CONFIDENTIAL
FOR WHO USE ONLY
Date 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 noninferiority controlled trial.
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Sponsor
Trial coordination unit
Principal investigators
Department of Reproductive Health & Research
World Health Organization
Avenue Appia 20
1211 Geneva 27
Switzerland
A. Metin Gülmezoglu (Trial coordinator)
Mariana Widmer (Trial manager)
Gilda Piaggio (Trial statistician)
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. Wanderley Taffo, nº 330 – Quintino Facci II - CEP 14070-250
Ribeirão Preto - 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
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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
Rahima Moosa Mother-and-Child Hospital
c/o Fuel & Oudtshoorn Street
Newclare
2112 Johannesburg
SOUTH AFRICA
Dr Pisake Lumbiganon
Faculty of Medicine - Khon Kaen University
Khon Kaen 40002
THAILAND
Dr Josaphat Byamugisha
Department of Obstetrics and Gynecology
Makerere University College of Health Sciences
Mulago Hospital
Kampala
UGANDA
Dr Arri Coomarasamy
Gynaecology and Reproductive Medicine
Birmingham Women’s NHS Foundation Trust
Mindelsohn Way Edgbaston Birmingham B15 2TG
UNITED KINGDOM
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Contents
1.
Project summary ___________________________________________________________ 8
2.
Description of the project ____________________________________________________ 9
2.1
Background information and rationale ____________________________________________ 9
2.2
Risk-Benefit Ratio ____________________________________________________________ 11
2.3
Study hypothesis and objectives _________________________________________________ 11
2.4
Study conceptual framework ___________________________________________________ 12
2.5
Study design _________________________________________________________________ 13
2.6
Procedures __________________________________________________________________ 13
2.6.1
Study centres ________________________________________________________________ 13
2.6.2
Study participants ____________________________________________________________ 13
2.6.3
Randomization and allocation __________________________________________________ 14
2.6.3.1 Unblinding of individual participant treatment _____________________________________ 13
2.6.4
Sample size calculation ________________________________________________________ 15
2.6.5
Description of the intervention __________________________________________________ 18
2.6.5.1 Description of the Investigational Medicinal Product ________________________________ 18
2.6.5.2 Packaging and labelling ________________________________________________________ 19
2.6.5.3 Handling and storage __________________________________________________________ 20
2.6.5.4 Dosage and administration _____________________________________________________ 20
2.6.5.5 Investigational Medicinal Product accountability ___________________________________ 21
2.6.5.6 Other drugs to be used in the trial _______________________________________________ 21
2.6.5.7 Concomitant medications and therapies __________________________________________ 21
2.6.6
Admission procedure _________________________________________________________ 23
2.6.7
Follow-up procedures _________________________________________________________ 23
2.6.8
Trial endpoints _______________________________________________________________ 23
2.6.9
Criteria for participant discontinuation ___________________________________________ 25
2.7
Study instruments ____________________________________________________________ 25
2.8
Project management __________________________________________________________ 25
2.8.1
Trial steering committee (TSC) __________________________________________________ 26
2.8.2
Data and safety monitoring committee (DSMC) ____________________________________ 26
2.9
Data quality assurance ________________________________________________________ 27
2.10
Data management ____________________________________________________________ 27
2.11
Data analysis plan ____________________________________________________________ 28
2.11.1
Final analysis ________________________________________________________________ 28
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2.11.2
Interim analysis ______________________________________________________________ 30
2.11.3
Analysis of secondary outcomes _________________________________________________ 31
2.12
Study timeline _______________________________________________________________ 31
2.13
Main problems anticipated and proposed solutions _________________________________ 31
2.14
Applicability of results _________________________________________________________ 32
2.15
Links with other projects _______________________________________________________ 32
3.
Gender considerations _____________________________________________________ 32
4.
Ethical issues _____________________________________________________________ 32
4.1.
Responsibilities of the Investigator_______________________________________________ 32
4.2
Forms required_______________________________________________________________ 33
4.2.1
Information sheet for participants _______________________________________________ 33
4.2.2
Informed consent form for participants ___________________________________________ 33
4.2.3
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ________________ 34
5.
Quality assurance and health authorities ______________________________________ 35
6.
Investigator site file and archiving ____________________________________________ 35
7.
Changes to the clinical trial protocol __________________________________________ 35
8.
Environmental impact of the project __________________________________________ 36
9.
Plans for dissemination and use of project results _______________________________ 36
10.
Clinical trial report and publication policy _____________________________________________ 36
11.
Research capacity strengthening _____________________________________________ 37
12.
References _______________________________________________________________ 37
Annex 1
Justification of the non-inferiority margin for the composite endpoint
Annex 2
The draft minutes of the MHRA meeting (9 December 2013)
Annex 3
Oxytocin product label
Annex 4
Informed consent
Annex 5
Centres’ characteristics
Annex 6
DSMC charter
Annex 7
HRP Standard operating procedures
Annex 8
CONSORT
Annex 9
Study timeline
Annex 10 WHO Data use regulations
Annex 11 Dummy tables
Annex 12 Interim analysis procedure
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Abbreviations
AER
Adverse Event Report form
CI
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
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1.
Project summary
Background: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in lowincome 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
stable carbetocin solution 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 mL or 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 100 µg 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.
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2.
Description of the project
2.1 Background 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 conditions 5. 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, including 11 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
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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. Carbetocin 100
µg/mL was first approved in Canada in June 1997 and is currently registered in more than 70
countries under the trade names PABAL/DURATOCIN/ LONACTENE/DURATOBAL for prevention of
uterine atony following 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, coldchain 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
Component
Function
Current carbetocin refrigerated formulation
Component
Function
Carbetocin
Active substance
Carbetocin
Active substance
Succinic acid
Mannitol
L-Methionine
Sodium hydroxide
Water for injection
Buffer
Isotonicity agent
Antioxidant
pH adjustment
Solvent
Sodium chloride
Glacial acetic acid
Water for injection
Isotonicity agent
pH adjustment
Solvent
Background to the Merck for Mothers-Ferring-WHO project
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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 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 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.
2.2 Risk-Benefit Ratio
This clinical trial will be conducted in compliance with the clinical trial protocol, good clinical
practice21 and the applicable regulatory requirements. 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.
2.3 Study 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.
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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 ≥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)). 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 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.
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.
2.4 Study 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:
P (participants): women who have had a vaginal birth.
I (intervention): carbetocin RTS 100 µg IM as uterotonic during the third stage of labour.
C (control): oxytocin 10 IU IM as uterotonic during the third stage of labour.
O (outcome): blood loss ≥1000 mL and ≥500 mL or additional uterotonics after vaginal delivery.
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T (timing of outcome measure): one hour or two hours postpartum if bleeding continues after one
hour.
2.5 Study design
This will be a hospital-based, multicenter, double-blind, randomized, non-inferiority, active
controlled trial in twelve countries. Each woman will be randomized within centres to receive
either oxytocin 10 IU IM or carbetocin RTS 100 µg IM.
A non-inferiority design was chosen because the aim of the trial is to determine if carbetocin RTS,
an alternative intervention with thermostability advantages, is similar in efficacy to the standard
intervention (oxytocin 10 IU IM).
Double-blindness will be ensured by placing identical ampoules (oxytocin and carbetocin RTS
ampoules will be identical in shape, size, colour and volume) in identical packs.
This clinical trial will be conducted in compliance with the clinical trial protocol, good clinical
practice (ICH Topic E6, GCP) and the applicable regulatory requirements.
2.6 Procedures
2.6.1 Study centres
Hospitals from Argentina, Brazil, Egypt, India, Kenya, Nigeria, Pakistan, Singapore, South Africa,
Thailand, Uganda and United Kingdom will participate. These centres, part of the WHO/HRP
research network, have a well-functioning antenatal care system with the capacity to monitor all
deliveries. They have extensive trial experience and can recruit substantial numbers of women. All
have expressed an interest in conducting this trial in compliance with good clinical practice, the
applicable regulatory requirements and the clinical trial protocol. These centres also agreed to
comply with procedures for data recording and to permit monitoring and auditing. Each centre,
before starting implementation of the trial, will sign the protocol to confirm agreement.
2.6.2 Study participants
Study participants will be pregnant women coming to the hospital for delivery.
Women will be eligible for the trial if:
 They 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. (see also section 2.6.6)

