CONFIDENTIAL
/ FOR WHO USE ONLYDate received by WHO:
Thematic area:
Single site proposal
"Core" proposal (for multicentre study)
Centre-specific proposal under multicentre study
Connect ID No:
HRP Research Proposal
Trial A65870
Carbetocin RTS for preventing postpartum haemorrhage: a randomized non-inferiority controlled trial.
Version 30 June 2014
Sponsor / Department of Reproductive Health & ResearchWorld Health Organization
Avenue Appia 20
1211 Geneva 27
Switzerland
Trial coordination unit / A. Metin Gülmezoglu (Trial coordinator)
Mariana Widmer (Trial manager)
Gilda Piaggio (Trial statistician)
Principal investigators / Dr Guillermo Carroli
CENTRO ROSARINO DE ESTUDIOS PERINATALES
Moreno 878 6º Piso
2000 ROSARIO
ARGENTINA
Dr Joao Paulo Dias de Souza
CENTRO DE REFERÊNCIA DA SAÚDE DA MULHER DE RIBEIRÃO PRETO – MATER
Av. WanderleyTaffo, nº 330 – QuintinoFacci II - CEP 14070-250
RibeirãoPreto - Sao Paulo
BRAZIL
Dr Hany Abdel-Aleem
Department of Obstetrics and Gynecology
Women's Health Hospital
ASSIUT UNIVERSITY HOSPITAL
71511 Assiut
EGYPT
Dr Shivaprasad S Goudar
Women's and Children's Health Research Unit, KLE University's
Jawaharlal Nehru Medical College
Belgaum 590010 Karnataka
INDIA
Dr Zahida Qureshi
Department of Obstetrics and Gynaecology
College of Health Sciences
University of Nairobi
Nairobi
KENYA
Dr.Bukola Fawole
Department of Obstetrics & Gynaecology
University College Hospital
Ibadan
NIGERIA
Dr Syeda Batool Mazhar
Head of Department
MCH Centre, Pakistan Institute of Medical Sciences,
G-8/3, Islamabad.
PAKISTAN
Dr Chong Yap Seng
Department of Obstetrics and Gynaecology
Yong Loo Lin School of Medicine, National University of Singapore
1E, Kent Ridge Road,
NUHS Tower Block, Level 12,
SINGAPORE
Dr Ebrahim Bera
Department of Obstetrics & Gynaecology
RahimaMoosa Mother-and-Child Hospital c/o Fuel & Oudtshoorn Street
Newclare
2112 Johannesburg
SOUTH AFRICA
Dr Pisake Lumbiganon
Faculty of Medicine - KhonKaen University
KhonKaen 40002
THAILAND
Dr JosaphatByamugisha
Department of Obstetrics and Gynecology
Makerere University College of Health Sciences
Mulago Hospital
Kampala
UGANDA
Dr ArriCoomarasamy
Gynaecology and Reproductive Medicine
Birmingham Women’s NHS Foundation Trust
Mindelsohn Way Edgbaston Birmingham B15 2TG
UNITED KINGDOM
Contents
1.Project summary
2.Description of the project
2.1Background information and rationale
2.2Risk-Benefit Ratio
2.3Study hypothesis and objectives
2.4Study conceptual framework
2.5Study design
2.6Procedures
2.6.1Study centres
2.6.2Study participants
2.6.3Randomization and allocation
2.6.3.1Unblinding of individual participant treatment ______13
2.6.4Sample size calculation
2.6.5Description of the intervention ______18
2.6.5.1Description of the Investigational Medicinal Product ______18
2.6.5.2Packaging and labelling ______19
2.6.5.3Handling and storage ______20
2.6.5.4Dosage and administration ______20
2.6.5.5Investigational Medicinal Product accountability ______21
2.6.5.6Other drugs to be used in the trial ______21
2.6.5.7Concomitant medications and therapies ______21
2.6.6 Admission procedure
2.6.7 Follow-up procedures
2.6.8Trial endpoints
2.6.9 Criteria for participant discontinuation
2.7Study instruments
2.8Project management
2.8.1Trial steering committee (TSC)
2.8.2Data and safety monitoring committee (DSMC)
2.9Data quality assurance
2.10Data management
2.11Data analysis plan
2.11.1Final analysis
2.11.2Interim analysis
2.11.3Analysis of secondary outcomes
2.12Study timeline
2.13Main problems anticipated and proposed solutions
2.14Applicability of results
2.15Links with other projects
3.Gender considerations
4.Ethical issues
4.1. Responsibilities of the Investigator
4.2 Forms required
4.2.1 Information sheet for participants
4.2.2 Informed consent form for participants
4.2.3 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
5.Quality assurance and health authorities
6.Investigator site file and archiving
7. Changes to the clinical trial protocol
8.Environmental impact of the project
9.Plans for dissemination and use of project results
10. Clinical trial report and publication policy
11.Research capacity strengthening
12.References
Annex 1Justification of the non-inferiority margin for the composite endpoint
Annex 2The draft minutes of the MHRA meeting (9 December 2013)
Annex 3Oxytocin product label
Annex 4Informed consent
Annex 5Centres’ characteristics
Annex 6DSMC charter
Annex 7HRP Standard operating procedures
Annex 8 CONSORT
Annex 9Study timeline
Annex 10WHO Data use regulations
Annex 11Dummy tables
Annex 12Interim analysis procedure
Abbreviations
AER / Adverse Event Report formCI / Confidence interval
CRF / Case Report Form
CRO / Clinical (Contract) Research Organisation
CTR / Clinical trial report
DSMC / Data Safety and Monitoring Committee
FDA / Food and Drug Administration
GCP / Good Clinical Practice
GMP / Good Manufacturing Practice
HRP / Special Programme of Research, Development and Research Training in Human Reproduction
ICH / International Conference on Harmonisation
IEC / Independent Ethics Committee
IM / Intramuscular
IMP / Investigational Medicinal Product
IRB / Institutional Review Board
ITT / Intention-to-Treat
IV / Intravenous
PP / Per Protocol
PPH / Postpartum Haemorrhage
RHR / Reproductive Health and Research
RR / Risk ratio
RTS / Room Temperature Stable
SAE / Serious Adverse Event report form
SOPs / Standard operating procedures
sPPH / severe Postpartum Haemorrhage
TMT / Trial monitoring team
TSC / Trial steering committee
1.Project summary
Background: 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. Merck for Mothers, Ferring Pharmaceuticals and the World Health Organization would like to evaluate the room temperature stablecarbetocinsolution for injection as a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain.
Objectives: i)To evaluate non-inferiority of carbetocin RTS 100 µg IM versus oxytocin 10 IU IM in the prevention of the composite outcome blood loss ≥500 mLor the use of additional uterotonic drugs following vaginal delivery of the baby;(ii)To evaluate non-inferiority of carbetocin RTS 100 µg IM versus oxytocin 10 IU IM in the prevention of blood loss ≥1000 mL.
Methods: This will be a hospital-based, multicentre, double-blind, randomized, non-inferiority, active controlled trial. Centres from twelve countries will participate. Each woman will be randomized to receive either oxytocin 10 IU IM or carbetocin RTS 100 µg IM.We aim to recruit approximately 29,000 women delivering vaginally in health facilities within a 12 month recruitment period.
Management: Overall trial management will be from HRP/RHR in Geneva. There will be twelve centres located in Argentina, Brazil, Egypt, India, Kenya, Nigeria, Pakistan, Singapore, South Africa, Thailand, Uganda and United Kingdom. There will be an online data entry system managed from HRP/RHR.
Expected Outcomes: The main objective of this trial is to evaluate if carbetocin RTS 100µg IM is non-inferior to oxytocin 10 IU IM, as uterotonic during the third stage of labour, in preventing postpartum haemorrhage. If the trial objective is achieved, uterotonic PPH prevention coverage will be substantially expanded.
This trial forms part of the programme of work to reduce maternal deaths due to postpartum haemorrhage within the RHR department in collaboration with other research groups and organizations active in the field.
2.Description of the project
2.1Background information and rationale
Postpartum haemorrhage (PPH) is defined as a blood loss of 500 mL or more within 24 hours of delivery, while severe PPH (sPPH) is defined as a blood loss of 1000 mL or more within the same time frame1. 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.
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. Other injectable uterotonics and misoprostol are accepted as alternatives for the prevention of PPH in settings where oxytocin is not available .
Despite oxytocin being a well-known and extensively studied peptide hormone, there is limited information on its stability at tropical temperatures, mainly at extreme climate conditions5.The manufacturer recommends storage under refrigeration in most countries and there is general acknowledgement that cold storage would help to maintain quality of oxytocin especially in settings where it is difficult to obtain cold storage regularly. In low resource settings, it can be challenging to keep the drug at the right temperature. To ease this barrier, several groups have been researching heat stable oxytocin formulations6. Though some progress has been made in this area, the fact still remains that there is currently no heat stable oxytocin formulation for therapeutic use7.
Carbetocin appears to be a promising agent in the prevention of PPH. The clinical and pharmacological properties of carbetocin are similar to those of oxytocin. However, carbetocin is a more stable molecule and induces a prolonged uterine response, when administered postpartum, in terms of both amplitude and frequency of contractions due to its longer half-life.
In a Cochrane systematic review8, including11 studies (2635 women), six compared carbetocin with oxytocin; four of these were conducted in women undergoing caesarean deliveries, one was for women following vaginal deliveries and one did not state the mode of delivery clearly. The carbetocin was administered as 100 μg intravenous dosage across the trials, while oxytocin was administered intravenously but at varied dosages. Use of carbetocin resulted in a statistically significant reduction in the use of additional/therapeutic uterotonics (risk ratio (RR) 0.62; 95% confidence interval (CI) 0.44 to 0.88; four trials, 1173 women) compared to oxytocin for those who underwent caesarean section, but not for vaginal delivery. Compared to oxytocin, carbetocin was associated with reduced uterine massage following both caesarean delivery (RR 0.54; 95% CI 0.37 to 0.79; two trials, 739 women) and vaginal delivery (RR 0.70; 95% CI 0.51 to 0.94; one trial, 160 women). There were no statistically significant differences between carbetocin and oxytocin in terms of risk of any PPH or in risk of sPPH. Cost-effectiveness of carbetocin was investigated by one study published as an abstract, with limited data. Results from this Cochrane systematic review are not conclusive as they are based on small studies (11 studies, 2635 women), mostly assessing carbetocin for caesarean deliveries and there is very little data on substantive clinical endpoints such as maternal morbidity and blood loss ≥1000 mL. Further research is needed to evaluate the effectiveness of carbetocin in preventing PPH in vaginal deliveries.
Biochemical characteristics of carbetocin
Carbetocin (1-deamino-1-monocarba-(2-0-methyltyrosine)-oxytocin) is a long-acting synthetic agonist analogue of the human oxytocin9, resulting from the deamination of the N-terminal and the replacement of the 1-6 disulphide bridge by a methyl ether group. These structural modifications protect the molecule from the aminopeptidase and disulphidase cleavage and prolong its pharmacological effect10. The terminal elimination half-life of carbetocin after intravenous (IV) administration is approximately 40 minutes, while that of oxytocin is 4-10 minutes11-13. In animal models, carbetocin appeared to be less potent than oxytocin, but a significantly longer duration of action in vivo was consistently demonstrated14.Carbetocin100 µg/mL was first approved in Canada in June 1997 and is currently registered inmore than 70 countries under the trade names PABAL/DURATOCIN/ LONACTENE/DURATOBAL for prevention of uterine atonyfollowing delivery of the baby by caesarean section under epidural or spinal anaesthesia. In addition, carbetocin has been approved following vaginal delivery of the infant in Kazakhstan, Mexico and Russia, and there are several trials with carbetocin in women with vaginal delivery in the published literature15-20. The drug is licensed to be administered by slow IV single injection at a dose of 100 µg. Its current formulation requires refrigeration and therefore, cold-chain within the supply chain.
The manufacturer of carbetocin (Ferring Pharmaceuticals) has recently developed a room temperature stable variant, carbetocin solution for injection RTS (carbetocin RTS), which makes it an attractive option for countries where maintaining the cold chain is problematic. Current data indicates that the carbetocin RTS is stable for up to 36 months at 30°C.Carbetocin RTS differs from the current carbetocin formulation only in its excipients. In other words, the actual chemical structure of the carbetocin molecule is the same. The chemical components of the two molecules are described in table 1 below.
Table 1. Composition of carbetocin RTS and carbetocin
New carbetocin RTS formulation / Current carbetocin refrigerated formulationComponent / Function / Component / Function
Carbetocin / Active substance / Carbetocin / Active substance
Succinic acid / Buffer / Sodium chloride / Isotonicity agent
Mannitol / Isotonicity agent / Glacial acetic acid / pH adjustment
L-Methionine / Antioxidant / Water for injection / Solvent
Sodium hydroxide / pH adjustment
Water for injection / Solvent
Background to the Merck for Mothers-Ferring-WHO project
Merck for Mothers is a project launched by Merck Group in response to the United Nations Secretary General’s Global Strategy for Women’s and Children’s Health. Merck for Mothers focuses on postpartum haemorrhage and hypertensive disorders of pregnancy as priority areas.
Merck for Mothers, Ferring Pharmaceuticals and the World Health Organization met to discuss the evaluation of the carbetocin RTS as a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain. Following this initial meeting, 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 fourconsiderations:
(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 the Merck for Mothers Initiative 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.
2.2Risk-Benefit Ratio
This clinical trial will be conducted in compliance with the clinical trial protocol, good clinical practice21and the applicable regulatoryrequirements. The risk-benefit relationship has been carefully considered in the planning of the trial. Based on the pre-clinical and clinical data available to date, the conduct of the trial is considered justifiable using the dose(s) and dosage regimen(s) of the Investigational Medicinal Product(s) (IMPs) as specified in this clinical trial protocol. In this trial, a Data Safety Monitoring Committee(DSMC) has been established for the on-going assessment of the risk-benefit ratio. The trial shall be discontinued in the event of any new findings that indicate a relevant deterioration of the risk-benefit relationship and would render continuation of the trial unjustifiable.
2.3Study hypothesis and objectives
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.
These two primary objectives are independent because they respond to different initiatives. If the trial is successful regarding objective (1), the experimental intervention would be registered for the indication “prevention of postpartum haemorrhage” by stringent drug regulatory authorities.If it is successful regarding objective (2), the experimental intervention would be included in future WHO guidelines and the Model List of Essential Medicines. See section 2.6.8 for more details.
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≥500mL or use of additional uterotonic drugs after vaginal delivery within a non-inferiority margin of 1.16 on the relative risk scale (objective (1)),andthe proportion of women with blood loss ≥1000mLafter vaginal deliverywithin a non-inferiority margin of 1.23 on the relative risk scale (objective (2)). Rationale: 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 RTSare beingmore heat-stable than oxytocin and havinga 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 ≥500mL or use of additional uterotonic drugs (objective (1)), andin terms of the proportion of women with blood loss≥1000mLafter vaginal delivery (objective (2)). For each of the two primaryendpoints, superiority will be tested if non-inferiority has been demonstrated.
Rationale: Superiority of the new treatment for the primary outcome would be an additional benefit. If carbetocin is demonstrated to be superior to oxytocin in efficacy, it would be the preferred option.
2.4Study conceptual framework
The trial’s research question is the following:
In women delivering vaginally, is carbetocin RTS 100 µg IM non-inferior to oxytocin 10 IU IM when used as uterotonic during the third stage of labour, in preventing PPH or additional uterotonic use and sPPH?
The conceptual framework for the research question outlined following the PICOT format is as follows: