Condition category
Pregnancy and Childbirth
Date applied
03/09/2018
Date assigned
18/10/2018
Last edited
02/04/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Excessive bleeding after childbirth (postpartum haemorrhage, PPH) is a common and potentially serious problem affecting 1 in 20 women. Each year it causes 75,000 deaths worldwide. It also causes weakness from anaemia, delayed recovery, psychological trauma, and poor breastfeeding and bonding with their baby. Oxytocin is recommended as first line treatment for PPH as it is low cost, effective and has very few side effects. However, the PPH rate is increasing; laboratory studies suggest that repeated use of oxytocin leads to reduced effectiveness. Carboprost is an alternative treatment and there is evidence that it is more effective than oxytocin, but it is usually reserved for second/third line treatment due to side effects of diarrhoea and vomiting and its cost. The aim of this study is to compare the two drugs, carboprost and oxytocin, currently used to treat PPH, to find out whether it is better to use carboprost or oxytocin as the first drug for treatment for PPH.

Who can participate?
Woman aged 16 and over with PPH

What does the study involve?
Participants are randomly allocated to one of two groups. Two injections are administered. One group receives carboprost and placebo (dummy drug) and the other group receives oxytocin and placebo (dummy drug). There are no extra clinic visits required. Data is collected from medical records. Each participant is followed up 24 hours and 4 weeks later to complete a questionnaire and collect information regarding their healthcare resource use and quality of life. Paper follow-up documents are posted to the homes of participants for their completion.

What are the possible benefits and risks of participating?
The results will help doctors know which treatment is better for PPH treatment. The benefits of participation are that women will receive optimal care, with researchers, clinicians and regulators observing and checking their care carefully so as to ensure that no mistakes are made. This is why clinical outcomes of participants in any study tend to be much better than those of non-participants, irrespective of what treatment they receive. The risks are that of the treatments, both of which are already commonly used as part of PPH management. The common side effects of both treatments are as follows: oxytocin: headache, nausea, vomiting, low blood pressure, water retention; carboprost: diarrhoea, vomiting, high temperature, increased blood pressure.

Where is the study run from?
1. Liverpool Women’s Hospital (lead centre) (UK)
2. Birmingham Women’s Hospital (UK)
3. St Thomas Hospital (UK)
4. Sunderland Royal Hospital (UK)
5. University College Hospital (UK)

When is the study starting and how long is it expected to run for?
September 2018 to September 2021

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
Miss Charlotte Van Netten
cope@liverpool.ac.uk

Trial website

www.copestudy.uk

Contact information

Type

Scientific

Primary contact

Miss Charlotte Van Netten

ORCID ID

Contact details

The University of Liverpool
Medicines for Children Clinical Trials Unit
Clinical Trials Research Centre
University of Liverpool
Institute of Child Health
Alder Hey Children’s NHS Foundation Trust
Liverpool
L12 2AP
United Kingdom
+44 (0)151 795 8760
cope@liverpool.ac.uk

Additional identifiers

EudraCT number

2018-001829-11

ClinicalTrials.gov number

Protocol/serial number

39362

Study information

Scientific title

Carboprost vs Oxytocin as the First Line Treatment of Primary Postpartum Haemorrhage: A phase IV, double-blind, double-dummy, randomised controlled trial.

Acronym

COPE

Study hypothesis

COPE is a research study to compare the two drugs, carboprost and oxytocin, currently used to treat PPH. About 4000 women will take part across approximately 40 UK NHS hospitals, and we want to know if it is better to use carboprost or oxytocin as the first drug for treatment of PPH.

Ethics approval

West Midlands - Coventry & Warwickshire Research Ethics Committee, 04/10/2018, REC ref: 18/WM/0227

Study design

Randomised; Both; Design type: Treatment, Drug, Qualitative

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

See additional files

Condition

Postpartum haemorrhage

Intervention

COPE aims to recruit 3,948 women across 40 UK hospitals via two recruitment pathways:
1. Women at high risk of PPH (defined as relative risk of > 3) will be invited to prospectively consent to participation within COPE and will be approached antenatally by a COPE recruiter who will provide information and the opportunity for discussion. At this point, women will have the opportunity to decline participation in the study, in which case a ""COPE declined"" sticker will be placed in the woman's case notes.
2. Women at low risk of PPH who meet eligibility criteria will be randomised into the trial in the emergency situation, where treatment needs to be given urgently and there is no time for prior consent. Postnatally, full study information will be provided and the woman will be asked to sign the emergency consent form. In the event that capacity is not regained or delayed, a personal or professional legal representative will be approached for informed emergency consent.

Participants will be randomised in a 1:1 ratio using random variable block size, stratified by mode of birth (caesarean section or vaginal birth) to one of the following treatment arms:
Intervention: Carboprost 250 micrograms by deep intramuscular injection and 1ml placebo by slow intravenous injection.
Control: Oxytocin 10 international units by slow intravenous injection and 1ml placebo by deep intramuscular injection.

Centres will be provided with a series of sequentially numbered, sealed treatment kits to be received by the pharmacy department and distributed to an appropriate secure location within the delivery suite for ready access upon presentation of eligible patients. A placebo vial will be administered intravenously alongside carboprost and intramuscularly alongside oxytocin in order to conserve the blinding of treatments for both healthcare professionals and participants. This will eradicate any potential bias.

The design of this study has been developed to have minimal impact on families, resulting in the need for no extra clinic visits within the trial. Clinical outcome data will be collected from medical records. Each participant will be followed up at 24 hours and 4 weeks post randomisation to obtain data for the childbirth experience questionnaire, and information regarding their resource use and quality of life, where applicable. Such follow-up documents will be paper based and posted to the homes of participating women for their completion.

At the time of consent to the main study, participants will also be invited to take part in an embedded study, including;
1. Audio recording of COPE antenatal consent discussions between women and their birth partner (if applicable) and trial recruiters
2. Interviews with women and their birth partners (if applicable) who agree or decline consent including bereaved women; either by telephone or at an agreed location
3. A questionnaire for both women who agree or decline consent to the main trial
4. Focus groups and/or interviews with COPE trial recruiters at each pilot site

Intervention type

Other

Phase

Phase IV

Drug names

Primary outcome measure

Blood transfusion - any RBC blood transfusion or cell salvage of ≥ 300ml commenced any time between randomisation and 48 hours after randomisation (or hospital discharge if earlier than 48 hrs), measured using medical notes

Secondary outcome measures

1. Volume of blood transfusion from randomisation up to 48 hours (or hospital discharge if earlier), measured using medical notes
2. Use of a further uterotonic drug from randomisation up to 24 hours after randomisation, measured using medical notes
3. Composite outcome of any organ dysfunction based on WHO near-miss approach for maternal health (2) from randomisation up to hospital discharge (or 4 weeks whichever is earlier)
4. Hysterectomy from randomisation up to hospital discharge (or 4 weeks whichever is earlier) , measured using medical notes
5. Blood loss in ml commencing in the first 24 hours from randomisation, up to cessation of active bleeding, measured using medical notes
6. Blood loss ≥ 1000 ml, measured using medical notes
7. Haemoglobin closest to 24 hours after randomisation, measured using medical notes
8. Shock within 24 hours of randomisation, measured using medical notes
9. Maternal death within 4 weeks of the birth where postpartum haemorrhage was a contributing factor (it does not need to be the primary cause), measured using medical notes
10. Non pharmacological approach to treat or investigate bleeding from randomisation up to hospital discharge, measured using medical notes
11. Manual removal of placenta post randomisation up to hospital discharge, measured using medical notes
12. Any adverse reactions of the intervention for the mother (hypotension occurring within 2 mins of IMP administration, all other adverse reactions occurring within 2 hrs of administration) , measured using medical notes
13. ‘Skin to skin’ care with baby within the first hour after birth, measured using medical notes
14. Separation from new-born in first hour after birth, measured using medical notes
15. Breastfeeding, measured using [method] at 24 hrs, 48 hrs (or hospital discharge if sooner) and 4 weeks
16. Woman’s experience, measured using Childbirth Experience Questionnaire (CEQ) at 4 weeks
17. Resource use, measured using EQ-5D-5L, resource use questionnaire and hospital episode statistics at 24 hrs and 4 weeks

Overall trial start date

01/09/2018

Overall trial end date

01/09/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. ≥ 16 years of age
2. Requirement for medical treatment for primary PPH

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

Planned Sample Size: 3948; UK Sample Size: 3948

Participant exclusion criteria

1. Known to have opted out of participation antenatally
2. Known oxytocin or carboprost hypersensitivity
3. Known active cardiac or pulmonary disease
4. Known to have previously been treated as part of COPE
5. Has already received uterotonic drug treatment for postpartum haemorrhage (this does not include PPH prophylaxis)
6. Stillbirth

Recruitment start date

01/12/2018

Recruitment end date

01/12/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Liverpool Women’s Hospital (lead centre)
Crown Street
Liverpool
L8 7SS
United Kingdom

Trial participating centre

Birmingham Women’s Hospital
Mindelsohn Way Edgbaston
Birmingham
B15 2TG
United Kingdom

Trial participating centre

St Thomas Hospital
Westminster Bridge Road Lambeth
London
SE1 7EH
United Kingdom

Trial participating centre

Sunderland Royal Hospital
Kayll Road
Sunderland
SR4 7TP
United Kingdom

Trial participating centre

University College Hospital
235 Euston Road
London
NW1 2BU
United Kingdom

Sponsor information

Organisation

University of Liverpool

Sponsor details

c/o Mr Alex Astor
Address Research Support Office
2nd Floor Block D Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
United Kingdom
+44 (0)1517948739
sponsor@liverpool.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 16/16/06

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Protocol will be made available at a later date. Planned publication of the results in a high-impact peer reviewed journal.

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

01/09/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Editorial Notes

02/04/2019: The participant information sheet has been uploaded. 25/03/2019: The condition has been changed from "Specialty: Reproductive Health and Childbirth, Primary sub-specialty: Intrapartum Care; Health Category: Reproductive health and childbirth; Disease/Condition: Complications of labour and delivery" to "Postpartum haemorrhage" following a request from the NIHR. 18/10/2018: The participant information sheet has been uploaded.