title: Room temperature stable carbetocin for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and contributes to nearly a quarter of maternal deaths globally. The current available interventions for prevention of postpartum haemorrhage, oxytocin and carbetocin, are limited by their need for refrigeration to maintain potency, as the ability to maintain a cold chain across the drug distribution and storage network is inconsistent, thus restricting their use in countries with the highest burden of maternal mortality. We describe a randomized, double-blind non-inferiority trial comparing a newly developed room temperature stable formulation of carbetocin to the standard intervention (oxytocin) for the prevention of PPH after vaginal birth.
  
  
  METHODS
  Approximately 30,000 women delivering vaginally will be recruited across 22 centres in 10 countries. The primary objectives are to evaluate the non-inferiority of room temperature stable carbetocin (100 μg intramuscular) versus oxytocin (10 IU intramuscular) in the prevention of PPH and severe PPH after vaginal birth. The primary endpoints are blood loss ≥500 mL or the use of additional uterotonics (composite endpoint required by drug regulatory authorities) and blood loss ≥1,000 mL (WHO requirement). Non-inferiority will be assessed using a two-sided 95 % confidence interval for the relative risk of the above endpoints for room temperature stable carbetocin versus oxytocin. The upper limit of the two-sided 95 % confidence interval for the relative risk for the composite endpoint of blood loss ≥500 mL or the use of additional uterotonics, and for the endpoint of blood loss ≥1,000 mL, will be compared to a non-inferiority margin of 1.16 and 1.23, respectively. If the upper limit is below the corresponding margin, non-inferiority will have been demonstrated. The safety analysis will include all women receiving treatment. Safety and tolerability will be assessed by a review of adverse events, by conducting inferential testing with significance levels for between-group comparisons.
  
  
  CONCLUSIONS
  If the results of the study show that room temperature stable carbetocin is a safe and effective alternative to oxytocin, this could have a substantial impact on the prevention of postpartum haemorrhage and maternal survival worldwide.
  
  
  BACKGROUND
  ACTRN12614000870651 (14 August 2014).
authors.affiliation: Department of Reproductive Health and Research, World Health Organization, UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Avenue Appia 20, Geneva, 1201, Switzerland. widmerm@who.int.
authors.forename: Mariana
authors.initials: M
authors.lastname: Widmer
authors.affiliation: Medical Statistics deparment, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Gilda
authors.initials: G
authors.lastname: Piaggio
authors.affiliation: Department of Obstetrics and Gynecology, Women's Health Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Hany
authors.initials: H
authors.lastname: Abdel-Aleem
authors.affiliation: Centro Rosarino de Estudios Perinatales, Rosario, Argentina.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Carroli
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Hospital Singapore, Singapore, Singapore.
authors.forename: Yap-Seng
authors.initials: YS
authors.lastname: Chong
authors.affiliation: Birmingham Women's NHS Foundation Trust, Birmingham, UK.
authors.forename: Arri
authors.initials: A
authors.lastname: Coomarasamy
authors.affiliation: Department of Obstetrics and Gynaecology, College of Medicine, University of Ibadan, Ibadan, Nigeria.
authors.forename: Bukola
authors.initials: B
authors.lastname: Fawole
authors.affiliation: Department of Medical Education, K L E Society's J N Medical College, Belgaum, India.
authors.forename: Shivaprasad
authors.initials: S
authors.lastname: Goudar
authors.affiliation: Effective Research Care Unit, University of Witwatersrand, University of Fort Hare, East London, South Africa.
authors.forename: G Justus
authors.initials: GJ
authors.lastname: Hofmeyr
authors.affiliation: Department of Obstetrics and Gynaecology, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Pisake
authors.initials: P
authors.lastname: Lumbiganon
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Kidza
authors.initials: K
authors.lastname: Mugerwa
authors.affiliation: Department of Reproductive Health and Research, World Health Organization, UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Avenue Appia 20, Geneva, 1201, Switzerland.
authors.forename: Thi My Huong
authors.initials: TM
authors.lastname: Nguyen
authors.affiliation: Department of Obstetrics and Gynaecology, Kenyatta National Hospital, University of Nairobi, Nairobi, Kenya.
authors.forename: Zahida
authors.initials: Z
authors.lastname: Qureshi
authors.affiliation: Department of Social Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Joao Paulo
authors.initials: JP
authors.lastname: Souza
authors.affiliation: Department of Reproductive Health and Research, World Health Organization, UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Avenue Appia 20, Geneva, 1201, Switzerland.
authors.forename: A Metin
authors.initials: AM
authors.lastname: Gülmezoglu
mesh_terms: D002985:Clinical Protocols; D036861:Delivery, Obstetric / Q000009:adverse effects*; D004311:Double-Blind Method; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D006801:Humans; D007749:Labor Stage, Third; D010120:Oxytocics / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D010121:Oxytocin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry; D036801:Parturition; D006473:Postpartum Hemorrhage / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D011247:Pregnancy; D012107:Research Design; D012307:Risk Factors; D013696:Temperature; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D010120:Oxytocics; D010121:Oxytocin; C020731:carbetocin
keywords: Non-inferiority trial; Oxytocin; Postpartum haemorrhage; Room temperature stable carbetocin