WHO/HRP/PP/1999 - ANZCTR
FOR WHO USE ONLYDate received by WHO:Thematic area: FORMCHECKBOX Single site proposal FORMCHECKBOX "Core" proposal (for multicentre study) FORMCHECKBOX Centre-specific proposal under multicentre studyConnect ID No:HRP Research ProposalTrial A65870Carbetocin RTS for preventing postpartum haemorrhage: a randomized non-inferiority controlled trial.Version 30 June 2014SponsorDepartment of Reproductive Health & ResearchWorld Health OrganizationAvenue Appia 201211 Geneva 27SwitzerlandTrial coordination unitA. Metin Gülmezoglu (Trial coordinator)Mariana Widmer (Trial manager)Gilda Piaggio (Trial statistician)Principal investigatorsDr Guillermo CarroliCENTRO ROSARINO DE ESTUDIOS PERINATALESMoreno 878 6? Piso2000 ROSARIOARGENTINADr Joao Paulo Dias de Souza CENTRO DE REFER?NCIA DA SA?DE DA MULHER DE RIBEIR?O PRETO – MATER Av. Wanderley Taffo, n? 330 – Quintino Facci II - CEP 14070-250Ribeir?o Preto - Sao PauloBRAZILDr Hany Abdel-AleemDepartment of Obstetrics and GynecologyWomen's Health HospitalASSIUT UNIVERSITY HOSPITAL71511 AssiutEGYPT Dr Shivaprasad S Goudar Women's and Children's Health Research Unit, KLE University'sJawaharlal Nehru Medical CollegeBelgaum 590010 KarnatakaINDIADr Zahida QureshiDepartment of Obstetrics and GynaecologyCollege of Health SciencesUniversity of NairobiNairobiKENYA Dr. Bukola FawoleDepartment of Obstetrics & GynaecologyUniversity College HospitalIbadanNIGERIADr Syeda Batool MazharHead of DepartmentMCH Centre, Pakistan Institute of Medical Sciences,G-8/3, Islamabad.PAKISTANDr Chong Yap SengDepartment of Obstetrics and GynaecologyYong Loo Lin School of Medicine, National University of Singapore1E, Kent Ridge Road,NUHS Tower Block, Level 12,SINGAPORE Dr Ebrahim BeraDepartment of Obstetrics & Gynaecology Rahima Moosa Mother-and-Child Hospital c/o Fuel & Oudtshoorn StreetNewclare2112 JohannesburgSOUTH AFRICADr Pisake LumbiganonFaculty of Medicine - Khon Kaen UniversityKhon Kaen 40002THAILANDDr Josaphat ByamugishaDepartment of Obstetrics and GynecologyMakerere University College of Health SciencesMulago HospitalKampala UGANDADr Arri CoomarasamyGynaecology and Reproductive MedicineBirmingham Women’s NHS Foundation TrustMindelsohn Way Edgbaston Birmingham B15 2TGUNITED KINGDOMContents TOC \o "1-3" \h \z \u 1.Project summary PAGEREF _Toc390161602 \h 72.Description of the project PAGEREF _Toc390161603 \h 82.1Background information and rationale PAGEREF _Toc390161604 \h 82.2Risk-Benefit Ratio PAGEREF _Toc390161605 \h 102.3Study hypothesis and objectives PAGEREF _Toc390161606 \h 102.4Study conceptual framework PAGEREF _Toc390161607 \h 112.5Study design PAGEREF _Toc390161608 \h 122.6Procedures PAGEREF _Toc390161609 \h 122.6.1Study centres PAGEREF _Toc390161610 \h 122.6.2Study participants PAGEREF _Toc390161611 \h 122.6.3Randomization and allocation PAGEREF _Toc390161612 \h 132.6.3.1Unblinding of individual participant treatment _____________________________________ 132.6.4Sample size calculation PAGEREF _Toc390161613 \h 142.6.5Description of the intervention __________________________________________________ 182.6.5.1Description of the Investigational Medicinal Product ________________________________ 18 2.6.5.2Packaging and labelling ________________________________________________________ 192.6.5.3Handling and storage __________________________________________________________ 20 2.6.5.4Dosage and administration _____________________________________________________ 20 2.6.5.5Investigational Medicinal Product accountability ___________________________________ 21 2.6.5.6Other drugs to be used in the trial _______________________________________________ 21 2.6.5.7Concomitant medications and therapies __________________________________________ 21 2.6.6 Admission procedure PAGEREF _Toc390161616 \h 222.6.7 Follow-up procedures PAGEREF _Toc390161617 \h 222.6.8Trial endpoints PAGEREF _Toc390161618 \h 222.6.9 Criteria for participant discontinuation PAGEREF _Toc390161619 \h 242.7Study instruments PAGEREF _Toc390161620 \h 242.8Project management PAGEREF _Toc390161621 \h 242.8.1Trial steering committee (TSC) PAGEREF _Toc390161622 \h 252.8.2Data and safety monitoring committee (DSMC) PAGEREF _Toc390161623 \h 252.9Data quality assurance PAGEREF _Toc390161624 \h 262.10Data management PAGEREF _Toc390161625 \h 262.11Data analysis plan PAGEREF _Toc390161626 \h 272.11.1Final analysis PAGEREF _Toc390161627 \h 272.11.2Interim analysis PAGEREF _Toc390161628 \h 292.11.3Analysis of secondary outcomes PAGEREF _Toc390161629 \h 302.12Study timeline PAGEREF _Toc390161630 \h 302.13Main problems anticipated and proposed solutions PAGEREF _Toc390161631 \h 302.14Applicability of results PAGEREF _Toc390161632 \h 312.15Links with other projects PAGEREF _Toc390161633 \h 313.Gender considerations PAGEREF _Toc390161634 \h 314.Ethical issues PAGEREF _Toc390161635 \h 314.1. Responsibilities of the Investigator PAGEREF _Toc390161636 \h 314.2 Forms required PAGEREF _Toc390161637 \h 324.2.1 Information sheet for participants PAGEREF _Toc390161638 \h 324.2.2 Informed consent form for participants PAGEREF _Toc390161639 \h 324.2.3 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) PAGEREF _Toc390161642 \h 335.Quality assurance and health authorities PAGEREF _Toc390161643 \h 346.Investigator site file and archiving PAGEREF _Toc390161644 \h 347. Changes to the clinical trial protocol PAGEREF _Toc390161645 \h 348.Environmental impact of the project PAGEREF _Toc390161646 \h 359.Plans for dissemination and use of project results PAGEREF _Toc390161648 \h 3510. Clinical trial report and publication policy PAGEREF _Toc390161651 \h 3511.Research capacity strengthening PAGEREF _Toc390161660 \h 3612.References PAGEREF _Toc390161662 \h 36Annex 1Justification of the non-inferiority margin for the composite endpointAnnex 2The draft minutes of the MHRA meeting (9 December 2013)Annex 3Oxytocin product labelAnnex 4Informed consentAnnex 5Centres’ characteristicsAnnex 6DSMC charterAnnex 7 HRP Standard operating proceduresAnnex 8 CONSORT Annex 9Study timelineAnnex 10WHO Data use regulationsAnnex 11Dummy tablesAnnex 12Interim analysis procedureAbbreviationsAERAdverse Event Report formCIConfidence intervalCRFCase Report FormCROClinical (Contract) Research OrganisationCTRClinical trial reportDSMCData Safety and Monitoring CommitteeFDAFood and Drug AdministrationGCPGood Clinical PracticeGMPGood Manufacturing PracticeHRPSpecial Programme of Research, Development and Research Training in Human ReproductionICHInternational Conference on HarmonisationIECIndependent Ethics CommitteeIMIntramuscularIMPInvestigational Medicinal ProductIRBInstitutional Review BoardITTIntention-to-TreatIVIntravenousPPPer ProtocolPPHPostpartum HaemorrhageRHRReproductive Health and ResearchRRRisk ratioRTSRoom Temperature StableSAESerious Adverse Event report formSOPsStandard operating proceduressPPHsevere Postpartum HaemorrhageTMTTrial monitoring teamTSCTrial steering committee1.Project summaryBackground: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and it contributes to nearly a quarter of maternal deaths globally. The majority of deaths due to PPH could be avoided through the use of prophylactic uterotonics during the third stage of labour and by timely and appropriate management. Oxytocin (IM/IV, 10 IU) is recommended as the uterotonic drug of choice. Based on the manufacturer’s recommendations, oxytocin should be stored under refrigeration. Carbetocin appears to be a promising agent in the prevention of PPH, is a more stable molecule and induces a prolonged uterine response, when administered postpartum. The manufacturer of carbetocin (Ferring Pharmaceuticals) has recently developed a room temperature stable formulation (carbetocin RTS) which makes it an attractive option for countries where maintaining the cold chain is problematic. Merck for Mothers, Ferring Pharmaceuticals and the World Health Organization would like to evaluate the room temperature stable carbetocin solution for injection as a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain.Objectives: i) To evaluate non-inferiority of carbetocin RTS 100 ?g IM versus oxytocin 10 IU IM in the prevention of the composite outcome blood loss ≥500 mL or the use of additional uterotonic drugs following vaginal delivery of the baby; (ii) To evaluate non-inferiority of carbetocin RTS 100 ?g IM versus oxytocin 10 IU IM in the prevention of blood loss ≥1000 mL.Methods: This will be a hospital-based, multicentre, double-blind, randomized, non-inferiority, active controlled trial. Centres from twelve countries will participate. Each woman will be randomized to receive either oxytocin 10 IU IM or carbetocin RTS 100 ?g IM. We aim to recruit approximately 29,000 women delivering vaginally in health facilities within a 12 month recruitment period.Management: Overall trial management will be from HRP/RHR in Geneva. There will be twelve centres located in Argentina, Brazil, Egypt, India, Kenya, Nigeria, Pakistan, Singapore, South Africa, Thailand, Uganda and United Kingdom. There will be an online data entry system managed from HRP/RHR. Expected Outcomes: The main objective of this trial is to evaluate if carbetocin RTS 100 ?g IM is non-inferior to oxytocin 10 IU IM, as uterotonic during the third stage of labour, in preventing postpartum haemorrhage. If the trial objective is achieved, uterotonic PPH prevention coverage will be substantially expanded.This trial forms part of the programme of work to reduce maternal deaths due to postpartum haemorrhage within the RHR department in collaboration with other research groups and organizations active in the field.2.Description of the project2.1Background information and rationalePostpartum haemorrhage (PPH) is defined as a blood loss of 500 mL or more within 24 hours of delivery, while severe PPH (sPPH) is defined as a blood loss of 1000 mL or more within the same time frame ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>2012</Year><RecNum>24</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">24</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>WHO Recommendations for the prevention and treatment of postpartum haemorrhage.</title></titles><dates><year>2012</year></dates><publisher>World Health Organization</publisher><work-type>WHO Publication</work-type><urls></urls></record></Cite></EndNote>1. PPH is the leading cause of maternal mortality in low-income countries and it contributes to nearly a quarter of maternal deaths globally. PPH is a significant contributor to severe maternal morbidity and long term disability, as well as to a number of other severe maternal conditions, generally associated with more substantial blood loss, including shock and organ dysfunctionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGFuPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 2-4. Improving health care for women during childbirth in order to prevent and treat PPH is an essential step towards the achievement of the United Nations Millennium Development Goals. The majority of deaths due to PPH could be avoided through the use of prophylactic uterotonics during the third stage of labour and by timely and appropriate management. Oxytocin (IM/IV, 10 IU) is recommended as the uterotonic drug of choice. Other injectable uterotonics and misoprostol are accepted as alternatives for the prevention of PPH in settings where oxytocin is not available ADDIN EN.CITE <EndNote><Cite Hidden="1"><Author>WHO</Author><Year>2012</Year><RecNum>24</RecNum><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">24</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>WHO Recommendations for the prevention and treatment of postpartum haemorrhage.</title></titles><dates><year>2012</year></dates><publisher>World Health Organization</publisher><work-type>WHO Publication</work-type><urls></urls></record></Cite></EndNote>.Despite oxytocin being a well-known and extensively studied peptide hormone, there is limited information on its stability at tropical temperatures, mainly at extreme climate conditions ADDIN EN.CITE <EndNote><Cite><Author>Hogerzeil HV</Author><Year>1993</Year><RecNum>26</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">26</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Hogerzeil HV, Walker GJA, Goeje MJ.</author></authors><tertiary-authors><author>World Health Organization</author></tertiary-authors></contributors><titles><title>Stability of Injectable Oxytocics in Tropical Climates: Results of Field Surveys and Simulation Studies on Ergometrine, Methylergometrine and Oxytocin.</title><secondary-title>EDM Research Series No. 008</secondary-title></titles><pages>50</pages><dates><year>1993</year></dates><work-type>WHO publication</work-type><urls></urls></record></Cite></EndNote>5. The manufacturer recommends storage under refrigeration in most countries and there is general acknowledgement that cold storage would help to maintain quality of oxytocin especially in settings where it is difficult to obtain cold storage regularly. In low resource settings, it can be challenging to keep the drug at the right temperature. To ease this barrier, several groups have been researching heat stable oxytocin formulations ADDIN EN.CITE <EndNote><Cite><Author>PATH</Author><Year>2013</Year><RecNum>40</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">40</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>PATH</author></authors></contributors><titles><title>HeatStable Oxytocin - Technology Opportunity Assessment</title></titles><dates><year>2013</year></dates><publisher>PATH</publisher><urls><related-urls><url> . Though some progress has been made in this area, the fact still remains that there is currently no heat stable oxytocin formulation for therapeutic use ADDIN EN.CITE <EndNote><Cite><Author>Paul Ashigbie</Author><RecNum>41</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">41</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Paul Ashigbie, B. Pharm</author></authors></contributors><titles><title>Priority Medicines for Europe and the World "A Public Health Approach to Innovation".</title></titles><dates><pub-dates><date>January 2013</date></pub-dates></dates><urls><related-urls><url> . Carbetocin appears to be a promising agent in the prevention of PPH. The clinical and pharmacological properties of carbetocin are similar to those of oxytocin. However, carbetocin is a more stable molecule and induces a prolonged uterine response, when administered postpartum, in terms of both amplitude and frequency of contractions due to its longer half-life. In a Cochrane systematic reviewPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 8, including 11 studies (2635 women), six compared carbetocin with oxytocin; four of these were conducted in women undergoing caesarean deliveries, one was for women following vaginal deliveries and one did not state the mode of delivery clearly. The carbetocin was administered as 100 μg intravenous dosage across the trials, while oxytocin was administered intravenously but at varied dosages. Use of carbetocin resulted in a statistically significant reduction in the use of additional/therapeutic uterotonics (risk ratio (RR) 0.62; 95% confidence interval (CI) 0.44 to 0.88; four trials, 1173 women) compared to oxytocin for those who underwent caesarean section, but not for vaginal delivery. Compared to oxytocin, carbetocin was associated with reduced uterine massage following both caesarean delivery (RR 0.54; 95% CI 0.37 to 0.79; two trials, 739 women) and vaginal delivery (RR 0.70; 95% CI 0.51 to 0.94; one trial, 160 women). There were no statistically significant differences between carbetocin and oxytocin in terms of risk of any PPH or in risk of sPPH. Cost-effectiveness of carbetocin was investigated by one study published as an abstract, with limited data. Results from this Cochrane systematic review are not conclusive as they are based on small studies (11 studies, 2635 women), mostly assessing carbetocin for caesarean deliveries and there is very little data on substantive clinical endpoints such as maternal morbidity and blood loss ≥1000 mL. Further research is needed to evaluate the effectiveness of carbetocin in preventing PPH in vaginal deliveries.Biochemical characteristics of carbetocinCarbetocin (1-deamino-1-monocarba-(2-0-methyltyrosine)-oxytocin) is a long-acting synthetic agonist analogue of the human oxytocin ADDIN EN.CITE <EndNote><Cite><Author>Sweeney</Author><Year>1990</Year><RecNum>10</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sweeney, G.</author><author>Holbrook, A. M.</author><author>Levine, M.</author><author>Yip, M.</author><author>Alfredsson, K.</author><author>Cappi, S.</author><author>Ohlin, M.</author><author>Schulz, P.</author><author>Wassenaar, W.</author></authors></contributors><auth-address>Sweeney, G
Mcmaster Univ,Fac Hlth Sci,1200 Main St W,Rm 4w8f,Hamilton L8n 3z5,Ontario,Canada
Mcmaster Univ,Fac Hlth Sci,1200 Main St W,Rm 4w8f,Hamilton L8n 3z5,Ontario,Canada
Ian W French & Associates,Div Pharmacokinet,Toronto,Ontario,Canada
Ferring Ab,Dept Pharmaceut Dev,Malmo,Sweden
Ferring Ab,Dept Clin Res,Malmo,Sweden
Ferring Inc,Dept Clin Res,Toronto,Ontario,Canada</auth-address><titles><title>Pharmacokinetics of Carbetocin, a Long-Acting Oxytocin Analog, in Nonpregnant Women</title><secondary-title>Current Therapeutic Research-Clinical and Experimental</secondary-title><alt-title>Curr Ther Res Clin E</alt-title></titles><periodical><full-title>Current Therapeutic Research-Clinical and Experimental</full-title><abbr-1>Curr Ther Res Clin E</abbr-1></periodical><alt-periodical><full-title>Current Therapeutic Research-Clinical and Experimental</full-title><abbr-1>Curr Ther Res Clin E</abbr-1></alt-periodical><pages>528-540</pages><volume>47</volume><number>3</number><dates><year>1990</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0011-393X</isbn><accession-num>WOS:A1990CU97300016</accession-num><urls><related-urls><url><Go to ISI>://WOS:A1990CU97300016</url></related-urls></urls><language>English</language></record></Cite></EndNote>9, resulting from the deamination of the N-terminal and the replacement of the 1-6 disulphide bridge by a methyl ether group. These structural modifications protect the molecule from the aminopeptidase and disulphidase cleavage and prolong its pharmacological effect ADDIN EN.CITE <EndNote><Cite><Author>Engstrom</Author><Year>1998</Year><RecNum>3</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Engstrom, T.</author><author>Barth, T.</author><author>Melin, P.</author><author>Vilhardt, H.</author></authors></contributors><auth-address>Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark. engstrom@mfi.ku.dk</auth-address><titles><title>Oxytocin receptor binding and uterotonic activity of carbetocin and its metabolites following enzymatic degradation</title><secondary-title>Eur J Pharmacol</secondary-title><alt-title>European journal of pharmacology</alt-title></titles><periodical><full-title>Eur J Pharmacol</full-title><abbr-1>European journal of pharmacology</abbr-1></periodical><alt-periodical><full-title>Eur J Pharmacol</full-title><abbr-1>European journal of pharmacology</abbr-1></alt-periodical><pages>203-10</pages><volume>355</volume><number>2-3</number><keywords><keyword>Animals</keyword><keyword>Female</keyword><keyword>Kidney/*metabolism</keyword><keyword>Myometrium/*drug effects/physiology</keyword><keyword>Oxytocics/*metabolism/pharmacology</keyword><keyword>Oxytocin/*analogs & derivatives/metabolism/pharmacology</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Receptors, Oxytocin/*metabolism</keyword><keyword>Receptors, Vasopressin/*metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Aug 21</date></pub-dates></dates><isbn>0014-2999 (Print)
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ADDIN EN.CITE.DATA 11-13. In animal models, carbetocin appeared to be less potent than oxytocin, but a significantly longer duration of action in vivo was consistently demonstrated HYPERLINK \l "_ENREF_14" \o "Cort, 1979 #6" ADDIN EN.CITE <EndNote><Cite><Author>Cort</Author><Year>1979</Year><RecNum>6</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cort, N.</author><author>Einarsson, S.</author><author>Viring, S.</author></authors></contributors><titles><title>Actions of oxytocin and a long-acting carba oxytocin analog on the porcine myometrium in vitro and in vivo</title><secondary-title>Am J Vet Res</secondary-title><alt-title>American journal of veterinary research</alt-title></titles><periodical><full-title>Am J Vet Res</full-title><abbr-1>American journal of veterinary research</abbr-1></periodical><alt-periodical><full-title>Am J Vet Res</full-title><abbr-1>American journal of veterinary research</abbr-1></alt-periodical><pages>430-2</pages><volume>40</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Delayed-Action Preparations</keyword><keyword>Female</keyword><keyword>Myometrium/*drug effects</keyword><keyword>Oxytocin/*analogs & derivatives/*pharmacology</keyword><keyword>Swine/*physiology</keyword><keyword>Uterine Contraction/drug effects</keyword><keyword>Uterus/*drug effects</keyword></keywords><dates><year>1979</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0002-9645 (Print)
0002-9645 (Linking)</isbn><accession-num>475101</accession-num><urls><related-urls><url>. Carbetocin 100 ?g/mL was first approved in Canada in June 1997 and is currently registered in more than 70 countries under the trade names PABAL/DURATOCIN/ LONACTENE/DURATOBAL for prevention of uterine atony following delivery of the baby by caesarean section under epidural or spinal anaesthesia. In addition, carbetocin has been approved following vaginal delivery of the infant in Kazakhstan, Mexico and Russia, and there are several trials with carbetocin in women with vaginal delivery in the published literaturePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3VjaGVyPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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ADDIN EN.CITE.DATA 15-20. The drug is licensed to be administered by slow IV single injection at a dose of 100 ?g. Its current formulation requires refrigeration and therefore, cold-chain within the supply chain. The manufacturer of carbetocin (Ferring Pharmaceuticals) has recently developed a room temperature stable variant, carbetocin solution for injection RTS (carbetocin RTS), which makes it an attractive option for countries where maintaining the cold chain is problematic. Current data indicates that the carbetocin RTS is stable for up to 36 months at 30°C. Carbetocin RTS differs from the current carbetocin formulation only in its excipients. In other words, the actual chemical structure of the carbetocin molecule is the same. The chemical components of the two molecules are described in table 1 below.Table SEQ Table \* ARABIC 1. Composition of carbetocin RTS and carbetocinNew carbetocin RTS formulationCurrent carbetocin refrigerated formulationComponentFunctionComponentFunctionCarbetocinActive substanceCarbetocinActive substanceSuccinic acidBufferSodium chlorideIsotonicity agentMannitolIsotonicity agentGlacial acetic acidpH adjustmentL-MethionineAntioxidantWater for injectionSolventSodium hydroxidepH adjustmentWater for injectionSolventBackground to the Merck for Mothers-Ferring-WHO projectMerck for Mothers is a project launched by Merck Group in response to the United Nations Secretary General’s Global Strategy for Women’s and Children’s Health. Merck for Mothers focuses on postpartum haemorrhage and hypertensive disorders of pregnancy as priority areas.Merck for Mothers, Ferring Pharmaceuticals and the World Health Organization met to discuss the evaluation of the carbetocin RTS as a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain. Following this initial meeting, an international technical consultation was convened and it was agreed to proceed with a randomized controlled trial to evaluate the effectiveness of carbetocin RTS compared to oxytocin when used intramuscularly. This was based on four considerations: (i) frequent concerns and documentation of the quality of oxytocin and its stability in some developing countries; (ii) the potential advantage of carbetocin RTS due to its longer half-life (than oxytocin) especially when administered intramuscularly, in addition to its heat stability; (iii) research will be funded by the Merck for Mothers Initiative and, conducted by WHO independently in terms of the management, analysis and publication of the research results.(iv) if non-inferior to oxytocin, carbetocin RTS formulation will be made available in high-burden countries at an accessible public sector price comparable to the current oxytocin price based on a signed memorandum of understanding between WHO, Ferring and Merck.2.2Risk-Benefit RatioThis clinical trial will be conducted in compliance with the clinical trial protocol, good clinical practice ADDIN EN.CITE <EndNote><Cite><Author>ICH</Author><RecNum>29</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">29</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>ICH Harmonised Tripartite Guideline</author></authors></contributors><titles><title>Guideline for good clinical practice E6 (R1)</title></titles><dates><year>1996</year></dates><publisher>International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use</publisher><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>21 and the applicable regulatory requirements. The risk-benefit relationship has been carefully considered in the planning of the trial. Based on the pre-clinical and clinical data available to date, the conduct of the trial is considered justifiable using the dose(s) and dosage regimen(s) of the Investigational Medicinal Product(s) (IMPs) as specified in this clinical trial protocol. In this trial, a Data Safety Monitoring Committee (DSMC) has been established for the on-going assessment of the risk-benefit ratio. The trial shall be discontinued in the event of any new findings that indicate a relevant deterioration of the risk-benefit relationship and would render continuation of the trial unjustifiable.2.3Study hypothesis and objectivesThe trial has two primary objectives:(1) To evaluate non-inferiority of carbetocin RTS 100 μg IM versus oxytocin 10 IU IM after vaginal delivery in the prevention of the composite endpoint “blood loss of 500 mL or more or the use of additional uterotonics” at one hour and up to two hours for women who continue to bleed after one hour.(2) To evaluate non-inferiority of carbetocin RTS 100 ?g IM versus oxytocin 10 IU IM in the prevention of sPPH (≥1000 mL blood loss) at one hour and up to two hours for women who continue to bleed after one hour. These two primary objectives are independent because they respond to different initiatives. If the trial is successful regarding objective (1), the experimental intervention would be registered for the indication “prevention of postpartum haemorrhage” by stringent drug regulatory authorities. If it is successful regarding objective (2), the experimental intervention would be included in future WHO guidelines and the Model List of Essential Medicines. See section 2.6.8 for more details.For both objectives the hypotheses are:i) Carbetocin RTS 100 ?g/ml IM is non-inferior to oxytocin 10IU IM in terms of the proportion of women with blood loss ≥500 mL or use of additional uterotonic drugs after vaginal delivery within a non-inferiority margin of 1.16 on the relative risk scale (objective (1)), and the proportion of women with blood loss ≥1000 mL after vaginal delivery within a non-inferiority margin of 1.23 on the relative risk scale (objective (2)). Rationale: In the conventional superiority trial, the aim is to determine whether one intervention is superior to another, for example, whether an uterotonic is superior to nothing. By contrast, in a non-inferiority trial, the aim is to determine whether an alternative intervention with certain advantages is similar to a gold standard. Oxytocin 10 IU (IM or IV) represents the gold standard management strategy for reducing blood loss in the third stage of labour. The advantages of carbetocin RTS are being more heat-stable than oxytocin and having a longer half-life. In order to evaluate the effectiveness of carbetocin RTS, which has these advantages, it has to be compared to oxytocin to assess whether it is non-inferior to it in efficacy.ii) Carbetocin RTS 100 ?g IM is superior to oxytocin 10 IU IM in terms of the proportion of women with blood loss ≥500 mL or use of additional uterotonic drugs (objective (1)), and in terms of the proportion of women with blood loss ≥1000 mL after vaginal delivery (objective (2)). For each of the two primary endpoints, superiority will be tested if non-inferiority has been demonstrated.Rationale: Superiority of the new treatment for the primary outcome would be an additional benefit. If carbetocin is demonstrated to be superior to oxytocin in efficacy, it would be the preferred option.2.4Study conceptual frameworkThe trial’s research question is the following: In women delivering vaginally, is carbetocin RTS 100 ?g IM non-inferior to oxytocin 10 IU IM when used as uterotonic during the third stage of labour, in preventing PPH or additional uterotonic use and sPPH? The conceptual framework for the research question outlined following the PICOT format is as follows:P (participants): women who have had a vaginal birth.I (intervention): carbetocin RTS 100 ?g IM as uterotonic during the third stage of labour.C (control): oxytocin 10 IU IM as uterotonic during the third stage of labour.O (outcome): blood loss ≥1000 mL and ≥500 mL or additional uterotonics after vaginal delivery.T (timing of outcome measure): one hour or two hours postpartum if bleeding continues after one hour.2.5Study design This will be a hospital-based, multicenter, double-blind, randomized, non-inferiority, active controlled trial in twelve countries. Each woman will be randomized within centres to receive either oxytocin 10 IU IM or carbetocin RTS 100 ?g IM.A non-inferiority design was chosen because the aim of the trial is to determine if carbetocin RTS, an alternative intervention with thermostability advantages, is similar in efficacy to the standard intervention (oxytocin 10 IU IM).Double-blindness will be ensured by placing identical ampoules (oxytocin and carbetocin RTS ampoules will be identical in shape, size, colour and volume) in identical packs. This clinical trial will be conducted in compliance with the clinical trial protocol, good clinical practice (ICH Topic E6, GCP) and the applicable regulatory requirements.2.6Procedures2.6.1Study centresHospitals from Argentina, Brazil, Egypt, India, Kenya, Nigeria, Pakistan, Singapore, South Africa, Thailand, Uganda and United Kingdom will participate. These centres, part of the WHO/HRP research network, have a well-functioning antenatal care system with the capacity to monitor all deliveries. They have extensive trial experience and can recruit substantial numbers of women. All have expressed an interest in conducting this trial in compliance with good clinical practice, the applicable regulatory requirements and the clinical trial protocol. These centres also agreed to comply with procedures for data recording and to permit monitoring and auditing. Each centre, before starting implementation of the trial, will sign the protocol to confirm agreement.2.6.2Study participantsStudy participants will be pregnant women coming to the hospital for delivery. Women will be eligible for the trial if:They are expected to deliver vaginally.They have a cervical dilatation equal to or less than 6cm.They provide written informed consent before any trial-related activities are carried out. (see also section 2.6.6)Known singleton pregnancy.Women will be excluded from participating in the trial if they are/have:In an advanced first stage of labour (>6 cm cervical dilatation) or too distressed to understand, confirm and give informed consent regardless of cervical dilatation.Non-emancipated minors (as per local regulations) without a guardian.Scheduled for a planned caesarean section.Birth considered an abortion according to local guidelines.Allergic to carbetocin, other oxytocin homologues or excipients.Serious cardiovascular disorders. Not capable of giving consent due to other health problems such as obstetric emergencies (e.g. antepartum haemorrhage) or mental disorder.2.6.3Randomization and allocationDuring the second stage of labour when vaginal delivery is imminent, eligible women will be randomized to receive either oxytocin 10 IU IM or carbetocin RTS 100 ?g IM. Once the treatment is assigned to the woman, the participant number that appears on the treatment pack will be entered in the correspondent case report form and the woman will be considered to be recruited into the trial.The random allocation sequence will be generated centrally at WHO Headquarters using computer-generated random numbers. Randomization will be to two groups, stratified by centre and will use permuted blocks. Allocation of the randomly generated sequence will be by consecutively numbered treatment packs arranged in containers or dispensers. Randomization assignment will be kept confidential at the trial coordinating centre in WHO.2.6.3.1 Unblinding of individual participant treatmentTrial coordinator, principal investigators and staff involved in the trial at the centres will be blinded to the trial’s treatment. The trial statistician will not be blinded. Clinical circumstances that will necessitate unblinding are not anticipated. However, an emergency decoding possibility (code envelope) will be available to the investigator and designated person at WHO. Breaking of the blind for individual participants in emergency situations is only permitted in case of a suspected unexpected serious adverse reaction or in case of an important adverse event where the knowledge of the IMP in question is required for therapeutic decisions for the management of the participant. It may be necessary to unblind an individual participant’s treatment for the purposes of expedited reporting of any unexpected serious adverse reaction (SUSAR) to the authorities and/or Independent Ethics Committees / Institutional Review Boards. In that situation, every effort will be made to maintain blinding of personnel involved in data analysis and interpretation. Other personnel may be unblinded for SUSARs, including trial site staff.In summary:It is the investigator’s decision to unblind.It is the investigator who says whether or not there is time for discussion with the trial coordinator before unblinding.In case of disagreement between the investigator and the trial’s coordinator, it is the investigator’s opinion which prevails. It is the wellbeing of the patient affected that overrides any other consideration.The person who opens a code envelope must record on it the reason and the date of opening, and then sign and date the opened envelope. It should be recorded in the CRF that the code is broken, why, when and by whom. The investigator must record the event of unblinding in the participant’s medical record, including the reason for unblinding, but not the treatment allocation if this can be rmation on whether the blinding has been broken for any participants will be collected before the database is declared clean and is released to the statistician at the end of the project.2.6.4Sample size calculationThere are two important endpoints that guide the sample size estimation for the trial. These are: severe postpartum haemorrhage (sPPH), defined as blood loss ≥1000 mL, and postpartum haemorrhage (PPH) defined as blood loss ≥500 mL or the use of additional uterotonics. Severe PPH is a more serious endpoint that is closer to severe maternal morbidity and related to additional interventions. The sPPH endpoint is also less frequent and thus guides the overall sample size estimation. A requisite to determine the sample size for a non-inferiority trial is to define the margin of non-inferiority (Δ) for the difference in effectiveness between the active control and the new treatment. Because proof of exact equality is impossible, non-inferiority is defined within a certain margin, which is the maximum magnitude of the difference considered clinically non-relevant, or the minimum magnitude of the difference which is considered clinically relevant. As opposed to superiority trials, non-inferiority trials need external data to demonstrate that the new treatment is effective. There should be evidence that the active treatment is effective compared to placebo, because if it is not, the non-inferiority trial might demonstrate non-inferiority of two ineffective treatments. 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ADDIN EN.CITE.DATA 22, 23. In order to construct a plausible non-inferiority margin the following evidence has been considered. The active treatment is active management of the third stage of labour with oxytocin 10 IU as uterotonic. Placebo is expectant management, in which signs of placental separation are awaited and the placenta is delivered spontaneously. We looked at the following Cochrane systematic reviews for relevant comparisons: Begley 2011 ADDIN EN.CITE <EndNote><Cite><Author>Begley</Author><Year>2011</Year><RecNum>15</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Begley, C. M.</author><author>Gyte, G. M.</author><author>Devane, D.</author><author>McGuire, W.</author><author>Weeks, A.</author></authors></contributors><auth-address>School ofNursing andMidwifery, Trinity CollegeDublin, Dublin, Ireland. cbegley@tcd.ie.</auth-address><titles><title>Active versus expectant management for women in the third stage of labour</title><secondary-title>Cochrane Database Syst Rev</secondary-title><alt-title>The Cochrane database of systematic reviews</alt-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title><abbr-1>The Cochrane database of systematic reviews</abbr-1></periodical><alt-periodical><full-title>Cochrane Database Syst Rev</full-title><abbr-1>The Cochrane database of systematic reviews</abbr-1></alt-periodical><pages>CD007412</pages><number>11</number><keywords><keyword>Birth Weight</keyword><keyword>Constriction</keyword><keyword>Delivery, Obstetric/adverse effects/*methods</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Labor Stage, Third/*physiology</keyword><keyword>*Oxytocics/administration & dosage/adverse effects</keyword><keyword>Placenta</keyword><keyword>Postpartum Hemorrhage/*prevention & control</keyword><keyword>Pregnancy</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>*Watchful Waiting</keyword></keywords><dates><year>2011</year></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>22071837</accession-num><urls><related-urls><url>, which includes the comparison active versus expectant management for blood loss ≥1000 mL. However, among the three trials included in this comparison, two did not use oxytocin and in one only 19% of the women did, so active management is mostly using other uterotonic different to oxytocin. Cotter 2011 ADDIN EN.CITE <EndNote><Cite><Author>Cotter A.</Author><Year>2001</Year><RecNum>31</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>31</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">31</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cotter A., Ness A., Tolosa J. </author></authors></contributors><titles><title>Prophylactic oxytocin for the third stage of labour.</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title><abbr-1>The Cochrane database of systematic reviews</abbr-1></periodical><number>4</number><dates><year>2001</year></dates><urls></urls></record></Cite></EndNote>25 includes the comparison oxytocin versus no uterotonics for blood loss ≥1000 mL. However, it is not clear whether 'oxytocin' is part of a package of active management and whether 'no uterotonics' implies expectant management. We concluded that the constancy assumption (that the historical difference between the active control and placebo holds in the setting of the new trial if a placebo control were used) would not hold ADDIN EN.CITE <EndNote><Cite><Author>FDA</Author><Year>2010</Year><RecNum>30</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">30</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>FDA</author></authors></contributors><titles><title>Guidance for Industry, Non-Inferiority Clinical Trials.</title></titles><dates><year>2010</year></dates><publisher>US Food and Drug Administration (FDA).</publisher><urls><related-urls><url> it was decided to use reliable estimates of prevalence of blood loss ≥1000 mL under active management with oxytocin as part of the package and under expectant management, coming from different trials or systematic reviews. With active management, the risk of sPPH was estimated as 2% in a multicenter large trial ADDIN EN.CITE <EndNote><Cite><Author>Gülmezoglu AM</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="5eewpdffpf99z4e9wdb5exxp5tfara50w020">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gülmezoglu AM, Lumbiganon P, Landoulsi S, Widmer M, Abdel-Aleem H, Festin M, Carroli G, Qureshi Z, Souza JP, Bergel E, Piaggio G, Goudar SS, Yeh J, Armbruster D, Singata M, Pelaez-Crisologo C, Althabe F, Sekweyama P, Hofmeyr J, Stanton ME, Derman R, Elbourne D.</author></authors></contributors><titles><title> Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial</title><secondary-title>Lancet </secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1721-7</pages><volume>379</volume><number>9827</number><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>26. With expectant management, the systematic review of Carroli et al ADDIN EN.CITE <EndNote><Cite><Author>Carroli</Author><Year>2008</Year><RecNum>32</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Carroli, G.</author><author>Cuesta, C.</author><author>Abalos, E.</author><author>Gulmezoglu, A. M.</author></authors></contributors><auth-address>Centro Rosarino de Estudios Perinatales (CREP), Rosario, Argentina. gcarroli@.ar</auth-address><titles><title>Epidemiology of postpartum haemorrhage: a systematic review</title><secondary-title>Best Pract Res Clin Obstet Gynaecol</secondary-title><alt-title>Best practice & research. Clinical obstetrics & gynaecology</alt-title></titles><periodical><full-title>Best Pract Res Clin Obstet Gynaecol</full-title><abbr-1>Best practice & research. Clinical obstetrics & gynaecology</abbr-1></periodical><alt-periodical><full-title>Best Pract Res Clin Obstet Gynaecol</full-title><abbr-1>Best practice & research. Clinical obstetrics & gynaecology</abbr-1></alt-periodical><pages>999-1012</pages><volume>22</volume><number>6</number><keywords><keyword>Female</keyword><keyword>Humans</keyword><keyword>Labor Stage, Third</keyword><keyword>Maternal Mortality</keyword><keyword>Placenta, Retained/*epidemiology</keyword><keyword>Postpartum Hemorrhage/*epidemiology</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications, Hematologic/*epidemiology</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1532-1932 (Electronic)
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ADDIN EN.CITE.DATA 22, 23. Taking 1.84% as an estimate of the effect of active management with oxytocin over expectant management, a reasonable criterion is to preserve 75% of this benefit (which corresponds to an effect of 1.38% for carbetocin RTS over expectant management). Preserving a higher percentage (say 80% or 90%) will push the sample size calculations very high while a smaller percentage (say 50%) may not be considered acceptable.To preserve 75% of the benefit of oxytocin over expectant management, assuming a 3.84% risk of sPPH with expectant management and 2% with oxytocin as part of the active management package, provides a margin of non-inferiority of Δ=(1-0.75) x (3.84-2)= (1-0.75) x 1.84=0.46% (Figure 1). In relative terms (relative risk), this gives a margin of non-inferiority of [2 + 0.46] / 2 = 2.46 / 2) = 1.23.The above margin Δ reflects the clinical judgment about how much of the effect of the active control should be preserved by ruling out a loss of Δ ADDIN EN.CITE <EndNote><Cite><Author>FDA</Author><Year>2010</Year><RecNum>30</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">30</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>FDA</author></authors></contributors><titles><title>Guidance for Industry, Non-Inferiority Clinical Trials.</title></titles><dates><year>2010</year></dates><publisher>US Food and Drug Administration (FDA).</publisher><urls><related-urls><url> . Figure 1. Determination of the non-inferiority margin Δ using past trials estimates for expectant management and for full active management with oxytocin as uterotonicIn addition, to complete the clinical assessment of this margin, we considered the number of women needed to be treated for one additional patient to be harmed (NNH). The lower the NNH, the worse is the new treatment compared to the standard. In the context of this non-inferiority trial, the margin of non-inferiority Δ is the minimum magnitude of the difference in the proportion of women with blood loss ≥1000 mL (carbetocin RTS-oxytocin) which is considered clinically relevant. The margin in terms of NNH is the reciprocal of Δ. It is calculated as 100/0.46=217. This means that non-inferiority will be demonstrated if NNH is 217 or more. This difference is considered to be clinically meaningful for decision making.It is expected that carbetocin RTS will not be worse in effectiveness compared to oxytocin. If carbetocin RTS happens to be better, the sample size required to demonstrate non-inferiority will be smaller compared to the case in which the two treatments are supposed to be equally effective. Therefore the maximum sample size will be calculated assuming equal sPPH prevalence for the two products.Table 2 and Figure 2 show the total sample size required to assess non-inferiority at the 2.5% level for different scenarios.Table 2. Total sample size for non-inferiority with different scenariosAssumed sPPH rate for oxytocin(%)Assumed sPPH rate for carbetocin(%)NI margin ? (%)Relative NI marginPower (%)80901.51.50.41.2728282378600.461.3121454287200.51.3318932253442.02.00.41.2038460514880.461.2329082389320.51.252461632952Figure 2. Total sample size for non-inferiority with equal proportions=1.5% or 2%, 80% power and different values of the margin on the relative scaleIn order to demonstrate non-inferiority within a margin of 0.46%, with a power of 80% and with a significance level of 2.5%, a total of 29,082 women are needed assuming equal sPPH prevalence of 2% with both treatments. Assuming 3% drop-outs due to exclusion of women with a caesarean section or abortion after randomization and those who are not protocol-compliant in any other way (see section 2.11), brings the sample size to 30,000. This sample size will provide 90% power for a conventional two-sided 5% test of superiority to detect a minimum significant difference between 1.5% and 2% in the sPPH of the two treatment products.The above sample size makes assumptions that in reality might not hold. For example, if the efficacy of oxytocin is much better than that of carbetocin RTS, this would imply that non-inferiority is not likely to be demonstrated and the trial should be stopped for futility. If oxytocin is just slightly better than carbetocin RTS, the sample size above could have been underestimated, but this is not likely given previous evidence (see background, Cochrane systematic reviewPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 8). Similarly, we have calculated the sample size for the composite endpoint defined as blood loss ≥500 mL or administration of additional uterotonics. With active management, the risk of this event was estimated as 16% in the Gulmezoglu et al trial ADDIN EN.CITE <EndNote><Cite><Author>Gülmezoglu AM</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="5eewpdffpf99z4e9wdb5exxp5tfara50w020">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gülmezoglu AM, Lumbiganon P, Landoulsi S, Widmer M, Abdel-Aleem H, Festin M, Carroli G, Qureshi Z, Souza JP, Bergel E, Piaggio G, Goudar SS, Yeh J, Armbruster D, Singata M, Pelaez-Crisologo C, Althabe F, Sekweyama P, Hofmeyr J, Stanton ME, Derman R, Elbourne D.</author></authors></contributors><titles><title> Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial</title><secondary-title>Lancet </secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1721-7</pages><volume>379</volume><number>9827</number><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>26(personal communication). Assuming equal prevalence for this event of 16% with both treatments, in order to demonstrate non-inferiority within a margin of 1.16 on the relative scale (equivalent to a margin of 2.6% on the absolute scale), with a power of 80% and with a significance level of 2.5%, a total of 6242 women are needed. With 30,000 women the power obtained would be more than 99%. This sample size will provide a power of 99.5% for a conventional two-sided 5% test of superiority to detect a minimum significant difference between 16% and 18% in the occurrence of PPH or administration of additional uterotonics of the two treatment products. See Annex 1 for the justification of the non-inferiority margin for this composite endpoint.The estimates from the centres that have expressed interest in participating in the trial indicate that close to 30,000 women can be recruited in a 12 month recruitment period.2.6.5Description of the interventionThe trial’s intervention (Investigational Medicinal Product - IMP) consists of Carbetocin RTS 100 ?g/mL IM (investigational drug undergoing trial), as well as of Oxytocin 10 IU IM (comparator drug). The investigator will provide the woman the trial’s treatment immediately after the birth of the baby (preferably within one minute). Once the treatment is provided the investigator will follow the management of the third stage of labour as recommended in WHO guidelines ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>2012</Year><RecNum>24</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">24</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>WHO Recommendations for the prevention and treatment of postpartum haemorrhage.</title></titles><dates><year>2012</year></dates><publisher>World Health Organization</publisher><work-type>WHO Publication</work-type><urls></urls></record></Cite></EndNote>1 (see details in the trial’s manual of operations).2.6.5.1 Description of Investigational Medicinal ProductCarbetocin RTS is a heat-stable formulation of carbetocin 100 ?g/mL solution for injection (1mL ampoule) developed by Ferring Pharmaceuticals. The oxytocic activity is approximately 50 IU of oxytocin/ampoule. The local tolerance safety of the carbetocin RTS has been assessed based on single intramuscular and intravenous injection in rabbits. No clinically meaningful treatment related differences were revealed by macroscopic and histopathological examinations between Carbetocin RTS and the reference product PABAL?. In addition, the local irritative potential of both formulations were lower after intramuscular administration compared to the intravenous route.Table 2 shows the composition of carbetocin RTS. The stability data from long-term studies performed at 30°C/75% relative humidity (RH) and accelerated at 40°C/75% RH indicate that a shelf life of at least 36 months at 30°C is feasible for the new heat-stable formulation of carbetocin.Table 2. Composition of carbetocin RTS formulationIngredientAmount (mg/mL)Carbetocin0.100Mannitol47.0Succinic acid1.19L-Methionine1.00Sodium hydroxide 2 Nto pH 5.45Water for injectiona.d. 1.0 mLAs mentioned earlier in the protocol (section 2.1) the active substance remains the same as in the currently approved carbetocin product and the excipients are already approved for injections. In addition, in two scientific advice meetings with the UK Medicines and Health products Regulatory Agency (MHRA) in March 2011 and the 9 December 2013 where HRP/RHR was present, the MHRA concluded that the available clinical and non-clinical documentation (i.e. local tolerability and blood compatibility) for carbetocin RTS is considered sufficient to support a single intramuscular dose of up to 100 ?g to women (MHRA 2011 letter included in annex 2).Oxytocin 10 IU/mL is the comparator of carbetocin RTS and is a solution for injection (1 mL ampoule). It is a product manufactured by Novartis (trade name Syntocinon). The excipients are sodium acetate, glacial acetic acid, chlorbutol, ethanol, water for injections. The approved product label is enclosed in Annex 3.Figure 2. Molecular description of carbetocin RTS and oxytocin.2.6.5.2 Packaging and labellingPackaging and labeling will be done in accordance with applicable local regulatory requirements and applicable good manufacturing practice guidelines (GMP).Carbetocin RTS will be supplied in single-use 1 mL ampoule containing 100 ?g carbetocin RTS. It will be packed in a suitable box which is labeled with (but not limited to) the following required information: trial number, number of ampoules per box, route of administration, storage condition, the words “For clinical trial use”, participant number (randomization number), lot number, expiry date and the Sponsor.Oxytocin will be supplied as a single-use ampoule containing 10 IU oxytocin. It will be packed in a suitable box which is labeled with (but not limited to) the following required information: trial number, number of ampoules per box, route of administration, storage condition, the words “For clinical trial use”, participant number (randomization number), lot number, expiry date and the Sponsor.2.6.5.3 Handling and storageThe IMPs (carbetocin RTS and oxytocin) shall be stored in the original package in a locked refrigerator at 2°C to 8°C.Do not freeze carbetocin RTS or oxytocin.Any temperature excursion from the recommended storage conditions should be immediately reported to the Sponsor, and the IMP should not be used until authorization for use has been received from the Sponsor. Centres will be provided with a temperature monitoring sheet for fridges where the IMP is stored. Temperatures inside the fridge will be checked twice during the day (morning, late afternoon). These sheets will be controlled by the monitors during the site visits.Both Carbetocin RTS and oxytocin are presented as a 1 mL solution in an ampoule (type I glass). Since an opened ampoule cannot be resealed in such a way to further guarantee the sterility of the contents, the solution should be used immediately after opened. Any remaining solution, the empty ampoule and the broken pieces after single use should be stored into a special container for infectious wastes.IMP will be discarded only after IMP accountability has been performed by the Monitor. The pharmacy will handle the IMP in accordance with the IMP Handling Procedure.The ampoule(s) shall be left at room temperature for the shortest possible time before administration.The reason for keeping both trial interventions in a refrigerator is to provide the comparison between oxytocin and carbetocin at the optimal storage condition for oxytocin. If both products are kept at room temperature then this may provide an unfair advantage to carbetocin since there may the possibility of oxytocin deterioration while awaiting use in the trial. The current heat stability data of carbetocin RTS has been provided by Ferring to WHO.2.6.5.4 Dosage and administrationThe IMPs will be administered, as a single IM dose of 100 ?g (in a 1 mL solution) for carbetocin RTS and as a single IM dose of 10 IU (in a 1 mL solution) for oxytocin, to the participant as soon as possible after the birth of the baby, preferably within one minute, once all of the pre-defined IMP administration criteria are met (see Section 2.6.3).2.6.5.5 Investigational Medicinal Product (IMP) accountabilityThe Investigator is responsible for ensuring accountability for IMP, including reconciliation of drugs and maintenance of drug records.Upon receipt of IMP, the Investigator (or designee) will check for accurate delivery and acknowledge receipt by signing (or initialing) and dating the documentation provided by the Sponsor and returning it to the Sponsor. A copy will be retained for the Investigator File.The dispensing of the IMP will be carefully recorded on the appropriate drug accountability forms provided by the Sponsor and an accurate accounting will be available for verification by the Monitor at each monitoring visit. IMP accountability records will include:Confirmation of IMP delivery to the trial centre.The inventory at the centre of IMP provided by the Sponsor.The use of each dose by each participant.The return to the Sponsor or alternative disposition of unused IMP.Dates, quantities, batch numbers, expiry dates and participants’ trial numbers.The Investigator should maintain records that adequately document:That participants were provided the doses specified by the clinical trial protocol/amendment(s), andThat all IMP provided by the Sponsor was fully reconciled.Unused IMP must not be discarded or used for any purpose other than the present trial. IMP that has been dispensed to a participant must not be re-dispensed to a different participant.The Monitor will periodically collect the IMP accountability forms and will check all returns (both unused and used containers) before arranging for their return to the Sponsor or authorizing their destruction by the trial site.2.6.5.6 Other drugs to be used in the trialThere is no other drug whose use is mandated by the clinical trial protocol. 