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Trial registered on ANZCTR


Trial ID
ACTRN12614000870651
Ethics application status
Approved
Date submitted
17/07/2014
Date registered
14/08/2014
Date last updated
29/09/2015
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] 285007 0
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 292517 0
Condition category
Condition code
Reproductive Health and Childbirth 292822 292822 0 0
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] 289842 0
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] 292684 0
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] 292684 0
60 minutes after delivery or 120 minutes for women who continue to bleed after one hour.
Primary outcome [2] 292685 0
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] 292685 0
60 minutes after delivery or 120 minutes for women who continue to bleed after one hour
Secondary outcome [1] 309501 0
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] 309501 0
One hour (or two hours if the bleeding continues beyond one hour).
Secondary outcome [2] 309852 0
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] 309852 0
One hour (or two hours if the bleeding continues beyond one hour).
Secondary outcome [3] 309853 0
Proportion of women receiving additional uterotonics within one hour (or two hours postpartum if the bleeding continues beyond one hour).
Timepoint [3] 309853 0
One hour (or two hours postpartum if the bleeding continues beyond one hour).
Secondary outcome [4] 309854 0
Proportion of women receiving additional uterotonics up to time of discharge.
Timepoint [4] 309854 0
Hospital discharge
Secondary outcome [5] 309855 0
proportion of women receiving blood transfusion up to time of discharge
Timepoint [5] 309855 0
Hospital discharge
Secondary outcome [6] 309856 0
Proportion of women with manual removal of placenta up to time of discharge.
Timepoint [6] 309856 0
Hospital discharge
Secondary outcome [7] 309857 0
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] 309857 0
Hospital discharge
Secondary outcome [8] 309858 0
Proportion of maternal death.
Timepoint [8] 309858 0
Hospital discharge
Secondary outcome [9] 309859 0
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] 309859 0
Hospital discharge
Secondary outcome [10] 309860 0
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] 309860 0
Hospital discharge
Secondary outcome [11] 317905 0
Newborn outcomes (vital status, APGAR score at 5 minutes, resuscitation of the baby, mechanical ventilation). (composite outcome)
Timepoint [11] 317905 0
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
Gender
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
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 6224 0
Argentina
State/province [1] 6224 0
Rosario
Country [2] 6226 0
Egypt
State/province [2] 6226 0
Assiut
Country [3] 6227 0
India
State/province [3] 6227 0
Belgaum
Country [4] 6228 0
Kenya
State/province [4] 6228 0
Nairobi
Country [5] 6229 0
Nigeria
State/province [5] 6229 0
Ibadan
Country [6] 6231 0
Singapore
State/province [6] 6231 0
Singapore
Country [7] 6232 0
South Africa
State/province [7] 6232 0
Johannesburg
Country [8] 6233 0
Thailand
State/province [8] 6233 0
Khon Kaen
Country [9] 6234 0
Uganda
State/province [9] 6234 0
Kampala
Country [10] 6235 0
United Kingdom
State/province [10] 6235 0
Birmingham
Country [11] 7193 0
Nigeria
State/province [11] 7193 0
Akura

Funding & Sponsors
Funding source category [1] 289620 0
Other
Name [1] 289620 0
Merck for Mothers (Merck Sharp & Dohme Corp.)
Address [1] 289620 0
One Merck Drive
Whitehouse State, New Jersey 08889
Country [1] 289620 0
United States of America
Primary sponsor type
Other
Name
World Health Organization
Address
20 Avenue Appia - 1211 Geneva
Country
Switzerland
Secondary sponsor category [1] 288308 0
None
Name [1] 288308 0
Address [1] 288308 0
Country [1] 288308 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291363 0
WHO Ethics Review Committee
Ethics committee address [1] 291363 0
20 Avenue Appia - 1211 Geneva
Ethics committee country [1] 291363 0
Switzerland
Date submitted for ethics approval [1] 291363 0
Approval date [1] 291363 0
02/06/2014
Ethics approval number [1] 291363 0

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 50030 0
Dr A. Metin Gulmezoglu
Address 50030 0
World Health Organization
20 Avenue Appia - 1211 Geneva
Country 50030 0
Switzerland
Phone 50030 0
+41227913417
Fax 50030 0
Email 50030 0
gulmezoglum@who.int
Contact person for public queries
Name 50031 0
Dr A. Metin Gulmezoglu
Address 50031 0
World Health Organization
20 Avenue Appia - 1211 Geneva
Country 50031 0
Switzerland
Phone 50031 0
+41227913417
Fax 50031 0
Email 50031 0
gulmezoglum@who.int
Contact person for scientific queries
Name 50032 0
Dr A. Metin Gulmezoglu
Address 50032 0
World Health Organization
20 Avenue Appia - 1211 Geneva
Country 50032 0
Switzerland
Phone 50032 0
+41227913417
Fax 50032 0
Email 50032 0
gulmezoglum@who.int