Known singleton pregnancy.
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.
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
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.
2.6.3 Randomization and allocation
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 µg 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.
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.
Randomization assignment will be kept confidential at the trial coordinating centre in WHO.
2.6.3.1 Unblinding of individual participant treatment
Trial coordinator, principal investigators and staff involved in the trial at the centres will be blinded
to the trial’s treatment. The trial statistician will not be blinded. Clinical circumstances that will
necessitate unblinding are not anticipated. However, an emergency decoding possibility (code
envelope) will be available to the investigator and designated person at WHO. Breaking of the
blind for individual participants in emergency situations is only permitted in case of a suspected
unexpected serious adverse reaction or in case of an important adverse event where the
knowledge of the IMP in question is required for therapeutic decisions for the management of the
participant. It may be necessary to unblind an individual participant’s treatment for the purposes
of expedited reporting of any unexpected serious adverse reaction (SUSAR) to the authorities
and/or Independent Ethics Committees / Institutional Review Boards. In that situation, every
effort will be made to maintain blinding of personnel involved in data analysis and interpretation.
Other personnel may be unblinded for SUSARs, including trial site staff.
In summary:

It is the investigator’s decision to unblind.
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
It is the investigator who says whether or not there is time for discussion with the trial
coordinator before unblinding.

In case of disagreement between the investigator and the trial’s coordinator, it is the
investigator’s opinion which prevails.

It is the wellbeing of the patient affected that overrides any other consideration.
The person who opens a code envelope must record on it the reason and the date of opening, and
then sign and date the opened envelope. It should be recorded in the CRF that the code is broken,
why, when and by whom. The investigator must record the event of unblinding in the participant’s
medical record, including the reason for unblinding, but not the treatment allocation if this can be
avoided.
Information on whether the blinding has been broken for any participants will be collected before
the database is declared clean and is released to the statistician at the end of the project.
2.6.4 Sample size calculation
There are two important endpoints that guide the sample size estimation for the trial. These are:
severe postpartum haemorrhage (sPPH), defined as blood loss ≥1000 mL, and postpartum
haemorrhage (PPH) defined as blood loss ≥500 mL or the use of additional uterotonics. Severe PPH
is a more serious endpoint that is closer to severe maternal morbidity and related to additional
interventions. The sPPH endpoint is also less frequent and thus guides the overall sample size
estimation.
A requisite to determine the sample size for a non-inferiority trial is to define the margin of noninferiority (Δ) for the difference in effectiveness between the active control and the new
treatment. Because proof of exact equality is impossible, non-inferiority is defined within a certain
margin, which is the maximum magnitude of the difference considered clinically non-relevant, or
the minimum magnitude of the difference which is considered clinically relevant.
As opposed to superiority trials, non-inferiority trials need external data to demonstrate that the
new treatment is effective. There should be evidence that the active treatment is effective
compared to placebo, because if it is not, the non-inferiority trial might demonstrate noninferiority of two ineffective treatments. When placebo cannot be included in the trial, the effect
of the active treatment compared to placebo should be searched in historical (past) trials 22, 23.
In order to construct a plausible non-inferiority margin the following evidence has been
considered. The active treatment is active management of the third stage of labour with oxytocin
10 IU as uterotonic. Placebo is expectant management, in which signs of placental separation are
awaited and the placenta is delivered spontaneously. We looked at the following Cochrane
systematic reviews for relevant comparisons: Begley 201124, which includes the comparison active
versus expectant management for blood loss ≥1000 mL. However, among the three trials included
in this comparison, two did not use oxytocin and in one only 19% of the women did, so active
management is mostly using other uterotonic different to oxytocin. Cotter 2011 25 includes the
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comparison oxytocin versus no uterotonics for blood loss ≥1000 mL. However, it is not clear
whether 'oxytocin' is part of a package of active management and whether 'no uterotonics' implies
expectant management. We concluded that the constancy assumption (that the historical
difference between the active control and placebo holds in the setting of the new trial if a placebo
control were used) would not hold 23.
Therefore it was decided to use reliable estimates of prevalence of blood loss ≥1000 mL under
active management with oxytocin as part of the package and under expectant management,
coming from different trials or systematic reviews. With active management, the risk of sPPH was
estimated as 2% in a multicenter large trial26. With expectant management, the systematic review
of Carroli et al 27 reported a prevalence of 3.84 (95% CI 3.31 to 4.37). We considered that
prevalence of 2% for active management with oxytocin as part of the package, and of 3.84% for
expectant management were reliable, so that the effect of the active control would be 1.84%.
The following step was to use a clinical criterion to preserve a minimal fraction of the risk
reduction provided by the active control22, 23. Taking 1.84% as an estimate of the effect of active
management with oxytocin over expectant management, a reasonable criterion is to preserve 75%
of this benefit (which corresponds to an effect of 1.38% for carbetocin RTS over expectant
management). Preserving a higher percentage (say 80% or 90%) will push the sample size
calculations very high while a smaller percentage (say 50%) may not be considered acceptable.
To preserve 75% of the benefit of oxytocin over expectant management, assuming a 3.84% risk of
sPPH with expectant management and 2% with oxytocin as part of the active management
package, provides a margin of non-inferiority of Δ=(1-0.75) x (3.84-2)= (1-0.75) x 1.84=0.46%
(Figure 1). In relative terms (relative risk), this gives a margin of non-inferiority of
[2 + 0.46] / 2 = 2.46 / 2) = 1.23.
The above margin Δ reflects the clinical judgment about how much of the effect of the active
control should be preserved by ruling out a loss of Δ 23.
Figure 1. Determination of the non-inferiority margin Δ using past trials estimates for expectant
management and for full active management with oxytocin as uterotonic
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In addition, to complete the clinical assessment of this margin, we considered the number of
women needed to be treated for one additional patient to be harmed (NNH). The lower the NNH,
the worse is the new treatment compared to the standard. In the context of this non-inferiority
trial, the margin of non-inferiority Δ is the minimum magnitude of the difference in the proportion
of women with blood loss ≥1000 mL (carbetocin RTS-oxytocin) which is considered clinically
relevant. The margin in terms of NNH is the reciprocal of Δ. It is calculated as 100/0.46=217. This
means that non-inferiority will be demonstrated if NNH is 217 or more. This difference is
considered to be clinically meaningful for decision making.
It is expected that carbetocin RTS will not be worse in effectiveness compared to oxytocin. If
carbetocin RTS happens to be better, the sample size required to demonstrate non-inferiority will
be smaller compared to the case in which the two treatments are supposed to be equally
effective. Therefore the maximum sample size will be calculated assuming equal sPPH prevalence
for the two products.
Table 2 and Figure 2 show the total sample size required to assess non-inferiority at the 2.5% level
for different scenarios.
Table 2. Total sample size for non-inferiority with different scenarios
Assumed
sPPH rate
for
oxytocin
(%)
1.5
Assumed NI margin
sPPH rate
∆ (%)
for
carbetocin
Relative
NI margin
Power (%)
80
90
(%)
1.5
0.4
1.27
28282
37860
0.46
1.31
21454
28720
0.5
1.33
18932
25344
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2.0
2.0
0.4
1.20
38460
51488
0.46
1.23
29082
38932
0.5
1.25
24616
32952
Figure 2. Total sample size for non-inferiority with equal proportions=1.5% or 2%, 80% power and
different values of the margin on the relative scale
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 (see section 2.11), 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.
The above sample size makes assumptions that in reality might not hold. For example, if the
efficacy of oxytocin is much better than that of carbetocin RTS, this would imply that noninferiority is not likely to be demonstrated and the trial should be stopped for futility. If oxytocin is
just slightly better than carbetocin RTS, the sample size above could have been underestimated,
but this is not likely given previous evidence (see background, Cochrane systematic review8).
Similarly, we have calculated the sample size for the composite endpoint defined as blood loss
≥500 mL or administration of additional uterotonics. With active management, the risk of this
event was estimated as 16% in the Gulmezoglu et al trial26(personal communication). Assuming
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equal prevalence for this event of 16% with both treatments, in order to demonstrate noninferiority within a margin of 1.16 on the relative scale (equivalent to a margin of 2.6% on the
absolute scale), with a power of 80% and with a significance level of 2.5%, a total of 6242 women
are needed. With 30,000 women the power obtained would be more than 99%. This sample size
will provide a power of 99.5% for a conventional two-sided 5% test of superiority to detect a
minimum significant difference between 16% and 18% in the occurrence of PPH or administration
of additional uterotonics of the two treatment products. See Annex 1 for the justification of the
non-inferiority margin for this composite endpoint.
The estimates from the centres that have expressed interest in participating in the trial indicate
that close to 30,000 women can be recruited in a 12 month recruitment period.
2.6.5 Description of the intervention
The trial’s intervention (Investigational Medicinal Product - IMP) consists of Carbetocin RTS 100
µg/mL IM (investigational drug undergoing trial), as well as of Oxytocin 10 IU IM (comparator
drug).
The investigator will provide the woman the trial’s treatment immediately after the birth of the
baby (preferably within one minute). Once the treatment is provided the investigator will follow
the management of the third stage of labour as recommended in WHO guidelines 1 (see details in
the trial’s manual of operations).
2.6.5.1 Description of Investigational Medicinal Product
Carbetocin RTS is a heat-stable formulation of carbetocin 100 µg/mL solution for injection (1mL
ampoule) developed by Ferring Pharmaceuticals. The oxytocic activity is approximately 50 IU of
oxytocin/ampoule. The local tolerance safety of the carbetocin RTS has been assessed based on
single intramuscular and intravenous injection in rabbits. No clinically meaningful treatment
related differences were revealed by macroscopic and histopathological examinations between
Carbetocin RTS and the reference product PABAL®. In addition, the local irritative potential of both
formulations were lower after intramuscular administration compared to the intravenous route.
Table 2 shows the composition of carbetocin RTS. The stability data from long-term studies
performed at 30°C/75% relative humidity (RH) and accelerated at 40°C/75% RH indicate that a
shelf life of at least 36 months at 30°C is feasible for the new heat-stable formulation of
carbetocin.
Table 2. Composition of carbetocin RTS formulation
Ingredient
Amount (mg/mL)
Carbetocin
0.100
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Mannitol
47.0
Succinic acid
1.19
L-Methionine
1.00
Sodium hydroxide 2 N
to pH 5.45
Water for injection
a.d. 1.0 mL
As mentioned earlier in the protocol (section 2.1) the active substance remains the same as in the
currently approved carbetocin product and the excipients are already approved for injections.
In addition, in two scientific advice meetings with the UK Medicines and Health products
Regulatory Agency (MHRA) in March 2011 and the 9 December 2013 where HRP/RHR was present,
the MHRA concluded that the available clinical and non-clinical documentation (i.e. local
tolerability and blood compatibility) for carbetocin RTS is considered sufficient to support a single
intramuscular dose of up to 100 µg to women (MHRA 2011 letter included in annex 2).
Oxytocin 10 IU/mL is the comparator of carbetocin RTS and is a solution for injection (1 mL
ampoule). It is a product manufactured by Novartis (trade name Syntocinon). The excipients are
sodium acetate, glacial acetic acid, chlorbutol, ethanol, water for injections. The approved product
label is enclosed in Annex 3.
Figure 2. Molecular description of carbetocin RTS and oxytocin.
2.6.5.2 Packaging and labelling
Packaging and labeling will be done in accordance with applicable local regulatory requirements
and applicable good manufacturing practice guidelines (GMP).
Carbetocin RTS will be supplied in single-use 1 mL ampoule containing 100 µg carbetocin RTS. It
will be packed in a suitable box which is labeled with (but not limited to) the following required
information: trial number, number of ampoules per box, route of administration, storage
condition, the words “For clinical trial use”, participant number (randomization number), lot
number, expiry date and the Sponsor.
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Oxytocin will be supplied as a single-use ampoule containing 10 IU oxytocin. It will be packed in a
suitable box which is labeled with (but not limited to) the following required information: trial
number, number of ampoules per box, route of administration, storage condition, the words “For
clinical trial use”, participant number (randomization number), lot number, expiry date and the
Sponsor.
2.6.5.3 Handling and storage
The IMPs (carbetocin RTS and oxytocin) shall be stored in the original package in a locked
refrigerator at 2°C to 8°C.
Do not freeze carbetocin RTS or oxytocin.
Any temperature excursion from the recommended storage conditions should be immediately
reported to the Sponsor, and the IMP should not be used until authorization for use has been
received from the Sponsor. Centres will be provided with a temperature monitoring sheet for
fridges where the IMP is stored. Temperatures inside the fridge will be checked twice during the
day (morning, late afternoon). These sheets will be controlled by the monitors during the site
visits.
Both Carbetocin RTS and oxytocin are presented as a 1 mL solution in an ampoule (type I glass).
Since an opened ampoule cannot be resealed in such a way to further guarantee the sterility of
the contents, the solution should be used immediately after opened. Any remaining solution, the
empty ampoule and the broken pieces after single use should be stored into a special container
for infectious wastes.
IMP will be discarded only after IMP accountability has been performed by the Monitor. The
pharmacy will handle the IMP in accordance with the IMP Handling Procedure.
The ampoule(s) shall be left at room temperature for the shortest possible time before
administration.
The reason for keeping both trial interventions in a refrigerator is to provide the comparison
between oxytocin and carbetocin at the optimal storage condition for oxytocin. If both products
are kept at room temperature then this may provide an unfair advantage to carbetocin since there
may the possibility of oxytocin deterioration while awaiting use in the trial.
The current heat stability data of carbetocin RTS has been provided by Ferring to WHO.
2.6.5.4 Dosage and administration
The IMPs will be administered, as a single IM dose of 100 µg (in a 1 mL solution) for carbetocin RTS
and as a single IM dose of 10 IU (in a 1 mL solution) for oxytocin, to the participant as soon as
possible after the birth of the baby, preferably within one minute, once all of the pre-defined IMP
administration criteria are met (see Section 2.6.3).
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2.6.5.5 Investigational Medicinal Product (IMP) accountability
The Investigator is responsible for ensuring accountability for IMP, including reconciliation of drugs
and maintenance of drug records.
Upon receipt of IMP, the Investigator (or designee) will check for accurate delivery and
acknowledge receipt by signing (or initialing) and dating the documentation provided by the
Sponsor and returning it to the Sponsor. A copy will be retained for the Investigator File.
The dispensing of the IMP will be carefully recorded on the appropriate drug accountability forms
provided by the Sponsor and an accurate accounting will be available for verification by the
Monitor at each monitoring visit. IMP accountability records will include:





Confirmation of IMP delivery to the trial centre.
The inventory at the centre of IMP provided by the Sponsor.
The use of each dose by each participant.
The return to the Sponsor or alternative disposition of unused IMP.
Dates, quantities, batch numbers, expiry dates and participants’ trial numbers.
The Investigator should maintain records that adequately document:
 That participants were provided the doses specified by the clinical trial
protocol/amendment(s), and
 That all IMP provided by the Sponsor was fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. IMP that
has been dispensed to a participant must not be re-dispensed to a different participant.
The Monitor will periodically collect the IMP accountability forms and will check all returns (both
unused and used containers) before arranging for their return to the Sponsor or authorizing their
destruction by the trial site.
2.6.5.6 Other drugs to be used in the trial
There is no other drug whose use is mandated by the clinical trial protocol.
2.6.5.7 Concomitant medications and therapies
Permitted medicines and interventions
Any medications (other than those excluded by the clinical trial protocol) that are considered
necessary for the participant’s welfare and will not interfere with the trial medication may be
given at the discretion of the clinician in charge. The Investigator will record all concomitant
medications taken by the participant during the trial, from the date of signature of informed
consent, in the appropriate section of the CRF.
Additional interventions or examinations due to uterine atony and/or blood loss are permitted.
Any additional interventions or examinations due to PPH or a suspicion of PPH should be
performed according to WHO recommendations for atonic PPH management and should be
recorded.
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Non-permitted medicines
Any additional concomitant therapy that becomes necessary during the trial must be recorded in
the corresponding section of the CRF, noting the name, dose, duration and indication of each
drug.
2.6.6 Admission procedure
The care provider in charge of antenatal care visits at the hospital will inform potentially eligible
pregnant women (women with no allergies to carbetocin, other oxytocin homologues or
excipients, or serious cardiovascular disorders) about the trial and will invite them to sign the
consent form. (Annex 4 - Information sheet during ANC and consent form).
At admission for labour at the hospital, if the woman has a cervical dilatation of 6cm or less, is
expected to deliver vaginally and if she meets the eligibility criteria (protocol item 2.6.2) the
investigator will ask her to confirm her willingness to participate in the trial and sign again the
consent form. If the woman is seen for the first time in the labour ward, she will be invited to give
informed consent only if she is in early labour, the vital signs are normal and she is not stressed.
For purposes of clarity, signs that will be considered as indicating stress are tachycardia and
tachypnea as well as the woman presenting in general state of distress.
In the second stage of labour when vaginal delivery is imminent, the investigator will assign the
woman the treatment. At this point the woman is considered to be part of the trial.
2.6.7 Follow-up procedures
Once the cord is clamped (1-3 minutes after delivery of the baby) and cut, the investigator will
place the drape under the woman’s buttocks and blood loss will be measured for one hour or two
hours postpartum if the bleeding continues beyond one hour.
The woman will end her participation in the trial after discharge or if transferred to a higher care
unit. For the latter, data will be collected in a serious adverse event report form.
2.6.8 Trial endpoints
The primary endpoints are:
i.
ii.
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.
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.
Blood loss will be measured using a calibrated drape 28. The details of the procedure are provided
in the trial’s manual of operations. Blood loss weight in grams will be converted to milliliters by
dividing the figure in grams by 1.06 (blood density in grams per milliliter)29.
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Justification of primary endpoints: The trial will have two primary endpoints. In third stage of
labour trials, blood loss measurements are the preferred endpoints. Since it is not possible to
predict which women will bleed and oxytocin is safe and effective in reducing blood loss, all
women are offered oxytocin prophylactically to reduce blood loss and to reduce the likelihood of
severe adverse outcomes. While volume of bleeding itself is not morbidity per se, it is in the
pathway to severe adverse outcomes including death.
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
stringent drug regulatory authorities if it is shown to be non-inferior or superior to the gold
standard control. 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 clinical effectiveness and
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 panel30.
Since the two primary endpoints serve independent objectives, we will not adjust the Type I error
rate for multiplicity of endpoints.
Secondary outcomes are:

proportion of women with blood loss of 500mL or more within one hour (or two hours
postpartum if the bleeding continues beyond one hour).

blood loss in mL within one hour (or two hours postpartum if the bleeding continues
beyond one hour).

proportion of women receiving additional uterotonics within one hour (or two hours
postpartum if the bleeding continues beyond one hour).

proportion of women receiving additional uterotonics up to time of discharge.

proportion of women receiving blood transfusion up to time of discharge.

proportion of women with manual removal of placenta up to time of discharge.

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.

proportion of maternal death.

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.
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
incidence and severity of adverse or serious adverse events up to time of discharge.
An adverse event is defined as any untoward medical occurrence in a participant who received the
trial’s treatment and who does not necessarily have a causal relationship with this treatment. All
adverse events up to time of discharge will be recorded in Adverse Event Report form (AER), which
will collect information on the nature of the event, the relatedness of the event to the
intervention, timing of the event, treatment for the event, and date of resolution. Report and
handling of AER will be in accordance with GCP guidelines.
An adverse event is considered serious when it results in death, is life-threatening, causes
prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or
requires intervention to prevent permanent impairment or damage. Serious adverse events up to
time of discharge will be recorded in Serious Adverse Event Report forms. SAE will be returned by
the investigators to the trial coordination unit within 24 hours of the event. The trial coordination
unit will then transmit any information on SAEs related to the use of the IMP to the WHO Ethics
committee as well as to the relevant authorities in the countries where the trial is conducted as
well as to Ferring.
2.6.9 Criteria for participant discontinuation
Women would be discontinued from the trial if:
a. Informed consent is withdrawn. Women will have the right to withdraw from the trial and to
withdraw Informed Consent. Women who withdraw will not be replaced, i.e., randomized
numbers will be uniquely linked to each participant. These women will be asked if the data
collected until that point could be included in the final analysis.
b. Baby is delivered by caesarean section. In the previous 3rdstage labour trials despite all efforts to
randomize women when vaginal delivery was more or less certain, around 3% of women were
eventually delivered by caesarean section. This is unavoidable, given the unpredictable nature of
births even at such a late stage. Those women will be documented and excluded from the analysis
since eligibility changes and the primary outcome assessment is no longer reliable.
2.7 Study instruments
Data for the trial will be collected in case report forms (CRFs). Instructions on how to complete the
CRFs as well as how to collect the blood loss will be in the trial’s Manual of Operations.
CRFs will be developed by the coordinating unit, approved by the Forms Review Committee at
WHO and validated (dry run) at each of the participating centres three months before starting
recruitment.
2.8 Project management
The trial will be coordinated and managed by the trial coordination unit at HRP/RHR in WHO. WHO
(sponsor) will be responsible for writing the protocol, registering the trial as well as for any
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resulting publication from the trial independent of the funder (Merck for Mothers) and the
manufacturer of the trial drugs (Ferring).
The trial coordination unit will monitor at each of the participating centres the progress of the trial
including adherence to the trial’s protocol, patient withdrawals, non-compliance, AER and SAE
through a clinical research organization (CRO). The CRO will ensure smooth flow of the data,
detect discrepancies between CRFs, hospital records and what was recorded in the web database
through regular visits to the sites.
The following committees and personnel will contribute to the coordination of the trial.
2.8.1 Trial steering committee (TSC)
The TSC is expected to provide overall supervision for the trial as well as to ensure that the trial is
conducted to the rigorous standards set out in the International Conference on Harmonization
(ICH) 21. The TSC will concentrate on progress of the trial, adherence to the protocol, and the
consideration of new information of relevance to the research question. The TSC will give advice
on any matter arising from the conduct or management of the trial.
The TSC will be constituted by:






Chairperson: Professor James Neilson (University of Liverpool, UK)
Trial coordination unit (WHO Secretariat): A. Metin Gülmezoglu (Trial coordinator);
Mariana Widmer (Trial manager); Armando Seuc (statistician).
Trial statistician: Gilda Piaggio
Principal investigators from the participating centres (Annex 5 – centres’ details)
Independent experts: Michel Boulvain (University of Geneva, Switzerland), Guilherme
Cecatti (University of Campinas, Brazil - tbc), Lelia Duley (Professor of Clinical Trials
Research, Director, Nottingham Clinical Trials Unit, Nottingham, United Kingdom –tbc)
Observers: One representative each from Merck for Mothers and Ferring will participate at
the Steering Committee meetings. The participation of one Merck and one Ferring
representative as observers at the trial steering committee meetings was checked and
endorsed by the WHO Legal Counsel.
2.8.2 Data and safety monitoring committee (DSMC)
A Data Safety Monitoring Committee (DSMC) with no direct involvement in the trial will be
appointed (see DSMC charter – Annex 6). The role of the DSMC will be to deal with any ethical
issues that may arise while the trial is in progress, and to scrutinize an interim analysis. The DSMC
will be expected to provide an ongoing evaluation of risk-benefit that addresses the uncertainty
necessary to continue.
The following individuals are being approached to serve in the DSMC:
Justus Hofmeyr (South Africa) - obstetrician and gynaecologist
Catherine Deneux-Tharaux (France) - epidemiologist
Daniel Wojdyla (USA) – statistician
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Diana Elbourne (UK) – statistician, trialist
The DSMC Damocles charter prepared by the WHO Coordination Unit is presented in annex 6.
2.9 Data quality assurance
The WHO coordinating unit will be responsible for implementing and maintaining the quality
assurance and quality control systems with HRP standard operating procedures (SOPs) (Annex 7)
to ensure that the trial is conducted and data generated, recorded and reported in compliance
with the protocol, GCP and the applicable regulatory requirements.
Quality control will be applied to each stage of data handling to ensure that all data are reliable
and have been processed correctly.
Monitoring visits will be made by the CRO and the WHO coordinating unit following HRP standard
operating procedures. The purpose of these visits will be to ensure the quality and accuracy of
data collected on the CRFs as well as data entered into the web system, determine that all
regulatory requirements surrounding clinical trials are met, and ensure that the study protocol is
being followed as written. During monitoring visits, study monitors will be given access to primary
source documentation that supports data entered into the original study CRFs, i.e. the original
patient records or registers. At each monitoring visit, 100% of the informed consents and 100% of
the CRFs’ blood loss and additional uterotonics variables will be verified against source
documents . In addition, all SAE forms will be verified against source documents.
A detailed clinical monitoring plan will be developed for the study. The monitoring plan will
specify the responsibilities and qualifications of the study monitors, back-up provisions, in-house
monitoring procedures, and site monitoring visit schedule and procedures. All monitoring visits
will be documented and reports written specifying any problem with conduct of the study or
quality of the data that needs to be addressed.
The study will be registered at http://www.anzctr.org.au/ before the start of data collection and
study results will be reported according to CONSORT guidelines 31. (Annex 8)
2.10 Data management
Data will be collected according to the trial’s CRFs. Age and parity will be registered, as well as
baseline conditions, concomitant medications, information pertaining to labour and delivery.
Instructions on how to complete the CRFs will be explained in the trial’s Manual of Operations.
Data will be collected prospectively by the investigator at the centre. Initial data collection will be
on paper CRFs and then data will be entered at each of the participating centres into a web-based
GCP compliant data management system for clinical trials, developed by the Centro Rosarino de
Estudios Perinatales, institution to which data management will be outsourced . All data will be
stored in a GCP compliant server with automatic backups, and data transmission will be encrypted
to assure data integrity and patient confidentiality. Access to the data management web system
will be password protected and only authorized users will have access. Data queries will be sent to
the centres on standardized query forms for further clarification. Data changes will be
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documented through an audit trial incorporated in the system. The procedure will be compliant
with 21 CFR Part 11 of the Code of Federal Regulations that deals with the United States Food and
Drug Administration (FDA) guidelines on electronic records.
Data entered into the web system will be checked by the data management team at WHO
coordinating unit on a weekly basis for completeness, accuracy, reliability and consistent intended
performance. The data management team will be responsible for generating the interim and final
data report.
Monitors, contracted from a CRO, will be visiting the centers regularly to ensure data quality.
These procedures have been used in previous HRP multicentre trials and proven to be efficient
and compliant with the HRP/WHO Standard Operating Procedures as well as with the 21 CFR Part
11 of the Code of Federal Regulations that deals with the United States Food and Drug
Administration (FDA) guidelines on electronic records.
2.11 Data analysis plan
2.11.1
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). In superiority trials an intention-to-treat analysis (ITT) is used in the primary
analysis because it will generally diminish the estimated treatment effect, being thus conservative.
In non-inferiority trials, on the other hand, use of ITT analysis is generally not conservative:
“Subjects who withdraw or drop out of the treatment group or the comparator group tend to have
a lack of response, and hence the results of using the full analysis set may be biased toward
demonstrating equivalence” or non-inferiority 32. Performing a PP analysis is desirable as a
protection from the increase in type I error risk in a non-inferiority test. In this trial, a modified ITT
analysis is defined by excluding only women having a caesarean section after randomization and
those 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.
We expect only a small number of protocol deviations and withdrawals because the personnel
involved in the study will receive intensive and continuous training and the trial will be closely
monitored by trial monitors. The DSMC will look at protocol deviations and withdrawals at interim
analysis by country and arm and discuss whether there is a concern. There may be withdrawals if a
woman who has earlier given consent and was randomly allocated to one group withdraws her
consent after randomization or she undergoes an emergency caesarean section after
randomization. These cases should be extremely rare since the random allocation will be made
when vaginal delivery is imminent.
Non-inferiority will be assessed using a two-sided 95% CI for the relative risk (RR) of sPPH and of
PPH or additional uterotonic use (carbetocin RTS vs. oxytocin). The upper limit of the two-sided
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95% CI for the RR for the 500 mL or additional uterotonic use endpoint will be compared to the
non-inferiority margin of 1.16. The upper limit of the two-sided 95% CI for the RR for the 1000
mL endpoint will be compared to the non-inferiority margin of 1.23. If the upper limit is below the
corresponding margin, non-inferiority will have been demonstrated. This upper limit is the same as
the upper limit of the one-sided 97.5% CI, therefore the significance level for the non-inferiority
test will be 2.5%. For each endpoint, if non-inferiority is demonstrated, a two-tailed superiority
test will be conducted at 5% level of significance. Interpretation will follow accepted guidelines 33.
Comparisons will also be expressed as risk differences with 95% confidence intervals.
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.
We will use the relative risk (RR) as measure of treatment effect on the relative scale for the two
primary endpoints. For the composite endpoint blood loss 500ml or more or use of additional
uterotonics, the margin has been justified as 1.2 on the odds ratio (OR) scale. To translate this
margin to the RR scale we use the following expression:
RR ~ OR/(1-Poxy+Poxy x OR) = 1.2/(1-0.15+0.15 x 1.2) = 1.17 for incidence of oxytocin=15%, or
= 1.2/(1-0.20+0.20 x 1.2) = 1.15 for incidence of oxytocin=20%,
where Poxy is the assumed prevalence for the control.
We define the margin on the RR scale as 1.16, which is the average of the two results from both
assumptions 15% and 20% as quoted in the justification document.
Heterogeneity across centres will be assessed by using a term in the logistic model for the
interaction between treatment and centres. If there is heterogeneity between the centres for any
of the results, the possible causes will be explored.
Analysis approach taken following the consultation with Medicines and Health Products Regulatory
Agency (MHRA), United Kingdom
The MHRA is an organization responsible for regulating all medicines and medical devices in the
UK. It also gives advice before regulatory trials are initiated on request of the sponsors and its
approval is often respected by other countries that may not have similar stringent assessment
capacity. The trial protocol and the overall approach were submitted to the MHRA (UK) for advice
and on 9 December 2013 a face-to- face meeting took place in London where representatives of
HRP/RHR, Ferring and Merck for Mothers were present. The draft minutes of the MHRA meeting
are presented in Annex 2.
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The MHRA agreed with the general approach and the specific questions posed to them overall.
The MHRA accepted that the probability of Type I error does not need to be adjusted for having
two primary endpoints if the two endpoints serve independent objectives.
2.11.2
Interim analysis
Two interim analyses will be conducted for review by the DSMC. The first interim analysis will be