2.6.5.7 Concomitant medications and therapiesPermitted medicines and interventionsAny medications (other than those excluded by the clinical trial protocol) that are considered necessary for the participant’s welfare and will not interfere with the trial medication may be given at the discretion of the clinician in charge. The Investigator will record all concomitant medications taken by the participant during the trial, from the date of signature of informed consent, in the appropriate section of the CRF.Additional interventions or examinations due to uterine atony and/or blood loss are permitted. Any additional interventions or examinations due to PPH or a suspicion of PPH should be performed according to WHO recommendations for atonic PPH management and should be recorded.Non-permitted medicinesAny additional concomitant therapy that becomes necessary during the trial must be recorded in the corresponding section of the CRF, noting the name, dose, duration and indication of each drug.2.6.6 Admission procedureThe care provider in charge of antenatal care visits at the hospital will inform potentially eligible pregnant women (women with no allergies to carbetocin, other oxytocin homologues or excipients, or serious cardiovascular disorders) about the trial and will invite them to sign the consent form. (Annex 4 - Information sheet during ANC and consent form). At admission for labour at the hospital, if the woman has a cervical dilatation of 6cm or less, is expected to deliver vaginally and if she meets the eligibility criteria (protocol item 2.6.2) the investigator will ask her to confirm her willingness to participate in the trial and sign again the consent form. If the woman is seen for the first time in the labour ward, she will be invited to give informed consent only if she is in early labour, the vital signs are normal and she is not stressed. For purposes of clarity, signs that will be considered as indicating stress are tachycardia and tachypnea as well as the woman presenting in general state of distress.In the second stage of labour when vaginal delivery is imminent, the investigator will assign the woman the treatment. At this point the woman is considered to be part of the trial.2.6.7 Follow-up proceduresOnce the cord is clamped (1-3 minutes after delivery of the baby) and cut, the investigator will place the drape under the woman’s buttocks and blood loss will be measured for one hour or two hours postpartum if the bleeding continues beyond one hour.The woman will end her participation in the trial after discharge or if transferred to a higher care unit. 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ADDIN EN.CITE.DATA 29. Justification of primary endpoints: The trial will have two primary endpoints. In third stage of labour trials, blood loss measurements are the preferred endpoints. Since it is not possible to predict which women will bleed and oxytocin is safe and effective in reducing blood loss, all women are offered oxytocin prophylactically to reduce blood loss and to reduce the likelihood of severe adverse outcomes. While volume of bleeding itself is not morbidity per se, it is in the pathway to severe adverse outcomes including death. The trial is being conducted as an effectiveness trial with the objective of the experimental intervention being registered for the indication “prevention of postpartum haemorrhage” by stringent drug regulatory authorities if it is shown to be non-inferior or superior to the gold standard control. For this purpose a primary endpoint of blood loss 500 mL or more or use of additional uterotonics is considered appropriate. For the purpose of clinical effectiveness and inclusion of the experimental intervention in future WHO guidelines and the Model List of Essential Medicines, the more substantive endpoint of blood loss 1000 mL or more is considered appropriate. The blood loss of 1000 mL or more was considered as one of the three critical endpoints (together with blood transfusion and maternal death) for the earlier 2007 WHO recommendations for PPH prevention where outcomes were rated by an independent panel ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>2007</Year><RecNum>37</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">37</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>WHO</author></authors></contributors><titles><title>WHO Recommendations for the prevention and treatment of postpartum haemorrhage.</title></titles><dates><year>2007</year></dates><publisher>World Health Organization</publisher><urls></urls></record></Cite></EndNote>30.Since the two primary endpoints serve independent objectives, we will not adjust the Type I error rate for multiplicity of endpoints.Secondary outcomes are:proportion of women with blood loss of 500mL or more within one hour (or two hours postpartum if the bleeding continues beyond one hour).blood loss in mL within one hour (or two hours postpartum if the bleeding continues beyond one hour).proportion of women receiving additional uterotonics within one hour (or two hours postpartum if the bleeding continues beyond one hour). proportion of women receiving additional uterotonics up to time of discharge. proportion of women receiving blood transfusion up to time of discharge.proportion of women with manual removal of placenta up to time of discharge.proportion of women having additional surgical procedures (e.g. suturing of cervix/high vaginal tear, exploration of uterine cavity under general anaesthetic, uterine compression suture, uterine or hypogastric ligation, hysterectomy) up to time of discharge.proportion of maternal death.proportion of women with composite outcome of maternal death or severe morbidity (admission to intensive care unit, hysterectomy, blood loss of two liters or more, uterine inversion, near miss event as defined in the manual of operations) up to time of discharge.incidence and severity of adverse or serious adverse events up to time of discharge.An adverse event is defined as any untoward medical occurrence in a participant who received the trial’s treatment and who does not necessarily have a causal relationship with this treatment. All adverse events up to time of discharge will be recorded in Adverse Event Report form (AER), which will collect information on the nature of the event, the relatedness of the event to the intervention, timing of the event, treatment for the event, and date of resolution. Report and handling of AER will be in accordance with GCP guidelines.An adverse event is considered serious when it results in death, is life-threatening, causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or requires intervention to prevent permanent impairment or damage. Serious adverse events up to time of discharge will be recorded in Serious Adverse Event Report forms. SAE will be returned by the investigators to the trial coordination unit within 24 hours of the event. The trial coordination unit will then transmit any information on SAEs related to the use of the IMP to the WHO Ethics committee as well as to the relevant authorities in the countries where the trial is conducted as well as to Ferring.2.6.9 Criteria for participant discontinuationWomen would be discontinued from the trial if:a. Informed consent is withdrawn. Women will have the right to withdraw from the trial and to withdraw Informed Consent. Women who withdraw will not be replaced, i.e., randomized numbers will be uniquely linked to each participant. These women will be asked if the data collected until that point could be included in the final analysis.b. Baby is delivered by caesarean section. In the previous 3rdstage labour trials despite all efforts to randomize women when vaginal delivery was more or less certain, around 3% of women were eventually delivered by caesarean section. This is unavoidable, given the unpredictable nature of births even at such a late stage. Those women will be documented and excluded from the analysis since eligibility changes and the primary outcome assessment is no longer reliable.2.7Study instrumentsData for the trial will be collected in case report forms (CRFs). Instructions on how to complete the CRFs as well as how to collect the blood loss will be in the trial’s Manual of Operations. CRFs will be developed by the coordinating unit, approved by the Forms Review Committee at WHO and validated (dry run) at each of the participating centres three months before starting recruitment.2.8Project management The trial will be coordinated and managed by the trial coordination unit at HRP/RHR in WHO. WHO (sponsor) will be responsible for writing the protocol, registering the trial as well as for any resulting publication from the trial independent of the funder (Merck for Mothers) and the manufacturer of the trial drugs (Ferring). The trial coordination unit will monitor at each of the participating centres the progress of the trial including adherence to the trial’s protocol, patient withdrawals, non-compliance, AER and SAE through a clinical research organization (CRO). The CRO will ensure smooth flow of the data, detect discrepancies between CRFs, hospital records and what was recorded in the web database through regular visits to the sites.The following committees and personnel will contribute to the coordination of the trial.2.8.1Trial steering committee (TSC)The TSC is expected to provide overall supervision for the trial as well as to ensure that the trial is conducted to the rigorous standards set out in the International Conference on Harmonization (ICH) ADDIN EN.CITE <EndNote><Cite><Author>ICH</Author><RecNum>29</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">29</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>ICH Harmonised Tripartite Guideline</author></authors></contributors><titles><title>Guideline for good clinical practice E6 (R1)</title></titles><dates><year>1996</year></dates><publisher>International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use</publisher><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>21. The TSC will concentrate on progress of the trial, adherence to the protocol, and the consideration of new information of relevance to the research question. The TSC will give advice on any matter arising from the conduct or management of the trial. The TSC will be constituted by:Chairperson: Professor James Neilson (University of Liverpool, UK) Trial coordination unit (WHO Secretariat): A. Metin Gülmezoglu (Trial coordinator); Mariana Widmer (Trial manager); Armando Seuc (statistician).Trial statistician: Gilda Piaggio Principal investigators from the participating centres (Annex 5 – centres’ details)Independent experts: Michel Boulvain (University of Geneva, Switzerland), Guilherme Cecatti (University of Campinas, Brazil - tbc), Lelia Duley (Professor of Clinical Trials Research, Director, Nottingham Clinical Trials Unit, Nottingham, United Kingdom –tbc)Observers: One representative each from Merck for Mothers and Ferring will participate at the Steering Committee meetings. The participation of one Merck and one Ferring representative as observers at the trial steering committee meetings was checked and endorsed by the WHO Legal Counsel.2.8.2Data and safety monitoring committee (DSMC)A Data Safety Monitoring Committee (DSMC) with no direct involvement in the trial will be appointed (see DSMC charter – Annex 6). The role of the DSMC will be to deal with any ethical issues that may arise while the trial is in progress, and to scrutinize an interim analysis. The DSMC will be expected to provide an ongoing evaluation of risk-benefit that addresses the uncertainty necessary to continue. The following individuals are being approached to serve in the DSMC:Justus Hofmeyr (South Africa) - obstetrician and gynaecologistCatherine Deneux-Tharaux (France) - epidemiologistDaniel Wojdyla (USA) – statisticianDiana Elbourne (UK) – statistician, trialist The DSMC Damocles charter prepared by the WHO Coordination Unit is presented in annex 6.2.9Data quality assuranceThe WHO coordinating unit will be responsible for implementing and maintaining the quality assurance and quality control systems with HRP standard operating procedures (SOPs) (Annex 7) to ensure that the trial is conducted and data generated, recorded and reported in compliance with the protocol, GCP and the applicable regulatory requirements.Quality control will be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.Monitoring visits will be made by the CRO and the WHO coordinating unit following HRP standard operating procedures. The purpose of these visits will be to ensure the quality and accuracy of data collected on the CRFs as well as data entered into the web system, determine that all regulatory requirements surrounding clinical trials are met, and ensure that the study protocol is being followed as written. During monitoring visits, study monitors will be given access to primary source documentation that supports data entered into the original study CRFs, i.e. the original patient records or registers. At each monitoring visit, 100% of the informed consents and 100% of the CRFs’ blood loss and additional uterotonics variables will be verified against source documents . In addition, all SAE forms will be verified against source documents. A detailed clinical monitoring plan will be developed for the study. The monitoring plan will specify the responsibilities and qualifications of the study monitors, back-up provisions, in-house monitoring procedures, and site monitoring visit schedule and procedures. All monitoring visits will be documented and reports written specifying any problem with conduct of the study or quality of the data that needs to be addressed.The study will be registered at before the start of data collection and study results will be reported according to CONSORT guidelines ADDIN EN.CITE <EndNote><Cite><Author>Hopewell</Author><Year>2008</Year><RecNum>20</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hopewell, S.</author><author>Clarke, M.</author><author>Moher, D.</author><author>Wager, E.</author><author>Middleton, P.</author><author>Altman, D. G.</author><author>Schulz, K. F.</author><author>Consort Group</author></authors></contributors><auth-address>UK Cochrane Centre, Summertown Pavilion, Oxford OX2 7LG, UK. shopewell@cochrane.co.uk</auth-address><titles><title>CONSORT for reporting randomised trials in journal and conference abstracts</title><secondary-title>Lancet</secondary-title><alt-title>Lancet</alt-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1></periodical><alt-periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1></alt-periodical><pages>281-3</pages><volume>371</volume><number>9609</number><keywords><keyword>Abstracting and Indexing as Topic/*standards</keyword><keyword>Editorial Policies</keyword><keyword>Periodicals as Topic</keyword><keyword>Publishing/*standards</keyword><keyword>Randomized Controlled Trials as Topic/*standards</keyword></keywords><dates><year>2008</year><pub-dates><date>Jan 26</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>18221781</accession-num><urls><related-urls><url>(07)61835-2</electronic-resource-num></record></Cite></EndNote>31. (Annex 8)2.10Data managementData will be collected according to the trial’s CRFs. Age and parity will be registered, as well as baseline conditions, concomitant medications, information pertaining to labour and delivery. Instructions on how to complete the CRFs will be explained in the trial’s Manual of Operations.Data will be collected prospectively by the investigator at the centre. Initial data collection will be on paper CRFs and then data will be entered at each of the participating centres into a web-based GCP compliant data management system for clinical trials, developed by the Centro Rosarino de Estudios Perinatales, institution to which data management will be outsourced . All data will be stored in a GCP compliant server with automatic backups, and data transmission will be encrypted to assure data integrity and patient confidentiality. Access to the data management web system will be password protected and only authorized users will have access. Data queries will be sent to the centres on standardized query forms for further clarification. Data changes will be documented through an audit trial incorporated in the system. The procedure will be compliant with 21 CFR Part 11 of the Code of Federal Regulations that deals with the United States Food and Drug Administration (FDA) guidelines on electronic records.Data entered into the web system will be checked by the data management team at WHO coordinating unit on a weekly basis for completeness, accuracy, reliability and consistent intended performance. The data management team will be responsible for generating the interim and final data report.Monitors, contracted from a CRO, will be visiting the centers regularly to ensure data quality.These procedures have been used in previous HRP multicentre trials and proven to be efficient and compliant with the HRP/WHO Standard Operating Procedures as well as with the 21 CFR Part 11 of the Code of Federal Regulations that deals with the United States Food and Drug Administration (FDA) guidelines on electronic records. 2.11Data analysis plan2.11.1Final analysis A per-protocol analysis (PP) for efficacy endpoints will be conducted excluding patients not on their intended treatment, those having caesarean section, those whose delivery is classified as abortion after randomization and those who are not protocol-compliant in any other way (e.g. withdrawing consent). In superiority trials an intention-to-treat analysis (ITT) is used in the primary analysis because it will generally diminish the estimated treatment effect, being thus conservative. In non-inferiority trials, on the other hand, use of ITT analysis is generally not conservative: “Subjects who withdraw or drop out of the treatment group or the comparator group tend to have a lack of response, and hence the results of using the full analysis set may be biased toward demonstrating equivalence” or non-inferiority ADDIN EN.CITE <EndNote><Cite><Author>ICH</Author><Year>1998</Year><RecNum>34</RecNum><DisplayText><style face="superscript">32</style></DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">34</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>ICH Steering Committee</author></authors></contributors><titles><title>Statistical principles for clinical trials E9</title></titles><dates><year>1998</year></dates><publisher>International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use
</publisher><urls><related-urls><url>. Performing a PP analysis is desirable as a protection from the increase in type I error risk in a non-inferiority test. In this trial, a modified ITT analysis is defined by excluding only women having a caesarean section after randomization and those withdrawing consent. To declare carbetocin RTS non-inferior to oxytocin, we will require non-inferiority to be demonstrated for both PP and the modified ITT analyses. For testing superiority of each endpoint, the modified ITT analysis will be the main analysis.We expect only a small number of protocol deviations and withdrawals because the personnel involved in the study will receive intensive and continuous training and the trial will be closely monitored by trial monitors. The DSMC will look at protocol deviations and withdrawals at interim analysis by country and arm and discuss whether there is a concern. There may be withdrawals if a woman who has earlier given consent and was randomly allocated to one group withdraws her consent after randomization or she undergoes an emergency caesarean section after randomization. These cases should be extremely rare since the random allocation will be made when vaginal delivery is imminent. Non-inferiority will be assessed using a two-sided 95% CI for the relative risk (RR) of sPPH and of PPH or additional uterotonic use (carbetocin RTS vs. oxytocin). The upper limit of the two-sided 95% CI for the RR for the 500 mL or additional uterotonic use endpoint will be compared to the non-inferiority margin of 1.16. The upper limit of the two-sided 95% CI for the RR for the 1000 mL endpoint will be compared to the non-inferiority margin of 1.23. If the upper limit is below the corresponding margin, non-inferiority will have been demonstrated. This upper limit is the same as the upper limit of the one-sided 97.5% CI, therefore the significance level for the non-inferiority test will be 2.5%. For each endpoint, if non-inferiority is demonstrated, a two-tailed superiority test will be conducted at 5% level of significance. Interpretation will follow accepted guidelines ADDIN EN.CITE <EndNote><Cite><Author>Piaggio</Author><Year>2012</Year><RecNum>21</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Piaggio, G.</author><author>Elbourne, D. R.</author><author>Pocock, S. J.</author><author>Evans, S. J.</author><author>Altman, D. G.</author><author>Consort Group</author></authors></contributors><auth-address>Statistika Consultoria, Sao Paulo, Brazil. gilda.piaggio@</auth-address><titles><title>Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement</title><secondary-title>JAMA</secondary-title><alt-title>JAMA : the journal of the American Medical Association</alt-title></titles><periodical><full-title>JAMA</full-title><abbr-1>JAMA : the journal of the American Medical Association</abbr-1></periodical><alt-periodical><full-title>JAMA</full-title><abbr-1>JAMA : the journal of the American Medical Association</abbr-1></alt-periodical><pages>2594-604</pages><volume>308</volume><number>24</number><keywords><keyword>Checklist</keyword><keyword>*Data Interpretation, Statistical</keyword><keyword>*Endpoint Determination</keyword><keyword>Quality Control</keyword><keyword>*Randomized Controlled Trials as Topic</keyword><keyword>Research Design</keyword><keyword>Sample Size</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2012</year><pub-dates><date>Dec 26</date></pub-dates></dates><isbn>1538-3598 (Electronic)
0098-7484 (Linking)</isbn><accession-num>23268518</accession-num><urls><related-urls><url>. Comparisons will also be expressed as risk differences with 95% confidence intervals. The statistical technique used to conduct tests and obtain confidence intervals for the main endpoints will be a logistic model with a binary endpoint, a binomial distribution and the log link to obtain relative risks. The identity link will be used to obtain risk differences. Stratifying variables (center) will be included in the model. The model will be fitted using SAS Software version 9.3 (SAS Institute Inc., Cary, NC, USA). A separate model will be fitted for each of the two primary endpoints.We will use the relative risk (RR) as measure of treatment effect on the relative scale for the two primary endpoints. For the composite endpoint blood loss 500ml or more or use of additional uterotonics, the margin has been justified as 1.2 on the odds ratio (OR) scale. To translate this margin to the RR scale we use the following expression:RR ~ OR/(1-Poxy+Poxy x OR) = 1.2/(1-0.15+0.15 x 1.2) = 1.17 for? incidence of oxytocin=15%, or??????????????????????????????????????????????? ??? = 1.2/(1-0.20+0.20 x 1.2) = 1.15 for? incidence of oxytocin=20%,where Poxy is the assumed prevalence for the control.We define the margin on the RR scale as 1.16, which is the average of the two results from both assumptions 15% and 20% as quoted in the justification document.Heterogeneity across centres will be assessed by using a term in the logistic model for the interaction between treatment and centres. If there is heterogeneity between the centres for any of the results, the possible causes will be explored. Analysis approach taken following the consultation with Medicines and Health Products Regulatory Agency (MHRA), United KingdomThe MHRA is an organization responsible for regulating all medicines and medical devices in the UK. It also gives advice before regulatory trials are initiated on request of the sponsors and its approval is often respected by other countries that may not have similar stringent assessment capacity. The trial protocol and the overall approach were submitted to the MHRA (UK) for advice and on 9 December 2013 a face-to- face meeting took place in London where representatives of HRP/RHR, Ferring and Merck for Mothers were present. The draft minutes of the MHRA meeting are presented in Annex 2.The MHRA agreed with the general approach and the specific questions posed to them overall. The MHRA accepted that the probability of Type I error does not need to be adjusted for having two primary endpoints if the two endpoints serve independent objectives. 2.11.2Interim analysisTwo interim analyses will be conducted for review by the DSMC. The first interim analysis will be conducted for the DSMC to look at safety when 5,000 have been recruited (2,500 per group). The second interim analysis will be conducted when 15,000 women have been recruited (7,500 per group) to look at both safety and efficacy. At each of these two interim analyses, to look at safety the DSMC will be provided with an unblinded description of adverse events (AE), including serious adverse events (SAE). The descriptions of AEs and SAEs will be recorded in the trial’s data collection forms. In addition to these descriptions, tables with numbers and percentages of AEs and SAEs by country and arm and by arm for all countries combined will be provided. The difference between arms for the occurrence of AEs and of SAEs will be tested using the country-stratified Mantel-Haenszel chi-square, if frequencies are sufficiently high or otherwise with exact methods taking stratification into account, and using the Haybittle-Peto rule to determine the threshold for stopping.For the second interim analysis, the DSMC will be requested also to give recommendations on whether to stop the trial for reasons of efficacy or futility, based on the following criteria applied to the sPPH endpoint only (see detailed procedure in Annex 12) and on unblinded data:Conduct a two-sided test of hypothesis to assess superiority of one of the products, using the Haybittle-Peto rule. If the result is significant at α=0.001, stop the trial for superiority of carbetocin or of oxytocin (superiority of one of the products implies harm of the other one).Calculate the conditional power at interim, supposing the observed trend continues ADDIN EN.CITE <EndNote><Cite><Author>Lan</Author><Year>1988</Year><RecNum>35</RecNum><DisplayText><style face="superscript">34, 35</style></DisplayText><record><rec-number>35</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">35</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lan, K.K.G. and J. Wittes </author></authors></contributors><titles><title>The B-value: a tool for monitoring data. </title><secondary-title>Biometrics</secondary-title></titles><periodical><full-title>Biometrics</full-title></periodical><pages>579-585</pages><volume>44</volume><section>579</section><dates><year>1988</year></dates><urls></urls></record></Cite><Cite><Author>Wang C.</Author><Year>2002</Year><RecNum>36</RecNum><record><rec-number>36</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">36</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Wang C., Keller D.S., Lan K.k.G.</author></authors><tertiary-authors><author>Joint statistical meetings</author></tertiary-authors></contributors><titles><title>Sample size re-estimation for binary data via conditional power.</title></titles><volume>Biopharmaceutical section</volume><dates><year>2002</year></dates><urls><related-urls><url>, 35. If the conditional power is less than a certain threshold, stop the trial for futility. The threshold depends on the true sPPH rate (see the results of simulations in Annex 12), therefore it will be established afterestimating the sPPH rate at interim, to make sure the probability of type I error is preserved at 2.5% and that the power is at least 80%.If none of the previous stopping criteria are met, continue the trial until the end and test for non-inferiority.The interim analysis will be conducted on the basis of the risk difference as described in Annex 12. For the test in 1 above, testing for the effect of treatment is equivalent whether it is based on the absolute or on the relative scale. As for the conditional power calculation, a margin of non-inferiority of 0.46% on the absolute scale will be used, equivalent to a margin of 1.23 on the relative scale. The final analysis will be conducted as described in section 2.11.The interim analyses will be masked to trial investigators, WHO, MfM and Ferring staff but not to DSMC members and the trial statistician.2.11.3Analysis of secondary outcomesThe secondary binary endpoints blood loss ≥500 mL, use of additional uterotonics, blood transfusion, manual removal of placenta, additional surgical procedures, maternal death, composite endpoint of maternal death or severe morbidity will be analyzed using the modified ITT population and will be assessed only for conventional superiority using risk differences and relative risks with 95% confidence intervals estimated with the same techniques described for the main endpoints.The secondary outcome blood loss in mL will be analyzed using the log transformation. This is based on the following: 1) the blood loss distribution is positively skewed; 2) different distributions were fitted to blood loss data from a large trial HYPERLINK \l "_ENREF_26" \o "Gülmezoglu AM, 2012 #1" ADDIN EN.CITE <EndNote><Cite><Author>Gülmezoglu AM</Author><Year>2012</Year><RecNum>1</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="5eewpdffpf99z4e9wdb5exxp5tfara50w020">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gülmezoglu AM, Lumbiganon P, Landoulsi S, Widmer M, Abdel-Aleem H, Festin M, Carroli G, Qureshi Z, Souza JP, Bergel E, Piaggio G, Goudar SS, Yeh J, Armbruster D, Singata M, Pelaez-Crisologo C, Althabe F, Sekweyama P, Hofmeyr J, Stanton ME, Derman R, Elbourne D.</author></authors></contributors><titles><title> Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial</title><secondary-title>Lancet </secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1721-7</pages><volume>379</volume><number>9827</number><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>26 and the lognormal distribution was found to have a very good fit (personal communication); and 3) the lognormal distribution was used for blood loss data in the literaturePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbHRoYWJlPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA 29. Therefore, a lognormal distribution will be fitted to the blood loss data and the probabilities of blood loss 500mL or more and of 1000 mL or more will be compared between treatments using parametric methods. The quintiles will be compared between treatments using quintile regression ADDIN EN.CITE <EndNote><Cite><Author>Koenker</Author><Year>1999</Year><RecNum>39</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Koenker, R.</author><author>Machado, J. A. F.</author></authors></contributors><auth-address>Koenker, R
Univ Illinois, Champaign, IL 61820 USA
Univ Illinois, Champaign, IL 61820 USA
Univ Illinois, Champaign, IL 61820 USA
Univ Nova Lisboa, Fac Econ, P-1070 Lisbon, Portugal</auth-address><titles><title>Goodness of fit and related inference processes for quantile regression</title><secondary-title>Journal of the American Statistical Association</secondary-title><alt-title>J Am Stat Assoc</alt-title></titles><periodical><full-title>Journal of the American Statistical Association</full-title><abbr-1>J Am Stat Assoc</abbr-1></periodical><alt-periodical><full-title>Journal of the American Statistical Association</full-title><abbr-1>J Am Stat Assoc</abbr-1></alt-periodical><pages>1296-1310</pages><volume>94</volume><number>448</number><keywords><keyword>bessel process</keyword><keyword>goodness of fit</keyword><keyword>quantile regression</keyword><keyword>rank test</keyword><keyword>regression rankscores</keyword><keyword>models</keyword><keyword>tests</keyword></keywords><dates><year>1999</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0162-1459</isbn><accession-num>WOS:000083879800031</accession-num><urls><related-urls><url><Go to ISI>://WOS:000083879800031</url></related-urls></urls><electronic-resource-num>Doi 10.2307/2669943</electronic-resource-num><language>English</language></record></Cite></EndNote>36.Safety analysis: The primary population for safety analysis will consist of all women receiving treatment.? Safety and tolerability will be assessed by a review of adverse events, by conducting inferential testing with significance levels for between-group comparisons. The between-treatment difference for the occurrence of adverse events will be tested using the stratified Mantel-Haenszel chi-square, if frequencies are sufficiently high or otherwise with exact methods taking stratification into account.Ferring will notify WHO and Merck, in writing, as soon as reasonably possible, of any information resulting in a change of the risk benefit balance of the existing carbetocin and/or carbetocin RTS. WHO will transmit any information on serious adverse events occurring in the course of the Trial with respect to the use of the Product, to the relevant authorities in the countries where the Trial will be conducted, as well as to Ferring.2.12Study timelineIt is anticipated that the recruitment into the study in the centres can be completed in approximately 12 months. Recruitment will begin in September 2014 after approval by the local competent authorities and materials have been procured and distributed to the study centres (Annex 9). 2.13Main problems anticipated and proposed solutionsOne centre declared that in their routine practice the oxytocin is given intravenously. The principal investigator of this centre is fully aware of the trial’s treatment route and committed to follow the trial’s protocol. In order to avoid deviations of the protocol, this centre will be monitored closely in this respect.2.14Applicability of resultsResults of this trial will be extremely useful, particularly in tropical settings, where cold storage is difficult to achieve and maintain. Should this trial demonstrate that carbetocin RTS is non-inferior to oxytocin in preventing postpartum haemorrhage, in settings where the cold chain could not be guaranteed,? oxytocin could be replaced by carbetocin RTS as the uterotonic used during the third stage of labour. 2.15Links with other projectsThis trial is conducted as part of the maternal and perinatal health research programme of HRP for the prevention and treatment of leading causes of maternal mortality. HRP/RHR has been working with the WHO Maternal, Newborn, Child and Adolescent Health Department, United States Agency for International Development (USAID), International Federation of Gynaecologists and Obstetricians (FIGO) and the International Confederation of Midwives in developing standards and identifying research needs in this field. The trial results will show whether oxytocin will remain as the gold standard for PPH prevention or whether carbetocin RTS can replace oxytocin given its other advantages and comparable public sector pricing.3.Gender considerationsPostpartum haemorrhage is one of the leading causes of maternal mortality worldwide. Improving health care for women during childbirth in order to prevent and treat PPH is an essential step toward the achievement of the MDGs as well as reducing inequities between women living in developing and developed countries. Investing in better maternal health not only improves a mother’s health and that of her family, but also increases the number of women in the workforce and promotes the economic well-being of communities and countries. Untreated pregnancy and birth complications mean that 10-20 million women become disabled every year, undermining their ability to support their families.4.Ethical issues4.1. Responsibilities of the InvestigatorThe Investigator is responsible for the conduct of the trial at his/her centre. He/she will ensure that the trial is performed in accordance with the clinical trial protocol and with the ethical principles that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on GCP (ICH Topic E6) ADDIN EN.CITE <EndNote><Cite><Author>ICH</Author><RecNum>29</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">29</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>ICH Harmonised Tripartite Guideline</author></authors></contributors><titles><title>Guideline for good clinical practice E6 (R1)</title></titles><dates><year>1996</year></dates><publisher>International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use</publisher><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>21 and applicable regulatory requirements. In particular, the Investigator must ensure that only subjects who have given their informed consent are included into the trial.An unconditional prerequisite for a woman’s participation in the trial is her written informed consent. The woman’s written informed consent to participate in the trial must be given before any trial-related activities are carried out.4.2 Forms required 4.2.1 Information sheet for participantsAdequate information must therefore be given to the participant by the Investigator before informed consent is obtained (a person designated by the Investigator may give the information, if permitted by local regulations). A participant information sheet in the local language and prepared in accordance with the Note for Guidance on GCP ADDIN EN.CITE <EndNote><Cite><Author>ICH</Author><RecNum>29</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">29</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>ICH Harmonised Tripartite Guideline</author></authors></contributors><titles><title>Guideline for good clinical practice E6 (R1)</title></titles><dates><year>1996</year></dates><publisher>International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use</publisher><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>21 will be provided by the Sponsor for the purpose of obtaining informed consent. In addition to providing this written information to a potential participant, the Investigator or his/her designate will inform the woman verbally of all pertinent aspects of the trial. The language used in doing so must be chosen so that the information can be fully and readily understood by lay persons. Depending on national regulations, a person other than the Investigator may inform the participant and sign the informed consent form, as above.4.2.2 Informed consent form for participantsWomen will be approached primarily during antenatal care and informed about the trial. Those women who accept to participate will be asked to sign a consent form. At delivery, women will be reminded about the trial and asked to sign the consent form again. If the woman attended the antenatal care visits at that hospital but was never invited to give informed consent, then, she cannot be asked to give informed consent at the time of delivery. If the woman has never attended the antenatal care visits at that hospital and is seen for the first time in the labour ward, she may be offered the opportunity to participate in the trial if she is approached for consent process when she is early in labour, her vital signs are normal and she is not stressed. Those women willing to participate in the trial will be asked to sign the consent form (Annex 4). If the woman is illiterate somebody independent from the trial will read the informed consent to the woman and if the woman accepts, she will print her thumb onto the form. The informed consent process will ensure the privacy and autonomy of the potential participant. If after reading the informed consent the woman decides not to participate in the trial she will not be obliged to sign the form and this decision will not affect her care at the hospital.If the woman suffers any unexpected event possibly related to the trial’s intervention treatment, the hospital will provide immediately care free of charge. The trial will be covered with insurance for any injury as a result of their participation in the trial.Where the information is provided by the Investigator, the informed consent form must be signed and personally dated by the participant and the Investigator. The signed and dated declaration of informed consent will remain at the Investigator’s centre, and must be safely archived by the Investigator so that the forms can be retrieved at any time for monitoring, auditing and inspection purposes. A copy of the signed and dated information and Informed Consent Form should be provided to the participant prior to participation.Whenever important new information becomes available that may be relevant to the participant’s consent, the written participant information sheet and any other written information provided to participants will be revised by the Sponsor and be submitted again to the IEC/IRB for review and favourable opinion. The agreed, revised information will be provided to each participant in the trial for signing and dating. The Investigator will explain the changes to the previous version.Participant identification and privacyA unique participant number will be assigned to each participant at inclusion, immediately after informed consent has been obtained. This number will serve as the participant’s identifier in the trial as well as in the clinical trial database.The participant’s data collected in the trial will be stored under this number. Only the Investigator will be able to link the participant’s trial data to the participant via an identification list kept at the centre. The participant’s original medical data that are reviewed at the centre during source data verification by the Monitor, audits and Health Authority inspections will be kept strictly confidential.Data protection and privacy regulations will be observed in capturing, forwarding, processing, and storing participant data. Participants will be informed accordingly, and will be requested to give their consent on data handling procedures in accordance with national regulations.Clinical Trial Insurance and Compensation to ParticipantsInsurance coverage shall be provided for participants in each country participating in the trial. Insurance conditions shall meet good local standards, as applicable.4.2.3 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)The trial protocol is submitted to the HRP Research Proposal Review Panel (RP2) and to the WHO Ethics Review Committee (ERC) in advance of trial site review and ethical clearances.Prior to commencement of the trial at a given centre, the clinical trial protocol will be submitted together with its associated documents to the responsible IEC/IRB for its favourable opinion/approval. The written favourable opinion/approval of the IEC/IRB will be filed in the Investigator Site File, and a copy will be filed in the Trial Master File at Sponsor and the designated clinical research organization (CRO).The trial will not start at a centre before the Sponsor has obtained written confirmation of favourable opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide documentation of the date of the meeting at which the favourable opinion/approval was given, and of the members and voting members present at the meeting. Written evidence of favourable opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Participant Information and Informed Consent Form version reviewed should be provided. Where possible, copies of the meeting minutes should be obtained.Amendments to the clinical trial protocol will also be submitted to the concerned IEC/IRB, before implementation in case of substantial changes. Relevant safety information will be submitted to the IEC/IRB during the course of the trial in accordance with national regulations and requirements.All the centres participating in this trial will follow exactly the same protocol.5.Quality assurance and health authoritiesThe clinical trial protocol and any applicable documentation (e.g. Investigational Medicinal Product Dossier, Participant Information and Informed Consent Form) will be submitted or notified to the Health Authorities in accordance with the regulations of the countries involved in the trial.This trial will be monitored in accordance with the ICH Note for Guidance on GCP Topic E6 ADDIN EN.CITE <EndNote><Cite><Author>ICH</Author><RecNum>29</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="r9a5t5dstsvse7e2xdlv9xp52pfpw9ra9tza">29</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>ICH Harmonised Tripartite Guideline</author></authors></contributors><titles><title>Guideline for good clinical practice E6 (R1)</title></titles><dates><year>1996</year></dates><publisher>International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use</publisher><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>21. The Monitor will perform visits to the trial centre at regular intervals. Representatives of the Sponsor’s Quality Assurance unit or a designated organization, as well as Health Authorities, must be permitted to inspect all trial-related documents and other materials at the site, including the Investigator Site File, the completed CRFs, the IMP(s), and the participants’ original medical records/files.The Clinical Trial Protocol, each step of the data captures procedure, and the handling of the data, including the final Clinical Trial Report (CTR), will be subject to independent Quality Assurance activities. Audits may be conducted at any time during or after the trial to ensure the validity and integrity of the trial data.6.Investigator site file and archivingThe Investigator will be provided with an Investigator Site File upon initiation of the trial. This file will contain all documents necessary for the conduct of the trial and will be updated and completed throughout the trial. It must be available for review by the Monitor, and must be ready for Sponsor audit as well as for inspection by health authorities during and after the trial, and must be safely archived for at least 15 years (or per local requirements or as otherwise notified by the Sponsor) after the end of the trial. The documents to be thus archived include the Participant Identification List and the signed participant Informed Consent Forms. If archiving of the Investigator Site File is no longer possible at the centre, the Investigator must notify the Sponsor.All original participant files (medical records) must be stored at the centre (hospital, research institute, or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no destruction of medical records is performed without the written approval of the Sponsor.7. Changes to the clinical trial protocolChanges to the clinical trial protocol will be documented in written protocol amendments. Major (substantial, significant) amendments will usually require submission to the health authorities and to the relevant IEC/IRB for approval or favourable opinion. In such cases, the amendment will be implemented only after approval or favourable opinion has been obtained. Minor (non-substantial) protocol amendments, including administrative changes, will be filed by the Sponsor and at the centre. They will be submitted to the relevant IEC/IRB or to health authorities only where requested by pertinent regulations.Any amendment that could have an impact on the participant’s agreement to participate in the trial requires the participant’s informed consent prior to implementation.8.Environmental impact of the projectThis trial will not present any environmental risk. The trial’s procedures are the same as the ones followed in routine hospital practice.9.Plans for dissemination and use of project results The trial results will be published in high profile peer-reviewed open access journals and presented at international and national conferences and other events. The WHO recommendations will be revised and updated accordingly. If the carbetocin RTS is found to be the drug of choice HRP/RHR will undertake the application to the WHO Model List of Essential Medicines. It is anticipated that Ferring would submit a pre-qualification application as well.10.Clinical trial report and publication policyClinical Trial ReportAfter completion of the trial, according to ICH Topic E3, a CTR will be written by the Sponsor or delegate.PublicationThe trial protocol will be published in an open access journal before the trial recruitment starts.The main publication (first publication) will be a publication of the results of the overall analysis of the primary outcome(s). The sponsor (WHO) will be responsible for the main publication.For secondary analysis, the WHO Data Use Regulations will be followed (Annex 10). A WHO Secondary Analysis Committee will be constituted. This committee is a panel formed by the WHO Coordinating Unit to prioritize, coordinate and ensure consistency amongst secondary analyses, as well as resolving conflicts where necessary. All planned analyses should be communicated as a proposal to the committee before analysis commences. The committee will inform the investigator whether the proposal is approved. If approved, necessary datasets will be provided by the committee to the investigator. The final analysis and manuscript will be reviewed by the committee for methodological and quality appraisal. The committee reserves the right to recommend changes to the analysis and/or manuscript.The investigator will inform the Sponsor in advance about any plans to present data from the trial. Any presentations of the results (oral presentations, etc.), either in whole or in part, by Investigators or their representatives will require pre-submission review and approval by the Sponsor. Authorship policyThe authorship will follow the standards set by the International Committee of Medical Journal Editors (ICMJE). The HRP/RHR trial coordination unit will be responsible for drafting the manuscript. The authors will be trial steering committee members and the trial coordination unit staff followed by the group name (WHO Carbetocin Postpartum Haemorrhage Prevention Trial Group or similar). 11.Research capacity strengtheningHRP will prioritize research capacity strengthening concomitantly with its large research projects as a main focus within its HRP Alliance. Investigators will identify secondary analyses and methodological studies that could support publications or degree theses alongside the project. Such proposals should be discussed with the WHO coordination unit who will determine the need for support and operationalization within one or multiple sites.12.References ADDIN EN.REFLIST 1.WHO Recommendations for the prevention and treatment of postpartum haemorrhage. World Health Organization, 2012.2.Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367(9516): 1066-74.3.Campbell OM, Graham WJ, Lancet Maternal Survival Series steering g. Strategies for reducing maternal mortality: getting on with what works. Lancet 2006; 368(9543): 1284-99.4.Souza JP GA, Vogel J, Carroli G, Lumbiganon P, Qureshi Z, Costa MJ, Fawole B, Mugerwa Y, Nafiou I, Neves I, Wolomby-Molondo JJ, Bang HT, Cheang K, Chuyun K, Jayaratne K, Jayathilaka CA, Mazhar SB, Mori R, Mustafa ML, Pathak LR, Perera D, Rathavy T, Recidoro Z, Roy M, Ruyan P, Shrestha N, Taneepanichsku S, Tien NV, Ganchimeg T, Wehbe M, Yadamsuren B, Yan W, Yunis K, Bataglia V, Cecatti JG, Hernandez-Prado B, Nardin JM, Narváez A, Ortiz-Panozo E, Pérez-Cuevas R, Valladares E, Zavaleta N, Armson A, Crowther C, Hogue C, Lindmark G, Mittal S, Pattinson R, Stanton ME, Campodonico L, Cuesta C, Giordano D, Intarut N, Laopaiboon M, Bahl R, Martines J, Mathai M, Merialdi M, Say L. Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study. Lancet 2013; 9879(381): 1747-55.5.Hogerzeil HV, Walker GJA, de Goeje MJ. Stability of Injectable Oxytocics in Tropical Climates: Results of Field Surveys and Simulation Studies on Ergometrine, Methylergometrine and Oxytocin, 1993.6.Heat Stable Oxytocin - Technology Opportunity Assessment. PATH, 2013.7.Paul Ashigbie, B Pharm. Postpartum haemorrhage: opportunities to address pharmaceutical gaps. Priority Medicines for Europe and the World: A Public Health Approach to Innovation. who.int/medicines/areas/priority.../BP6_16PPH.pdf8.Su LL, Chong YS, Samuel M. Carbetocin for preventing postpartum haemorrhage. The Cochrane database of systematic reviews 2012; 4: CD005457.9.Sweeney G, Holbrook AM, Levine M, et al. Pharmacokinetics of Carbetocin, a Long-Acting Oxytocin Analog, in Nonpregnant Women. Curr Ther Res Clin E 1990; 47(3): 528-40.10.Engstrom T, Barth T, Melin P, Vilhardt H. Oxytocin receptor binding and uterotonic activity of carbetocin and its metabolites following enzymatic degradation. European journal of pharmacology 1998; 355(2-3): 203-10.11.Ryden G, Sjoholm I. Half-life of oxytocin in blood of pregnant and non-pregnant women. Acta endocrinologica 1969; 61(3): 425-31.12.Fabian M, Forsling ML, Jones JJ, Pryor JS. The clearance and antidiuretic potency of neurohypophysial hormones in man, and their plasma binding and stability. The Journal of physiology 1969; 204(3): 653-68.13.Chard T, Boyd NR, Forsling ML, McNeilly AS, Landon J. The development of a radioimmunoassay for oxytocin: the extraction of oxytocin from plasma, and its measurement during parturition in human and goat blood. The Journal of endocrinology 1970; 48(2): 223-34.14.Cort N, Einarsson S, Viring S. Actions of oxytocin and a long-acting carba oxytocin analog on the porcine myometrium in vitro and in vivo. American journal of veterinary research 1979; 40(3): 430-2.15.Boucher M, Nimrod CA, Tawagi GF, Meeker TA, Rennicks White RE, Varin J. Comparison of carbetocin and oxytocin for the prevention of postpartum hemorrhage following vaginal delivery:a double-blind randomized trial. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC 2004; 26(5): 481-8.16.Ngan L, Keong W, Martins R. Carbetocin versus a combination of oxytocin and ergometrine in control of postpartum blood loss. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 2007; 97(2): 152-3.17.Nirmala K, Zainuddin AA, Ghani NA, Zulkifli S, Jamil MA. Carbetocin versus syntometrine in prevention of post-partum hemorrhage following vaginal delivery. The journal of obstetrics and gynaecology research 2009; 35(1): 48-54.18.Su LL, Rauff M, Chan YH, et al. Carbetocin versus syntometrine for the third stage of labour following vaginal delivery--a double-blind randomised controlled trial. BJOG : an international journal of obstetrics and gynaecology 2009; 116(11): 1461-6.19.Askar AA, Ismail MT, El-Ezz AA, Rabie NH. Carbetocin versus syntometrine in the management of third stage of labor following vaginal delivery. Archives of gynecology and obstetrics 2011; 284(6): 1359-65.20.Leung SW, Ng PS, Wong WY, Cheung TH. A randomised trial of carbetocin versus syntometrine in the management of the third stage of labour. BJOG : an international journal of obstetrics and gynaecology 2006; 113(12): 1459-64.21.Guideline for good clinical practice E6 (R1): International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, 1996.22.D'Agostino RB Sr, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics. Statistics in medicine 2003; 22(2): 169-86.23.Guidance for Industry, Non-Inferiority Clinical Trials. US Food and Drug Administration (FDA). 2010.24.Begley CM, Gyte GM, Devane D, McGuire W, Weeks A. Active versus expectant management for women in the third stage of labour. The Cochrane database of systematic reviews 2011; (11): CD007412.25.Cotter A, Ness A, Tolosa J. Prophylactic oxytocin for the third stage of labour. The Cochrane database of systematic reviews 2001; (4).26.Gülmezoglu AM, Landoulsi S, Widmer M, Abdel-Aleem H, Festin M, Carroli G, Qureshi Z, Souza JP, Bergel E, Piaggio G, Goudar SS, Yeh J, Armbruster D, Singata M, Pelaez-Crisologo C, Althabe F, Sekweyama P, Hofmeyr J, Stanton ME, Derman R, Elbourne D. Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial. Lancet 2012; 379(9827): 1721-7.27.Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best practice & research Clinical obstetrics & gynaecology 2008; 22(6): 999-1012.28.Patel A, Goudar SS, Geller SE, et al. Drape estimation vs. visual assessment for estimating postpartum hemorrhage. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 2006; 93(3): 220-4.29.Althabe F, Aleman A, Tomasso G, et al. A pilot randomized controlled trial of controlled cord traction to reduce postpartum blood loss. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 2009; 107(1): 4-7.30.WHO Recommendations for the prevention and treatment of postpartum haemorrhage. World Health Organization, 2007.31.Hopewell S, Clarke M, Moher D, et al. CONSORT for reporting randomised trials in journal and conference abstracts. Lancet 2008; 371(9609): 281-3.32.Statistical principles for clinical trials E9: International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use1998.33.Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG, Group C. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA : the journal of the American Medical Association 2012; 308(24): 2594-604.34.Lan KK, Wittes J. The B-value: a tool for monitoring data. Biometrics 1988; 44: 579-85.35.Wang C. KDS, Lan K.k.G. Sample size re-estimation for binary data via conditional power. 2002. R, Machado JAF. Goodness of fit and related inference processes for quantile regression. J Am Stat Assoc 1999; 94(448): 1296-310. ................
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