PPH is the leading cause of maternal mortality in low-income countries and it contributes to nearly a quarter of maternal deaths globally. PPH is a significant contributor to severe maternal morbidity and long term disability, as well as to a number of other severe maternal conditions, generally associated with more substantial blood loss, including shock and organ dysfunction2-4. Improving health care for women during childbirth in order to prevent and treat PPH is an essential step towards the achievement of the United Nations Millennium Development Goals.

Despite oxytocin being a well-known and extensively studied, there is limited information on its stability at tropical temperatures, mainly at extreme climate conditions and storage under refrigeration is recommended, however carbetocin RTS is a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain.

Merck for Mothers is a 10-year initiative focused on creating a world where no woman has to die from complications of pregnancy and childbirth. Two of its priority areas are postpartum haemorrhage (PPH) and hypertensive disorders of pregnancy.

carbetocin RTS is a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain. An international technical consultation was convened and it was agreed to proceed with a randomized controlled trial to evaluate the effectiveness of carbetocin RTS compared to oxytocin when used intramuscularly. This was based on four considerations:

(i) frequent concerns and documentation of the quality of oxytocin and its stability in some developing countries;

(ii) the potential advantage of carbetocin RTS due to its longer half-life (than oxytocin) especially when administered intramuscularly in addition to its heat stability;

(iii) research will be funded by Merck for Mothers and conducted by WHO independently in terms of the management, analysis and publication of the research results

(iv) if non-inferior to oxytocin, carbetocin RTS formulation will be made available in high-burden countries at an accessible public sector price comparable to the current oxytocin price based on a signed memorandum of understanding between WHO, Ferring and Merck.

The trial is being conducted as an effectiveness trial with the objective of the experimental intervention being registered for the indication “prevention of postpartum haemorrhage” by drug regulatory authorities if it is shown to be non-inferior or superior to the gold standard control, oxytocin. For this purpose a primary endpoint of blood loss 500 mL or more or use of additional uterotonics is considered appropriate. For the purpose of evaluating clinical effectiveness and for inclusion of the experimental intervention in future WHO guidelines and the Model List of Essential Medicines, the more substantive endpoint of blood loss 1000 mL or more is considered appropriate. The blood loss of 1000 mL or more was considered as one of the three critical endpoints (together with blood transfusion and maternal death) for the earlier 2007 WHO recommendations for PPH prevention where outcomes were rated by an independent panel. Since the two primary endpoints serve independent objectives, the Type I error rate for multiplicity of endpoints was not adjusted. 

The trial has two primary objectives:

(1) To evaluate non-inferiority of carbetocin RTS 100 μg IM versus oxytocin 10 IU IM after vaginal delivery in the prevention of the composite endpoint “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.

(2) To evaluate non-inferiority of carbetocin RTS 100 µg IM versus oxytocin 10 IU IM in the prevention of sPPH (≥1000 mL blood loss) at one hour and up to two hours for women who continue to bleed after one hour.

For both objectives the hypotheses are:

i) Carbetocin RTS 100 μg/ml IM is non-inferior to oxytocin 10IU IM in terms of the proportion of women with blood loss ≥500 mL or use of additional uterotonic drugs after vaginal delivery within a non-inferiority margin of 1.16 on the relative risk scale (objective (1)), and the proportion of women with blood loss ≥1000 mL after vaginal delivery within a non-inferiority margin of 1.23 on the relative risk scale (objective (2)).

Justification: In the conventional superiority trial, the aim is to determine whether one intervention is superior to another, for example, whether an uterotonic is superior to nothing. By contrast, in a non-inferiority trial, the aim is to determine whether an alternative intervention with certain advantages is similar to a gold standard. Oxytocin 10 IU (IM or IV) represents the gold standard management strategy for reducing blood loss in the third stage of labour. The advantages of carbetocin RTS are being more heat-stable than oxytocin and having a longer half-life. In order to evaluate the effectiveness of carbetocin RTS, which has these advantages, it has to be compared to oxytocin to assess whether it is non-inferior to it in efficacy.

ii) Carbetocin RTS 100 μg IM is superior to oxytocin 10 IU IM in terms of the proportion of women with blood loss ≥500 mL or use of additional uterotonic drugs (objective (1)), and in terms of the proportion of women with blood loss ≥1000 mL after vaginal delivery (objective (2)). For each of the two primary endpoints, superiority will be tested if non-inferiority has been demonstrated.