Title: COPE: The Carboprost or Oxytocin Postpartum haemorrhage Effectiveness study.
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: COPE website is currently under development: http://copestudy.uk/. Any information will be added at a later timepoint. Summary in plain English: Bleeding after childbirth (postpartum haemorrhage, PPH) is a common and potentially serious problem affecting 1 in 20 women, and killing 75,000 women worldwide each year. It also causes weakness from anaemia, delayed recovery, psychological trauma, and poor breastfeeding and bonding with the baby. The treatments, including drugs with side effects, blood transfusion, surgery and hysterectomy can also have an undesirable impact. Trials of PPH are very difficult to carry out because it is hard to predict and a clinical emergency when it occurs. This makes it difficult for researchers to recruit to PPH treatment studies. As a result, guidance on PPH treatment comes largely from studies of drugs for PPH prevention and expert opinion. UK and international health organisations have therefore called for studies to see which drug is the most effective for initial PPH treatment. This research will compare two common treatments – oxytocin and carboprost. Oxytocin is routinely used as first option as it is low cost, effective and has very few side effects. However, it is not as effective in women who have already received oxytocin during labour and can sometimes lead to low blood pressure. Carboprost (a prostaglandin) contracts the uterus through a different mechanism to oxytocin. There is evidence that it is more effective than oxytocin, but it is usually reserved for second/third line therapy due to side effects of diarrhoea and vomiting, and cost. In this 4-year study, we aim to recruit 3,948 women in up to 40 UK hospitals. Any woman who bleeds heavily after childbirth can be entered into the study (including those with twins, retained placenta, caesarean sections). She will be randomised following the doctor's decision to give treatment to stop bleeding. As many outcomes are subjective, and clinicians often feel carboprost is superior, we propose a double-blind study. This means the woman, researchers and hospital staff will not know which treatment she has received. This is usual practice in many trials. Each woman will receive an active treatment for PPH via 2 injections, one into her vein (containing oxytocin or identical placebo) and one into a muscle (containing carboprost or identical placebo). Staff will be asked not to give any other treatment for 15 minutes (unless the bleeding is severe). At 15 minutes, those who continue to bleed will be given the usual additional PPH treatments, including further oxytocin or carboprost. Immediate unblinding will be possible if absolutely necessary. The main outcome will be whether the woman receives a blood transfusion within 48 hours after birth. Other important outcomes will be use of 'rescue' drugs, blood loss, impaired function of the body's systems, uterus removal, death and cost. Satisfaction with care, breastfeeding and quality of life will be assessed at 6 weeks. Consent procedures for this emergency study will follow recommendations of consumer groups, Royal Colleges and the EU. Women will be informed about the study during pregnancy via posters, leaflets, websites and on social media. Women at high risk will be invited to give consent to take part prior to giving birth. However, those who bleed unexpectedly after childbirth will be asked to give just verbal assent to be in the study, or even have consent deferred. They will then receive the study medication and be visited the following day to request their written consent to use of their data and on-going follow-up.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH