Early Detection of Postpartum Haemorrhage and Treatment Using the World Health Organisation MOTIVE 'First Response' Bundle: a Cluster Randomised Trial With Health Economic Analysis and Mixed-methods Evaluation (E-MOTIVE Trial)
Phase: NA
Conditions: Post-Partum Haemorrhage
Sponsor: University of Birmingham

Page 1 of 51 
 
  
 
 
 
 
 
 
 
Early detection of postpartum haemorrhage and treatment 
using the World Health Organization MOTIVE ‘first 
response’ bundle: a cluster randomised trial with health 
economic analysis and mixed-methods evaluation 
 
  
 
 
 
 
 
 
 
Version Number: V6.0 
Version Date: 24-Jul-2023 
E-MOTIVE TRIAL PROTOCOL 
 
INSERT COUNTRY 
INSTITUTION LOGO 
 

Page 2 of 51 
 
 
Protocol development 
 
Protocol Amendments  
The following amendments and/or administrative changes have been made to this protocol since the implementation 
of the first approved version. 

Page 3 of 51 
 
Amendment 
number 
Date of 
amendment 
Protocol 
version 
number 
Type of amendment    
Summary of amendment 
1 
16/07/2020 
2.0 
Substantial 
Addition of clinical trials.gov number, 
change of DMC member, edit to list of 
ITMG members, addition of definition for 
‘spoke’, removal of India as a participating 
country, clarification of health facility 
eligibility criteria (section 3.3), edit to 
outcomes (section 6), change in number of 
facilities used for adaptive cycles (section 
5.3), removal of PPH rate per health facility 
as minimisation criteria (section 3.4), 
clarification regarding randomisation of 
health facilities (section 3.4), addition of 
option for qualitative interviews to be 
completed via video/teleconference 
(section 5.3 and 6.3), addition of sections 
regarding measurement of blood loss and 
Blinded Endpoint Review Committee 
(section 6.1), changes to list of secondary 
clinical and implementation outcomes 
(section 6.2), change to aims and 
objectives of process evaluation (section 
6.3), change to observations for process 
evaluation (section 6.3), clarification that 
DMC will monitor maternal deaths and ICU 
admissions (section 7), clarification 
regarding source data (section 8.1) and 
clarification regarding statistical analysis 
(section 11) 
 

Page 4 of 51 
 
2 
18/06/2021 
3.0 
 
 
 
Substantial 
 
 
 
Change of logo for UCL Centre for 
Behaviour Change, changes to trial team – 
Rachel Lillywhite has replaced Adam Devall 
as Team Leader and Kristie-Marie 
Mammoliti added as Programmer 
Manager, E-MOTIVE kit changed to trolley 
or carry case for intervention, Quality of 
oxytocin added as minimisation variable 
for randomisation, amendment to 
statement regarding consent to confirm 
consent for observations will not be sought 
in a separate consent form (section 4), 
change to objectives for adaptive cycle 
process evaluation, change to timeframe 
for adaptive cycles – adaptive cycles to last 
between 3-5 months rather than 4-5 
months (section 5.3), change to 
procedures for adaptive cycles to confirm 
baseline data will be collected for first 
month and online surveys will not be 
conducted (section 5.3), change to primary 
and secondary outcomes to specify 
timeframes for measurement of some 
outcomes (section 6.1-6.2), change to 
additional outcomes to confirm that 
number of vaginal births and number of 
caesarean sections will be extracted 
weekly rather than monthly (section 6.2), 
clarification that minimisation will be 
stratified in each country and will be 
performed by an independent statistician 
from BCTU (section 3.4) 
3 
30/09/2021 
4.0 
Minor 
Addition of Pakistan as a participating 
country 

Page 5 of 51 
 
4 
25/10/2022 
5.0 
 
Substantial 
 
In the initial months of the baseline period, 
we had concerns about data veracity from 
a pilot site and after consultation with the 
funder, the independent TSC and DMC 
committees, we decided to drop all the 
initial main trial data and adopted a 
complete source data verification 
approach for all births. As a result, the 
duration of study data collection was 
reduced from 24 months (11-month 
baseline phase, 2-month transition phase 
and 11-month intervention phase) to 16 
months (7-month baseline phase, 2-month 
transition phase and 7-month intervention 
phase). This decision was made in 
conjunction with updated sample size 
simulations, because of the following 
changes to the assumptions: a) increased 
numbers of study sites as 80 sites were 
successfully enrolled, and b) increased 
rates of the primary outcome based on 
accruing baseline data. Hence, we were 
confident the study could be conducted in 
a shorter length of time without unduly 
impacting on our ability to detect the same 
size of difference as originally planned 
(sample size updated in section 11.1).  
Changes to trial team - Dr Sindhu 
Kulandaipalayam Natarajan has replaced 
Kristie-Marie Mammoliti as Programme 
Manager and Marcelina Podesek and 
Isobelle Horne have replaced Rebecca 
Timms as Data Manager. Removal of Sri 
Lanka as a participating country (Sri Lanka 
formally withdrew from the study) and 
change in number of countries from 6 to 5. 
Change in number of adaptive cycle sites 
from 3-4 to 2-3 and change in approximate 
timeframe for adaptive cycles from 3-5 to 
2-5 months. Changes to randomisation 
(section 3.4) including data used for 
randomisation changed from first 6 
months to first 5 months baseline data and 
number of facilities added as minimisation 
variable. Details added to treatment supply 
and storage (section 5.1). Changes made to 
measurement of blood loss (section 6.1), 
changes made to secondary 
implementation outcomes (section 6.2), 
changes made to process evaluation 
(section 6.3), changes made to on-site 
monitoring (section 9.2), changes made to 

Page 6 of 51 
 
analysis of outcomes measures (section 
11.2) including addition of section on 
source verified data. Update to reference 
list 
5 
24/07/2023 
6.0 
Substantial  
Change to Dr Adam Devall job title, change 
in QA Manager, clarification regarding 
patient eligibility criteria for the study 
(section 3.3), additional details added to 
randomisation section (section 3.4), 
clarification regarding measurement of 
blood loss process (section 6.1), 
clarification made to secondary clinical and 
implementation outcomes section (section 
6.2), clarification made to analysis of 
outcome measures section (section 11.2), 
update to reference list (section 18) and 
addition of appendix for Pakistan before-
and-after study 
  
 
Funding and Support in Kind 
 
Funder(s) 
 
Financial and non-financial 
support given: 
Bill and Melinda Gates Foundation 
Financial 
Funder’s reference number 
INV-001393 
Institute of Global Innovation, University of Birmingham 
Financial 
Funder’s reference number 
60058 
Disclaimer: The views expressed are those of the authors. 

Page 7 of 51 
 
Protocol Sign Off  
 
 
CI Signature Page 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol.  
I agree to ensure that the confidential information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of 
the Sponsor. 
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account of the 
study will be given; and that any discrepancies from the study as planned in this protocol will be explained. 
 
This protocol has been approved by: 
Trial Name: 
The E-MOTIVE trial 
Protocol Version Number: 
Version: 6.0 
Protocol Version Date: 
24-Jul-2023 
CI Name: 
Prof Arri Coomarasamy 
Trial Role: 
Chief Investigator 
Signature and date: 
    
              29-Jul-2023 
 
Team Leader Name: 
Rachel Lillywhite 
Signature and date: 
     
                                24-Jul-2023 
 
Senior Statistician Name: 
Mr Lee Middleton 
Signature and date: 
   
                25-Jul-2023 
Sponsor statement: 
Where the University of Birmingham takes on the sponsor role for protocol development oversight, a formal 
signed letter will be issued by the sponsor to serve as confirmation of approval of this protocol. 
Compliance statement: 
This protocol describes the E-MOTIVE trial only. The protocol should not be used as a guide for the treatment 
of participants not taking part in the E-MOTIVE trial.  
The study will be conducted in compliance with the approved protocol, UK Policy Framework for Health 
and Social Care Research 2017, the General Data Protection Regulations (GDPR) 2018, as well as the 
ethical research frameworks of all participating countries. Every care has been taken in the drafting of 
this protocol, but future amendments may be necessary, which will receive the required approvals prior to 
implementation. 
 
 

Page 8 of 51 
 
 
 
 
 
 
PI Signature Page 
The undersigned confirm that the following protocol has been agreed and accepted and that the Principal 
Investigator agrees to conduct the trial in compliance with the approved protocol.  
I agree to ensure that the confidential information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of 
the Sponsor. 
 
This protocol has been approved by: 
 
Trial Name: 
The E-MOTIVE trial 
Protocol Version Number: 
Version: 6.0 
Protocol Version Date: 
24-Jul-2023 
PI Name: 
Professor Lumaan Shaikh 
Country: 
Pakistan 
Signature and date: 
 
                                                                              
 
 
 
Reference  Numbers 
 
 
Sponsor number 
RG_19-231 
Clinicaltrials.gov reference number: 
NCT04341662  
Country level reference number (if applicable): 
TBC 

Page 9 of 51 
 
 
 
Administrative Information  
 
Chief Investigator  
 
Arri Coomarasamy 
Professor of Gynaecology 
Director, WHO Collaborating Centre for Global 
Women’s Health Research  
Director, Tommy’s National Centre for Miscarriage 
Research 
Institute of Metabolism and Systems Research 
University of Birmingham, UK 
 
+44 (0) 121 371 8202 
a.coomarasamy@bham.ac.uk 
 
Data Monitoring Committee – DMC  
Zarko Alfirevic (Chair) 
Pisake Lumbiganon (Clinical Member) 
Andrew Copas (Statistician) 
University of Liverpool, UK 
Khon Kaen University, Thailand 
University College London  
 
Trial Steering Committee – TSC 
Sabaratnam Arulkumaran (Chair) 
Deborah Armbruster (Clinical Member)   
Pierre Buekens (Clinical Member) 
Monica Taljaard (Statistician) 
Arri Coomarasamy (CI, Non-Independent 
Member) 
St George's University of London, UK 
United States Agency for International Development  
Tulane University, United States 
University of Ottawa, Canada 
University of Birmingham, UK 
 
 
 
 
 
Sponsor 
 
University of Birmingham 
Research Support Group  
Room 119, Aston Webb Building 
University of Birmingham, Edgbaston 
Birmingham, B15 2TT 
Contact Details: 
Dr Birgit Whitman 
Head of Research Governance and Integrity Research 
Support Group  
0121 415 8011 
researchgovernance@contacts.bham.ac.uk  

Page 10 of 51 
 
 
 
International Trial Management Group – ITMG  
Chief Investigator and ITMG Chair 
Prof Arri Coomarasamy 
Programme Coordinator and ITMG Deputy 
Chair 
Prof Ioannis Gallos 
Senior Statistician 
Prof Karla Hemming 
Senior Statistician  
Mr Lee Middleton 
Trial Statistician  
Dr James Martin  
Associate Professor of Maternal Health Clinical 
Trials 
Dr Adam Devall 
Trials Management Team Leader 
Rachel Lillywhite 
Programme Manager  
Dr Sindhu Kulandaipalayam Natarajan  
Programme Officer 
Mrs Leanne Beeson 
Data Manager 
Marcelina Podesek  
Isobelle Horne 
Co-Investigator 
Dr Fernando Althabe 
Co-Investigator* 
Dr Cherrie Evans 
Qualitative Researcher* 
Dr Meghan Bohren 
Co-Investigator* 
Prof Suellen Miller 
Qualitative Researcher* 
Dr Fabiana Lorencatto 
Health Economist* 
Prof Tracy Roberts 
Health Economics Research Associate  
Ms Eleanor Williams 
*as required 
 
BCTU Quality Assurance Team  
 
Walter-Rodney Nagumo 
Quality Assurance Manager 
Birmingham Clinical Trials Unit 
Public Health Building 
Institute of Applied Health Research 
University of Birmingham 
Edgbaston, B15 2TT 
+44 (0) 121 414 7557  
w.nagumo@bham.ac.uk  
 
 
 
 

Page 11 of 51 
 
Trial Office Contact Details  
 
Birmingham Clinical Trials Unit 
Public Health Building 
Institute of Applied Health Research 
University of Birmingham 
Edgbaston, B15 2TT 
 
  
Trial website 
http://www.birmingham.ac.uk/emotive 
Trial social media 
Twitter: https://twitter.com/EmotiveTrial  
Facebook: https://www.facebook.com/emotive.trial.9  
Email address  
emotive@trials.bham.ac.uk 
 
Country level investigators 
 
Co PI 
Professor Dr Zulfiqar A. Bhutta 
 Co PI 
Dr Rozina Karmalani  
 Co PI 
Dr Sidrah Nausheen  
 Co PI 
Professor Sajid Soofi  
 Co-Investigator 
Dr Arusa Lakhani 
 Co-Investigator 
Dr Kiran Mubeen 
Co-Investigator 
Dr Shah Muhammad  
 

Page 12 of 51 
 
  
ABBREVIATIONS 
Abbreviation 
Term 
BCTU 
Birmingham Clinical Trials Unit 
CI 
Chief Investigator 
CIOMS 
Council for International Organization of Medical Science 
COM-B 
Capabilities, Opportunities and Motivations for Behaviour Change 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
GDPR 
General Data Protection Regulation 
ICER 
Incremental Cost-Effectiveness Ratio 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
ISF 
Investigator Site File 
ITMG 
International Trial Management Group 
ITMS 
Integrated Trial Management System 
LMIC 
Low- and Middle-Income Countries 
MRC 
Medical Research Council 
NC 
National Coordinator 
NPI 
National Principal Investigator 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PPH  
Postpartum Haemorrhage 
REC 
Research Ethics Committee 
TAG 
Technical Advisory Group 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
TXA 
Tranexamic Acid 
UoB 
University of Birmingham 
WHO 
World Health Organization 
WMA 
World Medical Association 
 
DEFINITIONS 
Term 
Description 
Hub 
A country-specific collaborating institute acting as a central, coordinating centre. 
Spoke 
A health facility within a participating country  
 
 

Page 13 of 51 
 
TRIAL SUMMARY 
Title Early detection of postpartum haemorrhage and treatment using the World Health Organisation MOTIVE ‘first 
response’ bundle: a cluster randomised trial with health economic analysis and mixed-methods evaluation.  
Aim To evaluate the implementation of early detection and the use of the World Health Organisation (WHO) 
MOTIVE ‘first response’ treatment bundle for postpartum haemorrhage (PPH) on clinical, implementation and 
resource use outcomes. We will evaluate the implementation through mixed-methods and carry out a health 
economic evaluation from the public healthcare system perspective. 
Study Design Multi-country, parallel cluster randomised trial with a baseline control phase, along with mixed-
methods and health economic evaluations.  
Setting:  Secondary level health facilities in Kenya, Tanzania, Nigeria, South Africa, and Pakistan. 
Population Cluster: Health facility is the randomisation unit. Health facilities are eligible for inclusion if they have 
1000 to 5000 births a year and provide comprehensive obstetric care with ability to perform surgery for PPH. 
Research participants: All healthcare providers attending vaginal births in the study facilities.  
Intervention The E-MOTIVE intervention consists of three elements: 1) a strategy for early detection of PPH, which 
allows triggering of the ‘first response’ treatment bundle; 2) a ‘first response’ bundle called “MOTIVE”, based on the 
WHO guideline recommendations and consisting of uterine Massage, Oxytocic drugs, Tranexamic acid, IV fluids and 
Examination & Escalation; and 3) an implementation strategy, focusing on simulation-based training with peer-
assisted learning, local E-MOTIVE champions, feedback of actionable data to providers, calibrated drape with trigger 
line, and MOTIVE emergency trolley and/or carry case. 
Control Usual care with dissemination of the current guidelines. 
Outcomes Primary: Composite of the following three clinical outcomes: severe PPH defined as blood loss ≥1000 ml 
or postpartum laparotomy for bleeding or postpartum maternal death from bleeding. Key Secondary: 1) postpartum 
haemorrhage detection, and 2) compliance with MOTIVE bundle. Secondary: blood transfusion, uterine tamponade, 
Intensive Care Unit admissions or higher-level facility transfers, and new-born deaths along with implementation and 
resource use outcomes. 
Randomisation and sample size 80 health facilities will take part in the study. Initially, all health facilities will enter a 
7-month baseline period in which they will be following usual care. After this, we will randomise 40 of the 80 health 
facilities to the E-MOTIVE intervention for 7 months, allowing two months for transition. The other 40 health 
facilities will continue to follow usual care as per the baseline period for the entire trial duration (16 months). The 
anticipated sample size for the study will be 215,040 women. This sample size is expected to have over 90% power 
to detect a 25% relative reduction in the primary outcome from 4% to 3% after allowing for clustering. The number 
of clusters has been inflated by 10% to allow for drop out of health facilities and for varying cluster sizes. 
Randomisation will use a minimisation algorithm to balance the intervention and control facilities by the number of 
vaginal births per health facility, the health facility rate of the composite primary outcome during the baseline phase, 
the quality of oxytocin used per health facility, and the number of facilities in each arm. 
Mixed methods work During the 7-month baseline phase, we will refine and optimise the E-MOTIVE implementation 
strategy by piloting it in two to three facilities per country over up to two adaptive cycles for addressing barriers and 
enablers to delivery and implementation, ahead of the intervention phase.  
Process evaluation during the intervention phase We will conduct a mixed-methods process evaluation to assess 
the extent to which the E-MOTIVE intervention has been implemented as intended. The implementation outcomes 
of interest are fidelity, adoption, adaptation, acceptability, and sustainability, as well as contextual influences and 
barriers and enablers to implementation.  
Health economics We plan to assess the cost-effectiveness of the E-MOTIVE intervention compared with usual care 
from a public healthcare system perspective for each country, as measured by incremental cost-effectiveness ratios 
for a) severe PPH prevented, b) laparotomy for PPH prevented, c) death from PPH avoided, and (d) quality-adjusted 
life-years prevented. 

Page 14 of 51 
 
 Figure 1 Study flowchart  
 
 

Page 15 of 51 
 
TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE 
17 
1.1. 
Background 
17 
2. 
AIMS AND OBJECTIVES 
19 
3. 
TRIAL DESIGN AND SETTING 
19 
3.1. 
Justification for Trial Design 
19 
3.2. 
Trial Setting 
19 
3.3. 
Eligibility 
19 
3.4. 
Randomisation 
20 
4. 
CONSENT 
21 
5. 
TRIAL INTERVENTION 
21 
5.1. 
Treatment Supply and Storage 
22 
5.2.  
Standardisation of labour care 
22 
5.3.  
Design of the E-MOTIVE implementation strategy: Adaptive cycles 
22 
6. 
OUTCOME MEASURES AND STUDY PROCEDURES 
25 
6.1. 
Primary outcome 
25 
6.2  
Secondary clinical and implementation outcomes 
26 
6.3. 
Process evaluation 
28 
7. 
ADVERSE EVENT REPORTING 
31 
8. 
DATA HANDLING AND RECORD KEEPING 
31 
8.1. 
Source Data 
31 
8.2. 
Case Report Form (CRF) Completion 
32 
8.3. 
Data Management 
32 
8.4. 
Data Security and data protection 
32 
8.5. 
Archiving 
33 
9.  
QUALITY CONTROL AND QUALITY ASSURANCE 
33 
9.1. 
Site Set-up and Initiation 
33 
9.2. 
Monitoring 
34 
9.3. 
Audit and Inspection 
35 
9.4. 
Notification of Serious Breaches 
35 
10.  END OF TRIAL DEFINITION 
35 
11.  STATISTICAL CONSIDERATIONS 
36 
11.1. 
Sample Size 
36 
11.2. 
Analysis of Outcome Measures 
38 
11.3. 
Planned Interim Assessments 
40 
11.4. 
Planned Final Analyses 
40 
11.5. 
Health Economic Evaluation 
41 
12. 
TRIAL ORGANISATIONAL STRUCTURE 
41 

Page 16 of 51 
 
12.1. 
The Birmingham Clinical Trials Unit 
41 
12.2. 
Sponsor 
41 
12.3. 
International Trial Management Groups (ITMG) 
41 
12.4. 
Site Organisation 
41 
12.5 
Trial Steering Committee 
42 
12.6. 
Data Monitoring Committee 
42 
12.7. 
Finance 
42 
13. 
ETHICAL CONSIDERATIONS 
42 
13.1. 
Justifying the cluster randomized design 
43 
13.2. 
Research ethics committee review 
43 
13.3. 
Identifying research participants 
43 
13.4. 
Obtaining informed consent 
43 
13.5. 
Gatekeepers 
44 
13.6. 
Assessing benefits and harms 
44 
13.7. 
Protecting vulnerable participants 
44 
14. 
CONFIDENTIALITY AND DATA PROTECTION 
45 
15. 
FINANCIAL AND OTHER COMPETING INTERESTS 
45 
16. 
INSURANCE AND INDEMNITY 
45 
17. 
PUBLICATION POLICY 
46 
18. 
REFERENCE LIST 
46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 17 of 51 
 
 
1. BACKGROUND AND RATIONALE  
1.1. 
Background 
Every six minutes a mother dies from 
PPH in low-resource countries, in the 
prime of her life and often leaving behind a young family.1 In many settings, when a mother dies in 
childbirth, her infant has less than 
a 20% chance of surviving past the 
first month.1 PPH, defined as a 
blood loss of more than 500 ml, is 
the leading cause of maternal 
death worldwide, accounting for 
27% of maternal deaths.2 The 
WHO published 
“Recommendations for the 
Prevention and Treatment of 
Postpartum Hemorrhage” in 2012 
to provide evidence-informed 
recommendations for managing 
PPH.3 However, adherence to 
these recommendations is 
currently limited by a number of 
challenges. 
Challenges  proposed solutions  
1) PPH is often not detected early; thus life-saving treatment is not promptly initiated  Solution: 
Early detection and treatment of PPH 
Data from multiple LMICs show that most women with PPH do not receive life-saving treatment.4 
Analysis of the WHO CHAMPION (Carbetocin HAeMorrhage PreventION trial) trial data (n=29,645; 10 
countries) showed that only 26% (235/886) of women with a blood loss between 500 – 600 ml 
received a uterotonic drug for PPH treatment (Figure 2).4 Even with a blood loss of 1000 – 1100 ml, 
only 70% (68/96) of women 
received a uterotonic drug for 
treatment of PPH.4 Published data 
from 42 Nigerian and 61 Tanzanian 
hospitals as well as audit data from 
5 Kenyan hospitals show that the 
real-world PPH detection rates are 
low (Nigeria 2.2%, Tanzania 2.5%, 
and Kenya 1.8%).5,6 Such low 
detection rates would mean low or 
delayed usage of a ‘first response’ 
PPH treatment bundle. These 
facilities currently rely on visual 
estimation of blood loss, widely 
0
50%
100%
Women treated with uterotonics
Blood loss increments (100ml)
95% confidence intervals
Only 26% of women with PPH 
received a treatment uterotonic drug
Even with severe PPH>1000ml 30% 
of women did not receive a treatment 
uterotonic drug
Figure 3 The E-MOTIVE intervention 
Figure 2 Treatment of PPH from the multicountry WHO CHAMPION trial 

Page 18 of 51 
 
recognised as inaccurate, and can result in underestimation.7 Therefore, we will implement an early 
PPH detection strategy with objective measurements of blood loss to ensure that a ‘first response 
PPH treatment bundle’ is promptly triggered for maximum benefit. 
2) Delayed or inconsistent use of interventions for PPH management  Solution: the bundle 
PPH is often detected late; a sequential approach to administering life-saving interventions could 
mean more time – and lives – are lost. Furthermore, some treatment interventions recommended 
by WHO, may not be used at all. Survey data from the participating facilities in Kenya and Nigeria 
show that tranexamic acid (TXA) is used late and most often only for women requiring surgery for 
PPH. Other easy-to-implement interventions of standard PPH care, e.g., uterine massage and IV 
fluids, that could be critical are inconsistently used and may be considered optional by doctors and 
midwives. We aim to change provider behaviours so that they detect PPH early and rapidly 
implement all recommended interventions of the MOTIVE bundle (Figure 3) simultaneously, without 
waiting for response to individual components (sequential implementation). 
3) Despite guideline dissemination, many care providers do not provide effective care  Solution: 
Implementation strategy targeting Capabilities, Opportunities and Motivations for Behaviour change 
(COM-B)   
An extensive body of implementation research based in high income countries has identified that 
passive dissemination of new clinical guidelines, including care bundles, alone is unlikely to result in 
sustained behaviour changes and improved quality of care.8 We will design an implementation 
strategy to address known barriers and enablers for improving bundle implementation. This will be 
based on a model of behaviour change (COM-B), which recognises that individuals must have 
Capability, Motivation, and both physical and social Opportunity to perform the behaviour(s) of 
interest.8 Our implementation strategy and rationale are given in Figure 4.  
Figure 4   E-MOTIVE implementation strategy and rationale. 
 
4) Limited scale-up and coverage Solution: Engagement of strong implementation partners: 
WHO/HRP, Jhpiego, UCL Centre for Behaviour Change, and Concept Foundation 
Lack of knowledge and skills, 
lack of qualified staff, 
lack of self-efficacy, 
inappropriate expectations
Lack of awareness, lack of 
engagement or buy-in of staff or 
management, fear of reprisals, 
lack of supportive leadership or 
champions 
Physical: workflow inefficiencies, 
work overload, difficult access to 
required resources
Social: lack of team work and 
communication
Demonstrated barriers to bundle 
implementation 
Proposed implementation strategies to address 
barriers to bundle implementation
Simulation-based team learning at each site, 
followed by deliberate skills practice and 
repeated refresher training, facilitated by 
designated peers (peer-assisted learning)
Introduction of local E-Motive champions who 
encourage, support, and model bundle use. 
Introduction of calibrated drapes with trigger 
line to increase motivation for bundle use, 
Locally managed audit and feedback 
Physical: facilitated workflow through the 
introduction of MOTIVE emergency trolleys and 
carry-cases with all bundle components enabling 
easy and timely access to commodities 
Social: Peer assisted learning; local champions
Capability
Motivation
Opportunity

Page 19 of 51 
 
WHO/HRP is a leading collaborator in our 
program (Box 1). Jhpiego has deep 
knowledge in building resilient and self-
reliant implementation programmes; 
Jhpiego functions in over 40 countries, 
with strong presence in Africa and Asia. 
The University College London (UCL) 
Centre for Behaviour Change is credited 
with the development of the well-
recognised and used COM-B model for 
behaviour change;10 the Centre will use 
behavioural theory and frameworks to 
develop behavioural change interventions to improve PPH bundle use and outcomes. The Concept 
Foundation (Executive Director: Metin Gulmezoglu) will contribute by providing data and 
information on availability, quality, and access issues for the PPH commodities in the bundle.  
 
2. AIMS AND OBJECTIVES  
Primary objective:  
Evaluate the implementation of the E-MOTIVE intervention compared with usual care on clinical, 
implementation and resource use outcomes. 
Secondary objectives:  
1. Assess the cost-effectiveness of the E-MOTIVE intervention compared with usual care from a 
public healthcare system perspective. 
2. Develop, optimise and manualise an implementation strategy, with parallel process evaluation 
alongside the trial, ready for scaling-up of the E-MOTIVE intervention if found to be effective. 
Our purpose is to integrate the evidence into WHO guidance for programmatic implementation of 
the E-MOTIVE intervention, if found to be effective, for global impact. 
 
3. 
TRIAL DESIGN AND SETTING  
3.1. 
Justification for Trial Design   
This is a multi-country, parallel cluster randomised trial with a baseline control phase, along with 
mixed-methods pilot, process evaluation and health economic evaluations. A cluster design is 
necessary as the intervention is delivered at the health facility level, targeting the healthcare 
providers within them, and so it would not be feasible to randomise individual participants.  
3.2. 
Trial Setting   
Secondary-level health facilities across 5 countries (Kenya, Tanzania, Nigeria, South Africa, and 
Pakistan). 
3.3. 
Eligibility  
Cluster: Health facility is the randomisation unit. Health facilities are eligible for inclusion if they have 
1000 to 5000 births a year and provide comprehensive obstetric care with ability to perform surgery 
Box 1: What WHO/HRP partnership brings to the 
program?  
WHO/HRP (F Althabe) led the development of the Gates 
Foundation sponsored first response PPH treatment bundle 
(MOTIVE).9 Since then, the WHO has worked with the 
University of Birmingham to map out the E-MOTIVE 
programme on its Evidence to Decision framework, with 
particular emphasis on desirable and undesirable effects, 
values, required resources, equity, acceptability, and 
feasibility. This collaboration includes formative work, evidence 
synthesis, policy formulation, and stakeholder engagement. If 
E-MOTIVE is found to be effective, WHO/HRP will consolidate 
the research results by issuing normative guidance for the 
programmatic implementation of E-MOTIVE for global impact. 

Page 20 of 51 
 
for PPH. Health facilities are selected based on being administratively and geographically distinct 
from each other. Pre-existing implementation of early detection or bundled approach for PPH 
management are exclusion criteria. 
Research participants: All healthcare providers attending vaginal births at the study facilities.  
Patients: All verified vaginal births in the study facilities 
3.4. 
Randomisation  
After regulatory approvals, all 80 health facilities will enter an 7-month baseline period in which they 
will be following usual care with dissemination of the current guidelines. After this 7-month baseline 
period, we will randomise in a staggered fashion 40 of the 80 health facilities (1:1 ratio) to the E-
MOTIVE intervention for 7 months, allowing two months for full implementation and embedding of 
the intervention. The other 40 health facilities will continue to follow usual care as per the baseline 
period for the remainder of the intervention phase (Figure 1). To allow us to perform the 
randomisation sequentially, a minimisation algorithm will ensure a balance of the intervention and 
control facilities for the following measured at the level of the health facility during the first 5 
months of the baseline phase:  
1. Number of vaginal births;  
2. Proportion of births with the composite primary outcome; 
3. Quality of oxytocin 
4. Number of intervention and control clusters in each country  
Details of how these are calculated are presented below. The minimisation will be stratified in each 
country (separate minimisations) to increase the balance in all of the above covariates within a 
country. 
Number of vaginal births 
After the first five months of the baseline phase has completed, for each cluster, we will gather the 
total number of births and the number of months of data collection to calculate the cluster’s 
monthly birth rate. We will then use the cluster's monthly birth rate to determine the country’s 
median birth rate. The clusters above and below the country median will form the categories for the 
minimisation algorithm.  
The proportion of births with the composite primary outcome before randomisation 
After the first five months of the baseline phase has completed, for each cluster, we will gather the 
total number of births and the total number of events. The ratio of the number of events to the 
number of births will give us the proportion of births with the composite outcome for that cluster. 
We will then use the cluster’s primary outcome proportion to determine the country’s median 
primary outcome proportion. The clusters above and below the country median will form the 
categories for the minimisation algorithm. 
Oxytocin Quality 
The quality of oxytocin (measured during the baseline phase) will be dichotomised as ≤90% and 
>90% to form the categories for the minimisation algorithm. 
 

Page 21 of 51 
 
Number of intervention and control clusters in each country 
In an attempt to balance the number of clusters allocated to each arm, we will include a covariate 
that represents the number of clusters assigned to intervention and control, as there is evidence 
that this improves balance in the number of clusters in each arm11.  
The randomisation of health facilities will be performed using a validated minimisation algorithm 
that follows the Pocock and Simon range method12 using the “rct_minim” command in Stata 16. The 
first cluster in each country will be allocated completely at random. All further clusters will be 
allocated using the minimisation algorithm. To reduce the predictability of allocation and to ensure a 
balance in covariates across arms, a small random element (10%) will be included in the algorithm. A 
random element is typically included to better protect the blinding of treatment allocations when 
recruiting new facilities. A random element of 10% would mean we expect 90% of clusters to be 
allocated using the minimisation algorithm to the arm that minimises covariate imbalance, and 10% 
are not. 
The randomisation of health facilities will be performed using a validated minimisation algorithm 
and implemented by an independent statistician from the University of Birmingham Clinical Trials 
Unit (BCTU). Full details of the randomisation specification will be stored in a confidential document 
at the University of Birmingham Clinical Trials Unit (BCTU). 
 
 
4. 
CONSENT 
The E-MOTIVE intervention aims to change local healthcare providers’ behaviour for management of 
PPH and increase compliance with WHO recommendations for PPH treatment. All the interventions 
in the bundle are already recommended for all women with PPH and represent life saving measures 
administered to women in an emergency setting. The leadership at each facility will provide facility-
level permission for participation in the study and permission for staff employed at the health facility 
to extract anonymised routinely collected data on clinical outcomes. All healthcare providers will 
provide written informed consent before trial-specific training. A separate written informed consent 
will be obtained from healthcare providers during the adaptive cycles and process evaluation for 
trial specific data collection including interviews and surveys. Individual-level consent from women 
for participation in this evaluation is not required as women are not the direct target of the 
intervention; nor are they interacted with for the purpose of data collection; and no identifiable 
information on women will be held by the E-MOTIVE study investigators or BCTU (please see section 
13 for details). 
 
5. 
TRIAL INTERVENTION 
Intervention: The E-MOTIVE intervention targets healthcare providers and consists of an 
implementation strategy for early detection of PPH, which allows the initiation of the ‘first response’ 
treatment bundle, which is called MOTIVE, consisting of uterine Massage, Oxytocic drug, Tranexamic 
acid, IV fluids and Examination & Escalation (Box 2). The timing, dosing and manner with which 
these interventions will be implemented will be in line with WHO recommendations and local 
protocols where available.2,9 The implementation strategy focuses on simulation-based training on 
site with peer-assisted learning, local E-MOTIVE champions, feedback of actionable data to 
providers, calibrated drape with trigger line, and MOTIVE emergency trolley and/or carry case.   

Page 22 of 51 
 
Control: Usual care with dissemination 
of the current guidelines. In usual care, 
‘first response’ treatment may include 
some or all of the components of the 
MOTIVE treatment bundle. All 
components are routinely available in 
all facilities, recommended for all 
women with PPH, but currently are 
used inconsistently by healthcare 
providers.      
5.1. 
Treatment Supply and 
Storage 
Medicinal supplies used in the trial 
(oxytocic drugs, tranexamic acid and IV 
fluids) will be sourced from local stocks at the health facilities. Most health facilities do not require 
additional medicinal supplies, based on our facility surveys and discussions. However, where 
required, the BCTU will work with Hubs to provide supplies to both the intervention and the control 
facilities. The BCTU will centrally provide blood collection drapes (both non-calibrated and 
calibrated) and digital weighing scales to the Hubs. The Hubs will arrange for distribution of these 
supplies to the health facilities. The Hubs will request a report from individual health facilities for 
availability of interventions. 
The quality of oxytocin and tranexamic acid products used at individual health facilities across all 
participating countries will be evaluated by the Concept Foundation. This work is outlined in a 
separate protocol.  
5.2.  
Standardisation of labour care  
All other aspects of labour care will be as per the local protocols and determined by the attending 
obstetrician and healthcare team. The intervention health facilities will change their local protocols 
to implement the E-MOTIVE intervention. The individual components will not be enforced and 
compliance with the E-MOTIVE intervention will be measured. 
5.3.  
Design of the E-MOTIVE implementation strategy: Adaptive cycles  
Aims 
The overall aim is to conduct a small-scale, mixed-methods process evaluation in each country to 
explore two key implementation outcomes, which need to be optimised before progressing to trial: 
fidelity (extent to which the intervention is delivered and engaged with as intended) and 
acceptability.  
Box 2: Insights from members of the PPH Bundles 
Expert Advisory Group 
Four of this project’s collaborators (F Althabe, S Miller, GJ 
Hofmeyr, and D Lissauer) were among the WHO/HRP technical 
advisory group (TAG) that developed the PPH bundles as a way 
of implementing the WHO PPH recommendations.9 The set of 
four interventions included in the PPH First Response care 
bundle (uterotonic drugs, IV isotonic crystalloids, tranexamic 
acid, and uterine massage) was accepted by consensus by the 
21 advisors as being highly relevant and able to be used across 
all facility levels.9 The group agreed that the next phase for this 
bundle should be the development of an implementation 
strategy culminating in a model for use at the facility level in 
LMICs. At a minimum the TAG suggested that the strategy 
should include: training, teamwork, packaging the bundle 
elements in an easy-to-use trolley or kit and on-going 
monitoring and evaluation. However, a full implementation 
strategy was not developed during TAG process. The group 
advised undertaking implementation research.9 

Page 23 of 51 
 
Objectives 
 
1. To pilot the E-MOTIVE intervention and co-implementation strategy and assess: fidelity of delivery 
and enactment, acceptability, change in implementation outcomes, and barriers and enablers to 
implementing the interventions as intended.   
2. To refine and optimise the E-MOTIVE co-implementation strategy to address barriers and enablers 
to delivery and implementation, ahead of the intervention phase.  
Design 
We plan to use the 7-month baseline trial data collection period to pilot the feasibility of the 
provisional implementation strategy and tools in health facilities in each of the 5 countries over up 
to two adaptive cycles (Figure 5). Each adaptive cycle will last approximately between 2 and 5 
months. 
Figure 5 The E-MOTIVE study adaptive cycles, parallel cluster randomised trial, process evaluation 
and cost-effectiveness. The formative components of the project (qualitative research, quantitative 
survey, and co-design workshop) are outlined in a separate protocol.  
  
Sample 
Field-testing will be carried out in at least two, but up to three, facilities per country. These will be 
purposively sampled to ensure representativeness of the facilities participating in the trial. To 
maintain internal validity of the trial, facilities taking part in the pilot adaptive cycles will be excluded 
from the main trial.  
Procedure 
The clinician in charge of the labour ward will organise an E-MOTIVE team that includes senior 
clinicians and midwives, obstetric anaesthetists, a project officer for training and implementation 
support, another project officer for qualitative and quantitative evaluations, and a representative 
from a women’s group (e.g., White Ribbon Alliance).  
For the first adaptive cycle, in Month 1, the facility will collect baseline data. After approximately 
one month, we will implement the E-MOTIVE intervention and deliver the implementation co-
intervention on site [simulation-based with peer-assisted training, establish local champions, 
MOTIVE trolley and/or carry case, and establish procedures for ongoing audit and feedback].  

Page 24 of 51 
 
Following a one to two month embedding and implementation period, we will then collect a mixture 
of qualitative and quantitative data to explore fidelity, acceptability, and barriers and enablers to 
implementation. In line with the Medical Research Council (MRC) guidance for process evaluations 
of complex interventions, we will combine basic quantitative measures of implementation with in-
depth qualitative data to provide detailed understanding of intervention functioning on a small 
scale.13 Therefore, fidelity and adoption may be explored via a combination of: quantitative ‘site 
implementation logs’ and checklists completed by the local facilitators to document extent of 
implementation. We will also conduct in-depth qualitative interviews based on behavioural science 
theories and frameworks (e.g., COM-B model, Theoretical Domains Framework, and Theoretical 
Framework of Acceptability) to explore barriers and enablers to implementation.  
Semi-structured interviews will be conducted with healthcare providers, including nurses, midwives, 
and doctors of different levels of seniority and experience. We will aim to interview approximately 
five healthcare providers from each facility taking part in the adaptive cycle. We will identify and 
recruit healthcare providers to participate in the semi-structured interviews who have had a real 
experience in using the E-MOTIVE intervention in clinical care, so that their responses are guided by 
practice challenges rather than hypothetical. Interviews will explore self-reported adoption and 
perceived barriers and enablers to implementing the E-MOTIVE intervention with fidelity. Potential 
modifications and enhancements to the interventions will also be explored.  
We will obtain informed consent from participants prior to them taking part in interviews. The local 
clinical collaborator will identify eligible participants to take part in the interviews and will send the 
study information sheet to potential participants. Participants will then have the option to contact 
the local research coordinator to arrange an interview.  
Interviews will be conducted by a trained researcher from the local team in each country. This is 
likely to be a research midwife or social scientist. Interviews will be conducted in a private location in 
the participating facility or via video/teleconference (according to participant preference), audio-
recorded and transcribed verbatim. Transcripts will be de-identified so that no individual or 
organisation may be identified from the data. Study materials 
Information sheets, consent forms and draft interview topic guides are available on request.   
Analysis  
Quantitative data will be summarised descriptively and qualitative data analysed using rapid 
qualitative analysis approaches, such as framework analysis. We will triangulate the quantitative and 
qualitative feasibility data to identify areas or specific intervention components for which there is 
low fidelity or acceptability, and themes around barriers to implementation. We will convene a 
meeting involving multidisciplinary research team members and local clinical collaborators from 
each participating country to agree which issues identified need to be addressed and how best to 
refine or add to the existing intervention materials and components. The interview questions to 
explore barriers and enablers will be based on the COM-B model, which is mapped onto two 
behavioural and implementation science frameworks that specify different types of behaviour 
change strategies: Behaviour Change Wheel and Behaviour Change Technique Taxonomy.10 
Therefore, if we find that Capability, Opportunity, and Motivation are key barriers during the 
adaptive field-testing phase, we can consult these frameworks to identify additional intervention 
strategies to consider including in the refined intervention.  
If adaptations to the intervention are made following the first adaptive cycle which require testing, 
we will progress to a second cycle of piloting to test the adapted intervention, collecting the same 

Page 25 of 51 
 
qualitative and quantitative measures on fidelity and adaptation. Following analysis of feasibility 
data from Cycle 2, we will further discuss and adapt the intervention as needed, prior to finalising 
the intervention materials ahead of randomisation and the intervention phase of the trial. 
 
6. 
OUTCOME MEASURES AND STUDY PROCEDURES 
6.1. 
Primary outcome 
The primary outcome is a composite of the following three clinical outcomes: 1) primary severe PPH 
defined as blood loss ≥1000 ml following a vaginal birth in the facility measured up to 2 hours 
postpartum; 2) postpartum laparotomy for bleeding until discharge from the health facility*; and 3) 
postpartum maternal death from bleeding until discharge from the health facility*. If any of the 
components occur, this will be deemed as positive for the primary outcome.    
Measurement of blood loss  
Blood loss will be collected using blood collection drapes for all women after vaginal birth. All 
facilities will use non-calibrated drapes during the baseline phase. During the intervention phase, 
facilities allocated to the control arm will continue to use non-calibrated drapes and facilities 
allocated to the intervention arm will use calibrated drapes containing measurement and trigger 
lines. The calibrated drapes are identical to the non-calibrated drapes with the only difference of 
having measurement and trigger lines to aid healthcare providers detect and treat PPH early. Blood 
loss will be measured for all women by weighing the blood collection drapes  at the first hour 
postpartum or if bleeding continues, the blood collection will be extended to the second hour 
postpartum. The weight of the blood collection drape containing the blood will be recorded using 
digital weighing scales. If there is excessive, additional blood loss beyond the second hour 
postpartum up to 24 hours postpartum a visual estimation of blood loss will also be provided, and 
this will be included in the overall blood loss measurement as a secondary clinical outcome.  
Only blood loss data that has been source verified will be included in the primary analysis – see 
section 11.2 for details. Blood loss data that has not been source verified is included in a sensitivity 
analysis. 
Blinded Endpoint Review Committee 
A Blinded Endpoint Review Committee (BERC) will assess incoming data relevant to the primary 
outcome to confirm if any postpartum laparotomy was performed for bleeding and if any maternal 
death was due to bleeding. Initially, two central independent reviewers (identified by the ITMG) will 
review de-identified data via the online E-MOTIVE database where there is a case of postpartum 
laparotomy and/or maternal death. The reviewers will not be able to view the facility’s responses as 
to whether the postpartum laparotomy was for bleeding and/or the maternal death was due to 
bleeding. Each reviewer will be prompted to log in to the E-MOTIVE database and record their 
assessment on an electronic case report form (e-CRF) following receipt of an automated notification. 
If there is discordance between the assessments of the two reviewers or if their assessment conflicts 
with the assessment provided by the facility then a further assessment will be required by a central 
independent arbitration committee of five members convened by the ITMG. The committee will 
meet as frequently as required and a decision will be made by a majority vote. The arbitration 
committee will have access to the facility assessment (on the Discharge Outcome form) and the two 
reviewer assessments in order to make their decision. The Programme Manager (or delegate) will 
minute committee discussions and enter a summary of the discussions along with their decision on 

Page 26 of 51 
 
to the e-CRF. The review by the BERC members will be undertaken blinded to the randomised 
allocation of the health facility. Members of the BERC are required to formally register their assent 
to join the committee by signing a separate charter. Further details of the BERC can be found in their 
charter. 
 
Components of the primary composite outcome 
The three components of the primary composite outcome will be measured individually and are: 
1) Primary severe PPH defined as blood loss ≥1000 ml following a vaginal birth in the facility 
measured up to 2 hours postpartum;   
2) Postpartum laparotomy for bleeding until discharge from the health facility*;  
3) Postpartum maternal death from bleeding until discharge from the health facility* 
 
6.2  
Secondary clinical and implementation outcomes 
Secondary clinical outcomes  
These include the three individual components of the composite primary outcome. The secondary 
clinical outcomes (where we expect to see a reduction if E-MOTIVE is effective) are based on the 
Core Outcome Set for PPH treatment14, and are the following: 
1. Laparotomy postpartum until discharge from the health facility*; 
2. Laparotomy with compression sutures postpartum until discharge from the health 
facility*;  
3. Laparotomy with arterial ligation postpartum until discharge from the health facility*; 
4. Hysterectomy postpartum until discharge from the health facility*; 
5. Hysterectomy postpartum for bleeding until discharge from the health facility*; 
6. All cause maternal mortality postpartum until discharge from the health facility*;  
7. Blood loss (reported in ml) up to 24 hours postpartum; 
8. Primary PPH defined as blood loss ≥500 ml up to 24 hours postpartum†; 
9. Duration of hospitalisation postpartum;  
10. Duration of ICU hospitalisation postpartum until discharge from the health facility*;  
11. Transfers to higher-level facility postpartum until discharge from the health facility; 
12. All cause neonatal mortality postpartum until discharge from the health facility*; 
13. Use of Non-pneumatic anti-shock garment (NASG) postpartum†;  
14. Use of uterine balloon tamponade postpartum until discharge from the health facility †*;  
15. Blood transfusion postpartum until discharge from the health facility†*;  
16. Blood transfusion for postpartum haemorrhage until discharge from the health facility†*;  
17. Intensive Care Unit (ICU) admissions postpartum until discharge from the health facility†*;  
18. Primary severe PPH (defined as blood loss ≥1000 ml) following a vaginal birth in the facility 
measured up to 2 hours postpartum†;  
19. Postpartum laparotomy for bleeding until discharge from the health facility*;   
20. Postpartum maternal death from bleeding until discharge from the health facility*;   
 
†Combined clinical and quality of care exploratory outcomes where we may observe an increase or 
a reduction if E-MOTIVE is effective.  

Page 27 of 51 
 
*In cases where a woman is transferred to another facility postpartum, discharge from the health 
facility relates to the facility the woman is transferred to [and the relevant outcomes will be 
obtained from the facility to which the woman was referred].  
Secondary implementation outcomes 
The key secondary implementation outcomes of special interest are 1) PPH detection (with the 
following numerator and denominator: women who objectively had PPH (source-verified blood loss 
≥ 500 mL after weighing the drape) and were diagnosed with PPH by the birth attendants divided by 
the total number of women who objectively had PPH (source verified blood loss ≥ 500 mL after 
weighing the drape), and 2) compliance with MOTIVE bundle (with the following numerator and 
denominator: women who objectively had PPH and were treated with the PPH bundle following a 
diagnosis of PPH by the birth attendants divided by the total number of women who objectively had 
PPH (blood loss ≥ 500 mL after weighing of the drape). Compliance with the MOTIVE bundle is 
defined as adherence to three core elements of the bundle: administration of oxytocic drugs, TXA 
and IV fluids. If all three core elements are administered when a PPH is diagnosed, this will be 
deemed positive for bundle compliance. If any of the three core elements are not administered 
when a PPH is diagnosed, then this will be deemed negative for bundle compliance. It is 
hypothesised that the causal mechanism underpinning the intervention is that it will increase the 
rate at which PPH is diagnosed; and that an increase in awareness of women suffering from PPH will 
subsequently lead to an increase in uptake in the interventions to stop PPH from progressing to 
severe consequences. This will ultimately lead to a reduction in the proportion of women suffering 
adverse outcomes from PPH.  
Other implementation outcomes are:  
1. PPH treatment (with the following numerator and denominator: women diagnosed with 
PPH by the birth attendants divided by the total of women having a vaginal birth in the 
health facility) 
2. Bundle usage (with the following numerator and denominator: women treated with the 
PPH bundle following a diagnosis of PPH by the birth attendants divided by the total of 
women having a vaginal birth in the health facility)  
3. Bundle usage for PPH (with the following numerator and denominator: women treated 
with the PPH bundle following a diagnosis of PPH by the birth attendant divided by the 
total of women diagnosed with PPH by the birth attendants); 
4. Uterine massage; 
5. Oxytocin use; 
6. Misoprostol use; 
7. TXA use; 
8. Intravenous fluids use; 
9. Examination of the genital tract; 
10. Number of women receiving any treatment uterotonic; 
11. Number of women requiring additional treatment interventions (not responding to the 
MOTIVE bundle). 
All secondary implementation outcomes will be reported with three denominators: the total study 
population; women diagnosed with PPH by the birth; and women who objectively had PPH (blood loss 
≥ 500 mL after weighing the drape) unless otherwise specified. 
The data are routinely collected as part of normal clinical practice and women will not be approached 
for additional trial-specific data or follow up at any point. 

Page 28 of 51 
 
From each participating health facility, we will extract the following additional outcomes weekly: 
1. Vaginal births (number); 
2. Caesarean sections (number); 
 
From each participating health facility, we will extract the following additional outcomes monthly: 
 
3. Availability of bundle components;  
4. Availability of NASG; 
5. Availability of UBT; 
6. Availability of blood transfusion; 
7. Availability of surgical theatre for obstetrics;  
8. Availability of ICU; 
9. Availability of skilled birth attendants.  
 
6.3. 
Process evaluation 
Aims and objectives 
Alongside the trial, we plan to conduct a process evaluation to assess the extent to which the E-
MOTIVE interventions have been implemented as intended. We will adopt the UK-MRC guidance on 
process evaluations of complex interventions to evaluate E-MOTIVE based on three main domains: 
context, implementation, and mechanisms of impact. We will also be guided by the implementation 
outcomes framework.13 The implementation outcomes of interest are:   
• 
Fidelity and Dose: To what extent was the E-MOTIVE intervention and the implementation 
strategies delivered and engaged with as planned?  
• 
Adaptation: what modifications were made to the E-MOTIVE intervention to adapt to the 
study context, and achieve the study protocol?  
• 
Contamination and treatment differentiation: To what extent did the clinical actions taken 
to detect and treat PPH in the usual care control arm differ from those in the E-MOTIVE intervention 
arm? Is there evidence of cross-contamination between trial arms?  
We plan to assess mechanisms of impact as: 
• 
Acceptability and Participant responses: how did healthcare providers respond to and 
interact with the E-MOTIVE intervention? To what extent were the E-MOTIVE interventions 
considered acceptable?  
• 
Mediators: what were intermediate processes which explain subsequent changes in 
implementation outcomes, and what are the barriers and enablers to implementing E-MOTIVE 
interventions as intended?  
• 
Unanticipated consequences: what are the unintended consequences of the E-MOTIVE 
intervention? 
Design 

Page 29 of 51 
 
To answer these questions, we will use a range of methods, theoretical, and analytical approaches 
similar to those described earlier for the formative and adaptive phases of the programme of 
research. In line with MRC process evaluation guidance, we will balance in-depth qualitative data 
collection with a feasible, small sample of participants in each country, alongside quantitative 
measures across the full trial sample.9 Methods may include a combination of observations, 
checklists, document analyses, in-depth interviews, and surveys.  
Qualitative interviews with healthcare providers 
We will first conduct in-depth interviews with a purposive sub-sample of healthcare providers, 
including nurses, midwives, and doctors of different levels of experience and management 
responsibilities. We will do interviews in a sub-sample of both intervention and control arms to 
explore implementation as intended in the intervention arm, but also what current usual care is in 
control arm facilities so we can monitor for the extent of treatment differentiation and possible 
contamination.   
We will purposively sample up to three facilities per country (2 intervention arm, 1 control). In each 
facility, we will interview up to 4 healthcare providers, giving a total sample size of up to 60 
participants (i.e., 4 per facility x 3 facilities per country x 5 countries).  These facilities will be 
purposively sampled based on facility size (number of births) and high vs low performing facility. 
Facilities may also be sampled based on PPH burden and geographical location/country specific 
factors, to ensure diversity and representation.  
Intervention arm interviews will explore self-reported fidelity of delivery, adoption and enactment of 
the E-MOTIVE intervention, perceived acceptability of the interventions, and barriers and enablers 
to implementation in practice. We will also explore any other ongoing quality improvement 
initiatives and factors external to E-MOTIVE that may have influenced practice. Control arm 
interviews will explore current practice around detection and management of PPH, replicating the 
interviews done in the formative phase of the study (separate protocol). The interview topic guides 
will be based on behavioural science frameworks used to explore acceptability, clinical practice, 
mechanisms of change and barriers and enablers. Both topic guides will be semi-structured, that is, 
whilst we will have a fixed number of open-ended questions we will ask of all participants, there will 
be flexibility in the precise wording of the questions in order to adapt and reflect on earlier 
responses, and these questions will be followed up with open-ended, flexible prompts, to allow the 
researcher to respond to and further unpack participants’ views and responses to the initial 
questions.  
Intervention arm interviews will be done at 6-7 months at selected sites, to allow time for initial 
intervention delivery and embedding of the intervention in clinical practice. Control arm interviews 
will be done at 6-7 months in specific facilities if any areas require further exploration following the 
survey. Potentially eligible participants will be identified by a local collaborator, who will provide 
participants with a study information sheet. Participants will be asked to sign a consent form prior to 
taking part. Interviews will be conducted by a local trained researcher (i.e., research midwife, social 
scientist), in a private location at the participating facility or via video/teleconference- according to 
participant preference. Interviews will be audio-recorded, transcribed verbatim, and de-identified. 
These will then be analysed by post-doctoral researchers at UCL and the University of Melbourne, 
using a combined deductive framework and inductive thematic analysis approach.  
Surveys  

Page 30 of 51 
 
To balance the in-depth qualitative interviews, we will conduct a cross-sectional survey with a larger, 
more representative sample of healthcare providers across all participating facilities and countries. 
Like the interviews, the surveys will explore the perceived intervention acceptability, barriers and 
enablers to implementing E-MOTIVE and the co-interventions during the trial, and potentially 
sustaining implementation longer term. The survey will also be structured around the 
aforementioned behavioural science frameworks around acceptability and influences on 
implementation. It will include items to mirror the interview questions, but with a mixture of 
response formats (Likert-type scales, dichotomous yes/no questions). It will include a brief 
demographics section (e.g., role, years of experience), questions on general knowledge of PPH, how 
PPH is detected and managed in that facility, extent of implementation of the E-MOTIVE 
intervention components, and perceived acceptability and barriers and enablers to implementing 
the E-MOTIVE interventions (MOTIVE bundle and co-implementation strategy). We will also 
administer a survey to the control arm facilities to explore current practice and possible 
contamination. This will be the same current practice survey as administered in the formative 
research phase (separate protocol). The survey for control arm facilities will be administered at 6-7 
months.  
The survey for intervention arm facilities will be administered at one time point: at 6-7 months (to 
explore sustainability of implementation). Local collaborators will identify potentially eligible 
participants and email a study information sheet and link to the electronic survey. Eligible 
participants are those who work in the labour wards at the facilities recruited for E-MOTIVE. We aim 
to recruit 1-2 obstetricians, 3 medical officers/residents/junior doctors, and 5 midwives/nurses per 
facility. This is the information that will be given to the local collaborators. The first two screens of 
the digital survey will include a study information sheet and consent form, which participants must 
complete prior to progressing to the survey. No identifiable data will be collected and stored via the 
survey.  
Survey data will be summarised using descriptive statistics. We will compare responses according to 
participant role, across facilities, and countries.  
Quantitative fidelity of delivery assessment 
As part of data collection for the trial outcomes, we are collecting data on which E-MOTIVE 
intervention components were delivered when a PPH was detected. This will enable us to 
quantitatively assess fidelity of delivery of the E-MOTIVE intervention for all participating facilities. 
This will be calculated as a proportion of bundle components delivered for treating a PPH. General 
consensus criterion suggests less than 50% delivery = poor fidelity, 51-79% moderate fidelity, and 
80-100% high fidelity. We will compare proportions of bundle component delivery over the duration 
of the trial to explore sustainability and fidelity drift. We will also explore the potential to use such 
quantitative process evaluation data, including survey responses, to explore associations with 
observed outcomes.  
Observations 
We will also conduct structured observations of PPH detection and management. These 
observations will be simulations, led by Jhpiego using Objective Structured Clinical Examinations 
(OSCEs). OSCEs may be conducted at each intervention facility at different time points including pre-
training, immediately post-training, post-training when all practice sessions are complete and 
between 3-6 months following training. The OSCEs will be conducted using an adapted version of an 
existing Jhpiego OSCE checklist for PPH (i.e., adapted to reflect bundled approach of the E-MOTIVE 

Page 31 of 51 
 
intervention).  Medical records and facility logbooks may be evaluated to understand the broader 
context of maternity care, as well as any meeting notes from workshops, trainings, and meetings 
about the process of implementation. As appropriate, other documents will be included, for 
example, media coverage about the study or process during the time of implementation to 
understand how the intervention is viewed by communities and stakeholders involved and affected. 
These will be collected by local researchers of the E-MOTIVE team (i.e., research midwives, social 
scientists).  
Implications  
Findings from the process evaluation will also be fed back into the final iteration of the logic model, 
to provide a better understanding of the pathways to successful design of the E-MOTIVE 
intervention. The process evaluation will ultimately help to identify any threats to the internal 
validity of the trial, as well as to understand issues around equity, transferability, scalability, and 
sustainability of the intervention. Findings from the process evaluation will facilitate more accurate 
interpretation of observed outcomes, and inform future scalability and implementation of the E-
MOTIVE and co-interventions if shown to be effective. 
 
7. ADVERSE EVENT REPORTING  
As the interventions being tested as a bundle in this trial are recommended and used throughout the 
world, there are no adverse events which would be anticipated as a unique consequence of 
participation in the trial. No expedited reporting of adverse events is proposed. We are anticipating 
that there will be deaths in this trial. However, most of these deaths will be a consequence of the 
PPH or other postpartum complications. It is possible that there may be a difference in the rate of 
death between the two arms of the trial if the E-MOTIVE intervention reduces deaths in the 
intervention arm. However, this will not be detected by expedited reporting because (i) the 
proportion of deaths due to the trial intervention will be small compared to the background risk of 
death and differences will be difficult, if not impossible, to detect by reporting of individual deaths, 
and (ii) this is a cluster randomised trial so adjustment for the clustering will be required to explore 
whether crude differences in death rates are due to the intervention. Maternal deaths and ICU 
admissions will be collected for all participants in the trial and these outcomes will be monitored by 
the independent Data Monitoring and Ethics Committee. 
 
8. 
DATA HANDLING AND RECORD KEEPING  
8.1. 
Source Data 
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in source documents (original records or 
certified copies). In order to allow for the accurate collection of the data, source data will be accessible 
and maintained by health facility staff. Source data are generally kept as part of the medical records 
generated and maintained at site, but some data variables may be entered directly onto the CRF. The 
source data for the E-MOTIVE trial will also include birth registries, staff records, and for participants 
(healthcare providers) their responses to online surveys and interview transcripts. Health facility staff 
will fill in the CRFs in each facility and all data extracted will be entered onto the online E-MOTIVE 
database (https://bctu-redcap.bham.ac.uk/). BCTU and investigators will not have access to any 
identifiable information for any of the records entered onto the database.  

Page 32 of 51 
 
8.2. 
Case Report Form (CRF) Completion  
Data reported within the CRFs will be consistent with the source data and any discrepancies will be 
explained. In the cases where the CRF constitutes source data, this will be filed in the medical 
records as detailed above and entered into the online E-MOTIVE trial database. All missing and 
ambiguous data will be queried with health facility staff. Staff delegated to complete CRFs will be 
trained to adhere to the requirements of data capture as explained in the E-MOTIVE training slides. 
In all cases, it remains the responsibility of the health facility’s local champion to ensure that the CRF 
has been completed correctly and that the data are accurate. This may be evidenced by the 
signature of the health facility’s local champion, or delegate(s), on the paper CRF (if completed).  
For the E-MOTIVE trial this will be in the form of an electronic or paper CRF. The data held on the 
completed original electronic CRFs are the sole property of the respective local champions whilst the 
data set as a whole is the property of the BCTU and should not be made available in any form to 
third parties except for authorised representatives or appropriate regulatory authorities without 
written permission from the sponsor. Appropriate data sharing requests will be considered by the 
International Trial Management Group (ITMG) and the BCTU data sharing committee. 
It will be the responsibility of the investigator to ensure the accuracy of all data entered in the 
electronic CRFs and confirm accordingly. The E-MOTIVE Site Signature & Delegation Log will identify 
all those personnel with responsibilities for data collection. 
Staff delegated to complete the electronic CRFs will be trained to adhere to online completion of the 
CRFs in the trial database from source data. Online data entry is achieved via unique passwords and 
usernames, which must not be shared amongst the team. All time formats, where applicable, should 
be in accordance with the 24-hour clock. Rounding of numbers, where applicable, should be in the 
normal way (i.e., ≥x.5 is rounded up to the nearest whole number). Protocol non-compliances 
should be added to a Protocol Deviation Log, held by the site, and reported to the Trials Office on 
discovery. 
8.3. 
Data Management 
Data must be entered on paper via the CRF booklet or directly on the online E-MOTIVE database 
(https://bctu-redcap.bham.ac.uk/). Where Paper Case Report Forms (CRFs) are completed, these will 
be signed and dated, filed in the medical records, and data will be entered on to the online E-
MOTIVE database by a member of the research team at the local spoke health facilities.  
Participating health facility teams should transfer all data from paper CRF booklets into the online E-
MOTIVE database. E-MOTIVE Hub research staff will check all electronic CRFs for completeness, data 
consistency and compliance with the protocol. If discrepancies or missing data are identified, the 
Hub will raise queries with the research team at the spoke facility via the E-MOTIVE database. 
The central E-MOTIVE trial office at BCTU will liaise directly with each Hub to resolve any 
inconsistencies in data, identified centrally.  
8.4. 
Data Security and data protection 
The security of the Trial Database System is governed by the policies of the University of 
Birmingham. Data management and data security within BCTU will abide by the requirements of the 
General Data Protection Regulations (GDPR) and any subsequent amendments. The trial will be 
conducted at collaborating sites in accordance with the country-specific data protection 
requirements. Data will be acquired and stored on the REDCap platform. Access to data will be 

Page 33 of 51 
 
restricted by usernames and passwords, at participating health facilities, Hubs, and BCTU. Each 
record on the database will be allocated a unique trial number at entry in the database. All 
documents will use this as the identifier. All data will be analysed and reported in summary format. 
No individual will be identifiable.  
8.5. 
Archiving 
All records created by following trial procedures and all documents listed in guidance relating to the 
conduct of the trial must be retained and archived. Archiving will be authorised by the BCTU on 
behalf of the Sponsor following submission of the end of trial report. It is the responsibility of the 
National Principal Investigator and Local Champion to ensure all essential trial documentation and 
source documents at their site are securely retained in line with the relevant national laws and 
regulations. The final dataset will be stored for at least 10 years in accordance with UK Policy 
Framework for Health and Social Care Research 2017.  No documents should be destroyed without 
prior approval from the BCTU. 
 
9.  
QUALITY CONTROL AND QUALITY ASSURANCE 
9.1. 
Site Set-up and Initiation 
Staff at participating health facilities will undergo a standardised site set-up training package. This 
will include: 
● Online training modules (set-up, control, intervention). Templates will be provided and stored in 
the Investigator Site Files. Ongoing training will be documented and monitored throughout the study 
to ensure the intervention is delivered optimally. 
● Site initiation visit: from either BCTU or local Hub. Key members of the health facility research 
team will be required to attend either a meeting or video/teleconference covering aspects of the 
trial design, protocol procedures, data reporting and record keeping. The BCTU must be informed 
immediately of any change in the Site research team. 
● A two-month E-MOTIVE ‘transition phase’ to allow health facilities to adjust to change clinical 
practice for the delivery of the interventions. 
Site opening 

Page 34 of 51 
 
Hubs - Hubs are the central, 
country-specific coordinating 
centres (Figure 6). The Hubs will take 
responsibility for the management of 
the health facilities in the country 
called the Spoke facilities; will provide 
administrative services for the country 
network; will provide training for 
Spokes and will maintain regular 
communication with the University of 
Birmingham. Hubs will sign a contract 
with the University of Birmingham 
delineating the responsibilities of the 
Hub as lead site for the E-MOTIVE trial. 
Hubs should subsequently put 
agreements in place with each of the 
Spoke facilities (if required) and ensure 
that the necessary approvals are in 
place prior to commencing the trial at 
each health facility. 
All participating Local Champions will provide evidence of trial specific training to their national Hub. 
All members of the research team at health facilities will also be required to sign the E-MOTIVE Site 
Signature and Delegation Log, which details which tasks have been delegated to them by the Local 
Champion. 
9.2. 
Monitoring  
On-site Monitoring 
Monitoring visits and observations of healthcare providers managing real life vaginal births will also 
be conducted in health facilities during the baseline and intervention phases (both in sites 
randomised to the intervention and control groups) and in health facilities participating in the 
adaptive cycles. These will include observing the facility readiness for managing PPH and healthcare 
provider’s treatment of postpartum haemorrhage if PPH occurs. An observation guide has been 
developed for use in health facilities participating in the adaptive cycles and health facilities 
randomised to the intervention group. A separate observation guide has been developed for use in 
health facilities during the baseline phase and in health facilities randomised to the control group. 
Observations of vaginal births will be conducted in intervention and control facilities at 1 or 2 time 
points during the study. 
Additional on-site monitoring is carried out as required following trial specific risk assessment and as 
documented in the monitoring plan. The monitoring of spoke facilities will be conducted by the 
Hubs; the Hubs will be monitored by BCTU. 
Any monitoring activities will be reported to the central trials team at BCTU and any issues noted will 
be followed up to resolution. Additional on-site monitoring visits may be triggered, for example by 
poor CRF return, poor data quality, or poor compliance with the E-MOTIVE intervention. 
If an on-site monitoring visit is planned, the Hub trial team will contact the health facility to arrange 
a date for the proposed visit and will provide the health facility with written confirmation. 
Figure 6  Hub and spoke organization model for the E-MOTIVE study. 

Page 35 of 51 
 
Investigators will allow the Hub staff access to source documents as requested. During on-site 
monitoring visits the source data contained in source documents e.g., patient notes will be checked 
by the Hub team to ensure data are legible, original, accurate and well maintained.  
Central Monitoring  
E-MOTIVE trial staff from BCTU will be in regular contact with the Hub research teams to check on 
progress and address any queries that they may have. 
Hub trial staff will check CRFs from the spoke facilities for compliance with the protocol, data 
consistency, missing data and timing. Hubs will send spoke facilities data queries for missing data or 
clarification of inconsistencies or discrepancies. BCTU will centrally monitor data received from the 
Hubs. More detailed monitoring processes will be detailed in the Monitoring Plan. 
 
9.3. 
Audit and Inspection 
National Principal Investigators and Local Champions will permit trial-related monitoring, regulatory 
inspections, audits, and ethical review at their site. The investigator will comply with these visits and 
any required follow up. If there are any externally-conducted inspections, Hubs are requested to 
notify BCTU in advance of any relevant inspections of the Hub site. 
9.4. 
Notification of Serious Breaches 
The Sponsor of the trial is responsible for notifying the regulatory bodies in writing of any serious 
breach of the conditions of the trial protocol, within 7 days of becoming aware of that breach. 
For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a 
significant degree: 
- the safety or physical or mental integrity of the women giving birth in the study facilities; 
- the scientific value of the trial. 
Hubs must notify the BCTU and Spokes are therefore requested to notify the Hub, of any suspected 
trial-related serious breach of the trial protocol. Where BCTU is investigating whether or not a 
serious breach has occurred, sites are requested to provide sufficient information to report the 
breach to the regulatory bodies where required and in undertaking any corrective and/or preventive 
action. 
Any major problems identified during monitoring may be reported to BCTU, the TSC and the relevant 
regulatory bodies. 
 
10.  
END OF TRIAL DEFINITION 
The end of trial is defined as the final data capture from all participating health facilities. This will 
ensure completion of data collection, data input and analysis. The E-MOTIVE Trials Office at BCTU 
will notify each Hub that the trial has ended within 90 days of the end of trial and it will be their 
responsibility to notify the regulatory bodies of that country as relevant. A summary report will be 
sent to each Hub for submission to the regulatory bodies within 12 months of the end of the trial (if 
required). 
 

Page 36 of 51 
 
11.  
STATISTICAL CONSIDERATIONS  
11.1. Sample Size  
Following issues around study data collection, and in discussion with the funder and the 
independent TSC and DMC committees, the study was reduced from 24 months to 16 months. 
Below, we outline the original sample size calculation and present the updated sample size 
calculation.  
Original sample size calculation 
Assuming there are 80 health facilities in the trial, evenly split across the intervention and control 
groups, with an average number of 192 births per health facility per month, the anticipated total 
sample size for the study (running for 22 months) would be 337,920 (=80*192*22). The number of 
health facilities (80) has been inflated by 10% to allow for drop out from the number of health 
facilities required (72). This sample size is expected to be sufficient to provide approximately 90% 
power at 5% significance (two-sided) to detect a change from 2% to 1.5% (25% relative reduction) in 
the primary outcome, after allowing for clustering and for varying cluster sizes and across most 
realistic scenarios. Below, we describe this calculation in more detail, firstly providing the rationale 
for the choice of these key values, and then outlining the methodology used to calculate the sample 
size. We provide details of the sensitivity of power to any changes in these key design parameters. 
In the control condition, we expect the prevalence of the primary composite outcome to be around 
2%. This prevalence is informed by the prevalence of a similar outcome based on analysis of the 
CHAMPION trial4 and we have considered sensitivity to this prevalence between 1.5% and 4%. 
A relative risk reduction of 25% was considered to be a clinically meaningful difference to detect, 
though smaller reductions could also be worthwhile. Under some scenarios (such as a high value of 
the ICC) this target effect size might not be detectable at 90% power, and so we therefore consider a 
larger target effect size to demonstrate the size of effect size that can be demonstrated under these 
less conservative other scenarios.  We have thus considered sensitivity to the power for a relative 
reduction of 20% and 30%.  
Sample size calculations have allowed for the clustered nature of the design through the intra-
cluster correlation (ICC). As recommended, values for the ICC have been informed through a 
combination of the literature and analysis of available data on a similar set of outcomes. Analysis of 
the CHAMPION trial4 found an ICC of 0.03 (95% CI: 0.02 to 0.05) for a similar composite outcome of 
PPH ≥1000 ml, laparotomy and maternal death. This ICC was estimated using a linear mixed 
regression model and so is on the proportions scale as is appropriate for a sample size calculation. As 
the literature suggests, rare clinical outcomes tend to have small ICCs, for this reason we have 
considered an extended range for the ICC, from 0.001 to 0.05, with an expected ICC of 0.02.  
To allow for variations in clustering over time, we have allowed for a cluster by period random 
effect. This has been incorporated in the sample size calculations using the cluster autocorrelation 
(CAC).15,16 There is limited information from the literature on likely values of the CAC. Using data 
from the CHAMPION trial4, we created two 11-month periods, which match the planned study 
design. From this, we estimated a CAC of 0.97. No current methodology exists to calculate a 
confidence interval for this value. We have chosen to consider sensitivity to the CAC between the 
values of 0.95 and 1.0.  
Survey data from health facilities that was collected to obtain information on the number of births 
per health facility. From this survey data, we calculated an average number of births per health 

Page 37 of 51 
 
facility per month of 192. The health facilities varied in size. We have estimated a coefficient of 
variation of cluster sizes of 0.5 and have allowed for this in our sample size calculations using a 
conservative correction. 17 [Rutterford 2015].  
 
The methods to calculate the sample size in a parallel CRT with a baseline period have been 
described fully by Hooper and Bourke.15,16 These methods have been implemented in an RShiny App 
(https://clusterrcts.shinyapps.io/rshinyapp/), used to inform the sample size for this trial. 
 
Table 1 provides information on the expected level of power across the range of parameters 
outlined above. These suggest that the study has at least 80% power in almost all likely scenarios to 
detect a 25% relative risk reduction in the composite primary outcome from 2% to 1.5% (Table 1). If 
the ICC is at the upper limit (0.05), the study would have more than 80% power to detect a relative 
risk reduction of 30% in the composite primary outcome from 2% to 1.5% under every scenario 
considered except one (ICC=0.05 and CAC=0.95). 
 
Table 1: Original estimates of the power with changes to key design parameters. 
  
RR = 20% 
RR = 25% 
RR = 30% 
Control Prevalence 
1.5
% 
2.0
% 
4.0
% 
1.5% 2.0% 4.0% 1.5% 2.0% 4.0% 
CAC = 0.95 
IC
C 
0.00
1 
96.4 
99.2 
99.9 
99.6 
99.9 
99.9 
99.9 
99.9 
99.9 
0.02 
54.6 
67.1 
92.9 
68.1 
80.3 
98.0 
84.1 
92.8 
99.8 
0.05 
30.8 
39.2 
67.3 
38.9 
49.3 
79.1 
53.3 
65.7 
92.1 
CAC = 0.97 
0.00
1 
96.8 
99.3 
99.9 
99.7 
99.9 
99.9 
99.9 
99.9 
99.9 
0.02 
67.8 
80.1 
97.9 
81.9 
91.4 
99.7 
93.8 
98.2 
99.9 
0.05 
43.0 
54.2 
83.8 
54.4 
66.8 
92.8 
71.2 
83.0 
98.6 
CAC = 1.00 
0.00
1 
97.4 
99.9 
99.9 
99.6 
99.9 
99.9 
99.9 
99.9 
99.9 
0.02 
95.8 
98.9 
99.9 
99.7 
99.9 
99.9 
99.9 
99.9 
99.9 
0.05 
95.4 
98.8 
99.9 
99.9 
99.9 
99.9 
99.9 
99.9 
99.9 
Note: Power has been calculated assuming 72 health facilities, with an average number of 192 births per 
month (22 month study), and a coefficient of variation of cluster sizes of 0.5. CAC: Cluster autocorrelation; 
ICC: Intra cluster correlation. RR = Risk reduction 
 
Updated Sample Size Calculation 
In October 2021, a revised sample size calculation was performed, based on the study shortening 
from 24 months to 16 months (allowing for a 2-month transition period). As part of this, we 
evaluated some of the parameters made in the earlier calculation using estimates from the 
accrued baseline data (collected from October 2020 to September 2021) in sites with high quality 
data.  
 
Assuming there are 80 health facilities in the trial, evenly split across the intervention and control 
groups, with an average number of 192 births per health facility per month, the anticipated total 
sample size for the study (running for 14 months) would be 215,040 (=80*192*14). The number of 
health facilities (80) has been inflated by 10% to allow for dropout from the number of health 
facilities required (72).  

Page 38 of 51 
 
 
Table 2 provides information on the expected levels of power for a 16-month study (two 7-month 
periods and a 2-month transition period) across the range of parameters described earlier. These 
suggest that the study has at least 90% power at 5% significance (two-sided) to detect a 30% RRR 
for most scenarios after allowing for clustering and for varying cluster size. The study will have 
over 90% power to detect smaller RRR if the ICC is close to the lower bound (0.001), the CAC is at 
the upper bound (1.0), or the prevalence of the study is relatively large (4.0%). 
 
Table 2: Estimates of the power with changes to key design parameters. 
  
RR = 20% 
RR = 25% 
RR = 30% 
Control Prevalence 
1.50
% 
2.00
% 
4.00
% 
1.50
% 
2.00
% 
4.00
% 
1.50
% 
2.00
% 
4.00
% 
CAC = 
0.95 
ICC 
0.001 
86.8 
94.5 
99.9 
97.4 
99.5 
99.9 
99.7 
99.9 
99.9 
0.02 
43.2 
54.4 
84 
62 
74.6 
96.3 
78.8 
89.1 
99.5 
0.05 
24.8 
31.6 
56.1 
36.8 
46.7 
76.4 
50.6 
62.7 
90.3 
CAC = 
0.97 
0.001 
87.5 
95 
99.9 
97.6 
99.5 
99.9 
99.8 
99.9 
99.9 
0.02 
53.9 
66.3 
92.5 
74.1 
85.5 
99.1 
88.8 
95.7 
99.9 
0.05 
34.1 
43.4 
72.7 
50.2 
62.4 
90.1 
66.8 
79.1 
97.7 
CAC = 
1.00 
0.001 
89.7 
96.2 
99.9 
98.3 
99.7 
99.9 
99.9 
99.9 
99.9 
0.02 
83.7 
92.1 
99.9 
95.9 
99 
99.9 
99.5 
99.9 
99.9 
0.05 
83 
92.6 
99.9 
96.2 
99.1 
99.9 
99.4 
99.9 
99.9 
Note: Power has been calculated assuming 72 health facilities, with an average number of 192 births per 
month (14-month study), and a coefficient of variation of cluster sizes of 0.5. CAC: Cluster autocorrelation; 
ICC: Intra cluster correlation. RR = Risk reduction 
 
Analysis of the baseline data found a prevalence of the primary outcome of 3.6% (95% CI: 3.4% to 
3.8%) and an ICC of 0.018 (95% CI: 0.01 to 0.034). With large prevalence (4.0%), the study would 
have over 90% power to detect a 20% RRR for most likely scenarios (Table 2). A re-estimation of 
the CAC using two 7-month periods in CHAMPION data found a CAC of 0.99. With a CAC of 1.00, 
the study would have over 90% power to detect a 20% RRR for most likely scenarios.  
 
 
11.2. Analysis of Outcome Measures  
A separate Statistical Analysis Plan will be produced and will provide a more comprehensive 
description of the planned statistical analyses.  A brief outline of these analyses is given below. All 
analyses will be by intention to treat, which means that health facilities will be analysed according to 
their randomised allocation. The baseline characteristics, for example age, number of previous 
births, and pregnancy type, will be summarised as means and standard deviations, medians and 
inter-quartile ranges, or numbers and percentages, as appropriate, stratified by trial arm and time-
period.  A flowchart will be constructed to show the flow of both health facilities and patients 
throughout the trial.  
The primary comparison will be composed of those health facilities randomised to the E-MOTIVE 
intervention versus those randomised to the usual care. For the primary outcome, our aim is to fit a  
mixed-effect logistic model incorporating a constrained baseline analysis to calculate relative risks 

Page 39 of 51 
 
and risk differences. We will use marginal standardisation to obtain the risk difference and risk ratio. 
Under a constrained baseline analysis, each observation has a binary indicator for time – indicating 
whether the observation was made during the baseline phase or the post-randomisation phase 
(which represents the change in the control arm over time) – and a binary indicator for treatment – 
indicating whether the observation was allocated to the usual care or E-MOTIVE (which represents 
the treatment effect). The constrained part of the model assumes no differences at baseline as is 
appropriate under a randomised design. This approach is recommended in cluster randomised trials 
with a baseline assessment of outcome.18 No small sample correction will be used as there are 
expected to be in the region of 70 health facilities in the analysis and the mixed model is expected to 
have appropriate estimation of the standard errors in this situation.19 Clustering will be allowed for 
in all analyses through the use of random effects. Recent developments in the methodological 
literature for the design and analysis of multiple-period cluster randomised trials suggest that a 
simple exchangeable correlation structure is not sufficient to depict the correlation structure in 
multiple-period cluster randomised trials.15,16 We will explore including a random cluster by period 
interaction in addition to a random cluster effect to allow for the decay in correlation between 
observations made in the same cluster, but at different time periods. If models with complex 
correlation structures do not converge, we will fit models with a simpler correlation structure. Other 
secondary outcomes will be modelled similarly, using appropriate link and distribution function in 
the generalised linear mixed model family.  
The primary analysis will be unadjusted, except for factors used in the randomisation method 
(number of vaginal births per health facility, country, and quality of oxytocin per health facility 
during the baseline phase). As a sensitivity analysis, we will perform a propensity score (PS) based 
method – the direct PS adjustment as recommended by Leyrat et al20 [Leyrat 2013]. Under this 
method, the PS is obtained by fitting a multivariable logistic model with potential confounders (age; 
parity; multiple pregnancy; mode of birth; and birth weight). The potential confounders have been 
proposed by the E-MOTIVE TMG following a consensus meeting.  
The primary composite outcome (severe PPH, postpartum laparotomy for bleeding, and maternal 
mortality from bleeding) will be considered significant at the 5% level, and effect sizes and 95% CIs 
will be reported. Treatment effect measures with confidence intervals will be presented for the 
individual components of the primary composite (severe PPH, postpartum laparotomy for bleeding, 
and maternal mortality from bleeding), but it is not expected that there will be sufficient power to 
make definitive conclusions about any of them. 
Results on secondary clinical and implementation outcomes (listed in section 6.2), will be 
interpreted with caution. To this end, treatment effect measures with confidence intervals will be 
presented as supporting evidence only.  
All analysis will be carried out using Stata.  
Subgroup Analyses 
Tests for statistical heterogeneity (e.g., by including the treatment group by subgroup interaction 
parameter in the regression model) will be performed prior to any examination of effect estimate 
within subgroups. The subgroup analyses will be performed on the primary and key secondary 
implementation outcomes only.  
Planned subgroup analyses include A) Population subgroups: age (three levels categorised by tertiles 
of the distribution), previous birth (none vs any), type of pregnancy (singleton vs multiple), 
gestational age (term vs preterm), type of birth (e.g. spontaneous versus assisted), risk factors for 

Page 40 of 51 
 
PPH (diagnosis of preeclampsia, induction or augmentation of labour, previous caesarean, previous 
postpartum haemorrhage, antepartum haemorrhage, episiotomy, vaginal tears, retained placenta), 
baseline period PPH rate (low vs high PPH rate as objectively diagnosed by blood collection drape 
using data from the baseline period), country, number of vaginal births (above median vs below 
median as calculated using data from the baseline period); and B) Intervention subgroups: 
compliance with the E-MOTIVE intervention (defined as a minimum of administration of oxytocic 
drugs, TXA and IV fluids for objectively diagnosed PPHs; over the median and below the median; and 
time since intervention exposure (defined as number of months since cluster began post-
randomisation phase).  
Missing Data  
Every attempt will be made to collect routine clinical details on all women giving birth vaginally in 
the facilities using an efficient and pragmatic approach; it is thus anticipated that missing data will 
be minimal. Women with missing primary outcome data will not be included in the primary analysis 
in the first instance. This presents a risk of bias, and sensitivity analyses will be undertaken to assess 
the possible impact of the risk. In brief, this may include simulating missing responses using a 
multiple imputation approach. Full details will be included in the Statistical Analysis Plan. 
Source-verified Data  
Analyses of outcomes with blood loss data will only include blood loss that has been source-verified. 
Blood loss measured using the blood collection drape, which is source-verified will have a 
corresponding photograph, which is uploaded to a secure portal, of the drape on the E-MOTIVE 
digital weighing scale displaying the drape weight. The photograph should also display the drape 
weight documented on the E-MOTIVE stickers before being placed in the patient notes. The drape 
weight value entered on to the E-MOTIVE REDCap database is verified against the drape weight in 
the photograph and the photograph is linked to the patient record on the database using the E-
MOTIVE patient I.D number. 
 
11.3. Planned Interim Assessments 
The DMC will be tasked with reviewing the main effectiveness outcomes and ensuring that the trial 
is proceeding as planned (in particular does not exhibit any clear indicators of bias or large amounts 
of missing data). To this end, we expect the DMC to monitor the quality of the data; the pooled 
estimate of prevalence and within-period intra-cluster correlations (as a flag to indicate if the 
estimates used in the power calculation were accurate); and most importantly to monitor the 
characteristics of the participants in the control and intervention arms, so as to have some way of 
determining if any selection bias was occurring. The exact format and frequency of this monitoring 
will be determined with the DMC. Formal interim assessment of effectiveness is not anticipated due 
to the nature of the intervention and timing of the intervention period; however, the DMC will 
reserve the right to request a formal comparison if they see fit. Details of the agreed plan will be 
written into the Statistical Analysis Plan and DMC Charter. Further details of DMC arrangements are 
given in section 12.6. 
11.4. Planned Final Analyses  
The primary analysis for the study will be carried out once all outcome data have been entered onto 
the study database and validated as being ready for analysis. 

Page 41 of 51 
 
11.5. Health Economic Evaluation 
We plan to assess the cost-effectiveness of the E-MOTIVE intervention compared with usual care 
from a public healthcare system perspective, as measured by ICERs for a) severe PPH prevented, b) 
laparotomy for PPH prevented, c) death from PPH avoided, and (d) quality-adjusted life-years 
prevented.  
Base case analyses will be conducted from a public healthcare system perspective and we will 
undertake sensitivity analyses to assess the robustness of the results and explore their 
generalisability. We will record important resource use, including: staff time, meetings and training, 
clinical and administrative supplies, hospital inpatient days, medications, investigations, and other 
follow-on impacts associated with potential complications and additional treatments incurred 
relating to PPH. We will collect the resource use data for hospital inpatients stay for all women 
giving birth in both intervention and control facilities. We will attach unit costs to resource use to 
estimate the additional cost of the E-MOTIVE program. Country specific unit costs will be sought 
from the International Drug Price indicator guide, relevant WHO datasets (e.g., WHO-CHOICE), and 
participating countries. Cost data will be presented in US dollars. 
 
12. TRIAL ORGANISATIONAL STRUCTURE 
12.1. The Birmingham Clinical Trials Unit 
The BCTU is the International Coordinating Centre for the trial. Each country will appoint a National 
Principal Investigator (NPI), a National Coordinator (NC) and a National Coordinating Centre – the 
Hub – who will take responsibility for the study. 
12.2. Sponsor 
The University of Birmingham is the Sponsor of the E-MOTIVE trial in all collaborating countries. 
Sponsorship will be provided by the University of Birmingham upon signing of the Clinical Trial 
Agreement with the Hub. Each Hub will be responsible for implementation of Clinical Trial 
Agreements with local participating health facilities (spokes) if required. 
12.3 International Trial Management Groups (ITMG) 
The ITMG includes those individuals responsible for the day-to-day management of the trial. This will 
include the trial Chief Investigator, lead methodologists, and the E-MOTIVE trial management staff 
from BCTU. The Group will meet at least quarterly, but this may be more frequent if deemed 
necessary by the members. The role of the Group is to monitor all aspects of the conduct and 
progress of the trial, ensure that the protocol is adhered to and take appropriate action to safeguard 
participants and the quality of the trial itself. 
As E-MOTIVE is an international trial involving multiple countries, each country may wish to convene 
a country-specific TMG. This group may consist of the National Principal Investigator (NPI), the 
National Coordinator (NC), the local champion from each local spoke facility, the lead research nurse 
and other senior clinicians as deemed appropriate by the NPI. The dates of country-specific TMGs 
should be notified to the BCTU as should events deemed as significant by the country-specific TMGs. 
Once Hubs are open, the Hub NPIs and NCs may be invited to attend ITMG meetings. 
12.4 
Site Organisation 

Page 42 of 51 
 
Organisation of sites is adopting the Hub and Spoke model. The Hub will take responsibility for 
conduct and oversight of both its own site and its Spoke facilities. 
12.5 
Trial Steering Committee  
The remit of the TSC is to provide overall supervision of the trial and ensure that it is being 
conducted in accordance with the protocol and relevant regulations. 
The TSC will operate in accordance with a trial-specific TSC Charter. The TSC will meet approximately 
once a year (either face-to-face or via video/teleconferencing) or more often if required. 
The specific tasks of the TSC may include: 
● To approve and sign off the trial protocol and any protocol amendments. 
● To resolve problems brought to it by the International Coordinating Centre at BCTU. 
● To provide advice to the investigators on all aspects of the trial. 
● To review recruitment, data completeness, and protocol deviations. 
● To review recommendations from the DMC, and help with the decision-making that follows on 
from the recommendations of the DMC. 
12.6. Data Monitoring Committee  
Data will be supplied in strict confidence to an independent DMC, which will be asked to give advice 
on whether the accumulated data from the trial, together with the results from other relevant 
research, justifies the continuing recruitment of further participants. 
The DMC will operate in accordance with a trial specific charter based upon the template created by 
the Damocles Group.21  
The DMC is scheduled to meet prior to the trial commencing, half way and at the end of the control 
phase and then half way through the intervention phase after the point of randomisation 
(approximately 25%, 50% and 75% through recruitment to the whole study). Additional meetings 
may be called if recruitment is much faster than anticipated and the DMC may, at their discretion, 
request to meet more frequently or continue to meet following completion of the trial. An 
emergency meeting may also be convened if required. 
12.7. Finance 
E-MOTIVE is a commissioned trial by the Bill & Melinda Gates Foundation. The Institute of Global 
Innovation and Alumni Fund of University of Birmingham are also financially supporting the study. 
 
13. 
ETHICAL CONSIDERATIONS  
The E-MOTIVE trial is designed and will be conducted in accordance with the principles set out by 
the World Medical Association (WMA) in the Declaration of Helsinki – Ethical Principles for Medical 
Research Involving Human Subjects (2013). As the E-MOTIVE trial will be conducted in LMICs, the 
trial will also be performed in accordance with the Council for International Organisation of Medical 
Science (CIOMS) International Ethical Guidelines for Health-related Research Involving Humans 
(2016). Finally, as the E-MOTIVE trial is a cluster randomised trial, it will be performed in accordance 
with the Ottawa Statement for the Ethical Design and Conduct of Cluster Randomised Trials (2012).  

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The Ottawa Statement sets out seven ethical issues for cluster randomised trials. We use these to 
frame this section, with reference to the WMA Declaration of Helsinki and CIOMS International 
Ethical Guidelines as appropriate. 
13.1. Justifying the cluster randomized design 
The choice of a cluster randomised design must be justified (Ottawa Statement, recommendation 1; 
WMA, principle 22). The E-MOTIVE intervention aims to increase compliance with WHO 
recommendations for the treatment of PPH. The E-MOTIVE intervention targets healthcare 
providers to promote the uptake of evidence-based practice. Professional-level interventions like the 
E-MOTIVE intervention can only be rigorously evaluated with a cluster randomised design and, 
hence, the design is used by necessity.  
13.2. Research ethics committee review 
As the E-MOTIVE trial is research involving human participants, research ethics committee approval 
will be sought at all study sites (Ottawa Statement 2; WMA 23). 
13.3. Identifying research participants 
People who are targeted by the study intervention or control, with whom researchers interact, or 
whose identifiable private health information is collected ought to be considered research 
participants (Ottawa Statement 3; CIOMS, guideline 21). The E-MOTIVE evaluates a complex 
intervention to increase the early detection and evidence-based treatment of PPH by healthcare 
providers. As they are targeted by the E-MOTIVE intervention, healthcare providers attending 
childbirth are research participants. 
Patients are not research participants in the E-MOTIVE trial. As the Ottawa Statement explains, 
“simply being a patient or a professional participating in a cluster randomised trial of an educational, 
knowledge translation, or quality improvement intervention does not make one a research 
participant” (Ottawa Statement 3). The CIOMS International Ethical Guidelines agree: “In cluster 
randomised trials in which health-care providers are the research subjects, the intervention may not 
be targeted at patients, but aggregate data from patients’ records may be used to judge the 
effectiveness of the intervention… patients are not subjects in this type of study” (CIOMS 21). In the 
E-MOTIVE trial there will be no researcher interaction with patients, no additional data will be 
obtained specifically for the trial, and there is no non-clinically indicated follow-up. All patient data 
are routinely collected in clinical practice.  
13.4. Obtaining informed consent 
Informed consent will be sought from healthcare providers attending the E-MOTIVE training (Ottawa 
Statement 7; CIOMS 21; WMA 25, 26). Healthcare providers will receive the E-MOTIVE Information 
Sheet and Consent Form. The trial staff will be employed by the spoke facilities and will be carefully 
trained to discuss the proposed trial with participating healthcare providers and encourage them to 
ask as many questions as they need to understand the implications of enrolment. Healthcare 
providers will not be recruited in the presence of supervisors. 
As patients are not research participants in the E-MOTIVE trial, their informed consent for research 
purposes is not required. This is consistent with the Ottawa Statement (4), the CIOMS International 
Ethical Guidelines (21) and other trials studying the implementation of WHO recommendations. For 
an example, see: Haynes AB, ... Gawande AA; Safe Surgery Saves Lives Study Group. A surgical safety 

Page 44 of 51 
 
checklist to reduce morbidity and mortality in a global population. N Engl J Med 2009; 360(5): 491-
499. 
13.5. Gatekeepers 
“Gatekeepers are individuals or bodies who may be called upon to protect the group-based interests 
that are affected by enrolment in a CRT” (Ottawa Statement 8-10). The E-MOTIVE trial will enrol 80 
health facilities across 5 countries. In each case, permission will be obtained from the institutional 
leadership for the health facility to participate in the trial (Ottawa Statement 9; CIOMS 21).  
Before any healthcare providers are enrolled into the trial, the Local Champion at each health facility 
is required to obtain local approvals. Spoke facilities will not be permitted to train healthcare 
providers or record anonymised routinely collected clinical data on women until written 
confirmation of approval is received by the Hub. It is the responsibility of the Local Champion to 
ensure that all subsequent amendments gain the necessary local approval. This does not affect the 
individual clinician’s responsibility to take immediate action if thought necessary to protect a 
woman’s health. 
13.6. Assessing benefits and harms 
The benefits and harms of research participation must stand in reasonable relation (Ottawa 
Statement 11-13; WMA 16).  First, the study intervention must be justified (Ottawa Statement 11). 
PPH is the leading cause of maternal death worldwide; accounting for 27% of maternal deaths.1,2 The 
WHO published evidence-based “Recommendations for the Prevention and Treatment of 
Postpartum Hemorrhage” in 2012.3 However, adherence to these recommendations is limited in 
each of the host countries. The E-MOTIVE trial evaluates a complex intervention to promote early 
detection and evidence-based treatment of PPH. While the components of the MOTIVE bundle are 
evidence based, it is not currently known whether the E-MOTIVE implementation intervention will 
be successful in changing provider behaviour. Thus, there is “uncertainty in the relevant community 
of experts as to the preferred practice,” or equipoise, regarding the E-MOTIVE intervention (Ottawa 
Statement 11). 
 
Second, the control condition must be justified (Ottawa Statement 12). According to the Ottawa 
Statement, “individuals in the control arm must not be deprived of effective care or programs to 
which they would have access if there were no study being conducted.” Healthcare providers in 
health facilities randomised to the control condition will continue to provide care as they did before 
the trial, and they remain free to use uterine massage, oxytocin, tranexamic acid and intravenous 
fluids (the MOTIVE bundle) in the treatment of PPH. Additionally, WHO guidelines for the treatment 
of PPH will be distributed to healthcare providers in control facilities. Thus, the control condition is 
justified. 
Third, the risks of data collection procedures must (1) be minimised and (2) reasonable in relation to 
the knowledge to be gained (Ottawa Statement 13).  The E-MOTIVE trial only uses anonymised 
routinely collected clinical data. Health facility staff will extract anonymised data from registries for 
assessing health outcomes such as death or laparotomy. Patient information will be stored securely, 
and only people directly involved in the study will have access to anonymised data (WMA 24). Thus, 
risks of data collection are minimised, and reasonable in relation to the high social value of the study 
question. 
13.7. Protecting vulnerable participants 

Page 45 of 51 
 
Vulnerable participants are people who in the context of study participation “have an increased 
likelihood of being wronged” and they are entitled to additional protections (CIOMS 15). Healthcare 
providers work in hierarchical organisations and may be less able to express a free choice regarding 
study participation. In such circumstances: “When investigators are recruiting or obtaining consent 
from these individuals, they should conduct informed consent negotiations in such a way as to limit 
the potential for coercive influence from cluster or organizational leaders” (Ottawa Statement 15). 
Thus, in the E-MOTIVE trial healthcare providers will not be recruited in the presence of supervisors. 
When research is conducted in low-resource settings, the sponsor and researchers must ensure the 
“research is responsive to the health needs or priorities of the communities or populations where 
the research will be conducted” (CIOMS 2). PPH is the leading cause of maternal mortality globally, 
and the toll is disproportionate in LMICs. When mothers die during childbirth in an LMIC, only 20% of 
children survive.1 The E-MOTIVE trial seeks to enhance the early detection and evidence-based 
treatment of PPH and thereby prevent maternal morbidity and mortality in low-resource settings. 
If the E-MOTIVE implementation intervention is effective in reducing severe PPH, surgery and death, 
the researchers will work with the Gates Foundation and host countries to ensure it is rolled-out to 
control health facilities and beyond. 
 
14. 
CONFIDENTIALITY AND DATA PROTECTION  
Personal data recorded on all documents will be regarded as strictly confidential and will be handled 
and stored in accordance with all appropriate local and national guidelines.  
When data are transferred between Hubs and local spoke facilities, data will be de-identified and 
will be identified using their unique E-MOTIVE trial number only. Any correspondence between 
BCTU and the Hubs will use the E-MOTIVE trial number.  
The Investigator must maintain documents not for submission to BCTU (e.g., The E-MOTIVE Patient 
Identification Log) in strict confidence. In the case of specific issues and/or queries from the 
regulatory authorities, it will be necessary to have access to the complete anonymised trial records.  
BCTU will maintain the anonymity of all routinely collected data and will not disclose information by 
which women may be identified. Representatives of the E-MOTIVE trial team and sponsor will not 
access the medical records and routine clinical data collection, will rely solely on the health facility 
staff. The local champions of the spoke health facilities will be responsible for quality assurance 
purposes to audit information documents regularly to ensure the data are being reliably gathered.  
 
15. 
FINANCIAL AND OTHER COMPETING INTERESTS 
At the time of writing the protocol, not all sites and personnel had been identified. Information on 
financial and other competing interests (if any) will be collected and documented in the Trial Master 
File (TMF). 
 
16. 
INSURANCE AND INDEMNITY 
The University of Birmingham has in place Clinical Trials indemnity coverage for this trial which 
provides cover to the University for harm, which comes about through the University’s, or its staff’s, 
negligence in relation to the design or management of the trial.  

Page 46 of 51 
 
The risk of the trial is no greater than the risk of the usual clinical care. Responsibility for the 
participants at health facilities remains with the organisation responsible for the clinical facility and it 
is therefore indemnified through their normal arrangements. 
 
17. 
PUBLICATION POLICY 
A meeting will be held after the end of the trial to allow discussion of the main results among the 
collaborators prior to publication. Results of the formative phase, pilot, trial, process evaluation and 
health economic evaluations will be submitted as publications in peer-reviewed journals. 
The success of E-MOTIVE depends on the collaboration of a large number of healthcare providers 
across several countries. For this reason, all publications arising from this work will be attributed to 
the “E-MOTIVE Collaborative Group”, with the writing committee and order approved by the ITMG.  
Any secondary publications and presentations prepared by Investigators must be reviewed and 
approved by the ITMG. Manuscripts must be submitted to the ITMG in a timely fashion and in 
advance of being submitted for publication, to allow time for review and resolution of any 
outstanding issues. The ITMG are also obliged, by the terms of our contract to notify the funder (Bill 
& Melinda Gates Foundation) before submitting any publications. Authors must acknowledge that 
the trial was performed with the support of The University of Birmingham and funding from the Bill 
& Melinda Gates Foundation (including relevant acknowledgment text that will be provided by the 
ITMG). 
Site investigators may access the full dataset if a formal request describing the plans of the analysis 
is approved by the ITMG. Individual countries will be allowed to publish their efficacy results, 
however the publication of efficacy results from the pooled analysis will take precedence over 
efficacy result publications of individual countries, unless the ITMG decides otherwise. 
 
 
18. 
REFERENCE LIST 
1) Say L, Chou D, Gemmill A, Tunçalp Ö, Moller A-B, Daniels J, et al. Global causes of maternal death: 
a WHO systematic analysis. The Lancet Global Health. 2014;2(6):e323-e33. 
2) Family Care International. A price too high to bear: The costs of maternal mortality to families and 
communities. March 2014.  
3) World Health Organization. WHO recommendations for the prevention and treatment of 
postpartum haemorrhage. Geneva: World Health Organization; 2012.  
4) Widmer M, Piaggio G, Nguyen TMH, et al. Heat-Stable Carbetocin versus Oxytocin to Prevent 
Hemorrhage after Vaginal Birth. N Engl J Med. 2018;379(8):743–752. doi:10.1056/NEJMoa1805489 
5) Alwy Al-beity F, Pembe A, Hirose A, Morris J, Leshabari S, Marrone G, et al. Effect of the 
competency-based 'Helping Mothers Survive Bleeding after Birth' (HMS BAB) training on maternal 
morbidity: a cluster-randomised trial in 20 districts in Tanzania. BMJ Global Health. 
2019;4(2):e001214. 
6) Sotunsa J, Adeniyi A, Imaralu J, Fawole B, Adegbola O, Aimakhu C, et al. Maternal near‐miss and 
death among women with postpartum haemorrhage: a secondary analysis of the Nigeria Near‐miss 

Page 47 of 51 
 
and Maternal Death Survey. BJOG: An International Journal of Obstetrics & Gynaecology. 2019.doi: 
10.1111/1471-0528.15624.  
7) Hancock A, Weeks AD, Lavender DT. Is accurate and reliable blood loss estimation the'crucial step' 
in early detection of postpartum haemorrhage: an integrative review of the literature. BMC 
pregnancy and childbirth. 2015;15(1):230. 
8)Lennox L, Green S, Howe C, et al. Identifying the challenges and facilitators of implementing a 
COPD care bundle. BMJ Open Resp Res 2014;1:e000035. doi:10.1136/bmjresp-2014- 000035  
 
9) Althabe, F., Therrien, M.N., Pingray, V., Hermida, J., Gülmezoglu, A.M., Armbruster, D., Singh, N., 
Guha, M., Garg, L.F., Souza, J.P., Smith, J.M., Winikoff, B., Thapa, K., Hébert, E., Liljestrand, J., Downe, 
S., Garcia Elorrio, E., Arulkumaran, S., Byaruhanga, E.K., Lissauer, D.M., Oguttu, M., Dumont, A., 
Escobar, M.F., Fuchtner, C., Lumbiganon, P., Burke, T.F. and Miller, S. (2020), Postpartum 
hemorrhage care bundles to improve adherence to guidelines: A WHO technical consultation. Int J 
Gynecol Obstet, 148: 290-299. doi:10.1002/ijgo.13028 
10) Michie S, Van Stralen MM, West R. The behaviour change wheel: a new method for 
characterising and designing behaviour change interventions. Implementation science. 2011;6(1):42 
11) Hemming, K., et al., Interim data monitoring in cluster randomised trials: practical issues and a 
case study. Clinical Trials, 2021. 18(5): p. 552-561. 
12) Pocock, S.J. and R. Simon, Sequential treatment assignment with balancing for prognostic factors 
in the controlled clinical trial. Biometrics, 1975: p. 103-115. 
13) Proctor E, Silmere H, Raghavan R, Hovmand P, Aarons G, Bunger A, Griffey R, Hensley M. 
Outcomes for implementation research: conceptual distinctions, measurement challenges, and 
research agenda. Administration and Policy in Mental Health and Mental Health Services Research. 
2011 Mar 1;38(2):65-76. 
14) Meher S, Cuthbert A, Kirkham JJ, et al. Core outcome sets for prevention and treatment of 
postpartum haemorrhage: an international Delphi consensus study. BJOG. 2019;126(1):83–93. 
doi:10.1111/1471-0528.15335 
15) Hooper R, Bourke L. Cluster randomised trials with repeated cross sections: alternatives to 
parallel group designs BMJ. 2015;350:h2925. doi: 10.1136/bmj.h2925 
16) Kasza J, Forbes AB. Inference for the treatment effect in multiple-period cluster randomised 
trials when random effect correlation structure is misspecified. Stat Methods Med Res. 2019;28(10-
11):3112–3122. doi:10.1177/0962280218797151 
17) Rutterford C, Copas A, Eldridge S. Methods for sample size determination in cluster randomized 
trials. Int J Epidemiol. 2015;44:1051‐1067 
18) Hooper R, Forbes A, Hemming K, Takeda A, Beresford L. Analysis of cluster randomised trials with 
an assessment of outcome at baseline. BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k1121 
19) Leyrat C, Morgan K E, Leurent B, Kahan B C, Cluster randomized trials with a small number of 
clusters: which analyses should be used?, International Journal of Epidemiology, Volume 47, Issue 1, 
February 2018, Pages 321–331, https://doi.org/10.1093/ije/dyx169 

Page 48 of 51 
 
20) Leyrat C, Caille A, Donner A, Giraudeau B. Propensity scores used for analysis of cluster 
randomized trials with selection bias: a simulation study. Statistics in medicine. 2013 Aug 
30;32(19):3357-72. 
21) DAMOCLES Study Group, NHS Health Technology Assessment Programme. A proposed charter 
for clinical trial data monitoring committees: helping them to do their job well. Lancet. 
2005;365(9460):711–722. doi:10.1016/S0140-6736(05)17965-3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix A 
__________________________________________________________________________________________ 
Modification of the Pakistan study design: Protocol for an E-MOTIVE before-and-after 
(implementation) study design 
__________________________________________________________________________________________ 
Rationale for the modification of the Pakistan study design 
Pakistan was added as a participating country (8 main trial and 2 adaptive cycle sites) in September 
2022 to provide South Asian representation in the main E-MOTIVE trial. At this time, the other 78 
hospitals in the four African countries (Tanzania, Kenya, South Africa, and Nigeria) had already 
completed the baseline phase of the trial and commenced the post-randomisation phase. The Data 
Monitoring Committee (DMC) met on 24-Jan-2023 and observed that the pre-specified total study 
sample size had been achieved from the four African countries, therefore the trial data should be 
published without waiting for Pakistan to contribute data. This recommendation was subsequently 
ratified by the Trial Steering Committee (TSC) on 22-Feb-2023. It was unanimously agreed that there 
was no good scientific reason for the final analysis to be delayed, and that there was an ethical 
obligation to make the results available at the earliest, especially given that some of the settings across 
the world continue to see a high rate of PPH and maternal deaths. The African sites completed data 
collection on 03-Mar-2023. The final results, with data analysed from the four African countries 
showed that early (E) detection of postpartum haemorrhage and use of bundled treatment (MOTIVE) 
led to a lower risk of the primary outcome, that is a 60% reduction in the composite outcome (severe 
PPH, laparotomy for bleeding, or maternal death from bleeding) in the E-MOTIVE arm compared to 
the arm that received usual care (published in NEJM on 09-May-2023).  
Publication link: https://www.nejm.org/doi/full/10.1056/NEJMoa2303966 
Given the above result from the African setting, the study design in Pakistan will now be adapted to a 
‘before-and-after’ study to test the implementation of E-MOTIVE in a South Asian setting. 
__________________________________________________________________________________________ 
Aim 
To study the key implementation (process outcomes) of E-MOTIVE in Pakistan (as a representation of 
the South Asian setting)  
Methods 
Design: This is a before-and-after study design. The baseline data that was collected at the 8 sites (all 
sites followed usual care) as a part of the main E-MOTIVE trial will be used to represent the ‘before’ 
phase of the study.  
Setting: Eight secondary-level health facilities across Pakistan 
All the 8 health facilities that completed a 5 to 6-month baseline period (until 31-Mar-2023) in which 
they were following usual care with dissemination of the current guidelines, will enter a 2-month 
transition (allowing two months for full implementation and embedding of E-MOTIVE). Following this, 
all 8 sites will implement E-MOTIVE for 3-months. Mixed methods work along with baseline-and-
implementation phase healthcare provider observations will be conducted (Figure A1). 
 
Key implementation outcomes: 

Page 50 of 51 
 
Co-primary: 
1. PPH detection [women who objectively had PPH (source-verified blood loss ≥500 mL after 
weighing the drape) and were diagnosed with PPH by the birth attendants divided by the total 
number of women who objectively had PPH (source verified blood loss ≥ 500 mL after 
weighing the drape)] AND 
2. Compliance with MOTIVE bundle (women who objectively had PPH and were treated with the 
PPH bundle following a diagnosis of PPH by the birth attendants divided by the total number 
of women who objectively had PPH (blood loss ≥ 500 mL after weighing of the drape) 
Secondary: 
1. PPH treatment (women diagnosed with PPH by the birth attendants divided by the total of 
women having a vaginal birth in the health facility) 
2. Bundle usage (women treated with the PPH bundle following a diagnosis of PPH by the birth 
attendants divided by the total of women having a vaginal birth in the health facility) 
3. Bundle usage for PPH (with the following numerator and denominator: women treated with 
the PPH bundle following a diagnosis of PPH by the birth attendant divided by the total of 
women diagnosed with PPH by the birth attendants) 
4. Uterine massage 
5. Oxytocin use 
6. Misoprostol use 
7. TXA use 
8. Intravenous fluids use 
9. Examination of the genital tract 
10. Number of women receiving any treatment uterotonic 
11. Number of women requiring additional treatment interventions (not responding to the 
MOTIVE bundle). 
 
Sample size 
The power for the sample size calculated below is based on the two primary implementation 
outcomes (these will be the co-primary outcomes for this study) from the baseline data (PPH detection 
and adherence to MOTIVE bundle). Assuming eight health facilities in Pakistan, an average of 1,100 
women per cluster would give an expected number of 1,000 women in the baseline phase with PPH 
and 500 women in the post-randomisation phase with PPH. The study will have >90% power to detect 
a change from 50% to 90% in the co-primary outcomes, after accounting for clustering (ICC of 0.25), 
cluster size variation (cv = 0.5) and adjusting the alpha level for the co-primary outcomes (alpha = 
0.025).  
Analysis 
This will remain the same as per the analysis of implementation outcomes in the main protocol (as 
described above). 
__________________________________________________________________________________________ 

 
 
Figure A1. Timeline depicting the baseline, transition and implementation phase for E-MOTIVE 
‘before-and-after’ design in Pakistan along with process evaluation and healthcare provider 
observations