ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12614000870651

Ethics application status

Approved

Date submitted

17/07/2014

Date registered

14/08/2014

Date last updated

9/01/2019

Date data sharing statement initially provided

9/01/2019

Date results provided

9/01/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Carbetocin RTS for preventing postpartum haemorrhage: a randomized non-inferiority controlled trial.

Scientific title

A phase III, randomized, double-blind, active, controlled, multinational, multicentre, non-inferiority trial using carbetocin room temperature stable (RTS) for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally.

Secondary ID [1]

A65870

Universal Trial Number (UTN)

U1111-1162-8519

Trial acronym

CHAMPION

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Postpartum haemorrhage

Condition category

Condition code

Reproductive Health and Childbirth

Childbirth and postnatal care

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Carbetocin RTS 100 micrograms solution for intramuscular (IM) injection to be administered once during the third stage of labour.

Intervention code [1]

Prevention

Comparator / control treatment

Oxytocin 10 IU solution for intramuscular (IM) injection to be administered once during the third stage of labour.

Control group

Active

Outcomes

Primary outcome [1]

The proportion of women with 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.
(composite primary outcome).
The blood loss will be measured with a plastic drape placed under the woman's buttocks.

Timepoint [1]

60 minutes after delivery or 120 minutes for women who continue to bleed after one hour.

Primary outcome [2]

The proportion of women with blood loss of 1000 mL or more at one hour and up to two hours for women who continue to bleed after one hour.
The blood loss will be measured with a plastic drape placed under the woman's buttocks.

Timepoint [2]

60 minutes after delivery or 120 minutes for women who continue to bleed after one hour

Secondary outcome [1]

Proportion of women with blood loss of 500mL or more within one hour (or two hours postpartum if the bleeding continues beyond one hour).
The blood loss will be measured with a plastic drape placed under the woman's buttocks.

Timepoint [1]

One hour (or two hours if the bleeding continues beyond one hour).

Secondary outcome [2]

Blood loss in mL within one hour (or two hours postpartum if the bleeding continues beyond one hour).
The blood loss will be measured with a plastic drape placed under the woman's buttocks.

Timepoint [2]

One hour (or two hours if the bleeding continues beyond one hour).

Secondary outcome [3]

Proportion of women receiving additional uterotonics within one hour (or two hours postpartum if the bleeding continues beyond one hour).

Timepoint [3]

One hour (or two hours postpartum if the bleeding continues beyond one hour).

Secondary outcome [4]

Proportion of women receiving additional uterotonics up to time of discharge.

Timepoint [4]

Hospital discharge

Secondary outcome [5]

proportion of women receiving blood transfusion up to time of discharge

Timepoint [5]

Hospital discharge

Secondary outcome [6]

Proportion of women with manual removal of placenta up to time of discharge.

Timepoint [6]

Hospital discharge

Secondary outcome [7]

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

Timepoint [7]

Hospital discharge

Secondary outcome [8]

Proportion of maternal death.

Timepoint [8]

Hospital discharge

Secondary outcome [9]

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.

Timepoint [9]

Hospital discharge

Secondary outcome [10]

Incidence and severity of adverse or serious adverse events up to time of discharge.
Adverse events will be recorded in an adverse event form specifically designed for this trial and will include any unfavourable and unintended sign, symptom or disease temporally associated with the use of the investigational medicine product (IMP), whether or not considered to be caused by the IMP.

Serious adverse events will be recorded in a serious adverse event report form and will be include any event that results in death, or it is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or is a congenital anomaly/birht defect.

Timepoint [10]

Hospital discharge

Secondary outcome [11]

Newborn outcomes (vital status, APGAR score at 5 minutes, resuscitation of the baby, mechanical ventilation). (composite outcome)

Timepoint [11]

At birth

Eligibility

Key inclusion criteria

*Women who 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.
*Known singleton pregnancy.

