs 77%, P < 0.01)[Comment: The untreated group had a much higher number of patients with IgG>4g/L who would be expected to do better]Van Winkle et al., 2018USAMutli-centre within single organisation (5 sites)Retrospective cohortRoB: moderate (SIGN)N=118Sex (%) ♀/♂: 55(47)/63(53)Age, mean yrs at diagnosis (range):IVIg: 7.9(0.8-19.8)No IVIg: 7.1(1.5-18.7)High risk, Y/N (%):IVIg: 20(56)/16(44) No IVIg:30(37)/52(63)Serum IgG, mean mg/dL (range):IVIg*: 474(89–785)No IVIg: no data.*only available for n/N=31/36; 24/31 patients had IgG<LLNInclusion: ALL; 9 mo – 19 yr; tx between 1 January 2008 – 1 July 2014; completion of 12+ months maintenance tx.Exclusion: <6 months old at diagnosis; relapsed ALL without 12 months maintenance tx; receipt of BMT, concurrent or prior additional malignancies, and Down syndrome.Objectives: Study of IVIg in children with ALL in remission receiving maintenance chemotherapy; including indications for initiation and discontinuation.IVIg (n=36): 400mg/kg at 1 month intervals is standard in patients with serum IgG<LLN, decision to treat was physician’s choice and actual dosing may vary. Duration not stated.Reason for IVIg (n=36):Infect. before chemo: 5Infect. during chemo: 16Viral exposure: 4Hypo-GG: 11Reason ceased (n=36):End of chemo: 16IgG return to normal: 7Single dose only: 6Patient refused: 2[others: ongoing at study end (3); relapsed, excl. from analysis (2)]No IVIg (n=82): tx per patient medical recordsOutcomes: infectious complications before and during maintenance tx (including episodes of infection; hospitalisations and days of hospitalisation)Analyses: Groups were compared using nonparametric statistics (χ2, Wilcoxon rank sum, signed rank tests as appropriate). Univariate logistic regression of each variable with the outcome ‘IVIG given (group membership)’ was also computed. Multivariate analysis with all variables from univariate analysis with p<0.25 available prior to maintenance tx.Further details in paper.Follow-up: Not applicable. Ethics: study approved by Kaiser Permanente Southern California IRB.Funding: This research was supported by a grant from the Regional Research Committee of Kaiser Permanente Southern California.The author(s) have no conflicts of interest to disclose.The LLN […] for IgG ranged from 501 mg/dL to 757 mg/dLUnits conversion: 100mg/dL (units used in older studies) equals 1g/L; Risk of Bias was assessed using the SIGN checklist for controlled trials (for RCTs only); the SIGN checklist for cohort studies, and the IHE checklist for case series. Abbreviations are as for REF _Ref11162222 \h \* MERGEFORMAT Table 79. Table SEQ Table \* ARABIC 81Included study profiles for safety and effectiveness – case seriesAuthor, YearCountryStudy design Risk of bias (RoB)Population characteristics (at baseline unless specified)Eligibility criteria ObjectivesInterventionComparatorOutcomes assessedStatistical AnalysesDuration of follow-upCommentsNon-comparative studies – IVIg case seriesBesa, 1992USASingle centre.Case series (prospective); Open-labelRoB: moderate (IHE)N=23 (CLL)Age, median (range): 64.3 (31-83)♀/♂: 6/17Disease stage A (0): 1; A (I): 2B (II): 8C (Ill): 7; C (IV): 5Serum IgG, mean mg/dL (range):572 (200–1720)18/23 patients (78%) had hypo-GG (serum IgG <700mg/dL)Inclusion: CLL patients with stage A(0) to A(II) disease with increased lymphocyte doubling time; or stage B(II), C (III and IV) disease. Exclusion: none described.Objectives: to investigate whether IVIg has anti-leukaemic effects in CLL patients with lymphocytosis, based on previous pilot study in 3 patientsIVIg: 400 mg/kg daily for 5 days, followed by a maintenance dose at 21-day intervals for 12 months―Outcomes: lymphocyte counts; leukaemic response. Infections reported as a complication/ prognostic variable (before/after comparison presented).Analyses and follow-up not described.Funding: Supported by the Hematology-Oncology Research Fund of the Medical College of Pennsylvania.No conflict of interest statement included.IVIg (Sandoglobulin) supplied by Sandoz.Ethics: no statement of ethics committee oversight included. Brenner, 1996IsraelSingle centreBefore/after time seriesRoB: moderate (IHE)N=54 [CLL(22); MM(4); ITP(20); PAPS(8)]Sex, ♀/♂: 26/28 Median age yr (range), CLL: 61(39-80); MM: 65(61-70)Inclusion: for CLL – serum IgG <700mg/dL and/or recurrent infections with at least one infection requiring hospital admission; for MM – recurrent infectionsExclusion: none described.Objectives: to investigate the safety of Octagam in patients with CLL, MM, ITP and PAPS. To evaluate ability of Octagam to prevent infections in patients with CLL and MM.IVIg: 0.4g/kg every four weeks for six consecutive courses (Octagam, Octapharma).―Outcomes: adverse events; viral safety parameters (not presented); infections; infections requiring hospitalisation.History of infections is presented in a na?ve comparison with the infections observed during the study for CLL patients (MM patient numbers too small). Analyses: none presentedFollow-up: 6 months after last infusion.Funding: the article makes no funding disclosures but as a study that aims to demonstrate safety and efficacy of a single brand of IVIg, it is very likely a sponsor-funded study.Ethics: Informed consent approved by Rarnbam Medical Center ethical committee. Outcomes due to ITP and PAPS (both autoimmune diseases) are not relevant to this evaluation.Günther & Dreger 2013GermanySingle centreBefore/after time series: [Apr 1997–Nov 2010]Level IVRoB: Moderate (IHE)*N=10 patients [CLL(5), FL(2), immunocytoma(1), plasmacytoma(1), MDS(1)]Sex ♀/♂: 7/3Weight (kg): 77 (57–100)Age, median (range): 63 yr (38–73)Disease stage (n):Binet A (2); Binet B/Rai II (3); Rai III (4); not specified (1)Inclusion: adults indicated for IVIG with recurrent serious bacterial infections due to haematological malignancyExclusion: not described. Objectives: Effect of IVIg on severe recurrent infections in 10 patients with various haematological malignancies. IVIg: 0.35 g/kg body weight every 3–4 weeks (Flebogamma, Grifols)―Outcomes: incidence of bacterial infections; non-bacterial infections; antibiotic/anti-infective use; adverse events including death.Analyses and follow-up not described.Work was supported by Grifols (manufacturer of Flebogamma).Serum IgG at baseline not reported.Jurlander et al., 1994DenmarkSingle centre.Before/after time seriesLevel IVRoB: Moderate (SIGN)N=15 (CLL) (results reported for 14 only)Age median (range): 66 (50–81)Sex ♀/♂: 6/9Binet stage, n: A(3); B(4): C(8)Disease duration median (range):8.0 (2–19.5)Serum IgG mean±sd: 12.5±5.0 micromol/LInclusion: B-cell CLL, hypo-GG (serum IgG<LLN); history of recurrent infections; able to be treated as outpatientExclusion: Not described.Objectives: whether a 10g dose 3-weekly of IVIg in CLL patients with hypo-GG and a history of recurrent infections will show a benefit in terms of infection related events. IVIg: 10g every 3 weeks (Gammagard, Baxter)Dose duration not pre-specified. Paper describes tx until serum IgG normalised (or discontinuation)Number of infusions median (range): 19.5 (4–25), or ~13 mo―Outcomes: serum IgG levels; infection status; antibiotic use; hospital admission for infection; febrile episodesAnalyses: comparison of infection-related events in 12 months prior to IVIg and in 12 months after IVIg using Wilcoxon-Pratt test for paired nonparametric data.Follow-up: Median observation period 14 months (range 3–20)No mention of research ethics approval.No description of funding source or conflict of interest declaration. Non-comparative studies – SCIg case seriesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl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ADDIN EN.CITE.DATA (Dimou et al. 2018)GreeceSingle centreInterrupted time series without a concurrent control groupLevel III-3RoB: moderate (IHE)N=33 [CLL(25); MM(3); B-NHL(3); HL(1)]5 treatment na?ve (all CLL); 29 pretreated, 13 with IVIg Sex ♀/♂: 16/17Age, mean (range): 66.1 yrs (38-88)Inclusion: secondary hypogammaglobulinaemia due to haematological malignancyExclusion: not statedSCIg: 0.4-0.8mg/kg/month with dose intervals between 3-4 weeks. Administered using a variable rate portable pump. Historical comparison (12 months prior to SCIg)13 patients on IVIgOutcomes: infections, adverse eventsAnalyses: none performedNo funding or CoI stated.Non-comparative studies – any IgG (IVIg and SCIg) case seriesBenbrahim et al., 2018FranceMulti-centre (29 sites)Case series (prospective)RoB: low (IHE)N=231 [MM(64), CLL(84), aggressive NHL(32), indolent NHL(39), AL(6), HL(6)]23% of patients had received auto-HSCT, and 1% allo-HSCTAge, yr, mean±sd: 66±12 years old♀/♂: 80(35%)/ 151(65%)ECOG-PS0: 100 (43.7%)1: 84 (36.7%)2: 34 (14.9%)≥3: 11 (4.8%).Serum IgG, medianIgG: 4.20g/LIgA: 0.44g/LIgM: 0.20g/L[no ranges given, n=195/231]134/195 patients tested (68.7%) had serum IgG <5g/LInclusion: Consecutive adult patients with HM-associated 2° immunodeficiency who were newly prescribed IgG-RT (IVIg or SCIg).Exclusion: Patients having received IgG-RT at any time within the last 12 months.Patients also excluded from analysis due to: age <18 y; no haematological malignancy or diagnosis of MGUS.Objectives: efficacy and safety of IgRT with IVIg or SCIg, patient adherence and satisfaction of physician expectations over the follow-up period (preliminary report). IgRT with IVIg (N=106): median prescribed dose 385mg/kg/mo IVIg (Octagam, Octapharma).For both groups, antibiotic prophylaxis was reported except S+T which is conventional tx in France for immuno-compromised patients at risk of Pneumocystis spp. and valaciclovir for herpesviruses activation (zoster, CMV)IgRT with SCIg (N=113) median prescribed dose 99 mg/kg/wk SCIg (Gammanorm, Octapharma).For both groups, antibiotic prophylaxis was reported except S+T which is conventional tx in France for immuno-compromised patients at risk of Pneumocystis spp. and valaciclovir for herpesviruses activation (zoster, CMV)Baseline data only.Outcomes, analyses and follow-up: reported in Benbrahim et al., 2019.Ethics: study conducted under French Regulations for non-interventional studies (confirmed by French ethics committee (Comité de Protection des Personnes Ile-de-France VI). Funding: “study was funded by Octapharma-France”2 authors were pharma industry employees (CRO Soladis, Octapharma). Other authors declared wide range of advisory board and speaking engagements but no conflicts of interest.Benbrahim et al., 2019FranceMulti-centre (21 sites)As above.N=160 [MM(54), CLL(54), aggressive NHL(19), indolent NHL(29), HL(4)]. Age, yr, mean±sd: 67.3±11.2♀/♂: 61(38.1%)/ 99(61.9%)133/160 (83.1%) were ECOG-PS ≤1138/160 patients (86.3%) had Ig levels tested.Inclusion: available for follow-up since study initiation (see preliminary report).Exclusion and objectives: As for preliminary report. IgRT with IVIg (N=50):387±78 mg/kg/mo IVIg.Otherwise as for preliminary report.IgRT with SCIg (N=110): 97±45mg/kg/wk SCIg (equals 388mg/kg/mo).Otherwise as for preliminary report.Outcomes: change in serum IgG from baseline; annual incidence of infections. Analyses: Characteristics were compared according to route of administration, using χ2 test or Fisher’s exact test for categorical variables and Student’s t test for continuous variables.Follow-up: Mean follow-up duration was 8.7±4.0 months (median 10.8 months).(during which 17 patients died, 5 after developing sepsis)Ethics: as for preliminary report. This protocol was approved by the French CCTIRS and CNIL.Funding and disclosures – as for preliminary report. Aggressive NHL: lymphomas incl. T-cell ,T-lymphoblastic, Burkitt, DLBCL, and angio-immunoblastic T-cell. Indolent NHL: incl. FL and Waldenstr?m macro-globulinemia.Duraisingham et al., 2014United KingdomSingle centreCase series (retrospective)RoB: moderate (IHE)N=167, of which:PID (113); PID (prob.)(13); SID(26); SID(prob.)(13); undetermined(2)Haem. malignancy patients (15) in SID group: CLL(1), MM(1), NHL(11); MDS(1); MGUS(1) Sex ♀/♂: 98/ 69Median age, yr: SID 64.5; SID (prob.) 58hypo-GG (IgG <5.5g/L): SID 80.8%; SID (prob.) 69.2%Median 12mo serum IgG (SID): 3.30 g/L)Lung disease (SID):Bronchiectasis:28.2% Asthma and/or COPD: 34.1% Inclusion: Adults with primary (PID) or secondary immuno-deficiency (SID) receiving IgG-RT at data cut-off (May 2013)Exclusion: patients whose diagnosis as either PID or SID was not confirmedObjectives: comparison of PID and SID patients receiving IgG-RT; comparison of infection outcomes before and after tx.SID (n=39): initial dose of 0.1g/kg/week with adjustment based on infection IVIg: 13 (33.3%)SCIg: 26 (66.6%)SID+SID(prob.) group had patients with haem. malignancy (14+1) and autoimmune/ rheumato-logical disease (12+12).PID (n=126): IVIg initial dose of 0.1g/kg/week with adjustment based on infection (PID patients not relevant to PICO – for further details see paper)Outcomes: Patient demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, infection frequency.Analyses: comparisons by 2-tailed unpaired t-test with Welch’s correction (unequal variance t-test). 2-tailed paired t-test compared infection frequency pre-/post-treatment. Comparison between diagnostic sub-groups used Kruskal-Wallis test. Bronchiectasis data, only available for few patients, analysed using Mann-Whitney test. P <0.05 considered significant.Follow-up: 12 monthsEthics: in accordance with approval by the City and East London Research Ethics Committee.Funding: primary author’s salary funded by CSL Behring. Other authors disclosed a range of interests with plasma products manufacturers including CSL Behring, Baxter, Octapharma, Grifols, BPL and LFP. Supplementary data: the 11 NHL patients had: MCL(1); DLBCL(1); B lymphoblastic lymphoma(1); FL(4); MZL(2); unspecified NHL(2)1 patient with Waldenstr?m macroglobulinaemia was not included in the analysis as being ‘undetermined’ rather than SID.Reiser et al., 2017GermanyMulti-centre (48 sites)Case series (2009-2016) (Prospective)RoB: moderate (IHE)N=307 [CLL(130); indolent lymphoma (77); MM(43); NHL(22); other(35)]Mean age±sd, yr:63.7±14.4♀/♂: 47.6%/52.4%New IgG starters (tx <3mo): 31.3%Median (IQR) IgG tx duration: 3mo (0-13)Median IgG level: 5.8g/L (mean 7.2±6.9 g/L). Inclusion: receiving IgG maintenance or newly initiated on any IgG preparation as long-term therapy; due to CLL, MM, indolent lymphoma, other malignancies such as NHL or HIV (if infection or tumours).Exclusion: none describedObjectives: to systematically collect data on patient characteristics, IgG utilisation, and outcomes with respect to infection rates and QoL under real life conditions.IgG: Variable. Median (IQR) 4-weekly dose:IVIg (n=287); 163mg/kg (116-258)SCIg (n=20); 330mg/kg (255-420)Average dose: 205mg/kg per 4 weeks.Duration not reported.―Outcomes: Infection rate; severe infections; IgG trough levels; side-effects; QoL; mortality; IgG utilisationAnalyses: continuous variables were compared with t test, Mann-Whitney or Wilcoxon test depending on the underlying distribution. Categorical data were compared with the χ2-test. Survival was evaluated with Kaplan-Meier analysis.Follow-up: average follow-up 20.5 monthsEthics: It was approved by the ethics committee of the Medical Faculty of the Technical University of Dresden and further local ethics committees in Germany.Funding: study supported with unrestricted grant by Baxalta. The company had no influence on the concept, analysis and interpretation of data.Non-comparative studies – IVIg v SCIg case seriesSundin, 2012SwedenSingle centreCase series [2003 – 2010] (designed as a cohort study SCIg v IVIg)RoB: moderate (IHE)N=58 (HSCT), of which 26 had haem. malignancy: ALL(11); AML(7); JMML(3); NHL(2); MDS(3). Sex ♀/♂: 18/39Mean age, yr (range)IVIg: 7.2 (0–17)SCIg: 2.6 (0–9)Inclusion: paediatric (<18 yo) patients receiving HSCT who had hypo-GG for at least 3 mo post-HSCT.Exclusion: not described.Objectives: the use of SCIg vs. IVIg in 58 hypo-GG children post-HSCT with a prolonged need of IgG replacement.IVIg (n=46): 0.3–0.5 g/kg, every 2-4 weeksIgG initiated at median 3 mo post-HSCT (range 1-8 mo).24 of 46 patients had haem malignancy. SCIg (n=12): 0.1–0.2g/kg every 1-2 weeksIgG initiated at median 3 mo post-HSCT (range 0-8 mo).Most SCIg patients were initiated in the hospital on IVIg before switch to SCIg. 2 of 12 patients had haem. malignancy. Outcomes: rates of infections, IgG levels and family attitudes (in survivors)Analyses: Proportions were compared using Fisher’s exact test. For individual samples Mann–Whitney’s test was used. Statistic significance was set at p <0.05.Follow-up: Data cut-off December 2011 (HSCT received between 2003 – 2010)Ethics: approved by the Regional Ethical Review Board in Stockholm,Funding: funding disclosed from government and charitable sources, though no conflict of interest declaration was included.JMML is juvenile form of CML ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019)AustraliaSingle-centreSunshine Coast Hospital and Health ServiceCase seriesLevel IVRoB: Moderate (IHE)N=13 with acquired hypogammaglobulinaemia secondary to malignancy or associated treatmentSex ♀/♂: 8/5Age mean 62.5 (range 39-76)Inclusion: adult patients with acquired hypogammaglobulinaemia secondary to malignancy or associated treatment, who were on IVIg for at least 12 months before switching to SCIg Objectives: to determine whether SCIg is a cost-effective treatment in SID patientsIVIg administered by a registered nurse once every 4 weeks. Mean usage: 29.46 g/monthSCIg: administered weekly at a place convenient to them. Mean usage: 31.15 g/month―Outcome: infections, length of hospital stay per infection, Funding: University of the Sunshine Coast, the National Blood Authority, the Wishlist Coast Health Foundation and CSL Behring Australia. CoI not stated. ADDIN EN.CITE <EndNote><Cite><Author>Windegger</Author><Year>2019</Year><RecNum>55</RecNum><DisplayText>(Windegger et al. 2019)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1554263022">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Windegger, T.M.</author><author>Nghiem, S.</author><author>Nguyen, K.H.</author><author>Fung, Y.L.</author><author>Scuffham, P.A.</author></authors></contributors><titles><title>Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency</title><secondary-title>Vox Sanguinis</secondary-title></titles><periodical><full-title>Vox Sanguinis</full-title></periodical><edition>18th March 2019</edition><dates><year>2019</year></dates><urls></urls><research-notes>IVIG vs SCIG Received from Dept </research-notes></record></Cite></EndNote>(Windegger et al. 2019)AustraliaMulti-centreAs above.N=84 patients with acquired hypogammaglobulinaemia secondary to malignancy or associated treatment (including those who did not switch or switched without 12 months of IVIg data)Inclusion: adult patients with acquired hypogammaglobulinaemia secondary to malignancy or associated treatmentObjectives: to determine whether SCIg is a cost-effective treatment in SID patientsIVIg or SCIg―Outcomes: utilities associated with disease and infectionsAs above.Institutions: Sunshine Coast Hospital and Health Service and Gold Coast University HospitalOther (IVIg or SCIg) – dosing studiesChapel, Dicato et al. 1994UK, LU, DEMulti-centre (4 hospitals)Case series, though designed as RCT between two different doses of Ig (no ‘no Ig’ arm); double-blindLevel IVRoB: low (IHE)N=34 (CLL)High dose (n=16)Mean age±sd, yr:63.5±8.4Sex ♀/♂: 7/9Disease stage (IWCLL), n (%)1: 4 (25%)2: 5 (31%)3:7 (44%)Low dose (n=18)Mean age±sd, yr:64.2±8.7Sex ♀/♂: 5/13Disease stage (IWCLL), n (%)1: 7 (39%)2: 4 (22%)3:7 (39%)Inclusion: CLL and an IgG level below lower limit of normal for the local hospital laboratory or a recent history of one or more serious infections. Exclusion: taking prophylactic antibiotics, had total IgA deficiency or history of anaphylaxis to blood product. Objectives: to determine whether a reduction in the dose of immunoglobulin would still protect against bacterial infections in patients with CLL and NHLHigh dose IVIg (n=16)500 mg/kg body weight every 4 weeks as outpatient for 12 monthsLow dose IVIg (n=18)250 mg/kg body weight every 4 weeks as outpatient for 12 monthsGammaguard (Baxter Biotech Group)―Outcomes: adverse events, infectionsAnalyses: infection rates compared using Poisson rates with two-tailed p value. Numbers of infected patients compared by chi-square test for independence. Follow-up: 9 patients did not complete the study, (6/3 low/high dose) 4 of these patients died, 2 in each tx group; the 1 infective death was a low dose patient who died of meningitis.One author (M Lee) an employee of Baxter (IVIg manufacturer)Ethics: protocol approved by each hospital ethics committee; formal written consent obtained from all participants.Funding: The authors thank Baxter for a financial grant for this study. [Baxter manufactures Gammagard, IVIg used in this study]No declaration of CoI made. Stump, 2017USASingle centreCase series(interrupted time series comparison of different dosing strategies)[April 2014 ― September 2016]RoB: highN=79 (209 evaluable of 238 IVIg encounters)Pre-dose not baseline values as number of IgG na?ve recipients not reported.Infusions – condition:CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5)Age yr, mean±sdABW: 57.7±14.8IBW: 49.4±19.6♀/♂: 106(51)/103(49)IgG levels: tested prior to 133 of 238 infusions (56%)Of which, hypo-GG (<400mg/dL):47/133 (35%)Existing infection, IBW/ABW: 51.2%/33.6%Neutropenia ANC <0.5x109/L IBW/ABW: 65.5%/58.4%Inclusion: patients ≥18 yo with hematologic malignancies who received IVIG either as an inpatient or outpatient, including HSCT patients for malignancy.Exclusion: Patients who were pregnant, incarcerated, primary immunodeficiency, or received IVIG for indication unrelated to hematologic malignancy.Objectives: effectiveness of ideal body weight (IBW) versus actual body weight (ABW) dosing strategy for IVIG in patients with hematologic malignancies or undergoing HSCTIVIg-ABW (n=125 infusions): no information on dose level, frequency, duration or supportive care (including antibiotic use) provided. NB: some patients receiving consecutive doses had ABW and IBW calculated doses on different occasions.Note: Authors advise that median IVIg dose per patient during study period (30mo or 2.5yr) was 1 (range 1-18) or a mean of 2.6 doses (S Stump, pers. comm. May 2019)IVIg-IBW (n=84 infusions): no information on dose level, frequency, duration or supportive care (including antibiotic use) provided. NB: some patients receiving consecutive doses had ABW and IBW calculated doses on different occasions.See note in ABW column regarding doses per patient. Outcome: primary outcome was infection rate within 30 days of IVIg administration; Secondary outcomes incl. 60-day infection rate, IgG-level response (>400mg/dL), realised and potential IVIg savings.Infection defined as defined as a positive culture, respiratory viral panel, Clostridium difficile assay, or a chest radiograph.Analyses: A χ2 test used to analyse primary outcome and other categorical data; Student t test used for continuous data. Statistical significance defined as p<0.05Follow-up: 30 days for each infusion received during the period 1 April 2014 to 30 September 2016. N=209 did not include 26 patients who died in the initial 30 day period and 1 patient lost to follow-up who were excluded from the analysis.Ethics: The study was approved by the University of North Carolina institutional review board.Funding: the paper includes no statement of funding source nor conflict of interest declaration. But no ‘no IVIg’ baseline against which to measure infection rate.Type of infections, total patient numbers, how many infusions were received as consecutive doses by the same patient, dose levels, dose duration were not reported.49% of infusions were in patients who received HSCTUnits conversion: 100mg/dL (units used in older studies) equals 1g/L; Risk of Bias was assessed using the SIGN checklist for controlled trials (for RCTs only); the SIGN checklist for cohort studies, and the IHE checklist for case series. Abbreviations are as for REF _Ref11162222 \h \* MERGEFORMAT Table 79.*Notes: Günther & Dreger 2013 – the plasmacytoma case was IgA-secreting which is most likely not included in the WHO definition of MM depending on other clinical features (if extramedullary), thus is an ‘other haematological malignancy’; FL is included in the WHO definition of NHL; the case of WM (described by authors as an IgM-secreting immunocytoma) is an ‘other haematological malignancy’.Appendix SEQ Appendix \* ALPHABETIC EExcluded StudiesTable SEQ Table \* ARABIC 82List of the excluded systematic reviews or meta-analysesStudy Title+citationIndication (# RCTs)Reason for exclusionAhn et al., 2018.Effectiveness of immunoglobulin prophylaxis in reducing clinical complications of hematopoietic stem cell transplantation: a systematic review and meta-analysis', Transfusion, 58: 2437-52.HSCT(27)The review included all studies of IgG regardless of baseline infections risk and/or hypogamma-globulinaemia. Bass et al., (1993) Efficacy of immune globulin in preventing complications of bone marrow transplantation: a meta-analysis. Bone Marrow Transplant. 