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Trial registered on ANZCTR


Registration number
ACTRN12623001348640
Ethics application status
Approved
Date submitted
23/08/2023
Date registered
21/12/2023
Date last updated
23/05/2024
Date data sharing statement initially provided
21/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Heat-stable carbetocin for the treatment of postpartum haemorrhage
Scientific title
Heat-stable carbetocin for the treatment of postpartum haemorrhage: a phase III, randomized, double-blind, active controlled, multicountry, multicentre, non-inferiority trial
Secondary ID [1] 310363 0
None
Universal Trial Number (UTN)
Trial acronym
REACH trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
postpartum haemorrhage 331100 0
Condition category
Condition code
Reproductive Health and Childbirth 327887 327887 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The IMP for the trial will be: a once-off Intravenous infusion following PPH diagnosis of Heat Stable Carbetocin (HSC) 100 µg in 100 ml normal saline administered over 5 min, followed by a once-off infusion of 500 ml normal saline over 4 hours.
This will be documented directly within worksheets within the patient medical records.
Intervention code [1] 326759 0
Treatment: Drugs
Comparator / control treatment
The comparator for the trial will be: a once-off Intravenous infusion following PPH diagnosis of oxytocin 5 IU in 100 ml normal saline administered over 5 min, followed by infusion of 20 IU in 500 ml normal saline over 4 hours (at a rate of 5 IU per hour).
This will be documented directly within worksheets within the patient medical records.
Control group
Active

Outcomes
Primary outcome [1] 335730 0
The proportion of participants with additional blood loss greater than or equal to 500mls

The Blood loss will be collected in drapes for 90 min after treatment administration and weighed. This will be documented within worksheets within the patient medical records
Timepoint [1] 335730 0
90 minutes following randomisation
Secondary outcome [1] 425363 0
The proportion of participants with additional blood loss greater than or equal to 1000mls

The Blood loss will be collected in drapes for 90 min after treatment administration and weighed. This will be documented within worksheets within the patient medical records
Timepoint [1] 425363 0
90 minutes following randomisation
Secondary outcome [2] 425364 0
The proportion of participants with additional blood loss greater than or equal to 500mls or the proportion of participants with use of additional uterotonic(s).


This is a composite outcome.

The Blood loss will be collected in drapes for 90 min after treatment administration and weighed and documented on the worksheets within the patient medical records. The additional uterotonics outcome will be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [2] 425364 0
90 minutes following randomisation
Secondary outcome [3] 425365 0
The proportion of participants with use of surgical procedure(s) related to PPH.

This is a composite outcome.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [3] 425365 0
across 24 hours following randomization
Secondary outcome [4] 425366 0
Occurrence of clinically significant cardiac arrhythmia based on clinical judgement which requires treatment
This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This will be recorded onto worksheets which will be held within the patient medical records.
Timepoint [4] 425366 0
up to 24 hours following randomization
Secondary outcome [5] 425367 0
Occurrence of clinically significant cardiac arrhythmia based on clinical judgement which persists for longer than 10 minutes
This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This will be recorded onto worksheets which will be held within the patient medical records.
Timepoint [5] 425367 0
across 24 hours following randomisation
Secondary outcome [6] 425368 0
Occurrence of clinically significant cardiac arrhythmia based on clinical judgement which results in cardiac arrest.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This will be recorded onto worksheets which will be held within the patient medical records.
Timepoint [6] 425368 0
across 24 hours following randomisation
Secondary outcome [7] 425650 0
Amount of blood loss

The Blood loss will be collected in drapes for 90 min after treatment administration and weighed and documented on the worksheets within the patient medical records.
Timepoint [7] 425650 0
at 90 minutes following randomisation
Secondary outcome [8] 425651 0
Use of additional uterotonics.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [8] 425651 0
across the 24 hours following randomisation
Secondary outcome [9] 425652 0
Use of blood transfusion products.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [9] 425652 0
across the 24 hours following randomisation
Secondary outcome [10] 425653 0
Admission to Intensive care unit (ICU).

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [10] 425653 0
across the 24 hours following randomisation
Secondary outcome [11] 425654 0
Maternal Death.
Timepoint [11] 425654 0
across the 24 hours following randomisation
Secondary outcome [12] 425655 0
Clinically defined coagulopathy.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [12] 425655 0
across the 24 hours following randomisation
Secondary outcome [13] 425656 0
Breastfeeding.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [13] 425656 0
across the 24 hours following randomisation
Secondary outcome [14] 425657 0
Occurrence of shock

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [14] 425657 0
across the 24 hours following randomisation
Secondary outcome [15] 425658 0
frequency and severity of AE and SAE.

This is a composite outcome.

Some examples of known or possible adverse events include; 1) Tachycardia and the pulse will be clinically assessed at specified time points, 2) Hypotension and the blood pressure will be clinically assessed at specified time points 3) nausea and vomiting assessed by patient self report.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [15] 425658 0
across the 24 hours following randomisation
Secondary outcome [16] 425659 0
Composite outcome of maternal death or severe morbidity.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [16] 425659 0
across the 24 hours following randomisation
Secondary outcome [17] 425660 0
Any haemodynamic change requiring therapeutic intervention.

This outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This will be recorded onto worksheets which will be held within the patient medical records.
Timepoint [17] 425660 0
across the first 10 minutes following initiating treatment infusion
Secondary outcome [18] 425906 0
use of additional uterotonic(s).

The additional uterotonics outcome will be recorded from reviewing the clinical medical records to see any documentation of this outcome. This outcome will also be recorded prospectively onto worksheets which will be held within the patient medical records.
Timepoint [18] 425906 0
at 90 minutes following randomisation

Eligibility
Key inclusion criteria
Participants will be eligible for randomization if they fulfil all the following criteria:
• had a singleton pregnancy
• had a vaginal birth
• receive HSC for PPH prophylaxis during the vaginal birth
• have an indication to receive uterotonics for the first response treatment of PPH presumably due to uterine atony (clinically diagnosed, or measured blood loss of 500 ml or more from the vagina, and where known coagulopathy and retained placenta has been excluded as the cause of bleeding)
• provided written informed consent before any trial-related procedures are carried out.
Minimum age
10 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded from participating in the trial if they have any of the following criteria:
• known history of allergy to HSC or oxytocin or excipients in the medicinal products used in the trial
• known serious coagulopathy, epilepsy, hepatic, renal, or cardiovascular disease
• known intrauterine fetal death
• birth that is considered an abortion according to local gestational age limit
• other clinically significant condition(s) that, in the opinion of the investigator could represent increased health risk for the participation of the woman or interfere with the objectives of the trial
• a manual removal of placenta
• a placenta in-situ that has not been expelled or removed
• known administration of any uterotonic for PPH treatment (e.g. prostaglandins, oxytocin, ergometrine) following PPH prophylaxis.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The random allocation sequence will be generated centrally at WHO headquarters using computer-generated random numbers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be stratified by country. Participants will be randomly assigned to either experimental (HSC) or active control (oxytocin) arm (allocation ratio of 1:1) as per a computer-generated randomization sequence in permuted blocks within country
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample size has been determined using the lognormal approach. Assuming 20% of primary end-point rate with active control (oxytocin), a non-inferiority (NI) margin of 4% in absolute terms, 90% power, 2.5% alpha, and 1% loss to follow-up, 11,170 women with PPH would need to be recruited. However, considering that blood loss has a lognormal distribution and using the means and standard deviations in the lognormal scale, 6,200 women would provide 90% power to show noninferiority with 2.5% alpha, including 1% loss to follow-up. This sample size provides 90% power to demonstrate non-inferiority even if the primary end-point in the experimental arm reaches a clinically impactful rate of 21.5%.

The primary non-inferiority hypothesis will be assessed using a two-sided 95% CI for the risk difference (RD) of additional blood loss 500 ml or more (HSC vs. oxytocin). The upper limit of the two-sided 95% CI for the RD for the additional blood loss of greater than or equal to 500 mL primary end-point will be compared to the non-inferiority margin of 4% RD. If the upper limit is below the 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%.

The secondary binary end-points will be analysed using the modified ITT population and will be assessed only for conventional superiority using risk differences and relative risks with 95% confidence intervals estimated using logistic regression.

The secondary outcome blood loss in mL will be analysed using ANOVA and the log transformation, based on the lognormal distribution of blood loss, to compare the two treatments in terms of the means of the log-transformed blood loss. Numeric secondary outcomes will be analysed using ANOVA. The analyses will include centre in the model and possibly other covariates likely to affect the treatment effect.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2024
Actual
6/04/2024
Date of last participant enrolment
Anticipated
31/05/2028
Actual
Date of last data collection
Anticipated
1/06/2028
Actual
Sample size
Target
6200
Accrual to date
10
Final
Recruitment outside Australia
Country [1] 25703 0
South Africa
State/province [1] 25703 0
Country [2] 25704 0
United Kingdom
State/province [2] 25704 0
Country [3] 25705 0
Argentina
State/province [3] 25705 0
Country [4] 25706 0
Kenya
State/province [4] 25706 0
Country [5] 25707 0
Uganda
State/province [5] 25707 0
Country [6] 25708 0
India
State/province [6] 25708 0
Country [7] 25709 0
Nigeria
State/province [7] 25709 0

