Trial Design and Oversight

We conducted an international, randomized, double-blind, active-controlled, noninferiority trial, the Carbetocin Haemorrhage Prevention (CHAMPION) trial, comparing heat-stable carbetocin with oxytocin for the prevention of postpartum hemorrhage during the third stage of labor in women giving birth vaginally at 23 hospitals (sites) in 10 countries — Argentina, Egypt, India, Kenya, Nigeria, Singapore, South Africa, Thailand, Uganda, and the United Kingdom — between July 7, 2015, and January 30, 2018. The trial protocol (available with the full text of this article at NEJM.org) has been published previously.6 The trial protocol was approved by the relevant ethics committees and regulatory agencies in each country, by the research proposals review panel of the Special Program of Research in Human Reproduction (HRP) that is based at the WHO, and by the WHO Ethics Review Committee.

HRP oversaw the conduct of the trial, which was performed in accordance with Good Clinical Practice guidelines.7 An external data and safety monitoring committee provided independent oversight and reviewed two interim analyses: the first analysis was to evaluate safety when 5000 participants had been recruited, and the second was to evaluate safety and efficacy when 15,000 participants had been recruited. The interim analyses were blinded to everyone except the members of the data and safety monitoring committee. On both occasions, the data and safety monitoring committee recommended continuation of the trial.

Trial initiation, monitoring, and closure and safety monitoring at the trial sites were provided by IQVIA (formerly Quintiles IMS–Quintiles). Centro Rosarino de Estudios Perinatales in Rosario, Argentina, provided assistance with data management, including preparation of the trial online data-entry system, electronic case-record forms, and data monitoring and cleaning. Statistika Consultoria in Campinas, Brazil, provided statistical assistance. The trial protocol, statistical analysis plan, and the manuscript were written by HRP staff, the trial statistician, independent steering committee members who were not WHO staff or site investigators, and the site principal investigators.

The trial was supported by MSD, through the MSD for Mothers Program, an initiative of Merck; MSD had no commercial interest in the investigational drug. Heat-stable carbetocin was provided by Ferring Pharmaceuticals and oxytocin by Novartis free of charge. Novartis had no other role in the trial. MSD and Ferring Pharmaceuticals provided input into the protocol and could provide comments on the manuscript, although there was no obligation on the part of the team to incorporate them. No company had the right to final approval of the manuscript or to control the decision to submit the manuscript for publication. The authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of this report to the to the protocol.

Trial Participants and Interventions

Women who expected to give birth vaginally and who had a singleton pregnancy and cervical dilatation of 6 cm or less were eligible. Women were not eligible if they were in an advanced stage of labor (cervical dilatation >6 cm); were too distressed to provide informed consent; had known allergies to carbetocin, oxytocin homologues, or excipients; or had a serious cardiovascular disorder, serious hepatic or renal disease, or epilepsy. All the participants provided written informed consent.

Women underwent randomization when vaginal birth was imminent. Women were randomly assigned to receive a single intramuscular injection of either heat-stable carbetocin at a dose of 100 μg or oxytocin at a dose of 10 IU. Immediately after the birth of the baby, the drug was administered and the management of the third stage of labor was conducted as recommended in the WHO guidelines.2 Once the umbilical cord was clamped and cut, a plastic drape for blood collection (BRASSS-V Drape) was placed under the woman’s buttocks. Blood was collected for 1 hour or for 2 hours if the bleeding continued beyond 1 hour. The drape with the blood was then weighed by a digital scale, with the weight recorded in grams and then converted to volume (milliliters) after the weight of the drape was subtracted at the analysis stage.8

Participation in the trial ended at discharge from the facility, transfer of the woman to a higher care unit, or death. Information on serious and other adverse events was collected from the time of informed consent until the event resolved.

Heat-stable carbetocin and oxytocin were both supplied in 1-ml ampules in consecutively numbered treatment packs that were arranged in dispensers. The ampules, trial packs, and dispensers were identical in shape, size, and weight to ensure that investigators were unaware of the individual treatment assignments. Although carbetocin was heat stable and did not require cold storage, the dispensers were kept in cold storage (2 to 8°C) to give oxytocin maximum efficacy and to maintain double-blinding.

The random-assignment sequence was generated at the WHO with the use of computer-generated random numbers. Randomization was stratified according to country with the use of permuted blocks of 10, with an assignment ratio of 1:1. Assignment was performed by opening the consecutively numbered treatment pack in the dispenser.

Primary and Secondary Outcomes

There were two primary outcomes. The first was a composite outcome of the proportion of women with blood loss of at least 500 ml or the use of additional uterotonic agents at 1 hour and up to 2 hours for women who continued to bleed after 1 hour. This outcome was deemed to be sufficient and appropriate for submission for regulatory approval after discussion with the U.K. Medicines and Healthcare Products Regulatory Agency. The second primary outcome was the proportion of women with blood loss of at least 1000 ml at 1 hour and up to 2 hours for women who continued to bleed after 1 hour. This outcome had been used in earlier WHO guidelines regarding the prevention of postpartum hemorrhage. For these two primary outcomes, a noninferiority hypothesis was used.

Secondary outcomes included other measurements related to blood loss, such as the use of additional uterotonic agents, other interventions to stop bleeding (Table S1 in the Supplementary Appendix, available at NEJM.org), and expected adverse effects, including chest pain, flushing, abdominal pain, and vomiting. For secondary outcomes, a superiority hypothesis was used.

Statistical Analysis

Details of the statistical analysis have been published previously6 and are available with the trial protocol. For the primary outcome of blood loss of at least 500 ml or the use of additional uterotonic agents, we set a noninferiority margin of 1.16 on the relative scale to preserve at least 82% of the effect of oxytocin over placebo, assuming the prevalences from a systematic review (15 to 20% with oxytocin and 29 to 37% with placebo).9 For the primary outcome of blood loss of at least 1000 ml, we set the noninferiority margin to preserve at least 75% of the effect of oxytocin over placebo, assuming a prevalence of this outcome of 2% with oxytocin10 and 3.84% with placebo (derived from rates with expectant management in a systematic review).11 Preserving 75% of 1.84 percentage points (i.e., 3.84% − 2%) gave a margin on the absolute scale of 0.46 percentage points (or 2.46÷2=1.23 on the relative scale), assuming a 2% prevalence with oxytocin.

To show the noninferiority of heat-stable carbetocin as compared with oxytocin within a margin of 1.23 on the relative scale, with 80% power and at a significance level of 2.5%, we calculated that 29,082 women would need to be enrolled, assuming an equal prevalence of blood loss of at least 1000 ml of 2% in each treatment group. We assumed a 3% rate of loss to follow-up, which resulted in an estimated sample size of 30,000. This sample size provided the trial with more than 99% power for the outcome of blood loss of at least 500 ml or the use of additional uterotonic agents. The sample size was calculated for different scenarios as specified in the protocol. For the scenario of a prevalence of 1.5% for the outcome of blood loss of at least 1000 ml, the margin on the relative scale was 1.31. We defined a priori the number needed to harm (i.e., the number of women who would need to be treated with carbetocin instead of oxytocin to result in one woman with blood loss of ≥1000 ml) for noninferiority as an absolute measure and stated that noninferiority would be shown if the number needed to harm was 217 or more.

We present the primary-outcome results with adjustment for multiple comparisons as a complementary analysis. However, our conclusions are based on the unadjusted results.

Analyses were planned according to the modified intention-to-treat and per-protocol populations. The modified intention-to-treat population included all the participants who underwent randomization except those who withdrew consent, those whose consent form was missing from source documents, and those who underwent cesarean section. The per-protocol population included all the participants who received the assigned treatment within 3 minutes after delivery. To conclude that heat-stable carbetocin was noninferior to oxytocin, we required that noninferiority be shown in both the modified intention-to-treat and per-protocol analyses.

We used the Mantel–Haenszel method to calculate summary relative-risk estimates and common risk (proportion) differences for tables of the type country by trial group by binary outcome. The confidence intervals were obtained by the Wald method, and the P value was from the Mantel–Haenszel general association statistic. This approach differed from the modeling approach with the use of logistic regression as planned in the protocol, because the results from logistic regression were not reliable with scarce data. Missing values were not imputed. We planned to use complete-case analysis because missing values for primary outcomes were expected to be very few and balanced between groups. As a complementary analysis, a log-normal distribution was fitted to the blood-loss data, and the estimated probabilities of blood loss of at least 500 ml and of at least 1000 ml were compared between treatments with the use of relative risk and the bootstrap technique to obtain confidence intervals for the relative risk. Because this parametric method used all the blood-loss data (instead of dichotomizing), it was expected to improve efficiency in terms of the precision of the estimates (see the Supplementary Appendix).

The secondary outcomes were assessed only for superiority, with the use of relative risks with 95% confidence intervals that were estimated with the same techniques as described for the primary outcomes. Because the statistical analysis plan did not include a provision for correcting the confidence intervals for multiple comparisons, the widths of the confidence intervals were not adjusted for multiple comparisons, so the intervals should not be used to infer definitive treatment effects for secondary outcomes. Analyses were performed with SAS software, version 9.4 (SAS Institute), and JMP 13Pro software (JMP).