1993;12(3):273-82.HSCT/BMTIncluded studies (k=12) were a mix of interventions, outcomes and only included some randomised trials.Raanani et al., 2008Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantationCochrane Database Syst Rev(4): CD006501.HSCT(30), haem. malignancies (10)The review included all studies of IgG and CMV-IgG regardless of baseline infections risk and/or hypogamma-globulinaemia. Raanani et al., 2009Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: Systematic review and meta-analysis.Leukemia and Lymphoma 50(5): 764-772.CLL or MM (9)The review included all studies of IgG regardless of baseline infections risk and/or hypogammaglobulinaemia. Raanani, Gafter-Gvili et al., 2009Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: Systematic review and meta-analysis. J Clin Oncol 2009 Feb;27(5):770-81.HSCT (30)As above. Abbreviations are the same as those in REF _Ref11162222 \h \* MERGEFORMAT Table 79Table SEQ Table \* ARABIC 83List of the excluded studiesStudy Title+citationIndication (N patients)Reason for exclusionAzik et al., (2015). Comparison of prophylactic use of immunoglobulin M-enriched polyclonal immunoglobulin (Pentaglobins) versus standard immunoglobulin after pediatric hematopoietic stem cell transplatation.Bone marrow transplantation. 50: S573.HSCTN=59IgG tx commenced prior to conditioning; no record of serum IgG or infection history prior to tx. Abdel-Mageed et al., (1999)Comparison of two doses of intravenous immunoglobulin after allogeneic bone marrow transplants. Bone Marrow Transplant. 1999;23:929-32.HSCT (allo-BMT)N=350No serum IgG levels at baseline or during study; nor infections with/without IgGCasulo et al., (2013)Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk 13(2): 106-111.Sub-study: N=14 (NHL, CLL/SLL)All patients received B-cell depletion therapy, excluded under Criteria Version 3. Symptomatic IgG with IVIg tx only in n=14 sub-study.Chapel et al., (1993).Intravenous immunoglobulin therapy in patients with multiple myeloma. Immunodeficiency 4(1): 77-78.N=82 (MM)Preliminary report – results reported in Chapel & Lee, 1994; Chapel et al., 1994.Chapel & Lee (1994). The use of intravenous immune globulin in multiple myeloma. Clinical and Experimental Immunology, Supplement 97(1): 21-24.N=82 (MM)Same study as reported in Chapel et al., 1994 (Lancet). The Lancet paper was chosen to include as it presented better description of trial particulars. Compagno et al., 2014Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients.Haematologica, 99: 1101-6.N=61 (B-CLL[40]; NHL[21])B-cell depletion therapy, excluded under Criteria Version 3; n=42/61 patients (69%) received anti-CD20 MAbs prior to onset of hypo-GGCordonnier et al., (2003). Should immunoglobulin therapy be used in allogenic stem-cell transplantation? Ann Intern Med 139(1): 8-18.Allo-HSCT (N=200)Prophylactic tx (no evidence of infection); no evidence of hypo-GG status or history of infection at baseline. Demitrovicova et al., (2017). Infectious complications in chronic lymphocytic leukemia- a retrospective analysis: single institution experience. Neoplasma 64(3): 474-481.CLL (N=110)IgG given in an unidentified subset of patients with no outcomes reported according to IgG/No IgG received.Foster et al., (2018). Immunoglobulin prophylaxis in pediatric hematopoietic stem cell transplant.Pediatric Blood and Cancer 65(12).HSCTN=150Both tx groups received prophylactic IgG (no evidence of infection); only in 2nd group was tx based on hypo-GG status or serum IgG levels monitored. Viral infections only reported.Frangoul et al., (2013).Incidence and risk factors for hypogammaglobulinemia in pediatric patients following allo-SCT. Bone Marrow Transplant 48(11): 1456-1459.Allo-HSCT (paeds)N=185‘No IgG’ control patients all had normal IgG levels, compared to IgG recipients who had hypo-GG. No infections reported, only transplant-related mortality. Gimesi A, Eibl M, Koós R, et al. (1992) Immunoglobulin prophylaxis during intensive treatment of acute lymphoblastic leukemia in children. Acta Paediatr Hung 1992;32(2):115-25.ALL (N=60)Prophylactic use (no evidence of infection), without mention of hypo-GG status, infection history, or IgG levels.Hensel, M., et al. (2003)Disease activity and pretreatment, rather than hypogammaglobulinaemia, are major risk factors for infectious complications in patients with chronic lymphocytic leukaemia. Br J Haematol 122(4): 600-606.CLLN=187Prophylactic use (no evidence of infection). More than half patients had no hypo-GG; only 10 patients received IVIg. Not possible to identify infections occurring only in those receiving IVIg or in those with hypo-GG.Howell et al., (2012).Retrospective analysis of weekly intravenous immunoglobulin prophylaxis versus intravenous immunoglobulin by IgG level monitoring in hematopoietic stem cell transplant recipients. Am J Hematol 87(2): 172-174.Allo-HSCTN=229Both tx groups received prophylactic IgG (no evidence of infection); only in 2nd group was tx based on hypo-GG status or serum IgG levels monitored. Hussein et al., (2016).Incidence and risk factors of bacterial infections in children following autologous hematopoietic stem cell transplantation: Single-center experience from Jordan. Pediatr Transplant 20(5): 683-686.HSCT (paed)N=65, of which HL(12); NHL(6)Mixed population, mostly solid tumours. Patients that had HM and hypo-GG who also received IgG were not identifiable in infections data.Locatelli et al., (2017).Outcome of children with acute leukemia given HLA-haploidentical HSCT after ab T-cell and B-cell depletion.Blood 130(5): 677-685.Haplo-HSCT (ALL or AML)N=80 (paed)IgG-RT given to (all?) patients as part of supportive care (timing, dose, criteria for initiation unspecified). Serum IgG levels suggest patients include those with and without hypo-GG, but no outcomes reported based on hypo-GG status. Park et al., (2015).Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma. Transpl Infect Dis 17(5): 679-687.Auto-HSCT(N=162 MM patients)No criterion required or information reported regarding IgG serum levels at baseline nor infection history/risk. HSCT patients all given IVIg from d1 of transplant. Ruutu et al., (1997)No prevention of cytomegalovirus infection by anti-cytomegalovirus hyperimmune globulin in seronegative bone marrow transplant recipients. The Nordic BMT Group.Bone Marrow Transplant. 1997 Feb;19(3):233-6.HSCT (BMT)N=28Intervention: CMV hyperimmune globulin onlySpadaro et al., (2016). Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia. Clin Immunol 166-167: 103-104.N=14NHL(12); CLL(2)All patients received B-cell depletion therapy, excluded under Criteria Version 3. Sullivan et al., (1996).A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery. Biol Blood Marrow Transplant 2(1): 44-53.BMTN=254Extension study for Sullivan et al., 1990. Not clear that patients continue to meet criteria for tx. Untreated group serum IgG levels suggest patients no longer have hypo-GG. Visentin et al., (2015). Clinical profile associated with infections in patients with chronic lymphocytic leukemia. Protective role of immunoglobulin replacement therapy. Haematologica 100(12): e515-518.CLLN=706No information on infections at baseline, most patients did not have hypo-GG, nor was there any subsequent monitoring of IgG levels. Winston et al., (2001)A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation.Bone Marrow Transplant. 2001 Jul;28(2):187-96.HSCTN=618Tx commenced prior to transplant; no infection history or IgG levels at baseline.Winston DJ, Ho WG, Bartoni K, Champlin RE (1993) Intravenous immunoglobulin and CMV-seronegative blood products for prevention of CMV infection and disease in bone marrow transplant recipients. Bone Marrow Transplant 12:283–288HSCTProphylactic Ig use (not limited to treating hypo-GG)Winston et al., (1993)Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial. Ann Intern Med. 1993;118:179-84. HSCTProphylactic Ig use (not limited to treating hypo-GG)Wolff et al., (1993) High-dose weekly intravenous immunoglobulin to prevent infections in patients undergoing autologous bone marrow transplantation or severe myelosuppressive therapy. A study of the American Bone Marrow Transplant Group. Ann Intern Med 118:937–942Auto-BMT (125); AL (26); ‘other’ (19)N=170Only 8% of patients had hypo-GG; results not reported according to hypo-GG status. No information on history of infections. Zikos et al., (1998) A randomized trial of high dose polyvalent intravenous immunoglobulin (HDIgG) vs. cytomegalovirus (CMV) hyperimmune IgG in allogeneic hemopoietic stem cell transplants (HSCT). Haematologica 83:132–137HSCT (adults and paeds)(N=128)Wrong comparator (CMV globulin not ‘No IgG’), no evidence of hypo-GG in recipients prior to treatment; no untreated group to enable comparison of infection rates. Prophylactic tx prior to HSCT. Abbreviations are the same as those in REF _Ref11162222 \h \* MERGEFORMAT Table 79Appendix SEQ Appendix \* ALPHABETIC FSupporting clinical dataTable SEQ Table \* ARABIC 84Antibiotic use and infection prophylaxis in the included studiesStudyInfection prophylaxisAntibiotic prescribingRandomised studies – IVIg vs No IVIgBoughton et al., 1995On-study – none noted.Immediately prior to study, patients excluded if antibiotic prophylaxis received within 2 weeks. As prescribed by GPChapel et al., 1991None noted (likely the same as PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxlPC9BdXRob3I+PFllYXI+MTk4ODwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxlPC9BdXRob3I+PFllYXI+MTk4ODwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Gale et al. 1988), not allowed on study.)Not described, though infection severity was defined in terms of requirement for antibiotics – oral (moderate) IV (major) or none required (minor)Chapel et al., 1994Not allowed in 2 weeks prior to entry; ‘patients were not expected to receive such treatment during the study’.As required, by treating physician (blinded to study drug)Kobayashi et al., 2014Sub-study patients those who failed main study antibiotic prophylaxis received 2nd line MEPM:-until Apr 2010 60 mg/kg/d, [max 1.5g/d] for 72h; -after Apr 2010 120mg/kg/d [max 3.0g/d] for 72hG-CSF was used in 28 of 61 patients.Main study patients received one of two potential 1st line prophylactic agents:-until Apr 2010 cefepime or cefozopran-after Apr 2010 cefepime or piperacillin/ tazobactamSub-study patients:Anti-fungal drugs (micafungin or liposomal amphotericin) were given to patients with suspected fungal infections, other anti-infectives not described (noting 72h sub-study tx duration). Molica et al., 1996Not allowed on study.Not described.Musto et al., 1995Not allowed on study.Not described.Sullivan et al., 1990Pneumocystis spp. antibiotic prophylaxis until d120 (likely S+T or similar); enteric decontamination (presumably with non-absorbed antibiotics); other antibiotic prophylaxis was not permitted; the 1st 6 consecutive patients ‘inadvertently’ received unidentified antibiotic prophylaxis. Not described.Randomised studies – SCIg vs No SCIgVacca et al., 2018Antibiotic prophylaxis not allowed on study.All patients receiving bortezomib received acyclovir for the study duration. No antifungals were given. Prescribed on diagnosis of infection as they arose.Other comparative studies – IVIg vs No IVIgAmmann et al., 2016Not reported (variable)Not reported (variable)Blombery et al., 2011Not allowed on study.Antibiotics if any febrile neutropenia. Paxton et al., 2016Antibiotic prophylaxis was not routine practice for hypo-GG, but S+T and fluconazole were given with chemotherapy involving high-dose steroids, purine analogues or HSCT. Penicillin prophylaxis used in 1 patient after allo-HSCT.Per patient records.Van Winkle et al., 2018None noted.Per treating physician.Non-comparative studies – IVIg case seriesBesa, 1992None noted.Not describedBrenner, 1996None noted.Not describedGünther & Dreger 2013None noted.9 (out of 10) patients were on (unspecified) antibiotics at enrolment and continued to receive these as concomitant medication. Antibiotics prescribed during the study were reported by infection type. For example, the antibiotics prescribed for the 17 lower respiratory tract infections that occurred on study were: azithromycin, roxithromycin, ceftriaxone, ciprofloxacin, cefuroxime, clarithromycin and carbacephem. See Table 4 of the article for other antibiotics prescribed on study.Jurlander et al., 1994None notedNumber of prescriptions reported only.Non-comparative studies – SCIg case seriesDimou et al., 2018None noted.Not described. Any IgG (IVIg and SCIg) case seriesBenbrahim et al., 2018N/A (preliminary report)N/A (preliminary report)Benbrahim et al., 2019Prophylaxis with valaciclovir and S+T was acceptable but usage was not reported.8 patients (5%) received antibiotic prophylaxis at least once during follow-up (apart from the conventional [use] of valaciclovir and S+T, which was not reported).Duraisingham et al., 2014Patients on prophylactic antibiotics in SID group (N=39, of which 15 had HM):Before Ig-RT: 27 (69.2%)After Ig-RT: 23 (60.0%)Antibiotics other than prophylactic not described. Days on antibiotics before IgG-RT recorded but not after IgG-RT.Reiser et al., 2017As recorded in medical records.Not described.Non-comparative studies – IVIg v SCIg case seriesSundin et al., 2012Refers to previously published paper PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW1iZXJnZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW1iZXJnZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy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=
ADDIN EN.CITE.DATA (Remberger et al. 2011) that cited prophylaxis with antivirals (ganciclovir, acyclovir, foscarnet) and lysosomal amphotericin B for potential fungal infections, though it is not known how many patients received these in this study.Not described.Windegger et al. 2019None noted.Not described.Other (IVIg or SCIg) – dosing studiesChapel, Dicato et al. 1994Patients on prophylactic antibiotics ineligible for study entry; and it was implied though not explicit that this also applied to on-study tx.Not described.Stump et al., 2017None noted.Not described.Table SEQ Table \* ARABIC 85Randomised studies presenting infections – IVIg vs no IVIgStudyOutcomeInterventionComparatorComparisonBoughton et al., 1995Infections in 12 mo (%)(N=42)IVIg (n=24)No IVIg (albumin) (n=18)p valueCLLPatients with infections (n/N)18/42 (43%) (figures for tx groups not reported)Number of infections122 (figures for tx groups not reported)Patients with infections≥3 infections in 12mo7 (29%)11 (61%)p=0.04<3 infections in 12mo17 (71%)7 (39%)Patients with serious infections≥3 serious infections in 12mo5 (21%)10 (56%)p=0.02<3 serious infections in 12mo19 (79%)8 (44%)Chapel et al., 1991Infection incidence during 24 mo including cross-over (N=12)IVIg (n=6)Placebo (saline)(n=6)CLL, NHLPatients free of serious infection6/6 (100%)1/6 (17%)Total 3-weekly cycles (infusions)191162Years, mean/patient1.841.56Major infections per patient0.31.7Major infections/patient/year0.1821.070Major infections/patient/month0.0150.089p=0.001Major infectionsBacterial09Viral11Fungal10Total major infections210Moderate infectionsBacterial311Viral30Fungal01Unknown infection11Total moderate infections713Trivial infections2322Total overall infections3245Chapel et al., 1994Infections during 12 mo (N=82 not including 1 IVIg withdrawal)IVIg (n=41)Placebo (albumin)(n=41)p (2-tailed)MMPatients – any infection2426Patients – no infections65Serious infections – majorsepticaemia030.045pneumonia070.005Total serious (major) infections0100.002Serious infections – moderateother chest infections6180.0097UTIs85n.r.skins sepsis/abscess/cellulitis20n.r.pyrexia of unknown origin20n.r.other15n.r.Total serious (moderate) infections1928n.r.Total serious infections (57 of 138 infections of any severity)1938p=0.019 (95% CI 0.007-0.071)Serious infections rate (/patient/mo)0.0420.081n.r.Serious infections, bacterial15290.05Serious bacterial infections/patient/month0.0330.062Serious infections, bacterialSecondary comparison (not incl. outlier patient with 5 UTIs)10290.007Total patient months449470―Mean months per patient11.011.5Serious infections /patient/monthn.r.(calculated: 0.042)n.r.(calculated: 0.081)0.019 (95% CI 0.007-0.071)Minor infections*n.r.n.r.Recurrent infections any severity during 12 moIVIgPlacebo (albumin)p (2-tailed)Patients at risk30311 infection1242 infections4113 infections474+ infections44Patient months360372Recurrent infections /patient/monthn.r.n.r.0.021Kobayashi et al., 2014Tx success rate*, % of episodes(N=61; 146 episodes)MEPM+IVIg (n=62 episodes)MEPM alone (n=84 episdoes)AL Tx success rate overall69.4%65.5% p=0.862Tx success, patients with serum IgG <500 mg/dL81.3%62.5%p=0.238Tx success, patients with serum IgG >500 mg/dL66.0%66.7% p=1.000Tx successpatients with ANC <0.5×109/L64.3%53.7%p=0.460Molica et al., 1996Type and site (N=42; crossover tx in 2 groups of randomised n=21)IVIg therapy phase (N=42)Empirical phase (N=42)CLLMajor infectionsSepsis 21Bacterial pneumonia35Peritonitis01Mycotic pneumonia01Varicella01Total major infections59Minor infectionsBronchitis1419Bacterial skin infection12Bacterial stomatitis02Lower urinary tract infection10Fever of unknown origin1315Herpes zoster14Total minor infections3042Total serious (major+minor) infections3551Trivial infections611Total overall infections4162Patients with no infections 22*10**p<0.02 (χ-square).Calculated infections ratesPatient-months, total376368Patient months, mean8.958.76Infections per patient0.981.48Rate, infections /patient/month0.1090.168Major infections per patient0.1190.214Rate, major infections /patient/month0.0130.024Musto et al., 1995Infections outcomes (6+12+6 mo crossover of either IVIg or No IVIg [observation])During IVIg phases (N=25 received IVIg + observation)During No IVIg phases (N=25 received IVIg + observation)p-valueMMSerious infections1030p<0.002Of which, life-threatening (septicaemia or pneumonia)09Serious infections per patient0.41.2Minor infections2327n.s. Total infections3357Patient months, total261250Patient months, mean10.410.0Rate serious infections / patient /month0.040.12Sullivan et al., 1990Infectious Outcomes from d0 to d100 or discharge (N=369)IVIg (n=184)No IVIg (n=185)BMTInfectionsNo.Rate/100dNo.Rate/100 dRelative risk (p-value)Patient days at risk13,41513,878Septicaemiagram-positive140.1190.141.69 (n.s.)gram-negative110.08330.242.65 (0.0039)fungal130.1160.121.32 (n.s.)other1―0―Total, septicaemia390.29680.492.15 (0.0022)Rate, septicaemia per patient month0.0880.149Bacteraemiagram-positive1210.901220.880.98 (n.s.)gram-negative410.31380.270.88 (n.s.)fungal160.12130.090.83 (n.s.)Total, bacteraemia1781.331731.250.97 (n.s.)Rate, bacteraemia per patient month0.4040.379Local infectiongram-positive180.13270.191.32 (n.s.)gram-negative90.07120.090.96 (n.s.)fungal100.07220.161.82 (n.s.)viral330.25430.311.36 (n.s.)other2―3―clinical only220.16370.271.46 (n.s.)Total, local infection940.701441.041.36 (0.029)Rate, local infection per patient month0.2130.316Notes: Values in italics have been calculated for this evaluation. Boughton et al., (1995) – infections reported were mostly respiratory tract infections. Specific types of infection not reported, except where positive bacterial culture obtained (19/122 infectious episodes). Chapel et al., 1994 – ‘other chest infections’ included acute bronchitis and pleurisy not requiring hospitalisation; ‘all infections’ incidence was not reported by group thus recurrent infection rates could not be calculated; minor infections were not reported in the article though the authors state theses were mostly viral URT infections with similar rates in each group, thus total infections numbers were not derived either. Molica et al., 1996 – infections were pooled according to tx status (Ig or observation) not reported by randomised group or study part (group 1 or 2; part 1 [1st 6mo], part 2 [12mo after 1st crossover], part 3 [6mo after 2nd crossover]); The authors reported that 30 (of 42) patients completed 6 months of treatment and 17 completed 12 months (and that a further 17 did not complete the study) but not report how many patients completed the full 6+12+6 months protocol. Sullivan et al., 1990 – infections of URT or oral cavity and herpes simplex infections were not reported.ALL=acute lymphoblastic leukaemia; BMT=bone marrow transplant; BSI=bloodstream infections; CLL=chronic lymphocytic leukaemia; GI=gastrointestinal; IgG=immunoglobulin gamma; IVIg=intravenous immunoglobulin; HSCT=haematopoietic stem cell transplant; LRTI=lower respiratory tract infection; MM=multiple myeloma; mo=month; n.r.=not reported; n.s.=not significant; SEM=standard error of the mean; tx=treatment; URTI=upper respiratory tract infection; UTI=urinary tract infection; yr=year.Table SEQ Table \* ARABIC 86Randomised studies presenting infections – SCIg vs no SCIgStudyOutcomeInterventionComparatorComparisonVacca et al., 2018Infectious episodes (all outcomes adjusted to 365d)SCIg (n=24)No SCIg (n=22)MMMajor infectionsSepsis 024Bacterial pneumonia018Bronchitis with sepsis043Pharyngo-tracheitis with sepsis224Acute sinusitis05Erysipelas (skin infection)012Urinary infection with sepsis132Fever of unknown origin1332Major infections in 365d16190Minor infectionsTracheobronchitis3264Bacterial skin infection1116Bacterial stomatitis612Lower UTI1936Thoracic herpes zoster115Minor infections in 365d69143Upper respiratory tract infections229Lower respiratory tract infections32125Total overall infections85333Infection ratesSCIg (n=24)No SCIg (n=22)p valueMajor infections/patient/mo0.0560.720p<0.001Minor infections/patient/mo0.2400.542p<0.001Upper respiratory infections/patient/yr――p<0.001Lower respiratory infections/patient/yr――p<0.001Duration of infectionsSCIg (n=24)No SCIg (n=22)p valueTotal infection days per yr (range)62 (26-87)135 (88-194)p<0.01Notes: Values in italics have been calculated for the evaluation. Vacca et al., 2018 – The article describes infections as serious vs nild/non-serious in the graphs; major vs minor in tables and severe in the text – it is assumed Upper and lower respiratory tract infection rates were not calculated as patient numbers for these events were not reported. Infection rates presented as bar charts without values , thus rates were derived using the infection episodes above, assuming 365d and N=46 patients. Numbers approximating the authors’ graphs could not be replicated for the ‘No SCIg’ major infections rate. CLL=chronic lymphocytic leukaemia; GI=gastrointestinal; IVIg=intravenous immunoglobulin; HSCT=haematopoietic stem cell transplant; MM=multiple myeloma; mo=month; n.r.=not reported; n.s.=not significant; SCIg=sub-cutaneous immunoglobulin; SEM=standard error of the mean; tx=treatment; UTI=urinary tract infection; yr=year.Table SEQ Table \* ARABIC 87Cohort studies presenting infections – IVIg vs no IVIgStudyOutcomeInterventionComparatorComparisonBlombery et al., 2011Patients with infectious complications until d30 (fever; infections) (%)IVIg (n=130)No IVIg (n=110)p valueMM+HSCTFever (%)111 (85.4)93 (84.5)p=0.86BSI (%)46 (35.4) 35 (31.8)p=0.59Pneumonia (%) 23 (17.7)16 (14.5)p=0.60UTIs (%)2 (1.5)2 (1.8)p=1.00GI infections (%)6 (4.6)11 (10.0)p=0.13Total HSCTs with infections188157Crude rate infections per patient (30 d)1.451.43Crude rate / patient / year17.5917.37Total HSCTs with infections, not including fever7764Crude rate, not including fever (30 d)0.590.58Median no. febrile d [range]2 [0–15]2 [0–12]p=0.17Van Winkle et al., 2018Infectious complications during maintenance chemo.±IVIg, IVIg (N=36)No IVIG, (N=82)p-valueALLTreatment duration mo, mean (range)(based on mean # infusions which were given monthly)10.5 mo (range 1-31)―Prior: Days of treatment from induction to maintenance chemotherapy (taken to be equivalent to patient days of observation)(SEM)279 (11.0) 244 (6.7) 0.004Prior: mean episodes of bacteremia or fungemia (SEM)0.89 (0.2) [32.0 episodes]0.26 (0.1)[21.3 episodes] 0.002 Prior rate, bacteraemia or fungaemia0.0970.032During: Days of chemotherapy, mean patient-days(taken to be equivalent to patient days at risk) (SEM)713 (33.2)736 (22.8) p=0.617During: mean episodes of bacteraemia (SEM)0.25 (0.09)[9.0 episodes]0.15 (0.04)[12.3 episodes]0.336During: rate, bactermaemia (/patient/month)0.0110.006Mean no. infections treated with antibiotics, outpatient (SEM)4.8 (0.8)[172.8 episodes] 4.7 (0.4)[385.4 episodes] 0.756During: rate, infection + antibiotics (/patient/mo)0.2050.194Notes: Van Winkle et al., 2018 – p values took into account days of chemotherapy; otherwise no information about duration of observation or IgG treatment was provided in the paper. Days of chemotherapy were assumed to be equivalent to patient daysof observation or at risk for the purpose of this evaluation.Table SEQ Table \* ARABIC 88Studies presenting infections within sub-groups – Blombery et al., 2011Study, IndicationOutcomeIntervention 1Intervention 2ComparisonBlombery et al., 2011Patients with infections (%) – single vs multi-dose sub-groupsIVIg (multi-dose RT) (n=25)IVIg (single dose only) (n=105)p valueMM+HSCTBSI (%)9 (36.0%) 37 (35.2%)p=1.00Pneumonia (%) 8 (32.0%)15 (14.3%)p=0.046UTIs (%)02 (1.9%)p=1.00GI infections (%)2 (8.0%)4 (3.8%)p=0.33Total patients with infections1958Crude rate per patient0.760.55BSI=bloodstream infections; GI=gastrointestinal; HSCT=haematopoietic stem cell transplant; IVIg=intravenous immunoglobulin; MM=multiple myeloma; RT=replacement therapy; UTI=urinary tract infection.Table SEQ Table \* ARABIC 89Case series presenting within-patient (before/after) infections outcomes – IVIg Study, IndicationOutcomeComparatorInterventionComparisonBesa, 1992Infections – episodesBefore IVIg(3 yrs)(N=23)During IVIg tx (3 yrs)(N=23)CLLBacterialPneumonia80Sepsis20Sinusitis50Cellulitis42Bacterial infections (n patients)19 (in 13 patients)2 (in 1 patient)ViralZoster10Total n/N patients (%)13/23 (57)1/23 (4)Infections per patient per month0.0230.002Brenner, 1996Infections in CLL patients (N=54, of which 26 SID patients)Patient historyEquivalent to study period (no IVIg)During studyperiod (~12mo)(+IVIg)CLL(22), MM(4)*Evaluable patients, N212121Patients with infections21n.r.8Patients with no infections0n.r.13Infections requiring hospitalisationSepsis642Pneumonia1163UTI532Cellulitis657All requiring hospitalisation*32*21*14Rate /patient/month0.0830.056Treated ambulatoryFever, URI569Bronchitis743Others310All treated ambulatory151112All infections in CLL patients 473226Infections in MM patientsEvaluable patients n/N3/4n.r.3/4Bacterial infectionsn.r.n.r.0Günther & Dreger 2013Infections before/during IVIg (N=10)Prior to IVIg (N=10) (3 mo)During IVIg (N=10) (mean tx 51.2±25.4 mo)Various*Severe bacterial infections24 infections(≥2 in 7/10 patients)Or 96 events in 12mo29 infectionsOr 6.8 events in 12moURTIs56LRTIs11(or 44 events in 12mo)17(or 4 events in 12mo)Ear infections02Sinusitis10Skin & soft tissue infection01GI infection01Not specified72Mean severe bacterial infections (/patient/yr)9.70.7(rate /patient /month)0.8080.058Non-bacterial infectionsn.r.17 viral6 unclear4 fungalJurlander et al., 1994Infection-related outcomes (N=15)*12 months prior to study (N=14)12 months during study (median 14mo, range 3-20) (n=14)p-valueCLLPatient months168169Febrile episodes6331p=0.004Severe infection (septicaemia, pneumonia, meningitis)63p>0.05Rate of severe infections (/patient month)0.0360.018Death due to infection (septicaemia)―2*Notes: Brenner, 1996 studied a population (N=54) of CLL(22), MM(4) and also ITP and PAPS patients. The CLL and MM patient results are reported separately where possible. For CLL, the total numbers of infections requiring hospitalisation did not correspond with the individual contributing infections but this was not explained by the authors. No further MM data were presented due to small patient numbers. Günther & Dreger 2013 – underlying disease types: CLL(5), FL(2), WM(1), IgA-plasmacytoma (1), MDS(1)]; duration of IVIg ranged from 22.5 months to more than 9 years; LRTIs included acute bronchitis, bronchopulmonary infection and pneumonia. Jurlander et al., 1994 – 1 of 15 patients discontinued after 4 infusions and is not included, thus N=14. CLL=chronic lymphocytic leukaemia; ITP=idiopathic thrombocytopenic purpura; IVIg=intravenous immunoglobulin; MM=multiple myeloma; n.r.=not reported; PAPS= primary antiphospholipid syndrome; URI=upper respiratory tract infection.Table SEQ Table \* ARABIC 90Non-comparative studies presenting within-patient (before/after) infections outcomes – SCIg Study, IndicationOutcomeComparatorInterventionDimou et al. (2018)Patients with events (N=33)12 mo prior to SCIg commencementDuring SCIg(median follow up 11.2 mo)CLL(25), MM(3); NHL(3), HL(1)**Total patients with events26/33 (79%)6/33 (18%)Lower respiratory tract infection154Upper respiratory tract infection70Renal infections30Soft tissue infections20Herpes zoster reactivation10Nail infection01Flu-like infection and dermal infection (staphylococcus aureus)01Infections other than LRTIs132Total infections286Infections/patient/month0.0710.016Patients with no events727Infections incidence78.8% 18.2% *Notes: Dimou et al., 2018 – the individual haematological malignancy totals do not add up to N=33. In 12 mo prior to SCIg, 13/33 patients were receiving IVIg; 18/33 were tx na?ve. Patients switching from IVIg to SCIg (n=13) had a minimum 28 days washout period prior to SCIg commencement. 7 patients switching to SCIg had no history of infection but, as they were already receiving IVIg, it was assumed these individuals met the ESMO 2015 and BCSH 2012 guidelines criteria specified by the authors prior to IVIg commencement.Table SEQ Table \* ARABIC 91IVIg+SCIg studies – infections outcomes as a single groupStudy, IndicationOutcomeComparatorInterventionComparisonBenbrahim et al., 2019Infectious episodesBaseline Total (N=160)(IVIg n=50, SCIg n=110)Last visit (N=160)(IVIg n=50, SCIg n=110)MM(54), CLL(54), NHL(48), HL(4)Patients with hypo-GG69.2%15.9%p=0.14Incidence of infectious episodes /patient/year:Prior to study(95% CI)During follow-up (95% CI)p-valueSepsistotal eventsrate /patient/month2.43 (2.18–2.70)3890.2031.90 (1.46–2.49)3040.158 p=0.001WHO grade >2 infectionstotal eventsrate /patient/month0.51 (0.39–0.67) 820.0430.30 (0.21–0.42)480.025p=0.09Duraisingham et al., 2014Infections before / after IgG-RT (SID group N=39)Infections before IgG (1 yr)Infections duringIgG (1 yr)p-valueCLL(1), MM(1), NHL(11); MDS(1); MGUS(1) Evaluable patients, n/39IVIg: 13 (33.3%)SCIg: 26 (66.6%)28/3937/39Serious infections257p=0.0058Serious infections in haem. malignancy patients, n=1511(in 6 of 15 patients)3(in 2 of 15 patients)Serious infections per /patient /month in HM subset11 infections in 15 patients: 0.0613 infections in 15 patients: 0.017Pneumonia13 (52.0%)0 (0.0%)Sepsis8 (32.0%)3 (42.9 %)Meningitis0 (0.0%)0 (0.0%)Infective exacerbation, asthma or COPD1 (4.0%)2 (28.6%)Other3 (12%)2 (28.6%)Non-serious infections(Haem. malignancy patients n/N=15/39)122(37)56(21)p=0.0023Non-serious infections per /patient /month in HM subset37 infections in 15 patients: 0.20621 infections in 15 patients: 0.117Respiratory95 (77.9%)44 (75.9%)UTI3 (2.5%)4 (6.9%)Diarrhoea6 (4.9%)2 (3.4%)Skin2 (1.6%)1 (1.7%)Sinusitis7 (5.7%)3 (5.2%)Otitis6 (4.9%)0 (0.0%)Conjunctivitis1 (0.8%)1 (1.7%)HSV1 (0.8%)1 (1.7%)Other1 (0.8%)0 (0.0%)Infection-free subjects1 (2.6%)9 (23.1%)Reiser et al., 2017Infections (N=307; IVIg=287; SCIg=20)Infections in 12mo before studyInfections on studyCLL(130); NHL (99); MM(43); other(35)Groups:IgG new starters(n=96)IgG ongoing(n=211)IgG new starters(n=96)IgG ongoing(n=211)Patients with any infection79/96 (82%)137/211 (65%)6mo: 35%12mo: 21%18mo: 29%24mo: 42%6mo: 39%12mo: 41%18mo: 43%24mo: 44%Patients with serious bacterial infections 6/96 (6.3%)6/211 (2.9%)6mo: 2.4%12mo: 1.5%18mo: 0%24mo: 3.8%6mo: 0.5%12mo: 1.2%18mo: 1.9%24mo: 0.7%Patients with other serious infections 9/96 (9.4%) 17 events5/211 (2.4%)6mo: 2.4%12mo: 3.0%18mo: 8.6%24mo: 0%6mo: 2.6%12mo: 1.2%18mo: 3.2%24mo: 1.4%Patients with ‘general infections’ (non-serious)73/96(76%)131/211(62%)6mo: 30%12mo: 16%18mo: 21%24mo: 38%6mo: 38%12mo: 39%18mo: 39%24mo: 42%*3 or more serious infections2/96 (2.1%)n.r.n.r.n.r.Serious bacterial infection rate (/patient-yr)0.250(equals 77 events)0.036(equals 11 events)Serious bacterial infection rate (/patient-month)0.0210.003All serious infections rate (bacterial+other)(/patient/yr)n.r.0.122(equals 37 events)All serious infections rate (bacterial+other)(/patient/mo)―0.010(equals 3 events)Notes: Benbrahim et al., 2019 – study did not report total infections per patient or for the cohort; although the study reported rates per patient year, figures equivalent to 24 months prior/26 months during IgG treatment were used for the forest plots; Sepsis is a serious subset of septicaemia involving potential organ damage or organ failure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW5nZXI8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW5nZXI8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS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ADDIN EN.CITE.DATA (Singer et al. 2016). Sepsis numbers were higher than total infections requiring antibiotics and five times higher than those requiring IV antibiotics. Based on event numbers, this would be more consistent with a diagnosis of ‘fever’ or ‘clinical signs of infection’ instead of sepsis. The authors did not define sepsis. Duraisingham et al., 2014 – only data from n=39 SID patients presented; p-values are from Figure 3 (E & F) of the publication; figures for n=15 haematological malignancy subset in italics extracted from raw data in supplementary spreadsheet, note this included one patient with MGUS and excluded another with WM. CLL=chronic lymphocytic leukaemia; COPD=chronic obstructive pulmonary disease; HL=Hodgkin lymphoma; HM=haematological malignancy; HSV=herpes simplex virus; hypo-GG=hypogammaglobulinaemia; IgG=gamma immunoglobulin; IVIg=intravenous immunoglobulin; MDS=myelodysplastic syndrome; MGUS=monoclonal gammopathy of undetermined significance; MM=multiple myeloma; mo=month; NHL=non-Hodgkin lymphoma; n.r.=not reported; SCIg=subcutaneous immunoglobulin; UTI=urinary tract infection; WHO=World Health Organization; WM=Waldenstr?m macroglobulinaemia; yr=year.Table SEQ Table \* ARABIC 92Studies comparing infections outcomes between routes of administration – IVIg vs SCIg Study, IndicationOutcomeIntervention 1Intervention 2Comp-arisonSundin et al., 2012IgG replacement IVIg (N=46)n=24 haem. malignancy SCIg (N=12)n=2 haem. malignancy p-valueHSCTInitiation post-HSCT, at median months (range) 3 (0–8)3 (1–8) Duration, median months from initiation (range)9 (6–20)5 (3–47) Number of patients (%) with chronic need for IgG-RT4 (8.7%)5 (41.7%) p=0.01Number of clinical infectionsmean (range)mean (range)Bacterial1.5 (0–81.8 (0–5) )Viral2.1 (0–9)2.1 (1–4) Fungal0.5 (0–5)0.1 (0–1) Unidentified2 (0–10)2.5 (0–4) Total clinical infections per patient5.5 (0–23)6.4 (3–13) Windegger et al. (2019)Infections requiring hospitalisation/total annual (N=13)Initial 12 mo IVIgMean per patientSubsequent 12 mo SCIgMean per patient(undefined)Mean annual no. infections1.852.31n.s.Rate, infections/patient/mo0.150.19Notes: Sundin et al., 2012 – no observation period for events reported thus infection rate per patient month not derived.GP=general practitioner; IgG-RT=immunoglobulin gamma replacement therapy; LoS = length of hospital stay; n.s.=not statistically significantTable SEQ Table \* ARABIC 93Supportive studies comparing infections outcomes between dose levelsStudy, IndicationOutcomeIntervention 1Intervention 2ComparisonChapel, Dicato et al (1994)Infections overallHigh doseIVIg 500mg/kg(n=16)Low doseIVIg 250 mg/kg(n=18)p-valueCLL (N=34)Patient monthspatient years1801519816.5Total infections23 episodes22 episodesp=0.64Serious infectionsBacterial57Serious bacterial infections (/patient year)0.33 0.42p=0.68Rate infection (/patient/mo)0.0280.035Viral02Fungal00Unknown12Minor infectionsBacterial22Viral 57Fungal11Unknown 91Stump et al., 2017Infections post-infusion episode (n/N (%) episodes)IgG-ABWIgG-IBWp-value*VariousWithin 30 days20/125 (16%) 13/84 (15.5%) 0.823Within 60 days24/121 (19.8%) 19/82 (23.2%) 0.568*Notes: Stump et al., 2017 – patients who died within 30 / 60 days of receiving IVIG were not included in the respective totals. ‘Various’ = CLL(74); AL(65); MM(26); NHL(32); HL(7); CML(5); numbers represent patient encounters (i.e. infusions); patient numbers were not reported in the publication however the authors advised that the median IVIg dose per patient during the study period (30mo or 2.5yr) was 1 (range 1-18) or a mean of 2.6 doses and a total of 79 patients (S Stump, pers. comm. May 2019).ABW=actual body weight dosing; AL=acute leukaemia; CLL=chronic lymphocytic leukaemia; IBW=ideal (lean) body weight dosing; IgG=immunoglobulin gamma; IVIg=intravenous immunoglobulin; MM=multiple myeloma; mo=month; NHL=Non-Hodgkin lymphoma; HL=Hodgkin lymphoma; CML=chronic myeloid leukaemiaAppendix SEQ Appendix \* ALPHABETIC GEconomic analysis appendicesOverviewTable SEQ Table \* ARABIC 94Decision algorithm for undertaking an economic evaluation in the setting of the Ig ReviewComparative safety of IgComparative effectiveness of IgInferiorUncertainNon-inferiorSuperiorNo active comparatorActive comparatorInferiorxF?FbFaUncertainxFa??FaNon-inferiorxcF?