Minimum age

No limit

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Yes

Key exclusion criteria

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.
* Serious hepatic or renal disease
* Epilepsy

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

During 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 microgram 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.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

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.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes

Intervention assignment

Parallel

Other design features

Phase

Phase 3

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

In 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, 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.
Final 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). 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. 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.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/10/2014

Actual

7/07/2015

Date of last participant enrolment

Anticipated

1/03/2017

Actual

30/01/2018

Date of last data collection

Anticipated

Actual

30/01/2018

Sample size

Target

30000

Accrual to date

Final

29645

Recruitment outside Australia

Country [1]

Argentina

State/province [1]

Rosario

Country [2]

Egypt

State/province [2]

Assiut

Country [3]

India

State/province [3]

Belgaum

Country [4]

Kenya

State/province [4]

Nairobi

Country [5]

Nigeria

State/province [5]

Ibadan

Country [6]

Singapore

State/province [6]

Singapore

Country [7]

South Africa

State/province [7]

Johannesburg

Country [8]

Thailand

State/province [8]

Khon Kaen

Country [9]

Uganda

State/province [9]

Kampala

Country [10]

United Kingdom

State/province [10]

Birmingham

Funding & Sponsors

Funding source category [1]

Other

Name [1]

Merck for Mothers (Merck Sharp & Dohme Corp.)

Address [1]

One Merck Drive
Whitehouse State, New Jersey 08889

Country [1]

United States of America

Primary sponsor type

Other

Name

World Health Organization

Address

20 Avenue Appia - 1211 Geneva

Country

Switzerland

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

WHO Ethics Review Committee

Ethics committee address [1]

20 Avenue Appia - 1211 Geneva

Ethics committee country [1]

Switzerland

Date submitted for ethics approval [1]

Approval date [1]

02/06/2014

Ethics approval number [1]

Summary

Brief summary

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. 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.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr A. Metin Gulmezoglu

Address

World Health Organization
20 Avenue Appia - 1211 Geneva

Country

Switzerland

Phone

+41227913417

Fax

[email protected]

Contact person for public queries

Name

A. Metin Gulmezoglu

Address

World Health Organization
20 Avenue Appia - 1211 Geneva

Country

Switzerland

Phone

+41227913417

Fax

[email protected]

Contact person for scientific queries

Name

A. Metin Gulmezoglu

Address

World Health Organization
20 Avenue Appia - 1211 Geneva

Country

Switzerland

Phone

+41227913417

Fax

[email protected]

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 results

When will data be available (start and end dates)?

Start date: 1 July 2018
No end date

Available to whom?

Scientists who work in the area of PPH

Available for what types of analyses?

PPH related

How or where can data be obtained?

They have to contact RHR communications officer at WHO ([email protected] )

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

Source	Title	Year of Publication	DOI
Embase	Heat-stable carbetocin versus oxytocin to prevent hemorrhage after vaginal birth.	2018	https://dx.doi.org/10.1056/NEJMoa1805489
Embase	Maternal characteristics and causes associated with refractory postpartum haemorrhage after vaginal birth: a secondary analysis of the WHO CHAMPION trial data.	2020	https://dx.doi.org/10.1111/1471-0528.16040
Embase	Cost of hospital care of women with postpartum haemorrhage in India, Kenya, Nigeria and Uganda: a financial case for improved prevention.	2021	https://dx.doi.org/10.1186/s12978-020-01063-x
Embase	Duration of third stage labour and postpartum blood loss: a secondary analysis of the WHO CHAMPION trial data.	2021	https://dx.doi.org/10.1186/s12978-021-01284-8
Embase	Side-effects of carbetocin to prevent postpartum hemorrhage: A systematic review and meta-analysis of randomized controlled trials.	2021	https://dx.doi.org/10.1002/prp2.745
Embase	Side-effects of oxytocin in postpartum hemorrhage: a systematic review and meta-analysis.	2022
Embase	Heat stable carbetocin or oxytocin for prevention of postpartum hemorrhage among women at risk: A secondary analysis of the CHAMPION trial.	2024	https://dx.doi.org/10.1002/ijgo.14938

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically