A large trial across up to 40 UK hospital maternity units will test whether an injected drug called carboprost stops severe bleeding after childbirth better than the current standard treatment, oxytocin. Postpartum haemorrhage—heavy bleeding within 24 hours of birth—remains a leading cause of maternal death and serious illness worldwide. Current guidelines recommend oxytocin as the first-line treatment, with carboprost held in reserve for when oxytocin fails. But no large, rigorous trial has directly compared the two drugs head-to-head as initial therapy. This uncertainty means clinicians lack clear evidence on which drug works best first, and when to escalate care. If the trial shows carboprost is more effective at preventing blood transfusions—the primary outcome—it could change national and international guidelines, shifting carboprost from a second-line to a first-line option. That would give maternity teams a faster, more effective tool to stop bleeding, potentially reducing the need for emergency surgery, intensive care, and long-term physical and psychological harm for new mothers. The study also includes a full economic analysis, so the NHS would know whether any extra drug cost is offset by savings from fewer transfusions and shorter hospital stays.
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COPE website is currently under development: http://copestudy.uk/. Any information will be added at a later timepoint. Scientific abstract: Design: double-blind, double-dummy, randomised controlled trial Setting: up to 40 UK NHS hospital maternity units Target population: women giving birth either vaginally or by caesarean who require treatment for vaginal bleeding within 24 hours of birth. Exclusion criteria: Women with oxytocin or carboprost hypersensitivity, or active cardiac or pulmonary disease will be excluded. Health technologies being assessed: Oxytocin 10iu injected intravenously as a slow bolus compared to carboprost 250mcg injected intramuscularly. Measurements of costs and outcomes: The primary outcome is blood transfusion within 48 hours of birth. Other outcomes are those included in the PPH Core Outcome Set, agreed by an international panel of experts: any additional haemostatic used, mean blood loss, shock, coagulopathy, hysterectomy, organ dysfunction, death, breastfeeding, and participant interviews of satisfaction and quality of life at 6 weeks postnatally. A full economic analysis will also be conducted. Sample size: To detect a 2.3% absolute reduction in a 5.8% transfusion rate using a Fishers exact test with 90% power (alpha 0.05), we would require 1,880 participants per group, increasing to 3,948 allowing for 5% loss to follow up. Repeat uterotonic is an important secondary outcome and this number will provide 87% power, using a chi-square test, to detect a 4.2% reduction from a control group rate of 23.7%. Difference between current and planned pathways: Current guidelines suggest use of oxytocin 10iu as first line therapy, with carboprost 250mcg as one of several secondary therapies. Some clinicians also use a 4-hour oxytocin infusion alongside the initial dose of oxytocin, but the benefit of this is uncertain. We will ask clinicians to only use rescue uterotonics if bleeding persists 15 minutes following the randomised treatment. After 15 minutes the treatment regimen will revert to ‘normal care’. Project timetable including recruitment rate: Following 6 months set-up, there will be a 6-month internal pilot followed by 2 years 6 months of full recruitment before 6 months close down (total 48 months). This requires 4.5 recruits/centre/month, rising from 5 initial pilot centres to 40 centres by month 18. Expertise in team: The team is highly experienced in the design and conduct of clinical trials, with CIs both in PPH (AW: Release (WHO), MamaMiso (B&M Gates), PPH Butterfly (NIHR); DS: IMox (Ferring)) and other obstetric studies (ZA, ALB, SR, AS, DS, JT). SM and ZA have lead the development of core outcome sets for PPH as part of the COMET initiative, and we have experts on emergency (KW, CG) and intrapartum consent (ZA, DS, AW) and qualitative research to explore patient perspectives in clinical trials (TL, KW). CG and HH are deputy director and senior trial manager of the Liverpool Clinical Trials Research Centre respectively. DH is co-Director of the Centre for Health Economics & Medicines Evaluation at Bangor University, rated 3rd of 94 in the 2014 REF (UoA3) based on research outputs. The clinical team includes obstetricians (AW, ZA, DA, KH, NJ, SM, SR, AS, DS, JT), of which 1 is from a district hospital (KH), 2 midwives (ALB, TL), a haematologist (PC) and an anaesthetist (RC). We have experts on maternity skills training (KH, SM, DS). GG is Senior Research Networker with the NCT, and was consumer representative on the WHO PPH guidelines groups in 2009 & 2012 and the NICE Intrapartum guidelines group in 2007.
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