$FSuperiorxcFa?FbFIg = immunoglobulinx = health forgone (at cost). An economic evaluation is not warranted and continued use of Ig should not occur in this circumstance unless there are other supportive factors.F = undertake a full economic evaluation. These may take the form of cost-utility analyses (preferred if adequate data are available) or cost effectiveness analyses in terms of clinically relevant outcome(s). ? = high levels of uncertainty will occur in an economic evaluation (if it is feasible to construct one). A cost analysis (partial economic evaluation) could be performed.$ = cost minimisation analysis (partial economic evaluation that explicitly assumes no significant differences in health outcomes, associated with either effectiveness or safety, and analyses cost-differences only). a where the conclusions with respect to effectiveness and safety are not congruent, then analyses identifying all relevant health consequences (i.e. effectiveness and safety outcomes in opposing directions of benefit) need to be presented. If a CUA is presented, this should capture effectiveness and safety collectively. If a CUA is not possible, then a single CEA may not capture all health consequences adequately and so a CCA is likely to be required. Where possible, the CCA should be quantitative, but in the absence of adequate data, a minimum qualitative identification of consequences should be presented.b where effectiveness is assessed as non-inferior but safety differences exist, and in the absence of a CUA being possible, the outcomes component of the analysis should include a clinically relevant outcome which reflects the safety differences between Ig and the comparator.c The small but unavoidable potential risks associated with administering a blood product means that a conclusion of non-inferior or superior Ig safety relative to no active comparator, should never arise.Structure and rationale of the economic evaluationTable SEQ Table \* ARABIC 95Economic literature search termsSearchQueryItems foundPubmed--#1Hypogammaglobulinemia OR Hypogammaglobulinaemia OR hypogamma* OR “low immunoglobulin” OR “immunoglobulin deficiency”[mh] OR "low Ig" OR "low IgG" OR "immunoglobulin deficiency" OR "immunoglobulin deficient" OR "Ig deficiency" OR "IgG deficiency" OR immunoparesis OR immunodeficiency374,761#2 “secondary immunodeficiency” OR leukaemia* OR leukemia* OR “Leukemia, Lymphoid”[mh] OR “Leukemia, Mast-Cell”[mh] OR “Leukemia, Myeloid”[mh] OR “Leukemia, plasma cell”[mh] OR “Leukemia, Radiation-Induced”[mh] OR “Multiple myeloma”[mh] OR “multiple myeloma” OR “Lymphoma”[mh] OR lymphoma OR lymphoproliferative OR “non-hodgkin” OR nonhodgkin OR (("B-cell" OR haematological OR hematological) AND (malignancy OR malignancies OR neoplasm[mh])) OR “Hematologic Neoplasms”[mh] OR “Hematopoietic Stem Cell Transplantation”[mh] OR HSCT OR ((“stem cell” OR “progenitor cell”) AND (transplantation OR transplant OR transplants))650,396#3”Immunoglobulin G”[mh] OR immunoglob* OR “immune globulin” OR immunoglobulin OR “gamma globulin” OR gammaglobulin OR IVIg OR SCIg OR IgG OR Ig OR Intragam OR Privigen OR Hizentra OR Gamunex OR Flebogamma OR Intragam OR Evogam OR Panzyga OR Hyqvia OR Intratect OR Octagam OR Kiovig OR Gammanorm OR Cuvitru OR GammaSTAN OR BayGam OR Polygam OR GAMMAGARD OR Sandoglobulin OR Panglobulin OR Carimune OR GAMMAKED OR Iveegam OR Bivigam OR Gammaplex OR Intratect OR IQYMUNE OR SUBCUVIA OR Subgam OR Vigam OR CUTAQUIG OR GAMASTAN OR GAMIMUNE OR IGIVNEX OR RESPIGAM OR VIVAGLOBIN OR GammaQuin OR Nanogam OR CLAIRYG OR ENDOBULINE OR SANDOGLOBULINE OR TECTASIM OR TEGELINE OR “Kenketu Glovenin”)957,682#4"economics"[MeSH Terms] OR “costs and cost analysis”[MeSH Terms] OR “cost allocation”[MeSH Terms] OR “cost benefit analysis”[MeSH Terms] OR “cost control”[MeSH Terms] OR “cost savings”[MeSH Terms] OR “cost of illness”[MeSH Terms] OR “health care costs”[MeSH Terms] OR “drug costs”[MeSH Terms] OR “health expenditures”[MeSH Terms] OR “economics, medical”[MeSH Terms] OR “economics, pharmaceutical”[ MeSH Terms] OR “fees and charges”[MeSH Terms] OR “budgets”[MeSH Terms] OR “cost”[All fields] OR “high cost”[All Fields] OR “low cost”[All Fields] OR “cost utility”[All Fields] OR “cost-utility”[All Fields] OR “economics”[All Fields] OR “financial”[All Fields] OR “finance”[All Fields] OR “healthcare cost”[All Fields] OR “health care cost”[All Fields] OR “cost estimate”[All Fields] OR “unit cost”[All Fields] OR “economics, pharmaceutical”[MeSH Terms] OR (“economics”[All Fields] AND “pharmaceutical”[All Fields]) OR “pharmaceutical economics”[All Fields] OR “pharmacoeconomic”[All Fields] OR “commerce”[MeSH Terms] OR “commerce”[ All Fields] OR “price”[All Fields] OR ((“costs”[All Fields] OR “cost”[All Fields]) AND “analysis”[All Fields]) OR “costs and cost analysis”[All Fields] OR “pricing”[All Fields] OR “cost-effectiveness”[All Fields] OR "cost effectiveness”[All Fields] OR “economic evaluation”[All Fields]1,148,753#5#1 AND #2 AND #3 AND #467Embase--#1'immunoglobulin deficiency'/exp OR 'immunoglobulin deficiency' OR 'immunoparesis'/exp OR immunoparesis OR 'hypogammaglobulinaemia'/exp OR hypogammaglobulinaemia OR 'hypogammaglobulinemia'/exp OR hypogammaglobulinemia OR 'low immunoglobulin' OR 'low ig' OR 'low igg' OR 'immunoglobulin deficient' OR 'ig deficiency' OR 'igg deficiency'/exp OR 'igg deficiency' OR 'immunodeficiency'/exp OR immunodeficiency634,524#2'secondary immunodeficiency' OR leukemia OR leukaemia OR 'acute leukemia' OR 'myeloid leukemia' OR 'multiple myeloma' OR lymphoma OR 'nonhodgkin lymphoma' OR 'acute lymphoblastic leukemia' OR 'chronic lymphatic leukemia' OR 'chronic lymphocytic leukemia' OR 'small lymphocytic lymphoma' OR 'b cell malignancy' OR 'haematological malignancy' OR 'hematopoietic stem cell transplantation' OR 'progenitor cell transplant'788,651#3'immunoglobulin' OR 'immune globulin' OR immunoglobulin OR 'gamma globulin' OR gammaglobulin OR ivig OR scig OR igg OR ig OR privigen OR hizentra OR gamunex OR flebogamma OR intragam OR evogam OR panzyga OR hyqvia OR octagam OR kiovig OR gammanorm OR cuvitru OR gammastan OR baygam OR polygam OR gammagard OR sandoglobulin OR panglobulin OR carimune OR gammaked OR iveegam OR bivigam OR gammaplex OR intratect OR iqymune OR subcuvia OR subgam OR vigam OR cutaquig OR gamastan OR gamimune OR igivnex OR respigam OR vivaglobin OR gammaquin OR nanogam OR clairyg OR endobuline OR sandoglobuline OR tectasim OR tegeline OR 'kenketu glovenin'742,290#4'health economics'/exp OR 'cost'/exp OR 'cost effectiveness analysis'/exp OR 'health care cost'/exp OR 'drug cost'/exp OR 'pharmacoeconomics'/exp OR 'budget'/exp OR 'cost utility analysis'/exp OR 'cost' OR 'cost effectiveness analysis' OR 'cost utility analysis' OR 'health economics'1,157,537#5#1 AND #2 AND #3 AND #4253-Total, after duplicates were excluded292-Studies identified from pearling0Total studies included1Note: Searches were conducted on 3/4/19Inputs to the economic evaluationResource useTable SEQ Table \* ARABIC 96Estimation of Ig costs2017/18 Ig ReportPrice in $(m)Grams(weight,%)Price/gram in $Reference to Ig report sectionDomestic IVIg including plasma fractionation (excluding hyperimmune plasma)Intragam P* Intragam 10443.23,161,673(51.6%)140.18Calculation required for cost: Plasma fractionation costs of $252.2M (expenditure section) + total domestic product cost of $195M (Table 6) – Evogam product cost of $4M (Table 6) = $443.2M Calculation for grams: Total domestic grams 3,225,722 (Table 6) – Evogam grams 64,049 = 3,161,673Domestic IVIg excluding plasma fractionation Intragam P* Intragam 101913,161,673(51.6%)60.41Table 6: Calculation for price: Total domestic price – Evogam price Calculation for grams: Total domestic grams – Evogam gramsImported IVIg Flebogamma Privigen1242,759,266(45.0%)44.94Table 6: Calculation for price: Total imported price – Hizentra price Calculation for grams: Total imported grams – Hizentra gramsSCIg domestic Evogam464,049(1.0%)62.45Table 6SCIg imported Hizentra8143,729(2.3%)55.66Table 6Total domestic Ig grams?3,225,722?ExpenditureTotal imported Ig grams?2,902,995?ExpenditureIg = immunoglobulin; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin.Source: NBA ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Author>National Blood Authority [NBA]</Author><Year>2019</Year><RecNum>109</RecNum><DisplayText>(2019b)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="z0vwsepdwpt20pewwts5z9eup9e2r2pd2tad" timestamp="1563421468">109</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>National Blood Authority [NBA],</author></authors></contributors><titles><title>National Report on the Issue and Use of Immunoglobulin (Ig) Annual Report 2017-18</title></titles><dates><year>2019</year></dates><pub-location>Canberra</pub-location><publisher>National Blood Authority </publisher><urls><related-urls><url>;(2019b)Sensitivity analysesTable SEQ Table \* ARABIC 97Sensitivity analysesInc. costInc. QALYsICER% changeBase case analysis$41,0110.4109$99,803-Baseline annual infection rates (base case: Paxton, Hawkins & Crispin 2016, serious 0.43, non-serious 1.05)Chapel et al. (1991): serious 1.07, non-serious 3.75$53,0540.6163$86,079–14%Molica et al. (1996): serious 0.29, non-serious 1.73$50,1600.3819$131,32832%Chapel et al. (1994): serious 0.26, non-serious 1.75$51,3460.3653$140,55541%Musto, Brugiatelli & Carotenuto (1995): serious: 0.43, non-serious 2.30$51,1630.4612$110,93611%Vacca et al. (2018): serious 8.64, non-serious 6.50$69,3100.6529$106,1606%Sullivan et al. (1990): serious 1.79, non-serious 3.79$48,0620.7121$67,493–32%Duraisingham et al. (2014): serious 0.73, non-serious 2.47$46,8680.5604$83,627–16%IRR of Ig treatment effect (base case: serious, 0.15; non-serious 0.61)Serious infections, 0.05$36,9360.4450$82,992–17%Serious infections, 0.43$52,5260.3139$167,31568%Non-serious infections, 0.51$35,8280.4694$76,328–24%Non-serious infections, 0.72$46,2360.3523$131,23331%Non-randomised IRRs, serious: 0.25, 0.46$37,6250.4620$81,436–18%Dose of Ig (base case: 0.37 g/kg), 0.4 g/kg$45,8850.4109$111,66612%Duration of Ig treatment (base case: 2.2 years)1 year$19,1620.2450$78,222–22%3 years$55,2090.4771$115,71616%5 years$84,2610.5430$155,16855%10 years$125,0970.5457$229,233130%Exclude development of bronchiectasis$41,2130.0141$2,927,5252833%Time horizon (base case: 10 years)2.2 years (as per Ig treatment duration)$38,8690.0322$1,208,3431111%5 years$39,5520.1509$262,086163%Discount rate (base case: 5%)0%$43,8150.5525$79,305–21%3%$42,0680.4610$91,256–9%Ratio of non-serious to serious infections (base case: 2.45)0.75$33,5060.3519$95,202–5%5.9$52,9530.4660$113,64314%Transition probabilities (base case: adjusted)Transitions from infection health state, unadjusted$45,3090.3087$146,79247%Transitions from bronchiectasis health state, unadjusted (exc. cost of Ig in bronchiectasis)$27,2450.3237$84,176–16%Transitions from infection and bronchiectasis, unadjusted$29,9270.2335$128,15428%MortalityRR with haematological malignancy, lower limit 2.49 (base case: 2.55)$41,0180.4083$100,4551%RR with haematological malignancy, upper limit 2.60 (base case: 2.55)$41,0040.4130$99,279–1%Increased mortality risk (2.34) with a history of infections above CLL (base case: none)$39,9630.4686$85,283–15%RR with infections, ?50% to 2.09 (base case: 4.18)$40,3220.3437$117,31718%RR with infections, +50% to 6.27 (base case: 4.18)$41,5210.4668$88,945–11%RR with bronchiectasis, 2.14 (base case: 2.20)$40,9940.4047$101,3012%RR with bronchiectasis, 2.26 (base case: 2.20)$41,0270.4170$98,375–1%RR with P. aeruginosa infections, 1.772 (base case: 2.391)$40,8470.3977$102,6983%RR with P. aeruginosa infections, 3.125 (base case: 2.391)$41,1920.4259$96,727–3%Patient weight (base case: 75 kg)70 kg$37,1610.4109$90,434–9%80 kg$44,8680.4109$109,1909%Cost of Ig per gram, $58.23 (base case: $60.41)$38,9250.4109$94,727–5%Windegger et al. (2019) costsCost of disease management (base case: MBS item costs)$40,7790.4109$99,240–1%Cost of treating infections (base case: AR-DRG/MBS costs)$44,0970.4109$107,3138%Cost of P. aeruginosa health state (base case: AR-DRG costs)$41,1790.4109$100,2130%Cost of hospitalisation of serious infections (base case: $12,775)$9,961, based on AR-DRG E62A$42,5280.4109$103,4954%$15,261, based on AR-DRG I67A$39,6710.4109$96,542–3%$18,269, based on AR-DRG I64A$38,0500.4109$92,597–7%$25,381, based on AR-DRG T60A$34,2160.4109$83,268–17%$52,961, based on AR-DRG R01A$19,3490.4109$47,088–53%Cost of treating non-serious infections (base case: $184)$92 (i.e. ?50%)$41,3340.4109$100,5891%$276 (i.e. +50%)$40,6870.4109$99,016–1%Cost of serious bronchiectasis infections (base case: $9,143)$4,572 (i.e. ?50%)$43,0170.4109$104,6855%$13,715 (i.e. +50%)$39,0050.4109$94,921–5%Cost per week in the P. aeruginosa health state (base case: $1,322)$661 (i.e. ?50%)$47,1090.4109$114,64415%$1,983 (i.e. +50%)$34,9120.4109$84,962–15%UtilitiesNo disutility for IV infusion (base case: disutility per infusion included)$41,0110.4146$98,916–1%Utility decrement for serious infections, 0.205 (base case: 0.41)$41,0110.3966$103,3984%Utility decrement for non-serious infections, 0.01 (base case: 0.06)$41,0110.3914$104,7695%Utility with infections with bronchiectasis, 0.6278 (base case: 0.5355)$41,0110.3714$110,40711%Utility with infection, 0.6956 (base case: 0.5805 with Ig, 0.5532 without Ig)$41,0110.4042$101,4662%CLL = chronic lymphocytic leukaemia; ICER = incremental cost-effectiveness ratio; Ig = immunoglobulin; IRR = incidence rate ratio; IV = intravenous; QALY = quality-adjusted life year.Appendix SEQ Appendix \* ALPHABETIC HFinancial implications appendixIdentification, estimation and reduction of uncertaintyTable SEQ Table \* ARABIC 98Estimation of the average weighted cost per gram within the acquired hypogammaglobulinemia indictaionUsage (grams)Proportion of useCost per gramDomestic IVIg1,242,05188.6%$140.18Imported IVIg117,8638.4%$44.94Domestic SCIg 5,3450.4%$62.45Imported SCIg36,7662.6%$55.66Weighted price$129.66Ig = immunoglobulin; IVIg = intravenous immunoglobulin; SCIg = subcutaneous immunoglobulin.Source: REF _Ref13214532 \h Table 96, Appendix G and the 'HTA Data April2019.xlsx' workbook.Attachment 1IgG products TGA registered strengths and approved indications (search of January 2019 undertaken for PICO Confirmation)ProductRouteARTG#StrengthTGA Approved IndicationsIntragam 10IV infusion16248916248816248716248620g/200mL vial10g/100mL vial5g/50mL vial2.5g/25mL vialThrombocytopenic Purpura, in adults or children at high risk of bleeding or prior to surgery to correct the platelet count? Kawasaki disease? Guillain-Barré Syndrome? Chronic Inflammatory Demyelinating Polyneuropathy ? Multifocal Motor Neuropathy? Myasthenia Gravis (MG) in acute exacerbation (myasthenic crisis) or prior to surgery and/or thymectomy; as maintenance therapy for moderate to severe MG when other treatments have been ineffective or caused intolerable side effects? Short-term therapy for severely affected nonparaneoplastic Lambert-Eaton Myasthenic Syndrome patients? Treatment of significant functional impairment in patients who have a verified diagnosis of stiff person syndrome.Privigen 10%IV infusion21916014336814333714327340g (100g/L, 10%) bottle20g (100g/L, 10%) bottle10g (100g/L, 10%) bottle5g (100g/L, 10%) bottleReplacement therapy? Primary Immunodeficiency Diseases (PID).? Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.? Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.Immunomodulatory therapy? Idiopathic Thrombocytopenic Purpura (ITP) in patients at high risk of bleeding or prior to surgery to correct the platelet count.? Guillain-Barré Syndrome (GBS).? Kawasaki disease.? Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).? Multifocal Motor Neuropathy (MMN).? Myasthenia Gravis (MG) exacerbations.? Lambert-Eaton Myasthenic Syndrome (LEMS).? Stiff Person Syndrome (SPS).Hizentra SC infusion28534528534420738620738520738420738320% Solution 10 mL PFS20% Solution 5 mL PFS20% Solution 5 mL vial20% Solution 10 mL vial20% Solution 50 mL vial20% Solution 20 mL vialReplacement therapy in adults and children in:? Primary Immunodeficiency Disease (PID) and? Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.Immunomodulatory therapy in:? Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) as maintenance therapy after stabilisation with IVIg.Gamunex 10%IV infusion*11724011723911723811723711668920g/200mL vial10g/100mL vial5g/50mL vial2.5g/25mL vial1g/10mL vialReplacement therapy in:- Primary Immunodeficiency (PI) Diseases.- Symptomatic Hypogammaglobulinaemia secondary to underlying disease or treatment.Immunomodulation in:- Idiopathic Thrombocytopaenic Purpura (ITP), in patients at high risk of bleeding or prior tosurgery to correct the platelet count.- Guillain Barré Syndrome (GBS).- Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).- Kawasaki disease.Flebogamma 10%IV infusion1843531823591823585g/50mL vial20g/200mL vial10g/100mL vialReplacement therapy indications:? Primary Immunodeficiency (PI) Diseases? Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.Immunomodulation indications:? Idiopathic Thrombocytopaenic Purpura (ITP), in patients at high risk of bleeding orprior to surgery to correct the platelet count.? Guillain Barré syndrome.? Kawasaki disease.Flebogamma 5%IV infusion14380314380214380114380014060220g/400mL vial10g/200mL vial5g/100mL vial2.5g/50mL vial0.5g/10mL vialReplacement therapy in:Primary immunodeficiency syndromes such as:- congenital agammaglobulinaemia and hypogammaglobulinaemia- common variable immunodeficiency- severe combined immunodeficiency- Wiskott Aldrich syndromeMyeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.Children with congenital AIDS and recurrent infections.ImmunomodulationIdiopathic thrombocytopenic purpura (ITP), in children or adults at high risk of bleeding or prior to surgery to correct the platelet count.Guillain Barré syndrome.Allogeneic bone marrow transplantation.Intragam PIV infusion686356863468633686320.6g/10mL vial30g/500mL vial12g/200mL vial 3g/50mL vialIntragam P is indicated for replacement IgG therapy in:? Primary Immunodeficiency Diseases? Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.Intragam P is indicated for immunomodulatory therapy in:? Idiopathic Thrombocytopenic Purpura, in adults or children at high risk of bleeding or prior to surgery to correct the platelet count? Kawasaki disease? Guillain-Barré Syndrome.EvogamSC infusion17332417332317331516% solution 3.2g/20mL vial16% solution 1.6g/10mL vial16% solution 0.8g/5mL vialEvogam is indicated in adults and children for replacement therapy in:? Primary Immunodeficiency Diseases (PID) and? symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.PanzygaIV infusion2917402916452916482916472916462916441g/10mL vial2.5g/25mL vial10g/100mL bottle5g/50mL bottle20g/200mL bottle30g/300mL bottleReplacement therapy in:Primary immunodeficiency diseases.Myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent bacterial infections.Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.Immunomodulation in:Idiopathic thrombocytopenic purpura (ITP), in patients at high risk of bleedingor prior to surgery to correct the platelet count.Guillain Barré syndrome.Kawasaki disease.HyqviaSC infusion23517810% solution HYQVIA is indicated for replacement therapy in adults in:? Primary Immunodeficiency Disease (PID) and? Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatmentIntratect IV infusion23208523208423207823207716455116455016454916454820g in 200 mL vial10g in 100 mL vial5g in 50 mL vial1g in 10 mL vial5% 5g in 100mL vial5% 1g in 20 mL vial5% 10g in 200 mL vial5% 2.5g in 50mL vialReplacement therapy in. * Primary Immunodeficiency Diseases. * Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.Immunomodulation. * Idiopathic thrombocytopenic purpura, in adults or children at high risk of bleeding or prior to surgery to correct the platelet count.. *Guillain Barre syndrome. * Kawasaki disease.Octagam IV infusion15560415560315560215560111392811392711392611392520g/200mL [100 mg/mL]10g/100mL [100 mg/mL]5g/50mL [100 mg/mL]2g/20mL [100 mg/mL] 10g/200mL bottle [50 mg/mL]5g/100mL bottle [50 mg/mL]2.5g/50mL bottle [50 mg/mL] 1g/20mL vial [50 mg/mL]Replacement therapy Primary immunodeficiency syndromes:- congenital agammaglobulinaemia and hypogammaglobulinaemia- common variable immunodeficiency- severe combined immunodeficiencies- Wiskott Aldrich syndrome. Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections. Children with congenital Acquired Immune Deficiency Syndrome (AIDS) who have repeated bacterial infections.Immunomodulatory effect Idiopathic thrombocytopenic purpura, in adults or children with a high risk of bleeding or prior to surgery to correct the platelet count. Guillain Barré syndrome Kawasaki disease.Allogeneic bone marrow transplantationKiovig See indications19848813197313196913196813196613195330g/300mL vial (100 mg/mL)20g/200mL vial (100 mg/mL)10g/100mL vial (100 mg/mL)5g/50mL vial (100 mg/mL)2.5g/25mL vial (100 mg/mL)1g/10mL vial (100 mg/mL)KIOVIG administered intravenously is indicated for:(1) Replacement therapy indications- Primary immunodeficiency disorders (PID);- Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.(2) Immunomodulation indications- Idiopathic thrombocytopenia purpura (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count;- Guillain Barré Syndrome;- Kawasaki Disease;- Multifocal Motor Neuropathy (MMN).KIOVIG administered subcutaneously is indicated for:(1) Replacement therapy indications- Primary immunodeficiency disorders (PID).GammanormIM or SC infusion1287051287033300mg/20mL vial 1650mg/10mL vial Replacement therapy in adults and children with primary immunodeficiency syndromes such as:- congenital agammaglobulinaemia and hypogammaglobulinaemia- common variable immunodeficiency- severe combined immunodeficiencies- IgG subclass deficiencies with recurrent infections Replacement therapy in myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.CSL NORMAL IMMUNOGLOBULIN VFIM injection6121661215800mg/5mL vial320mg/2mL vialNormal Immunoglobulin-VF is indicated in the management of congenital and acquired forms of primary hypogammaglobulinaemia. It may also be of value in treating secondary forms of this disorder as in leukaemia, nephrosis and acute protein-losing enteropathy, particularly when there is a tendency to recurrent infection.CUVITRUSC infusion28257920% solution vialCUVITRU is indicated as replacement therapy in adult and paediatric patients for Primary immunodeficiency diseases (PID) and Symptomatic hypogammaglobulinaemia secondary to underlying disease or treatment.