Funding & Sponsors
Funding source category [1] 314565 0
Other Collaborative groups
Name [1] 314565 0
UNITAID
Country [1] 314565 0
Switzerland
Funding source category [2] 314614 0
Other Collaborative groups
Name [2] 314614 0
the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction
Country [2] 314614 0
Switzerland
Funding source category [3] 314615 0
Other Collaborative groups
Name [3] 314615 0
MSD for Mothers
Country [3] 314615 0
United States of America
Primary sponsor type
Other
Name
WHO
Address
Avenue Appia 201211Geneva 27
Country
Switzerland
Secondary sponsor category [1] 316524 0
None
Name [1] 316524 0
Address [1] 316524 0
Country [1] 316524 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313601 0
WHO Ethics Review Committee (ERC)
Ethics committee address [1] 313601 0
WHO Headquarters
Avenue Appia 20
1211
Geneva 27
Ethics committee country [1] 313601 0
Switzerland
Date submitted for ethics approval [1] 313601 0
Approval date [1] 313601 0
14/08/2023
Ethics approval number [1] 313601 0

Summary
Brief summary
This will be a phase III, hospital-based, parallel, two-arm, individually-randomized, double-blind, active controlled, international, multicentre, non-inferiority trial. Participating women will be randomized to receive either intravenous HSC or oxytocin as the ‘first-line’ uterotonic for PPH treatment.
The trial will be conducted across 21 tertiary level hospitals within the WHO “CHAMPION” Trial Network in Argentina, Kenya, India, Nigeria, Uganda, South Africa, and United Kingdom.
Care providers will inform potentially eligible pregnant women about the trial during their antenatal care visits to the hospital. If a woman is seen for the first time during her admission to the hospital for childbirth, the woman will be approached for participation in the trial if she is in early labour and if her vital signs are normal, and she is not distressed. Informed consent will be obtained from the woman before any trial-related procedures are carried out.
Women having a vaginal birth who have been consented in early labour will receive an intramuscular (IM) prophylactic 100 µg dose of HSC for PPH prevention. Following the birth of the baby, a calibrated drape will be placed under the woman’s buttocks to measure blood loss for the first 60 minutes. Should atonic PPH based on a clinical diagnosis or blood loss estimation of 500 ml or more occur, the woman will be randomized to receive a saline intravenous (IV) infusion of HSC 100 µg or oxytocin 5 IU over 5 minutes. Following this treatment, women in oxytocin arm (active control) will receive additional 20 IU at a lower saline infusion rate over 4 hours in line with standard clinical practice, while women in HSC arm will receive an equivalent amount of saline infusion but with no additional uterotonic for the same period. Upon randomization, a new calibrated drape will be placed under the woman’s buttocks to measure further blood loss for 90 minutes.
The investigational medicinal product (IMP) will be administered immediately following randomization of trial participants. Once the IMP has been administered to the woman as described above, the clinical staff will continue further PPH management in accordance with existing hospital PPH management protocol and WHO guidelines.
All women will be followed up for a minimum of 24 hours after randomization or until hospital discharge, or transfer to higher-level care, whichever is soonest.
The trial will be implemented with an internal safety sub-study. The first interim analysis will be conducted for an independent Data Safety Monitoring Committee (DSMC) to assess comparative safety of HSC versus oxytocin once the first 250 participants have been enrolled into the trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128710 0
Dr Olufemi Oladapo
Address 128710 0
WHO HeadquartersAvenue Appia 201211Geneva 27
Country 128710 0
Switzerland
Phone 128710 0
+41227914323
Fax 128710 0
Email 128710 0
oladapoo@who.int
Contact person for public queries
Name 128711 0
Mrs Mariana Widmer
Address 128711 0
WHO HeadquartersAvenue Appia 201211Geneva 27
Country 128711 0
Switzerland
Phone 128711 0
+41227914323
Fax 128711 0
Email 128711 0
widmerm@who.int
Contact person for scientific queries
Name 128712 0
Mrs Mariana Widmer
Address 128712 0
WHO HeadquartersAvenue Appia 201211Geneva 27
Country 128712 0
Switzerland
Phone 128712 0
+41227914323
Fax 128712 0
Email 128712 0
widmerm@who.int

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Trial data set
When will data be available (start and end dates)?
Q1 2028.
No end date
Available to whom?
Academics and researchers
Available for what types of analyses?
Secondary analyses for IPD meta-analyses
How or where can data be obtained?
Data can be obtained following request to trial team (widmerm@who.int).


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.