Protocol details - Home - Critical Care Nutrition
Protocol detailsPROTOCOL TITLE:The Effect of Higher Protein Dosing in Critically Ill Patients: A Multicenter Registry-based Randomized Trial. The EFFORT TrialNames (titles), roles and contact details of:SponsorName of Sponsoring Organisation/s: Queen’s University, Kingston General Hospital Name of Sponsor Representative: Helen Lee Address: Queen’s University, Kingston General Hospital, Clinical Evaluation Research Unit, Watkins 5C, Room 4-5-308-0, 76 Stuart Street, Kingston, ON, K7L 2V7Telephone: +14039155573Fax: n/aEmail: dkh2@queensu.caChief Investigator Name: Dr Daren HeylandAddress: Queen’s University, Kingston General Hospital, Clinical Evaluation Research Unit, Watkins 5C, Room 4-5-308-0, 76 Stuart Street, Kingston, ON, K7L 2V7Telephone: +14039155573Fax: n/aEmail: dkh2@queensu.caName and address of Investigator(s) Name: Prof Nicholas HartAddress: Lane Fox Respiratory Unit, Ground Floor, St Thomas’ Hospital, Westminster Bridge Rd, London SE1 7EHTelephone: 020 7188 87727Fax: n/aEmail: Nicholas.Hart@gstt.nhs.ukName: Miss Danielle BearAddress: Lane Fox Respiratory Unit, Ground Floor, St Thomas’ Hospital, Westminster Bridge Rd, London SE1 7EHTelephone: 020 7188 5642Fax: n/aEmail: Danielle.Bear@gstt.nhs.ukName: Prof Richard BealeAddress: Department of Critical Care, St Thomas’ Hospital, Westminster Bridge Rd, London SE1 7EHTelephone: 020 7188 3038Fax: n/aEmail: Richard.Beale@gstt.nhs.ukName: Dr Liesl WandragAddress: Department of Nutrition and Dietetics, St Thomas’ Hospital, 3rd floor, B Block South Wing, Westminster Bridge Rd, London SE1 7EHTelephone: 020 7188 3038Fax: n/aEmail: Liesl.Wandrag@gstt.nhs.ukStatisticianName: Andrew Day Address: Queen’s University Kingston, Kingston General Hospital, 76 Stuart St, Kingston, ON, CA, K7L 2N7Telephone: 6135496666 x4849Fax: n/aEmail: daya@kgh.Protocol detailsVersion number 1.0 (adapted for the UK)FinalDate 22nd February 2018This Protocol is intended for use with UK sites only.Contents Page TOC \o "1-3" \h \z \u 1Protocol details PAGEREF _Toc508094455 \h 11.1PROTOCOL TITLE: PAGEREF _Toc508094456 \h 11.2Names (titles), roles and contact details of: PAGEREF _Toc508094457 \h 11.3Protocol details PAGEREF _Toc508094458 \h 2Contents Page PAGEREF _Toc508094459 \h 32List of Abbreviations and Definitions PAGEREF _Toc508094460 \h 63Summary/Synopsis PAGEREF _Toc508094461 \h 84Introduction PAGEREF _Toc508094462 \h 104.1Background Rationale and Systematic Review of the Literature PAGEREF _Toc508094463 \h 104.1.1Current Practice PAGEREF _Toc508094464 \h 104.1.2Is more Better? PAGEREF _Toc508094465 \h 114.1.3Is it More Calories that Matter or More Protein? PAGEREF _Toc508094466 \h 124.1.4What do the RCTs demonstrate? PAGEREF _Toc508094467 \h 134.1.5Summary of Background Trials to Date PAGEREF _Toc508094468 \h 134.1.6Nutrition Risk Assessment in the Critically Ill PAGEREF _Toc508094469 \h 144.2How will the results of this trial be used? PAGEREF _Toc508094470 \h 155Trial objectives and purpose PAGEREF _Toc508094471 \h 165.1Trial hypothesis PAGEREF _Toc508094472 \h 165.2Primary objective PAGEREF _Toc508094473 \h 165.3Secondary objectives PAGEREF _Toc508094474 \h 166Study design & Flowchart PAGEREF _Toc508094475 \h 166.1Study Design PAGEREF _Toc508094476 \h 166.2Flowchart PAGEREF _Toc508094477 \h 187Subject selection PAGEREF _Toc508094478 \h 197.1Subject inclusion criteria PAGEREF _Toc508094479 \h 207.2Subject exclusion criteria PAGEREF _Toc508094480 \h 20Inclusion Criteria PAGEREF _Toc508094481 \h 21Rationale for Exclusion PAGEREF _Toc508094482 \h 218Study procedures PAGEREF _Toc508094483 \h 218.1Subject recruitment PAGEREF _Toc508094484 \h 218.2Screening Procedures PAGEREF _Toc508094485 \h 228.3Randomization Procedures PAGEREF _Toc508094486 \h 228.4Masking & other measures taken to avoid bias PAGEREF _Toc508094487 \h 238.4.1Masking PAGEREF _Toc508094488 \h 238.4.2Other measures taken to minimise / avoid bias PAGEREF _Toc508094489 \h 238.5Schedule of Treatment for each visit PAGEREF _Toc508094490 \h 238.5.1Nutrition assessment PAGEREF _Toc508094491 \h 248.6Follow up Procedures PAGEREF _Toc508094492 \h 268.7End of Study Definition PAGEREF _Toc508094493 \h 269Assessment of Safety PAGEREF _Toc508094494 \h 269.1Trial Steering Committee PAGEREF _Toc508094495 \h 279.2Ethics & Regulatory Approvals PAGEREF _Toc508094496 \h 2810Compliance and withdrawal PAGEREF _Toc508094497 \h 2810.1Subject compliance PAGEREF _Toc508094498 \h 2810.2Withdrawal / dropout of subjects PAGEREF _Toc508094499 \h 2810.3Protocol Compliance PAGEREF _Toc508094500 \h 2911Data PAGEREF _Toc508094501 \h 2911.1Data to be collected PAGEREF _Toc508094502 \h 2911.2Data handling and record keeping PAGEREF _Toc508094503 \h 3011.2.1Data collection and recording PAGEREF _Toc508094504 \h 3011.2.2Data quality and validity PAGEREF _Toc508094505 \h 3011.2.3Data security PAGEREF _Toc508094506 \h 3011.2.4Record retention and archiving PAGEREF _Toc508094507 \h 3112Statistical considerations PAGEREF _Toc508094508 \h 3112.1Sample size calculation PAGEREF _Toc508094509 \h 3112.2Recruitment rate PAGEREF _Toc508094510 \h 3212.3Statistical analysis PAGEREF _Toc508094511 \h 3312.4Interim analysis PAGEREF _Toc508094512 \h 3312.5Sub-group analysis PAGEREF _Toc508094513 \h 3412.6Data monitoring PAGEREF _Toc508094514 \h 3412.6.1Monitoring, quality control and assurance PAGEREF _Toc508094515 \h 3413Ethical considerations PAGEREF _Toc508094516 \h 3513.1Peer review PAGEREF _Toc508094517 \h 3613.2Informed consent PAGEREF _Toc508094518 \h 3614Financing and Insurance PAGEREF _Toc508094519 \h 3615Reporting and dissemination PAGEREF _Toc508094520 \h 3616References PAGEREF _Toc508094521 \h 45List of Abbreviations and Definitions AEAdverse EventAPACHEAcute Physiology and Chronic Health Evaluation ScoreASRAnnual Safety ReportASPENAmerican Society for Parenteral and Enteral NutritionCACompetent AuthorityCERUClinical Education Research UnitCIChief InvestigatorCOPDChronic Obstructive Pulmonary DiseaseCRFCase Report FormCROContract Research OrganisationDMCData Monitoring CommitteeECEuropean CommissionEDCSElectronic Data Capture SystemENEnteral NutritionGAfRECGovernance Arrangements for NHS Research Ethics CommitteesICFInformed Consent FormICUIntensive Care UnitINSInternational Nutrition SurveyIVIntravenousMAMarketing AuthorisationMSMember StateMain RECMain Research Ethics CommitteeNHS R&DNational Health Service Research & Development NUTRIC NUTrition Risk in the Critically IllPIPrinciple InvestigatorQAQuality AssuranceQCQuality ControlParticipantAn individual who takes part in a clinical trialRCTRandomised Controlled TrialRECResearch Ethics CommitteeSAESerious Adverse EventSCCMSociety for Critical Care MedicineSDVSource Document VerificationSOFASequential Organ Failure Assessment FormSOPStandard Operating Procedure SSASite Specific AssessmentTMGTrial Management GroupTSCTrial Steering CommitteeSummary/SynopsisTitle The Effect of Higher Protein Dosing in Critically Ill Patients: A Multicenter Registry-based Randomized Trial. The EFFORT TrialProtocol Short Title/AcronymEFFORT trialProtocol Version number and DateV1_16Oct18Study Phase if not mentioned in titlePhase IIIIs the study a Pilot?NoIRAS Number230338REC ReferenceSponsor ReferenceStudy Duration3 yearsMethodologyInternational, multicenter, registry-based, randomized controlled trialSponsor nameGuy’s and St Thomas’ NHS Foundation TrustChief InvestigatorProf. Nicholas HartFunder Namen/aMedical condition or disease under investigationCritical illnessPurpose of clinical trialTo investigate the effect of prescribing a higher dose (≥2.2g/kg/day) of protein / amino acids compared to a low dose (≤1.2g/kg/day) on clinical outcomes in critically ill patients considered at high nutritional risk. Primary objectiveTo determine the effect of higher protein dosing (≥2.2 g/kg/d) vs lower protein dosing (≤1.2 g/kg/d) on 60-day mortality (death) in critically ill patients considered at high nutritional risk.Secondary objective (s)In critically ill patients who are considered at high nutrition risk, what is the effect of higher protein dosing (≥2.2 g/kg/d) vs lower protein dosing (≤1.2 g/kg/d) on: Time to discharge alive from hospitalHospital mortalityDuration of mechanical ventilationICU stayHospital stayNumber of Subjects/Patients4000 participants will be recruited internationally with the aim of 400 in the United KingdomTrial Design Randomised controlled trialEndpoints60-day mortality Time to discharge alive from hospitalHospital mortalityDuration of mechanical ventilationICU stayHospital stayMain Inclusion CriteriaAdult (greater than or equal to 18 years old)Requiring mechanical ventilation with actual or expected total duration of mechanical ventilation greater than 48 hoursNutritionally 'high risk' meeting one of the following criteria:1.Low (<25) or High BMI (>35)2.Moderate to severe malnutrition (as defined by local assessments). 3.Frailty (Clinical Frailty Scale 5 or more from proxy)4.Sarcopenia- (SARC-F score of 4 or more from proxy)5.From point of screening, projected duration of mechanical ventilation >4 daysStatistical Methodology and AnalysisThe statistical plan has been devised by Andrew Day, trial statistician. Briefly, the primary analysis of 6 month mortality will be compared between the arms using the chi-square for two independent proportions. A secondary analysis will employ the generalized mixed effects model with a random site effect.IntroductionBackground Rationale and Systematic Review of the LiteratureCritically ill patients receiving mechanical ventilation are at high risk of dying or developing complications that delay their recovery. Patients who develop sepsis, multi-organ failure, or require prolonged mechanical ventilation or immobility are at particular risk for developing weakness and other neuromuscular abnormalities.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GYW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 4, 5 Current Practice In 2014, Heyland and colleagues conducted an International Nutrition Survey (INS) of actual clinical practice in 187 ICUs around the world involving almost 4000 patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWNvbG88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 6 These survey data clearly demonstrated that ICU patients worldwide are receiving nowhere near current protein recommendations. On average, patients were prescribed 94 grams of protein per day or approximately 1.3 grams/kg/day (interquartile range, 1.0-1.5 grams/kg/day, overall range, 0.5-3.8 grams/kg/day). Even within a site, we observed tremendous variability in the protein prescription. Median prescription within a site was 1.2 gram/kg/day but the range went from 0.86 to 2.6. Overall, patients from these participating ICUs received approximately 55% of prescribed protein requirements with site averages ranging from 15-101%. When reviewing individual sites, 11 sites (5.9%) averaged providing more than 80% of prescribed protein amounts in all included patients and 13 sites (7.3%) of the 179 sites with high nutritional risk patients as determined by the NUTrition Risk in the Critically Ill score (NUTRIC, explained below) managed to provide more than 80% of prescribed amounts of protein to these high-risk patients. At a patient level, 634 (16.1%) of patients received more than 80% of prescribed protein amounts and only 296 (16.3%) of high NUTRIC Score patients received more than 80% of prescribed amount. Note that the percentage of patients receiving 80% of prescribed protein is the same in all patients and in nutritionally high-risk patients suggesting that practitioners are not discriminating between low and high-risk patients.Overall, protein delivery was low with the majority of protein delivered coming from EN formulas (82.5%), an additional 11.5% coming from parenteral amino acid sources and very little coming from enteral protein supplements (5.9%) or intravenous (IV) amino acids alone without IV glucose and/or lipids (13 patients, 0.1%). Of note, parenteral nutrition (PN) was used in only 14.2% of included patients, enteral protein supplements were used in only 21.0% of patients, and only 7 sites used a feeding protocol that optimized the delivery of enteral nutrition (EN) (i.e., PEP uP Protocol). Is more Better?Statistical analysis of the same INS database, as well as other existing nutritional databases, revealed a relationship between increased nutrition intake (either 30 grams/day more of protein and/or 1000 more calories per day) and improved clinical outcomes. For example, we have shown that for an additional 30 grams of protein per day or 1000 calories per day, critically ill patients have reduced infectious complications, shorter duration of mechanical ventilation, and reduced mortality.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXlsYW5kPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA 5, 7, 8 Admittedly, the clinical inference we can make from these observational data is weak. But in the absence of stronger evidence from randomized trials, it is sufficient to inform clinical practice. Some of the most exciting recent developments in the world of critical care nutrition are the emerging evidences that our nutritional practices may impact the physical recovery of critically ill patients. A recent study found that IV amino acids in ICU patients improved protein balance and stimulated an anabolic response.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaWViYXU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 9 This suggests that our nutritional strategies may be used to preserve muscle mass and muscle function although data supporting this assertion is just accumulating. Such data include a small RCT demonstrating that greater protein intake is associated with improved pulmonary function in ICU patients with chronic obstructive pulmonary disease (COPD).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ic2llaDwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ic2llaDwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 10 In addition, a long-term follow up study of patients enrolled in a randomized trial was conducted investigating physical function using the Short-form 36 health status measure at 3 and 6 months.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWk8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 11 It was demonstrated that for every 25% increase in nutritional intake, surviving patients had a higher physical function or better physical recovery that was statistically significant at 3 months. At 6 months, the improvements with better nutritional intake were still present and clinically important but lost statistical significance. Is it More Calories that Matter or More Protein?In another recent analysis using the same INS data mentioned above, meeting protein requirements was found to be more important than meeting caloric requirements.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWNvbG88L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 6 When caloric intake was controlled for, a significant reduction in associated mortality was still seen when more than 80% of protein requirements are delivered compared to less than 80% (Odds Ratio [OR] for 60 day mortality, 0.68 and 95% Confidence Intervals [CI]: 0.50, 0.91). In contrast, when protein administration was controlled for, there was no incremental effect of increased caloric administration (OR 0.89; 95% CI 0.71, 1.12). Whilst the inference is weak from this statistical modelling, it is consistent with other observational studies that show an association between protein optimization and survival, but a negative or absent effect of caloric intake.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxpbmdzdHJ1cDwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll
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ADDIN EN.CITE.DATA 16 These investigators go on to postulate the mechanism of harm, that exogenous protein inhibits autophagy, a key cell survival strategy and recommend systematic underfeeding for the first 7 days of critical illness, ADDIN EN.CITE <EndNote><Cite><Author>Schetz</Author><Year>2013</Year><RecNum>913</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>913</rec-number><foreign-keys><key app="EN" db-id="fszaeet05pxs0se9vdm5x52wessewt0x9wf9" timestamp="1490790717">913</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schetz, M.</author><author>Casaer, M. P.</author><author>Van den Berghe, G.</author></authors></contributors><titles><title>Does artificial nutrition improve outcome of critical illness?</title><secondary-title>Crit Care</secondary-title><alt-title>Critical care (London, England)</alt-title></titles><periodical><full-title>Critical Care (London, England)</full-title><abbr-1>Crit. Care</abbr-1><abbr-2>Crit Care</abbr-2></periodical><alt-periodical><full-title>Critical Care (London, England)</full-title><abbr-1>Crit. Care</abbr-1><abbr-2>Crit Care</abbr-2></alt-periodical><pages>302</pages><volume>17</volume><number>1</number><edition>2013/02/05</edition><keywords><keyword>Critical Care</keyword><keyword>Critical Illness/*therapy</keyword><keyword>Hospital Mortality</keyword><keyword>Humans</keyword><keyword>*Intensive Care Units</keyword><keyword>Length of Stay</keyword><keyword>*Nutritional Support</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2013</year><pub-dates><date>Feb 01</date></pub-dates></dates><isbn>1364-8535</isbn><accession-num>23375069</accession-num><urls></urls><custom2>PMC4056754</custom2><electronic-resource-num>10.1186/cc11828</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>17 including publishing such statements in high profile journals, such as the New England Journal of Medicine. ADDIN EN.CITE <EndNote><Cite><Author>Casaer</Author><Year>2014</Year><RecNum>871</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>871</rec-number><foreign-keys><key app="EN" db-id="fszaeet05pxs0se9vdm5x52wessewt0x9wf9" timestamp="1485272139">871</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Casaer, M. P.</author><author>Van den Berghe, G.</author></authors></contributors><titles><title>Nutrition in the acute phase of critical illness</title><secondary-title>N Engl J Med</secondary-title><alt-title>The New England journal of medicine</alt-title></titles><periodical><full-title>New England Journal of Medicine</full-title><abbr-1>N. Engl. J. Med.</abbr-1><abbr-2>N Engl J Med</abbr-2></periodical><pages>2450-1</pages><volume>370</volume><number>25</number><edition>2014/06/19</edition><keywords><keyword>Animals</keyword><keyword>Critical Illness/*rehabilitation</keyword><keyword>Enteral Nutrition/*methods</keyword><keyword>Humans</keyword><keyword>*Nutritional Requirements</keyword><keyword>Parenteral Nutrition/*methods</keyword></keywords><dates><year>2014</year><pub-dates><date>Jun 19</date></pub-dates></dates><isbn>0028-4793</isbn><accession-num>24941189</accession-num><urls></urls><electronic-resource-num>10.1056/NEJMc1404896</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>18 Finally, others have published an additional post-hoc analysis of a small randomized trial of aggressive nutritional interventions compared to usual care and demonstrated that the amount of protein received in the first week was associated with a significant increased risk of death.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF1bnNjaHdlaWc8L0F1dGhvcj48WWVhcj4yMDE3PC9Z
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ADDIN EN.CITE.DATA 19 Whilst these observations are hypothesis-generating analyses, they are significant in that they suggest a significant harm associated with increased protein and further contribute to the uncertainty about the role of protein in critical illness. What do the RCTs demonstrate?As part of the development of the Canadian Clinical Practice Guidelines, the literature is systematically reviewed from 1980 looking for all RCTs related to critical care nutrition topics. To date, the data set is sparse. There are only 5 RCTs of ICU patients randomized to high versus a lower protein intake. These trials are summarized in Table 1 in Appendix 1. The trials vary in sample size (20-470), methodological quality (7-10), year of publication (1985-2016) and the outcomes assessed. Because of the heterogeneity of outcome assessment and incomplete data sets, only the effect of higher protein dosing on mortality (Risk Ratio 0.89, 95%CI 0.66-1.19, P=0.42, see Figure 1 in Appendix 1) was able to be aggregated. Thus the RCTs in the field, which are few and of varying quality and significance, do not settle the controversy about the optimal role of protein delivery. Summary of Background Trials to DateDespite provocative results from observational analyses, and the intuitive nature of the hypothesis related to supporting metabolism with adequate nutritional substrates, large-scale randomized trials examining the effect of increased EN intake have not provided supportive evidence. Why might that be? First, these trials have focused on increased amounts of calories, not protein. Protein dose was either kept the samePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmFiaTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 21 but regardless, prescribed amounts were well below recommended amounts noted above. Second, not all clinically important outcomes were reported. Short-term mortality may not be the best outcome used to evaluate the effect of increased protein administration. In fact, we posit that measures of muscle mass or function or patient-based performance measures (such as the 6 minute walk test) may be more sensitive to differential amounts of protein intake. Of note, the EDEN studyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYXRpb25hbCBIZWFydDwvQXV0aG9yPjxZZWFyPjIwMTI8
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ADDIN EN.CITE.DATA 22 A large scale trial of supplemental parenteral nutrition in the context of a relative contraindication to enteral nutrition also showed a significant improvement in 60-day quality of life.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb2lnPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 23 Yet, a large scale trial of IV amino acids infusing up to 2.0 gram/kg/day in over 400 ICU patients did not result in any impact in patient-reported outcomes (mortality or quality of life).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb2lnPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 24Nutrition Risk Assessment in the Critically IllWe propose that the conflict between observational and interventional studies can, in part, be resolved using our nascent understanding of nutrition risk assessment in the critically ill. Large-scale RCTs may have failed to demonstrate an impact of different amounts of nutrition intake because they enroll heterogeneous patient populations of varying nutritional risk, not all of whom will respond to optimal nutrition intake. We posit that not all critically ill patients are the same in terms of their nutritional risk. The evidence for this assertion comes from studies that demonstrate a differential treatment effect of artificial nutrition in different subgroups of ICU patients.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGJlcmRhPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA 28 In three distinct analyses from three separate databases, we have shown that patients with high NUTRIC scores are less likely to die if they received closer-to-goal calories or protein, when compared to low NUTRIC score patients where there is no relationship between nutrition intake and outcome.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db21waGVyPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA 32 Consistent with the overall results of the PERMIT trial,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmFiaTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 20 they did not demonstrate any differential effect of caloric intake in high vs. low NUTRIC patients. While the analysis was underpowered (as evidenced by very wide confidence intervals around point estimates), we point out that protein intake was the same in all patient groups and as noted above, protein intake is probably more important than caloric intake. Clearly definitive proof from prospective RCTs evaluating different levels of protein intake in nutritionally high-risk patients is lacking. Moreover, based on the arguments for and against higher dose of protein administration, there is clinical equipoise or uncertainty about the optimal dose of protein in ICU patients. Hence, we believe a trial, such as the EFFORT trial, that evaluates the effect of high protein intake in high nutritional risk critically ill patients is warranted.How will the results of this trial be used?Positive, neutral, or negative, the results of the EFFORT study will inform the clinical practice in ICU settings around the world. If positive, because of the pragmatic, multicentre nature of this trial, results will be broadly applicable to all critically ill patients worldwide. If the results are negative, we need to ensure that patients no longer receive high-dose protein/amino acid admixtures. If the trial is neutral or shows no overall effect on mortality or time-to-discharge alive, this will prompt our clinical research community to explore the effect of high protein on specific subpopulations or on other outcomes (such as functional outcomes).As it relates to critical care nutrition practice in general, we have a long history of practice-changing initiatives. We have a process of synthesizing (in the form of evidence-based clinical practice guidelines) and disseminating best practice ideas (in the form of web-based repository of tools and information [see ]). In addition, several large cluster RCTsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZXlsYW5kPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 33-35 to introduce system-changing practices in ICUs in North America and several large scale quality improvement audits of practice to define current practice have been undertaken by the lead research group.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYWhpbGw8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 36, 37Over the past several years, we have discussed this program of research with leaders of the American Society of Parenteral and Enteral Nutrition and this specific protocol at the annual Clinical Nutrition Week with society leaders, researchers, and the clinical nutrition community at large. We have formally partnered with ASPEN to further facilitate both our recruitment initiatives and, importantly, our knowledge translation initiatives. These efforts will increase the likelihood of the uptake of EFFORT results across the world. Trial objectives and purposeTrial hypothesisCompared to the control group, the administration of a higher dose of protein/amino acids (a consequence of having a higher prescription) to nutritionally high-risk critically ill patients will be associated with improved survival and a quicker rate of recovery. Primary objectiveTo determine the effect of prescribing a higher dose (>2.2 grams/kg/day) of protein/amino acids compared to a lower dose (<1.2 gram/kg/day) on 60 day mortality in critically ill patients with nutrition ‘risk factors’.Secondary objectivesIn critically ill patients with nutrition ‘risk factors’, to determine the effect of prescribing a higher dose (>2.2 grams/kg/day) of protein/amino acids compared to a lower dose (<1.2 gram/kg/day) on Time to discharge alive from hospitalHospital mortalityDuration of mechanical ventilationICU stayHospital stayStudy design & FlowchartStudy DesignThis is an international, multicenter, pragmatic, volunteer-driven, registry-based, randomized, clinical trial of 4000 nutritionally high-risk critically ill patients. Given the large sample size across numerous participating units, we have adopted a pragmatic philosophy in developing this trial protocol.The registry-based randomized controlled trial design was chosen to capitalize on data collected routinely for the INS. With this approach, patients who are entered into an existing registry and meet pre-specified enrollment criteria will be randomized to a treatment; the screening, data capture, and outcomes measures are already collected by the existing registry. This strategy allows investigators to control costs, focus on patient recruitment, and benefit from the power of randomization to draw the strongest possible conclusions about causation. One notable example of the RRCT method is the TASTE trial examining the use of thrombus aspiration in ST-segment elevation myocardial infarction.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gcm9iZXJ0PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 39 Reassuringly, both TASTE and TOTAL arrived at the same conclusion, namely that thrombus aspiration did not confer a significant benefit.Within 96 hours of admission to the ICU, eligible patients will be randomized to receive either ≥2.2g/kg/day protein / amino acids or ≤1.2g/kg/day protein / amino acids. The patient will remain in the randomized group for the duration of their ICU admission, unless clinically required otherwise. Nutrition can be provided either enterally, parenterally or via both routes. Currently, protein prescriptions for critically ill patients range from 0.5-3.8 g/kg/d and at a site level, from 0.8-2.6 gm/kg/day. There is an insufficient evidentiary basis to establish which level of protein administration is right for which patient population. We will take usual practices and create 2 groups randomizing eligible patients to a lower prescription (<1.2 g/kg/d) or to a higher prescribed protein intake (>2.2 g/kg/d).Data will be collected daily and entered into the secure electronic database (REDCAP). These data points include: admission category (surgical vs. medical), diagnosis, comorbidities, sex, age, height, weight, baseline APACHE II score, SOFA score. In addition, we will extract data on the nutrition care provided such as: nutrition prescription (protein and calories), recent weight loss or food intake changes, type of nutrition, received, amount of nutrition received (protein and calories), blood sugar levels, lowest phosphate level, use of pro-kinetics, and use of supplements. This daily data will be for 12 days except protein intake, which will continue for duration of ICU stay (maximum of 28 days). Finally, duration of mechanical ventilation, length of ICU and hospital stay, ICU readmissions, and hospital mortality will also be recorded.As per usual clinical routines, patient clinical status will be monitored daily during the ICU stay. Once discharged from intensive care unit, patients will no longer be followed daily but hospital outcomes will be abstracted from the chart. The maximal duration of follow up for patients in this trial is 60 days or hospital discharge, whichever comes first. For patients remaining in hospital at 60 days, outcomes will be censored at that point.FlowchartScreen Visit1Day 11Day 2Day 3Day 4Day 5 up to ICU dischargePatient information and informed consentXNutrition ScreeningxRandomisationxNutrition assessment2 xIndividualised nutrition prescription2xDelivery of the interventionxxxxxData collectionxxxxx1Within 96 hours of admission to ICU2May be undertaken on multiple days over the intervention period pending individual patient requirements.Subject selectionIt is expected that 100 International sites and approximately 15 sites within the United Kingdom will participate in the study. Using data from previous INS’s, participating sites have required 5-8 months to recruit a minimum of 20 eligible participants. However, the INS identifies eligible participants retrospectively. Given that EFFORT is prospective and the inclusion criteria has been modified, a lower rate of recruitment is expected. Recruitment rate for EFFORT has therefore been estimated at 0.5-1.0 patients per month per sire or 6-12 patients per site per year. Sites are expected to contribute a minimum of 30 participants and therefore we will allow 3 years for recruitment.Subject inclusion criteriaCritically ill patients will be eligible if they meet the following criteria (Table 1):Adult (>18 years old) Mechanically ventilated and expected to remain so for an additional 48 hours from screening Strong command of written and spoken EnglishHave one or more of the following risk factors that make them at high nutritional risk:Low (<25) or High BMI (>35)Moderate to severe malnutrition (as defined by local assessments). The means by which sites are making this determination and elements of the assessment (history of weight loss, history of reduced oral intake, etc.) will be collected.Frailty (Clinical Frailty Scale 5 or more from proxy)Sarcopenia- (SARC-F score of 4 or more from proxy)From point of screening, projected duration of mechanical ventilation >4 daysSubject exclusion criteria Exclusion criteria are (Table 1):>96 continuous hours of mechanical ventilation before screeningExpected death of withdrawal of life-sustaining treatment within 7 days from screeningPregnantThe responsible clinician feels that the patient needs either low or high proteinPatient requires parenteral nutrition only and site does not have products to reach the high protein dose group.Table 1. Inclusion and Exclusion Criteria for Study EntryInclusion CriteriaExclusion CriteriaRationale for Exclusion>18 years oldNutritionally ‘high-risk” (meeting one of above criteria)Requiring mechanical ventilation with actual or expected total duration of mechanical ventilation >48 hours>96 continuous hours of mechanical ventilation before screeningIntervention is likely most effective when delivered earlyExpected death or withdrawal of life-sustaining treatments within 7 days from screeningPatients unlikely to receive benefitPregnantUnknown effects on fetusThe responsible clinician feels that the patient either needs low or high protein Uncertainty doesn’t exist; patient safety issuesPatient requires parenteral nutrition only and site does not have products to reach the high protein dose group.Unable to provide the intervention adequatelyStudy proceduresSubject recruitmentPatients will be screened, evaluated, and randomized within 96 hours of admission to the ICU.As potential participants will not be able to consent for themselves due to the nature of critical illness, their personal consultee (usually next of kin) will be approached by a member of the research team. If there is no personal consultee, a professional consultee (usually a consultant not directly involved in the study) will be approached to make a decision regarding study participation on the patients behalf. Personal or professional consultees will be given adequate time to review the information sheets provided and ask questions before signing the agreement form. Only members of the research team who have undergone the appropriate GCP training will be able to seek agreement from potential participants’ personal or professional consultee.Once participants have regained capacity, they will be asked to consent to their continuation in the study. The study rationale and conduct will be explained to them outlining any interventions which have already been undertaken as well as those that are still required.Screening Procedures On admission to the ICU, patients will be screened for eligibility (criteria outlined above) by a member of the research team. Screening procedures will involve use of one (or more) of the nutrition screening tools as follows: Low (<25) or High BMI (>35)Moderate to severe malnutrition (as defined by local assessments). We will document the means by which sites are making this determination and capture the elements of the assessment (history of weight loss, history of reduced oral intake, etc.).Frailty (Clinical Frailty Scale 5 or more from proxy)Sarcopenia- (SARC-F score of 4 or more from proxy)From point of screening, projected duration of mechanical ventilation >4 daysThe assessment of nutrition risk can be undertaken by a member of the research team or the ICU dietitian. Randomization Procedures Once patients have been deemed eligible for entry into the study, a member of the research team will log on to the web-based randomization system at the Clinical Evaluation Research Unit () at Kingston General Hospital to randomize patients. The system will confirm eligibility prior to allowing randomization. The system will then provide the site representative with the treatment assignment (either low dose group or high dose protein) along with a reminder of the caloric targets to be used in this trial. The randomization system, which has proven reliable in several prior RCTs, has a robust audit trail, and will maintain concealment of future allocations. The randomization system will use a computer generated randomization schedule allocating patients 1:1 to either control group or high dose protein by the method of permuted blocks of random undisclosed size within strata. Randomization will be stratified by site. Given the large pragmatic nature of the trial, we will not stratify by additional factors. Patients will remain on the assigned study intervention for the entire duration of their ICU stay. If enrolled patients leave the ICU and return later during that hospitalization, the same treatment group will be applied. Masking & other measures taken to avoid bias MaskingGiven the nature of this pragmatic trial, it will not be possible to blind clinicians with the exception that future allocations will be concealed, as explained above. However, we expect patients to be unaware of their treatment assignment. Other measures taken to minimise / avoid biasConsistent with the pragmatic stance of this protocol and, in an effort to maximize generalizability of the trials’ findings, we will not make efforts to standardize other key co-interventions aside from providing guidance on caloric dosing. However, we will capture key nutrition process of care issues in our minimalistic data collection strategies.Schedule of Treatment for each visit Screening (within 96 hours of admission to the ICU)Confirm eligibility via review of medical records against inclusion and exclusion criteria +/- discussion with consultant intensivistPerform nutrition screening using one or more of the tools listed in section 8.1Discuss study with personal or professional consultee and provide appropriate information sheetsObtain agreement from personal or professional consultee with signatures on declaration formsRandomize via electronic systemDay 1 (within 96 hours of admission to the ICU)Nutrition assessment (see 9.5.1 below) undertaken by the ICU Dietitian, including calculation of protein and energy targetsPrescribe enteral and / or parenteral feed to meet energy and protein targets (see 9.5.1 below)Administer enteral and / or parenteral feedCollect data and enter into electronic databaseDay 2 until ICU dischargeAdminister enteral and / or parenteral feed to meet energy and protein targetsNutrition assessment (see 9.5.1 below) to re-calculate nutrition requirements +/- adjust enteral and or / parenteral feed as required to meet >80% of set targetsCollect data and enter into electronic database Assess patient suitability for retrospective consent and obtain if appropriateDay 2 until hospital dischargeAssess patient suitability for retrospective consent and obtain if appropriateDay 60Collect mortality data and enter into electronic databaseNutrition assessment A full nutrition assessment should be undertaken at the first available opportunity once eligible patients have been identified (but within 96 hours of admission to the ICU). This should include calculation of both energy and protein targets and a prescription to meet these targets. Further nutrition assessment should occur as per usual practice or when the participant’s clinical condition changes, but this should not be less than once per week. Protein targetsEligible participants will be randomized into one of two groups: either ≥ 2.2g/kg/day protein / amino acids or ≤ 1.2g/kg/day protein / amino acids. In both groups, protein targets will be set using pre-ICU dry actual weight. For patients with BMI >30, ideal body weight based on a BMI of 25 will be used. Where a pre-ICU dry actual weight is not available, family members should be asked to recall the participant’s weight or an estimation should be used. The method will be recorded in the case report form (CRF). Energy targetsAlthough this trial is not about caloric dose, we encourage participating clinicians to be conservative in meeting energy targets and avoid overfeeding. 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ADDIN EN.CITE.DATA 40For non-obese patients, we suggest that their caloric prescription be around 25 kcal/kg/day (+ 5 kcal/kg/day) using a simple weight based formula. However, sites can choose to use a more sophisticated equation or indirect calorimetry if it is available.For obese patients, if indirect calorimetry is used, the goal of the nutritional prescription should be to provide energy not to exceed 65%–70% of measured requirements. If indirect calorimetry is unavailable or not used, consistent with the American guidelines,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0NsYXZlPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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ADDIN EN.CITE.DATA 40 we suggest using the weight-based equation 11–14 kcal/kg actual body weight per day for patients with BMI in the range of 30–50 and 22–25 kcal/kg ideal body weight per day for patients with BMI >50.Delivery of the interventionIn both groups, targets can be achieved through any combination of enteral nutrition (high protein content if available), protein supplements, and parenteral nutrition or amino acids only (as clinically available). Similar efforts should be used in both groups to achieve at least 80% of these targets. The use of supplemental parenteral nutrition (SPN), intravenous amino acids and post-pyloric feeding in order to optimise nutrition delivery will be determined on an individual basis by the clinical team as per usual practice. The remainder of care provided to eligible patients will be at the discretion of ICU providers.Duration of the interventionParticipants will continue with the assigned intervention for the duration of their ICU admission. If enrolled patients leave the ICU and return later during that hospitalization, the same treatment group will be applied. In addition, if the participant transitions to oral intake during their ICU admission, the intervention and daily nutrition data collection will cease. Follow up ProceduresAs per usual clinical routines, participant clinical status will be monitored daily during the ICU stay. Once discharged from intensive care unit, participants will no longer be followed daily but hospital outcomes will be abstracted from the medical records. The maximal duration of follow up for participants in this trial is 60 days or hospital discharge, whichever comes first. For participants remaining in hospital at 60 days, outcomes will be censored at that point.End of Study Definition The end of the study is defined as the time that the 60-day mortality data for the last patient is entered into the electronic database.Assessment of SafetyGiven the nature of this trial of two different protein dosing strategies with the usual care practice in critically ill patients and that no pharmaceutical or investigational device are being studied, we will only report complications considered by the site PI to be related to study procedures. As many deaths are expected in this study population and since we are capturing deaths as our primary endpoint, we will not report these events. Loss of confidentiality?represents a risk of this study and we will report any loss of confidentiality event to R&D.? Typical complications of feeding critically ill patients and events considered to be a usual part of the course of critical illness will not be reported. Such events can be found in Appendix 2. The Data Monitoring Committee will provide a third-party assessment of all interim analyses and an assessment of the scientific literature as it evolves over the duration of the trial. Trial Steering Committee The day to day management of the international trial will be undertaken by the Clinical Education Research Unit (CERU) under the supervision of Dr Daren Heyland. Staff at CERU form the Executive Committee. The Trial Steering Committee consists of the following multidisciplinary and ASPEN board members:NameTitleCountryInstitutionDaren HeylandCERU Director, MDCanadaClinical Evaluation Research UnitMargot LemieuxProject Leader, RDCanadaClinical Evaluation Research UnitCharlene CompherPhD, RDUSAUniversity of PennsylvaniaNilesh MehtaMDUSABoston Children’s HospitalTodd Rice MD, MScUSAVanderbilt UniversityGordon SacksPharmDUSAAuburn UniversityRoseann NasserMSc, RDCanadaRegina Qu’Appelle Health RegionHeidi NixdorfRDCanadaCredit Valley HospitalDanielle BearRD, MResUKGuy’s and St Thomas’ NHS Foundation TrustThe Trial Steering Committee are a multidisciplinary group of critical care nutrition experts who will provide guidance, advice, and oversight of the study. Collectively with the Executive committee, they will provide specific scientific and operational input on a regular basis. As needed, we also plan to constitute a Stakeholder Committee to obtain input from a broader group of stakeholders (such as regional or national nutrition societies, basic scientists, key opinion leaders, industry liaisons, etc.). Ethics & Regulatory ApprovalsState the name and address of the REC to which the study protocol and other documentation will be submitted. Compliance and withdrawalSubject complianceIt is expected that participants will receive >80% of their target energy and protein prescription. This will be monitored by ICU dietitians as part of their usual nutrition review and assessment. The amount of energy and protein received will be recorded in the electronic database. Data collected to confirm compliance will include nutrition prescription (protein and calories), type of nutrition, and amount of nutrition received (protein and calories).On nutrition assessment, if a participant is found to not be meeting >80% of energy or protein intake, strategies commonly used in clinical practice may be used to rectify this. Such strategies include, but are not limited to:Use of high protein enteral feedsProtein supplements‘Catch up’ or ‘volume based’ feedingIntravenous amino acidsSupplemental / total parenteral nutritionPost-pyloric feedingWithdrawal / dropout of subjectsParticipants have the right to withdraw from the study at any time for any reason. The investigator also has the right to withdraw participants from the study for any other reason. It is understood by all concerned that an excessive rate of withdrawals can render the study un-interpretable; therefore, unnecessary withdrawal of participants should be avoided. Should a participant decide to withdraw from the study, all efforts will be made to report the reason for withdrawal as thoroughly as possible. Should a participant withdraw from study intervention only, their permission will be sought to use the study data already collected and to obtain follow-up data. Protocol Compliance Compliance with the protocol will be measured centrally by CERU and reported back to the sites periodically. As we will be analysing on an intention to treat basis, we will not be specifically reporting under dosing of nutrition to R&D as a serious breach of the protocol. DataData to be collectedA secure web-based data collection tool will be used to capture all relevant de-identified data. Each site will be asked to enter the characteristics of their hospital and ICU plus general aspects of nutrition practice (e.g. use of feeding protocol or algorithms). For randomized patients, members of the research team will be asked to extract data on the personal characteristics and clinical condition of participants from the medical records. These data points include: admission category (surgical vs. medical), diagnosis, comorbidities, sex, age, height, weight, baseline APACHE II score, SOFA score. In addition, data will be collected regarding the nutrition care provided such as: nutrition prescription (protein and calories), recent weight loss or food intake changes, type of nutrition, received, amount of nutrition received (protein and calories), blood sugar levels, lowest phosphate level, use of pro-kinetics, and use of supplements. This daily nutrition data will be for 12 days except protein intake, which will continue for duration of ICU stay (maximum of 28 days). Finally, duration of mechanical ventilation, length of ICU and hospital stay, ICU readmissions, and hospital mortality will also be recorded.Data handling and record keepingData collection and recordingEach site will be responsible for data collection and data entry into the electronic database (REDCap). Members of the research team will have the option of first collecting data onto paper CRFs before entering online, or entering directly online. Each member of the research team who is responsible for randomization and data entry will receive a unique username and password to access REDcap. Data quality and validityThe database (REDCap) has a built-in query system that checks for missing fields, values outside of a given range and inconsistencies across fields. In addition, CERU staff will perform a limited amount of remote source data verification. Data securityAll data will be collected and stored in accordance with the Data protection act 1998.Upon randomization, a study code will be assigned to the participant. No identifying data will be entered into REDCap. Only the research staff at the site, the sponsor and the study staff at the Clinical Evaluation Research Unit will know the participants unique study code. The information linking the participant to their study code will be kept at each site and is never entered in the electronic data capture system or sent by mail to the sponsor or CERU. The master patient list at each site will be kept on password protected NHS computers in a password protected file. Only authorized users will have access to enter data and they will be assigned a unique user name and password. The address of all attempts to access the server, successful or otherwise, will be logged. An SSL secure connection will be used for the website. This prevents network traffic between a user and the server from being read by malicious third parties. The study site, and the study staff at the Clinical Evaluation Research Unit will have access to the study data through the Electronic Data Capture System (EDCS).In addition, all information in the EDCS will be password protected, encrypted and stored in a secure area at Queen’s University Computing Facility. The server is on a private network at Queen’s University, only accessible through specifically created portals. Communication between each user's web browser and REDCap is secured using 256 bit encryption via HTTPS connection. Data access groups are used within REDCap to segregate data by site so that users may only view and/or edit data that has been entered under their data access group. The ability to export REDCap data is restricted to only CERU IT and statistical staff. Access to the MySQL database that houses the REDCap data is restricted only to CERU IT staff via SSH on a secure VPN connection.Record retention and archivingDuring the course of the study, all paper or electronic records kept with participant details (eg. paper CRFs, consent forms and master participant lists) are the responsibility of the Principal Investigator at each site and will be kept in secure conditions (eg. on password protected NHS computers and in password protected files. Hard copies will be kept in locked offices). When the study is complete, the records will be kept at each site for a further 5 years, as per Research Governance Framework and Health Board Policy. Study data entered in REDCap will be linked with the International Nutrition Survey data and used for both primary and secondary manuscripts. These data may be accessed for future research and / or manuscripts.Statistical considerationsThe statistician for the trial is Andrew Day, located at the CERU in Kingston, Ontario, Canada. Sample size calculation We aim to enrol 4000 patients in this trial examining the impact of different protein dosing strategies on 60-day mortality. From 2007-2014, the average 60-day mortality for all patients included in the INS (>20,000 subjects) was 25%. We expect a higher rate given we are selecting out patients with nutrition risk factors, which may also increase their mortality. For the sample size calculation, we assume a 30% 60-day mortality in the lower dose group. Given the pragmatic nature of this RCT, we feel we have to acknowledge that the signal, relative to the noise, will be reduced. Hence, we need to have a sample size large enough to detect these smaller treatment effects. Assuming an alpha error of 0.05, to have 89% power to detect a 15% relative risk reduction (Absolute risk reduction of 4.5%), we would require 2000 patients per group. Table in Appendix 3 shows the ‘n’ per arm under various assumptions and demonstrates that the sample size will be adequate to maintain >80% power to detect a 15% RRR over a plausible range of baseline rates. With an overall sample of 4000 patients, we would have 90% power to detect an improvement in time to discharge alive if the odds of a random person in the treatment arm having an earlier discharge time was 1.13 times the odds of a person in the control arm. To put this sample size in perspective, every year we host the INS, we get >200 ICUs worldwide contribute around 4000 patients per cycle. We feel this sample size is both realistic, given the large-scale, multinational, pragmatic nature of trial and yet is grounded in adequate scientific and statistical principles. Based on our prior experience with the International Nutrition Survey we expect loss to follow-up for the primary and secondary outcome to be trivial. Recruitment rateIn prior INS’s, participating sites have needed 5-8 months to recruit a minimum of 20 eligible patients. However, those patients were identified retrospectively (those adult mechanically ventilated patients that remained in ICU for more than 72 hours). In EFFORT, research teams will have to identify potentially eligible patients prospectively. Moreover, we have modified the inclusion/exclusion criteria such that only a select number of previously eligible patients may be eligible. We expect it to take much longer for sites to identify qualifying nutritionally high-risk mechanically ventilated critically ill patients. Hence, we estimate a site recruiting 0.5-1.0 patients per month or 6-12 patients per year. With a minimum of 30 patients required per site, we will allow for 3 years of recruitment. Statistical analysisThe primary analysis of 6-month mortality will be compared between arms using the Chi-square for two independent proportions. A secondary analysis will employ the generalized mixed effects model with a random site effect. This will provide a within site interpretation of effect, will allow us to explore between site heterogeneity and will meet regulatory guidance suggesting that site be incorporated in a sensitivity analysis if it is not used for the primary analysis.,, 57, 58,59The secondary outcome of this study is time to live discharge from hospital. Patients who die prior to hospital discharge will be treated as never being discharged from hospital by censoring them at day 61 (after last follow-up). The primary analysis will use the log-rank test. Since the log-rank test is rank based, the actual time value we assign to decedents is unimportant; they are simply considered worse (higher rank) than any patients discharged by 60 days. We expect minimal loss to follow up prior to hospital discharge, but if loss to follow up does occur due to hospital transfer or other reasons, patients will be censored at the last time known to be in the hospital. A secondary analysis will use a shared frailty model to incorporate site as a random effect. The methods used for the primary (excluding the interim analyses) and secondary outcome will be applied to the binary and time-to-event tertiary outcomes respectively. In accordance with the intent-to-treat principle, the analysis will include all patients in the arm to which they were randomized regardless of study compliance. Based on our substantial prior experience with this population we expect minimal missing data. 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ADDIN EN.CITE.DATA 41, 42 Interim analysis We plan to conduct one formal interim analysis with early stopping guideline after the 60-day mortality status is known for 2000 patients. We propose to use the alpha spending approach of Lan and DeMets with O’Brien-Fleming type boundaries. ADDIN EN.CITE <EndNote><Cite><Author>Lan</Author><Year>1983</Year><RecNum>986</RecNum><DisplayText><style face="superscript">43, 44</style></DisplayText><record><rec-number>986</rec-number><foreign-keys><key app="EN" db-id="fszaeet05pxs0se9vdm5x52wessewt0x9wf9" timestamp="1504471289">986</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Lan, K.K.G</author><author>DeMets, D.L.</author></authors></contributors><titles><title>Discrete sequential boundaries for clinical trials</title></titles><pages>70</pages><section>659-663</section><dates><year>1983</year></dates><publisher>Biometrika</publisher><urls></urls></record></Cite><Cite><Author>O'Brien</Author><Year>1979</Year><RecNum>987</RecNum><record><rec-number>987</rec-number><foreign-keys><key app="EN" db-id="fszaeet05pxs0se9vdm5x52wessewt0x9wf9" timestamp="1504471376">987</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>O'Brien, P.C.</author><author>Fleming, T.R. </author></authors></contributors><titles><title>A multiple testing procedure for clinical trials</title></titles><pages>35</pages><section>549-556</section><dates><year>1979</year></dates><publisher>Biometrics</publisher><urls></urls></record></Cite></EndNote>43, 44 This interim analysis would suggest stopping the study early if a two-side p-value of 0.003. To maintain the overall type I error rate of the study at 0.05, we will perform the final analysis at a nominal alpha of 0.049. This interim analysis has a trivial (less than 1%) effect on the overall power of the study. Using this rule and assuming a 30% mortality rate in the control arm, the study would be stopped at the interim if a 6% absolute difference in mortality was observed between arms. Sub-group analysisWe will perform a pre-specified subgroup analysis based on baseline NUTRIC score, as previously explained. In addition, we plan to evaluate the treatment effect within sub-populations of our enrolled patients (burns, trauma and BMI>30), depending on the numbers of patients in each of these subgroups. Finally, we will consider the effect of multiple nutrition risk factors vs. just one on magnitude of the treatment effect. The statistical significance of apparent effect modification will be assessed by testing a treatment by covariate interaction term using logistic regression for mortality and Cox PH model for time to discharge alive. Due to the increased risk of type I and type II error, subgroup specific inferences will be considered exploratory and hypothesis generating. Subgroup specific effects will be presented by forest plots. Data monitoringA Data Monitoring Committee (DMC) will be established for the study. The overall purpose of the DMC will be to ensure the protection of human subjects and to maintain trial integrity. They will be responsible for reviewing any SAEs that are reported and to make recommendations regarding the ongoing safety of the trial.Monitoring, quality control and assuranceAudit and Inspection may be carried out by the Canadian research team to determine whether the trial related activities are being conducted, and the data recorded, analysed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).Interim monitoring activities will be done remotely or on site and will include:Monitoring on an ongoing basis through the REDCap query system and regular reports.Monitoring the first 2 patients enrolled at every site on high priority data elementIf sites are identified as being “high risk” during the trial, remote monitoring will be conducted on an ad hock basis.Interim monitoring will involve source data review (SDR), which includes reconciliation of data entered into the CRF with source documentation resulting in document review to confirm correct implementation and conduct of study procedures. The monitor delegate will source verify data elements considered to be high priority for at least two patients at each site (either the first 2 patients or two picked randomly). If source documents for either of the selected subjects are not available at the time of the visit, an alternative patient will be chosen.The site’s study leaders will provide the following to the monitor delegate:Medical chart pages showing requested dataRequested data may vary by patient/site depending on the reason for monitoring. Any data sent electronically for source monitoring will be anonymysed. Reports of SAEs for the selected subjects.Calorie and protein breakdown of the enteral formulas received by selected subjects.Any updated ethics approvals (ie. annual approval, amendment approval, etc)?Data entered into the EDCS will be verified against source documents. In addition, any data identified in the source documents that are found to be missing in the EDCS will be discussed with the staff and entered into the EDCS.Ethical considerationsThe trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), the principles of GCP and in accordance with all applicable regulatory requirements including but not limited to the Research Governance Framework.This protocol and related documents will be submitted for review to XXXXXX Research Ethics Committee (REC). The Chief Investigator will submit a final report at conclusion of the trial to the REC within the timelines they mandate. Peer reviewThe study protocol has been reviewed and agreed by the ASPEN board of directors along with selected experts in critical care nutrition. Informed consentAs this study involves adult patients who are unable to consent for themselves, agreement to participate in the study will be sought from personal or professional consultees. Only members of the research team who have undergone GCP training will be able to seek agreement. If agreement from a professional consultee is sought, it is required that they are an independent physician (e.g. not directly involved in the study). Their agreement will be sought by a GCP trained member of the research team. See section 9.1 for specific details of the process. Financing and InsuranceFunding has been provided from CERU to the lead site in the UK for set-up activities. There is no additional funding available to participating sites.Insurance / Indemnity for the trial is provided by the sponsor, Queen’s University, Kingston General Hospital, Ontario, Canada.Reporting and disseminationIt is intended that the results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals.Appendix 1 RCTs of High vs Low Protein and Amino AcidsStudyPopulationMethods(score)InterventionMortality # (%)High protein Low ProteinInfections # (%)High protein Low ProteinMechanical VentilationHigh protein Low Protein1) Clifton 1985**Head injured patients comatose for 24 hrsN=20C.Random: not sureITT: yesBlinding: no(8)22% pro, 38 % CHO, 41 % fat, 1.5 Kcal/ml (Traumacal) vs. 14 % pro, 50 % CHO, 36 % fat, 2.0 Kcal/ml (Magnacal) Isocaloric, 29 gm Nitrogen vs.17.6 gms Nitrogen3-month1/10 (10)3-month1/10 (10)3/10 (30)2/10 (20)NRNR2) Scheinkestel 2003**Critically ill ventilated pts on 6 days CRRT for renal failureN=50C.Random: yesITT: yesBlinding: no(9)1.5 g/kg/d protein x2 days, 2.0 g/kg/d protein x2 days and 2.5 g/kg/d protein x2 days while receiving CRRT vs 2.0 g/kg/d protein x6 days while receiving CRRTICU9/40 (23)ICU4/10 (40)NRNRNRNR3) Rugeles 2013Medical adult ICU patientsN=80C.Random: yesITT: noBlinding: double(7)Hypocaloric hyperproteic (15 kcal/kg, 1.7 g/kg/d) x 7 days vs standard (25 kcal/kg, 20% calories from protein).28 day*11/40 (28)28 day1*12/40 (29)NR1**NR1**8.5 + 4.69.7 + 4.94) Doig 2015Medical ICU adult patientsN=474C.Random: yesITT: yesBlinding: no(10)IV aa infusion (Synthamin, Baxter, 100g/L) providing a max 100 g aa/day. IV aa infusion was titrated to provide 2 g/kg/d of aa from all nutrition sources.ICU28/239 (11.7)Hospital37/239 (15.5)90-day42/236 (17.8)ICU30/235 (12.8)Hospital43/235 (18.3)90-day47/235 (20)NR**NR2**7.33 (7.0-7.68)Mean + SD**7.26 (6.94-7.61)Mean + SD**5) Ferrie 2016Medical/Surgical ICU adult patientsN=120C.Random: yesITT: yes (modified)Blinding: double(10)Patients on PN randomized to receive a higher aa vs lower aa solution with a goal of 1.2 vs 0.8 g/kg/d aa from EN and PN.ICU8/59 (14)Hospital12/59 (20)6 month15/59 (25)ICU6/60 (10)Hospital9/60 (15)6 month9/60 (15)31/59 (53)34/60 (57)2.0 (1.0–3.0)3.68 + 6.17*2.0 (1.0–5.0)5.87 + 14.273*StudyLOSHigh protein Low ProteinPhysical and QOL OutcomesHigh protein Low ProteinNutrition parametersHigh protein Low Protein1) Clifton 1985**NRNRCalories (kcal/kg/d)51 48Grams nitrogen/day0.42 0.242) Scheinkestel 2003** NRNRCalories per day2063 2095Nitrogen balance-0.56 -4,53) Rugeles 2013ICU9.5 + 5.5 days 10.4 + 5.0 days Hospital*19.5 + 6.5 days 20.5 + 5.0 daysNRCalories (kcal/kg/d)12 14Protein (g/kg/d)1.4 0.764) Doig 2015ICU11.6 (10.8 to 12.5) 10.7 (10.0 to 11.5)Mean + SD**Hospital26.0 (24.2 to 28.0) 24.8 (23.0 to 26.6)Mean + SD5** RAND-36 General Health, mean (SD)50.5 (27.2) (n=192) 52.8 (25.9) (n=180)P=0.41ECOG, mean (SD)1.31 (1.0) (n=192) 1.18 (1.0) (n=181)P=0.21Diff (95% CI): -0.13 (-0.34 to 0.07)RAND-36 Physical, mean (SD)47.7 (33.7) (n=192) 53.2 (33.0) (n=180)P=0.11Diff (95% CI): 5.5 (-1.31 to 12.3)Protein**Significantly more protein during first 7 ICU days in intervention group5) Ferrie 2016ICU5.0 (3.0–8.0) 6.0 (3.8–10.0)7.36 + 7.85* 5.87 + 14.276*Hospital25.0 (16.8–41.3) 27.5 (18.8–55.8)38.31 + 35.906* 41.75 + 37.366*Hand grip strength at ICU d/c, kg18.5 + 10.4 15.8 + 10.3, P=0.054% Expected Value51 45Hand grip strength at day 7, kg22.1 + 10.1 18.5 + 11.8, P=0.025% Expected Value62 52Fatigue Score at day 75.4 + 2.2 6.2 + 2.2, P=0.045Sum of 3 muscle sites on u/s at day 7, cm8.4 + 1.0 7.9 + 1.1, P=0.02Forearm muscle thickness on u/s at day 7, cm3.2 + 0.4 2.8 + 0.4, P=<0.0001Biceps muscle thickness on u/s at day 7, cm2.5 + 0.6 2.4 + 0.4, P=0.21Thigh muscle area on u/s at day 7, cm26.8 + 2.1 5.8 + 1.9, P=0.02Leg circumference at day 7, cm35.9 + 4.3 35.9 + 4.4, P=0.98Kcal/kg/d in first 3 study days23.5 + 3.9 26.0 + 3.8Kcal/kg/d in first 7 study days23.1 + 3.9 24.9 + 4.2 grams/kg/d in first 3 study days1.17 + 0.21 0.87 + 1.17grams/kg/d in first 7 study days1.09 + 0.22 0.90 + 0.21*Data/information was obtained directly from the author**Unable to obtain further data directly from the authorNR, not reported; LOS, length of stay; ICU, intensive care unit; ITT, intention to treat; C. random, concealed randomization; QOL, quality of life; u/s, ultrasound; d/c, discharge; SD, standard deviation; kg, kilograms; cm, centimeter; aa, amino acid; EN, enteral nutrition; PN, parenteral nutrition;Appendix 2: Non-exhaustive list of expected adverse events which do not require reportingAbdominal distensionAbdominal painElectrolyte disturbanceHaemo-pneumothoraxHepatomegalyHyperosmolar syndromeHypersensitivity reaction;(anaphylactic reaction)HypoglycaemiaIschaemic bowelJaundiceNausea requiring treatmentPneumothoraxRaised liver enzyme(s)Regurgitation/aspirationVascular catheter related infectionVomiting.Appendix 3: Sample Size JustificationRelative Risk Reduction (1-RR) @Control Group Event Rate (60-day Mortality)25%30%35%ARR80%Power90%PowerARR80%Power90%PowerARR80%Power90%Power10%2.50%4, 5486,0873.00%3,5544,7573.5%2,8443,80615%3.75%1,9842,6554.50%1,5542,0795.25%1,2471,66820%5.00%1,0941,4656.00%8591,1497.00%69192425%6.25%6869187.50%5407228.75%43558230%7.50%4666249.00%36749110.50%297397ARR, absolute risk reduction; RR, relative risk;Appendix 4 – Information with regards to Safety Reporting in Non-CTIMP ResearchTO CONFIRM WITH R&D AFER COLLABORATION AGREEMENT FINALISEDWhoWhenHowTo WhomSAEChief Investigator-Report to Sponsor within 24 hours of learning of the event-Report to the MREC within 15 days of learning of the eventSAE Report form for Non-CTIMPs, available from NRES website.Sponsor and MRECUrgent Safety Measures Chief Investigator Contact the Sponsor and MREC ImmediatelyWithin 3 days By phoneSubstantial amendment form giving notice in writing setting out the reasons for the urgent safety measures and the plan for future action.Main REC and Sponsor Main REC with a copy also sent to the sponsor. The MREC will acknowledge this within 30 days of receipt. Progress Reports Chief Investigator Annually (starting 12 months after the date of favourable opinion)Annual Progress Report Form (non-CTIMPs) available from the NRES websiteMain RECDeclaration of the conclusion or early termination of the studyChief Investigator Within 90 days (conclusion)Within 15 days (early termination)The end of study should be defined in the protocolEnd of Study Declaration form available from the NRES websiteMain REC with a copy to be sent to the sponsor Summary of final Report Chief InvestigatorWithin one year of conclusion of the ResearchNo Standard FormatHowever, the following Information should be included:-Where the study has met its objectives, the main findings and arrangements for publication or dissemination including feedback to participantsMain REC with a copy to be sent to the sponsorReferences ADDIN EN.REFLIST 1.Fan E, et al. 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