*SC infusion only recommended for replacement therapy in patients with primary immunodeficiencyReferences ADDIN EN.REFLIST Ammann, EM, Jones, MP, Link, BK, Carnahan, RM, Winiecki, SK, Torner, JC, McDowell, BD, Fireman, BH & Chrischilles, EA 2016, 'Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy', Blood, vol. 127, no. 2, Jan-14, pp. 200-207.Benbrahim, O, Viallard, JF, Choquet, S, Royer, B, Bauduer, F, Decaux, O, Crave, JC, Fardini, Y, Clerson, P & Levy, V 2018, 'A French observational study describing the use of human polyvalent immunoglobulins in hematological malignancy-associated secondary immunodeficiency', Eur J Haematol, vol. 101, no. 1, Jul, pp. 48-56.Benbrahim, O, Viallard, JF, Choquet, S, Royer, B, Bauduer, F, Decaux, O, Crave, JC, Fardini, Y, Clerson, P & Levy, V 2019, 'The use of octagam and gammanorm in immunodeficiency associated with hematological malignancies: a prospective study from 21 French hematology departments', Hematology, vol. 24, no. 1, Dec, pp. 173-182.Besa, EC 1992, 'Recent advances in the treatment of chronic lymphocytic leukemia: defining the role of intravenous immunoglobulin', Semin Hematol, vol. 29, no. 3, Jul, pp. 14-23.Blanchette, CM, Noone, JM, Stone, G, Zacherle, E, Patel, RP, Howden, R & Mapel, D 2017, 'Healthcare Cost and Utilization before and after Diagnosis of Pseudomonas aeruginosa among Patients with Non-Cystic Fibrosis Bronchiectasis in the U.S', Med Sci (Basel), vol. 5, no. 4, Sep 23.Blombery, P, Prince, HM, Worth, LJ, Main, J, Yang, M, Wood, EM & Westerman, DA 2011, 'Prophylactic intravenous immunoglobulin during autologous haemopoietic stem cell transplantation for multiple myeloma is not associated with reduced infectious complications', Ann Hematol, vol. 90, no. 10, Oct, pp. 1167-1172.Boughton, BJ, Jackson, N, Lim, S & Smith, N 1995, 'Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia', Clin Lab Haematol, vol. 17, no. 1, Mar, pp. 75-80.Brenner, B 1996, 'Clinical experience with Octagam, a solvent detergent (SD) virus inactivated intravenous gammaglobulin', Clinical and Experimental Rheumatology, vol. 14, 1996, pp. S115-S119.Brown, JS, Baxendale, H & Floto, RA 2011, 'Immunodeficiencies associated with bronchiectasis', in RA Floto & CS Haworth (eds), European Respiratory Society Monographs: Bronchiectasis, pp. 178-191.Carlisle, PS, Gucalp, R & Wiernik, PH 1993, 'Nosocomial infections in neutropenic cancer patients', Infect Control Hosp Epidemiol, vol. 14, no. 6, Jun, pp. 320-324.Chapel, HM, Dicato, M, Gamm, H, Brennan, V, Ries, F, Bunch, C & Lee, M 1994a, 'Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes', Br J Haematol, vol. 88, no. 1, Sep, pp. 209-212.Chapel, HM, Griffiths, H, Brennan, V, Bunch, C, Lea, J & Lee, M 1991, 'Hypogammaglobulinaemia in low grade B cell tumours; significance and therapy', Immunological investigations, vol. 20, no. 2, 1991, pp. 187‐191.Chapel, HM, Lee, M, Hargreaves, R, Pamphilon, DH & Prentice, AG 1994b, 'Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma', Lancet, vol. 343, no. 8905, Apr 30, pp. 1059-1063.de Jong, PA, Dodd, JD, Coxson, HO, Storness-Bliss, C, Pare, PD, Mayo, JR & Levy, RD 2006, 'Bronchiolitis obliterans following lung transplantation: early detection using computed tomographic scanning', Thorax, vol. 61, no. 9, Sep, pp. 799-804.Dimou, M, Iliakis, T, Maltezas, D, Bitsani, A, Kalyva, S, Koudouna, A, Kotsanti, S, Petsa, P, Papaioannou, P, Kyrtsonis, MC & Panayiotidis, P 2018, 'Efficacy-safety of Facilitated Subcutaneous Immunoglobulin in Immunodeficiency Due to Hematological Malignancies. A Single-Center Retrospective Analysis', Anticancer Res, vol. 38, no. 7, Jul, pp. 4187-4191.Duraisingham, SS, Buckl, , M, Dempster, J, Lorenzo, L, Grigoriadou, S & Longhurst, HJ 2014, 'Primary vs. secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement', PLoS One, vol. 9, no. 6, 2014, p. e100324.Eibl, MM 2008, 'History of immunoglobulin replacement', Immunol Allergy Clin North Am, vol. 28, no. 4, Nov, pp. 737-764, viii.Finch, S, McDonnell, MJ, Abo-Leyah, H, Aliberti, S & Chalmers, JD 2015, 'A Comprehensive Analysis of the Impact of Pseudomonas aeruginosa Colonization on Prognosis in Adult Bronchiectasis', Ann Am Thorac Soc, vol. 12, no. 11, Nov, pp. 1602-1611.Gale, RP, Chapel, HM, Bunch, C, Rai, KR, Foon, K, Courter, SG & Tait, D 1988, 'Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial', New England journal of medicine, vol. 319, no. 14, 1988, pp. 902‐907.Gunn, ML, Godwin, JD, Kanne, JP, Flowers, ME & Chien, JW 2008, 'High-resolution CT findings of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation', J Thorac Imaging, vol. 23, no. 4, Nov, pp. 244-250.Günther, G & Dreger, B 2013, 'Post-marketing observational study on 5% intravenous immunoglobulin therapy in patients with secondary immunodeficiency and recurrent serious bacterial infections', Microbiol Immunol, vol. 57, no. 7, Jul, pp. 527-535.Guyatt, G, Oxman, AD, Sultan, S, Brozek, J, Glasziou, P, Alonso-Coello, P, Atkins, D, Kunz, R, Montori, V, Jaeschke, R, Rind, D, Dahm, P, Akl, EA, Meerpohl, J, Vist, G, Berliner, E, Norris, S, Falck-Ytter, Y & Schunemann, HJ 2013, 'GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes', J Clin Epidemiol, vol. 66, no. 2, Feb, pp. 151-157.Independent Hospital Pricing Authority [IHPA] 2019, National Hospital Cost Data Collection Report, Public Sector, Round 21 (Financial year 2016-17), Independent Hospital Pricing Authority,, viewed 5 July 2019, <, J, Geisler, CH & Hansen, MM 1995, 'Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low-dose intravenous gammaglobulin', Eur J Haematol, vol. 53, no. 2, Aug, pp. 114-118.Kearney, PJ, Kershaw, CR & Stevenson, PA 1977, 'Bronchiectasis in acute leukaemia', Br Med J, vol. 2, no. 6091, Oct 1, pp. 857-859.Knowles, GK, Stanhope, R & Green, M 1980, 'Bronchiectasis complicating chronic lymphatic leukaemia with hypogammaglobulinaemia', Thorax, vol. 35, no. 3, Mar, pp. 217-218.Kobayashi, R, Suzuki, D, Sano, H, Kishimoto, K, Yasuda, K & Kobayashi, K 2014, 'Effect of meropenem with or without immunoglobulin as second-line therapy for pediatric febrile neutropenia', Pediatr Int, vol. 56, no. 4, Aug, pp. 526-529.Li, AM, Sonnappa, S, Lex, C, Wong, E, Zacharasiewicz, A, Bush, A & Jaffe, A 2005, 'Non-CF bronchiectasis: does knowing the aetiology lead to changes in management?', Eur Respir J, vol. 26, no. 1, Jul, pp. 8-14.Liberati, A, Altman, DG, Tetzlaff, J, Mulrow, C, Gotzsche, PC, Ioannidis, JP, Clarke, M, Devereaux, PJ, Kleijnen, J & Moher, D 2009, 'The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration', PLoS Med, vol. 6, no. 7, Jul 21, p. e1000100.Moher, D, Liberati, A, Tetzlaff, J, Altman, DG & Group, P 2009, 'Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement', PLoS Med, vol. 6, no. 7, Jul 21, p. e1000097.Molica, S, Musto, P, Chiurazzi, F, Specchia, G, Brugiatelli, M, Cicoira, L, Levato, D, Nobile, F, Carotenuto, M, Liso, V & et al. 1996, 'Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study', Haematologica, vol. 81, no. 2, 1996, pp. 121‐126.Morehead, RS 1997, 'Bronchiectasis in bone marrow transplantation', Thorax, vol. 52, no. 4, Apr, pp. 392-393.Musto, P, Brugiatelli, M & Carotenuto, M 1995, 'Prophylaxis against infections with intravenous immunoglobulins in multiple myeloma', Br J Haematol.National Blood Authority [NBA] 2019a, Data Analysis and Reporting, National Blood Authority Canberra, < Blood Authority [NBA] 2019b, National Report on the Issue and Use of Immunoglobulin (Ig) Annual Report 2017-18, National Blood Authority Canberra.Okada, F, Ando, Y, Kondo, Y, Matsumoto, S, Maeda, T & Mori, H 2004, 'Thoracic CT findings of adult T-cell leukemia or lymphoma', AJR Am J Roentgenol, vol. 182, no. 3, Mar, pp. 761-767.Orange, JS, Hossny, EM, Weiler, CR, Ballow, M, Berger, M, Bonilla, FA, Buckley, R, Chinen, J, El-Gamal, Y, Mazer, BD, Nelson, RP, Jr., Patel, DD, Secord, E, Sorensen, RU, Wasserman, RL, Cunningham-Rundles, C, Primary Immunodeficiency Committee of the American Academy of Allergy, A & Immunology 2006, 'Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology', J Allergy Clin Immunol, vol. 117, no. 4 Suppl, Apr, pp. S525-553.Parkman, R 2008, 'Antigen-specific immunity following hematopoietic stem cell transplantation', Blood Cells Mol Dis, vol. 40, no. 1, Jan-Feb, pp. 91-93.Paxton, L, Hawkins, C & Crispin, P 2016, 'Selecting haematological malignancy patients for intravenous immunoglobulin', Intern Med J, vol. 46, no. 10, Oct, pp. 1216-1218.Pijnenburg, MW, Cransberg, K, Wolff, E, Bouquet, J & Merkus, PJ 2004, 'Bronchiectasis in children after renal or liver transplantation: a report of five cases', Pediatr Transplant, vol. 8, no. 1, Feb, pp. 71-74.Quint, JK, Millett, ER, Joshi, M, Navaratnam, V, Thomas, SL, Hurst, JR, Smeeth, L & Brown, JS 2016, 'Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study', Eur Respir J, vol. 47, no. 1, Jan, pp. 186-193.Reiser, M, Borte, M, Huscher, D, Baumann, U, Pittrow, D, Sommer, C, Stangel, M, Fasshauer, M, Gold, R & Hensel, M 2017, 'Management of patients with malignancies and secondary immunodeficiencies treated with immunoglobulins in clinical practice: Long-term data of the SIGNS study', Eur J Haematol, vol. 99, no. 2, Aug, pp. 169-177.Remberger, M, Ackefors, M, Berglund, S, Blennow, O, Dahllof, G, Dlugosz, A, Garming-Legert, K, Gertow, J, Gustafsson, B, Hassan, M, Hassan, Z, Hauzenberger, D, Hagglund, H, Karlsson, H, Klingspor, L, Kumlien, G, Le Blanc, K, Ljungman, P, Machaczka, M, Malmberg, KJ, Marschall, HU, Mattsson, J, Olsson, R, Omazic, B, Sairafi, D, Schaffer, M, Svahn, BM, Svenberg, P, Swartling, L, Szakos, A, Uhlin, M, Uzunel, M, Watz, E, Wernerson, A, Wikman, A, Wikstrom, AC, Winiarski, J & Ringden, O 2011, 'Improved survival after allogeneic hematopoietic stem cell transplantation in recent years. A single-center study', Biol Blood Marrow Transplant, vol. 17, no. 11, Nov, pp. 1688-1697.Royle, JA, Baade, PD, Joske, D, Girschik, J & Fritschi, L 2011, 'Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a population-based study', Br J Cancer, vol. 105, no. 7, Sep 27, pp. 1076-1081.Sanchez-Ramon, S, Dhalla, F & Chapel, H 2016, 'Challenges in the Role of Gammaglobulin Replacement Therapy and Vaccination Strategies for Hematological Malignancy', Front Immunol, vol. 7, 2016, p. 317.Singer, M, Deutschman, CS, Seymour, CW, Shankar-Hari, M, Annane, D, Bauer, M, Bellomo, R, Bernard, GR, Chiche, JD, Coopersmith, CM, Hotchkiss, RS, Levy, MM, Marshall, JC, Martin, GS, Opal, SM, Rubenfeld, GD, van der Poll, T, Vincent, JL & Angus, DC 2016, 'The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)', JAMA, vol. 315, no. 8, Feb 23, pp. 801-810.Stump, SE, Schepers, AJ, Jones, AR, Alex, er, MD & Auten, JJ 2017, 'Comparison of Weight-Based Dosing Strategies for Intravenous Immunoglobulin in Patients with Hematologic Malignancies', Pharmacotherapy, vol. 37, no. 12, 2017, pp. 1530-1536.Sullivan, KM, Kopecky, KJ, Jocom, J, Fisher, L, Buckner, CD, Meyers, JD, Counts, GW, Bowden, RA, Peterson, FB, Witherspoon, RP & et al. 1990, 'Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation', N Engl J Med, vol. 323, no. 11, Sep 13, pp. 705-712.Sullivan, KM, Storek, J, Kopecky, KJ, Jocom, J, Longton, G, Flowers, M, Siadak, M, Nims, J, Witherspoon, RP, Anasetti, C, Appelbaum, FR, Bowden, RA, Buckner, CD, Crawford, SW, Deeg, HJ, Hansen, JA, McDonald, GB, Sanders, JE & Storb, R 1996, 'A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery', Biol Blood Marrow Transplant, vol. 2, no. 1, Feb, pp. 44-53.Sundin, M, Nordin, K, Jostemyr, Y & Winiarski, J 2012, 'Subcutaneous IgG replacement after pediatric SCT', Pediatric Transplantation, vol. 16, no. 8, 2012, pp. 866-871.Tanawuttiwat, T & Harindhanavudhi, T 2009, 'Bronchiectasis: pulmonary manifestation in chronic graft versus host disease after bone marrow transplantation', Am J Med Sci, vol. 337, no. 4, Apr, p. 292.Vacca, A, Melaccio, A, Sportelli, A, Solim, o, AG, Dammacco, F & Ria, R 2018, 'Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial', Clinical Immunology, vol. 191, 2018, pp. 110-115.Van Winkle, P, Burchette, R, Kim, R, Raghunathan, R & Qureshi, N 2018, 'Prevalence and Safety of Intravenous Immunoglobulin Administration During Maintenance Chemotherapy in Children with Acute Lymphoblastic Leukemia in First Complete Remission: A Health Maintenance Organization Perspective', Perm J, vol. 22, 2018, pp. 17-141.Visentin, A, Compagno, N, Cinetto, F, Imbergamo, S, Zambello, R, Piazza, F, Semenzato, G, Trentin, L & Agostini, C 2015, 'Clinical profile associated with infections in patients with chronic lymphocytic leukemia. Protective role of immunoglobulin replacement therapy', Haematologica, vol. 100, no. 12, Dec, pp. e515-518.Wadhwa, PD & Morrison, VA 2006, 'Infectious complications of chronic lymphocytic leukemia', Semin Oncol, vol. 33, no. 2, Apr, pp. 240-249.Weeks, JC, Tierney, MR & Weinstein, MC 1991, 'Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia', New England journal of medicine, vol. 325, no. 2, 1991, pp. 81‐86.Windegger, TM, Nghiem, S, Nguyen, KH, Fung, YL & Scuffham, PA 2019, 'Cost-utility analysis comparing hospital-based intravenous immunoglobulin with home-based subcutaneous immunoglobulin in patients with secondary immunodeficiency', Vox Sanguinis.Wong, J, Wood, EM, Crispin, P, Weinkove, R, McQuilten, ZK, Australasian, L & Lymphoma Group Supportive Care, G 2019, 'Managing hypogammaglobulinaemia secondary to haematological malignancies in Australia and New Zealand: a clinician survey', Intern Med J, vol. 49, no. 3, Mar, pp. 358-363. ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- monthly financial report template free
- performance report template in word
- accident report template free printable
- monthly financial report template word
- home inspection report template word
- financial report template samples
- simple annual report template free
- annual report template word
- financial report template word
- lab report template pdf
- free annual report template publisher
- student progress report template word