conducted for the DSMC to look at safety when 5,000 have been recruited (2,500 per group). The
second interim analysis will be conducted when 15,000 women have been recruited (7,500 per
group) to look at both safety and efficacy.
At each of these two interim analyses, to look at safety the DSMC will be provided with an
unblinded description of adverse events (AE), including serious adverse events (SAE). The
descriptions of AEs and SAEs will be recorded in the trial’s data collection forms. In addition to
these descriptions, tables with numbers and percentages of AEs and SAEs by country and arm and
by arm for all countries combined will be provided. The difference between arms for the
occurrence of AEs and of SAEs will be tested using the country-stratified Mantel-Haenszel chisquare, if frequencies are sufficiently high or otherwise with exact methods taking stratification
into account, and using the Haybittle-Peto rule to determine the threshold for stopping.
For the second interim analysis, the DSMC will be requested also to give recommendations on
whether to stop the trial for reasons of efficacy or futility, based on the following criteria applied
to the sPPH endpoint only (see detailed procedure in Annex 12) and on unblinded data:
1. Conduct a two-sided test of hypothesis to assess superiority of one of the products, using
the Haybittle-Peto rule. If the result is significant at α=0.001, stop the trial for superiority of
carbetocin or of oxytocin (superiority of one of the products implies harm of the other
one).
2. Calculate the conditional power at interim, supposing the observed trend continues 34, 35. If
the conditional power is less than a certain threshold, stop the trial for futility. The
threshold depends on the true sPPH rate (see the results of simulations in Annex 12),
therefore it will be established afterestimating the sPPH rate at interim, to make sure the
probability of type I error is preserved at 2.5% and that the power is at least 80%.
3. If none of the previous stopping criteria are met, continue the trial until the end and test
for non-inferiority.
The interim analysis will be conducted on the basis of the risk difference as described in Annex 12.
For the test in 1 above, testing for the effect of treatment is equivalent whether it is based on the
absolute or on the relative scale. As for the conditional power calculation, a margin of noninferiority of 0.46% on the absolute scale will be used, equivalent to a margin of 1.23 on the
relative scale. The final analysis will be conducted as described in section 2.11.
The interim analyses will be masked to trial investigators, WHO, MfM and Ferring staff but not to
DSMC members and the trial statistician.
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2.11.3
Analysis of secondary outcomes
The secondary binary endpoints blood loss ≥500 mL, use of additional uterotonics, blood
transfusion, manual removal of placenta, additional surgical procedures, maternal death,
composite endpoint of maternal death or severe morbidity will be analyzed using the modified ITT
population and will be assessed only for conventional superiority using risk differences and
relative risks with 95% confidence intervals estimated with the same techniques described for the
main endpoints.
The secondary outcome blood loss in mL will be analyzed using the log transformation. This is
based on the following: 1) the blood loss distribution is positively skewed; 2) different distributions
were fitted to blood loss data from a large trial26 and the lognormal distribution was found to have
a very good fit (personal communication); and 3) the lognormal distribution was used for blood
loss data in the literature29. Therefore, a lognormal distribution will be fitted to the blood loss data
and the probabilities of blood loss 500mL or more and of 1000 mL or more will be compared
between treatments using parametric methods. The quintiles will be compared between
treatments using quintile regression36.
Safety analysis: The primary population for safety analysis will consist of 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. The betweentreatment difference for the occurrence of adverse events will be tested using the stratified
Mantel-Haenszel chi-square, if frequencies are sufficiently high or otherwise with exact methods
taking stratification into account.
Ferring will notify WHO and Merck, in writing, as soon as reasonably possible, of any information
resulting in a change of the risk benefit balance of the existing carbetocin and/or carbetocin RTS.
WHO will transmit any information on serious adverse events occurring in the course of the Trial
with respect to the use of the Product, to the relevant authorities in the countries where the Trial
will be conducted, as well as to Ferring.
2.12 Study timeline
It is anticipated that the recruitment into the study in the centres can be completed in
approximately 12 months. Recruitment will begin in September 2014 after approval by the local
competent authorities and materials have been procured and distributed to the study centres
(Annex 9).
2.13 Main problems anticipated and proposed solutions
One centre declared that in their routine practice the oxytocin is given intravenously. The principal
investigator of this centre is fully aware of the trial’s treatment route and committed to follow the
trial’s protocol. In order to avoid deviations of the protocol, this centre will be monitored closely in
this respect.
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2.14 Applicability of results
Results of this trial will be extremely useful, particularly in tropical settings, where cold storage is
difficult to achieve and maintain. Should this trial demonstrate that carbetocin RTS is non-inferior
to oxytocin in preventing postpartum haemorrhage, in settings where the cold chain could not be
guaranteed, oxytocin could be replaced by carbetocin RTS as the uterotonic used during the third
stage of labour.
2.15 Links with other projects
This trial is conducted as part of the maternal and perinatal health research programme of HRP for
the prevention and treatment of leading causes of maternal mortality. HRP/RHR has been working
with the WHO Maternal, Newborn, Child and Adolescent Health Department, United States
Agency for International Development (USAID), International Federation of Gynaecologists and
Obstetricians (FIGO) and the International Confederation of Midwives in developing standards and
identifying research needs in this field. The trial results will show whether oxytocin will remain as
the gold standard for PPH prevention or whether carbetocin RTS can replace oxytocin given its
other advantages and comparable public sector pricing.
3.
Gender considerations
Postpartum haemorrhage is one of the leading causes of maternal mortality worldwide. Improving
health care for women during childbirth in order to prevent and treat PPH is an essential step
toward the achievement of the MDGs as well as reducing inequities between women living in
developing and developed countries.
Investing in better maternal health not only improves a mother’s health and that of her family, but
also increases the number of women in the workforce and promotes the economic well-being of
communities and countries. Untreated pregnancy and birth complications mean that 10-20 million
women become disabled every year, undermining their ability to support their families.
4.
Ethical issues
4.1. Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at his/her centre. He/she will ensure
that the trial is performed in accordance with the clinical trial protocol and with the ethical
principles that have their origin in the Declaration of Helsinki, as well as with the ICH Note for
Guidance on GCP (ICH Topic E6)21 and applicable regulatory requirements. In particular, the
Investigator must ensure that only subjects who have given their informed consent are included
into the trial.
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An unconditional prerequisite for a woman’s participation in the trial is her written informed
consent. The woman’s written informed consent to participate in the trial must be given before
any trial-related activities are carried out.
4.2
Forms required
4.2.1 Information sheet for participants
Adequate information must therefore be given to the participant by the Investigator before
informed consent is obtained (a person designated by the Investigator may give the information, if
permitted by local regulations). A participant information sheet in the local language and prepared
in accordance with the Note for Guidance on GCP21 will be provided by the Sponsor for the
purpose of obtaining informed consent. In addition to providing this written information to a
potential participant, the Investigator or his/her designate will inform the woman verbally of all
pertinent aspects of the trial. The language used in doing so must be chosen so that the
information can be fully and readily understood by lay persons. Depending on national
regulations, a person other than the Investigator may inform the participant and sign the informed
consent form, as above.
4.2.2 Informed consent form for participants
Women will be approached primarily during antenatal care and informed about the trial. Those
women who accept to participate will be asked to sign a consent form. At delivery, women will be
reminded about the trial and asked to sign the consent form again. If the woman attended the
antenatal care visits at that hospital but was never invited to give informed consent, then, she
cannot be asked to give informed consent at the time of delivery. If the woman has never
attended the antenatal care visits at that hospital and is seen for the first time in the labour ward,
she may be offered the opportunity to participate in the trial if she is approached for consent
process when she is early in labour, her vital signs are normal and she is not stressed. Those
women willing to participate in the trial will be asked to sign the consent form (Annex 4). If the
woman is illiterate somebody independent from the trial will read the informed consent to the
woman and if the woman accepts, she will print her thumb onto the form. The informed consent
process will ensure the privacy and autonomy of the potential participant. If after reading the
informed consent the woman decides not to participate in the trial she will not be obliged to sign
the form and this decision will not affect her care at the hospital.
If the woman suffers any unexpected event possibly related to the trial’s intervention treatment,
the hospital will provide immediately care free of charge. The trial will be covered with insurance
for any injury as a result of their participation in the trial.
Where the information is provided by the Investigator, the informed consent form must be signed
and personally dated by the participant and the Investigator. The signed and dated declaration of
informed consent will remain at the Investigator’s centre, and must be safely archived by the
Investigator so that the forms can be retrieved at any time for monitoring, auditing and inspection
purposes. A copy of the signed and dated information and Informed Consent Form should be
provided to the participant prior to participation.
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Whenever important new information becomes available that may be relevant to the participant’s
consent, the written participant information sheet and any other written information provided to
participants will be revised by the Sponsor and be submitted again to the IEC/IRB for review and
favourable opinion. The agreed, revised information will be provided to each participant in the
trial for signing and dating. The Investigator will explain the changes to the previous version.
Participant identification and privacy
A unique participant number will be assigned to each participant at inclusion, immediately after
informed consent has been obtained. This number will serve as the participant’s identifier in the
trial as well as in the clinical trial database.
The participant’s data collected in the trial will be stored under this number. Only the Investigator
will be able to link the participant’s trial data to the participant via an identification list kept at the
centre. The participant’s original medical data that are reviewed at the centre during source data
verification by the Monitor, audits and Health Authority inspections will be kept strictly
confidential.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and
storing participant data. Participants will be informed accordingly, and will be requested to give
their consent on data handling procedures in accordance with national regulations.
Clinical Trial Insurance and Compensation to Participants
Insurance coverage shall be provided for participants in each country participating in the trial.
Insurance conditions shall meet good local standards, as applicable.
4.2.3 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
The trial protocol is submitted to the HRP Research Proposal Review Panel (RP2) and to the WHO
Ethics Review Committee (ERC) in advance of trial site review and ethical clearances.
Prior to commencement of the trial at a given centre, the clinical trial protocol will be submitted
together with its associated documents to the responsible IEC/IRB for its favourable
opinion/approval. The written favourable opinion/approval of the IEC/IRB will be filed in the
Investigator Site File, and a copy will be filed in the Trial Master File at Sponsor and the designated
clinical research organization (CRO).
The trial will not start at a centre before the Sponsor has obtained written confirmation of
favourable opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide
documentation of the date of the meeting at which the favourable opinion/approval was given,
and of the members and voting members present at the meeting. Written evidence of favourable
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the
Participant Information and Informed Consent Form version reviewed should be provided. Where
possible, copies of the meeting minutes should be obtained.
Amendments to the clinical trial protocol will also be submitted to the concerned IEC/IRB, before
implementation in case of substantial changes. Relevant safety information will be submitted to
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the IEC/IRB during the course of the trial in accordance with national regulations and
requirements.
All the centres participating in this trial will follow exactly the same protocol.
5.
Quality assurance and health authorities
The clinical trial protocol and any applicable documentation (e.g. Investigational Medicinal Product
Dossier, Participant Information and Informed Consent Form) will be submitted or notified to the
Health Authorities in accordance with the regulations of the countries involved in the trial.
This trial will be monitored in accordance with the ICH Note for Guidance on GCP Topic E6 21. The
Monitor will perform visits to the trial centre at regular intervals. Representatives of the Sponsor’s
Quality Assurance unit or a designated organization, as well as Health Authorities, must be
permitted to inspect all trial-related documents and other materials at the site, including the
Investigator Site File, the completed CRFs, the IMP(s), and the participants’ original medical
records/files.
The Clinical Trial Protocol, each step of the data captures procedure, and the handling of the data,
including the final Clinical Trial Report (CTR), will be subject to independent Quality Assurance
activities. Audits may be conducted at any time during or after the trial to ensure the validity and
integrity of the trial data.
6.
Investigator site file and archiving
The Investigator will be provided with an Investigator Site File upon initiation of the trial. This file
will contain all documents necessary for the conduct of the trial and will be updated and
completed throughout the trial. It must be available for review by the Monitor, and must be ready
for Sponsor audit as well as for inspection by health authorities during and after the trial, and must
be safely archived for at least 15 years (or per local requirements or as otherwise notified by the
Sponsor) after the end of the trial. The documents to be thus archived include the Participant
Identification List and the signed participant Informed Consent Forms. If archiving of the
Investigator Site File is no longer possible at the centre, the Investigator must notify the Sponsor.
All original participant files (medical records) must be stored at the centre (hospital, research
institute, or practice) for the longest possible time permitted by the applicable regulations, and/or
as per ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no
destruction of medical records is performed without the written approval of the Sponsor.
7.
Changes to the clinical trial protocol
Changes to the clinical trial protocol will be documented in written protocol amendments. Major
(substantial, significant) amendments will usually require submission to the health authorities and
to the relevant IEC/IRB for approval or favourable opinion. In such cases, the amendment will be
implemented only after approval or favourable opinion has been obtained. Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by the Sponsor
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and at the centre. They will be submitted to the relevant IEC/IRB or to health authorities only
where requested by pertinent regulations.
Any amendment that could have an impact on the participant’s agreement to participate in the
trial requires the participant’s informed consent prior to implementation.
8.
Environmental impact of the project
This trial will not present any environmental risk. The trial’s procedures are the same as the ones
followed in routine hospital practice.
9.
Plans for dissemination and use of project results
The trial results will be published in high profile peer-reviewed open access journals and presented
at international and national conferences and other events. The WHO recommendations will be
revised and updated accordingly.
If the carbetocin RTS is found to be the drug of choice HRP/RHR will undertake the application to
the WHO Model List of Essential Medicines. It is anticipated that Ferring would submit a prequalification application as well.
10. Clinical trial report and publication policy
Clinical Trial Report
After completion of the trial, according to ICH Topic E3, a CTR will be written by the Sponsor or
delegate.
Publication
The trial protocol will be published in an open access journal before the trial recruitment starts.
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The main publication (first publication) will be a publication of the results of the overall analysis of
the primary outcome(s). The sponsor (WHO) will be responsible for the main publication.
For secondary analysis, the WHO Data Use Regulations will be followed (Annex 10). A WHO
Secondary Analysis Committee will be constituted. This committee is a panel formed by the WHO
Coordinating Unit to prioritize, coordinate and ensure consistency amongst secondary analyses, as
well as resolving conflicts where necessary. All planned analyses should be communicated as a
proposal to the committee before analysis commences. The committee will inform the
investigator whether the proposal is approved. If approved, necessary datasets will be provided by
the committee to the investigator. The final analysis and manuscript will be reviewed by the
committee for methodological and quality appraisal. The committee reserves the right to
recommend changes to the analysis and/or manuscript.
The investigator will inform the Sponsor in advance about any plans to present data from the trial.
Any presentations of the results (oral presentations, etc.), either in whole or in part, by
Investigators or their representatives will require pre-submission review and approval by the
Sponsor.
Authorship policy
The authorship will follow the standards set by the International Committee of Medical Journal
Editors (ICMJE). The HRP/RHR trial coordination unit will be responsible for drafting the
manuscript. The authors will be trial steering committee members and the trial coordination unit
staff followed by the group name (WHO Carbetocin Postpartum Haemorrhage Prevention Trial
Group or similar).
11. Research capacity strengthening
HRP will prioritize research capacity strengthening concomitantly with its large research projects
as a main focus within its HRP Alliance. Investigators will identify secondary analyses and
methodological studies that could support publications or degree theses alongside the project.
Such proposals should be discussed with the WHO coordination unit who will determine the need
for support and operationalization within one or multiple sites.
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