Clinical trial NCT04341662: A Clinical Trial to Study the Effectiveness of a Care Bundle to Prevent Bleeding After a Woman Has Given Birth
Official 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 (E-MOTIVE Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Post-Partum Haemorrhage
Keywords: post-partum haemorrhage
early detection
blood loss measurement
oxytocin
tranexamic acid
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: University College, London
name: University of Melbourne
name: University of California
name: World Health Organization
name: King's College London
name: University of Liverpool
name: Jhpiego
name: Concept Foundation
name: University of Nairobi
name: University of Cape Town
name: Bayero University Kano, Nigeria
name: Muhimbili University of Health and Allied Sciences
name: University of Witwatersrand, South Africa
name: Ammalife
name: Aga Khan University
First posted: 2020-04-10
Enrollment: 99659
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel cluster randomised trial with a baseline control phase, along with mixed-methods and health economic evaluations
Primary purpose: TREATMENT

Brief summary: Every six minutes a mother dies from postpartum haemorrhage (PPH) in low-resource countries, in the prime of her life and often leaving behind a young family. In many settings, when a mother dies in childbirth, her infant has less than a 20% chance of surviving past the first month. 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. The WHO published "Recommendations for the Prevention and Treatment of Postpartum Hemorrhage" in 2012 to provide evidence-informed recommendations for managing PPH. However, adherence to these recommendations is currently limited by a number of challenges.

This primary aim of this multi-country, parallel cluster randomised trial with a baseline control phase, along with mixed-methods and health economic evaluations, is 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. The investigators will evaluate the implementation through mixed-methods and carry out a health economic evaluation from the public healthcare system perspective.

Detailed description: The aim of this trial is evaluate the implementation of early detection and the use of the WHO MOTIVE 'first response' treatment bundle for PPH on clinical, implementation and resource use outcomes. The investigators will evaluate the implementation through mixed-methods and carry out a health economic evaluation from the public healthcare system perspective. The investigators will use a multi-country, parallel cluster randomised trial design with a baseline control phase, along with mixed-methods and health economic evaluations. The trial is conducted in secondary level health facilities in four low- and middle- income countries. For this trial, the 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. Pre-existing implementation of early detection or bundled approach are exclusion criteria. The research participants are all healthcare providers attending vaginal births in the study facilities. 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. The control health facilities will deliver usual care with dissemination of the current guidelines.

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.

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 of 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).

Secondary outcomes: blood transfusion, uterine tamponade, Intensive Care Unit admissions or higher-level facility transfers, and new-born deaths along with implementation and resource use outcomes.

Eighty 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.

During the 7-month baseline phase, the investigators 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.

The investigators will also 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.

The investigators 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.

Following the publication of the E-MOTIVE trial findings, a prospective pre-post intervention study of the E-MOTIVE intervention was planned in eight secondary-level care District Head Quarter (DHQ) hospitals in the Sindh and Punjab provinces of Pakistan. Pakistan was originally scheduled to be part of the multi-country, cluster-randomised E-MOTIVE trial. However, the catastrophic floods in Pakistan in 2022 delayed the start of recruitment, whilst the other participating countries progressed to complete the trial. At this stage, as the required sample size for the trial had been achieved, the Independent Data Monitoring Committee advised completing and analysing the trial without the participation of Pakistan. The definitive effects found by the E-MOTIVE trial made it unethical to conduct further randomised trials of the intervention. As all countries that contributed to the E-MOTIVE trial were from Africa, an outstanding question on generalisability of the findings outside of Africa remained. The E-MOTIVE study in Pakistan was, therefore, planned as a pre-post study to assess the implementation and generalisability of E-MOTIVE in a South Asian healthcare setting. The amended protocol was approved by the University of Birmingham, UK and the Pakistan ethics and regulatory review committee. The study retained the same primary clinical and implementation outcomes as the main trial.

Eligibility criteria: 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. Health facilities are selected based on being administratively and geographically distinct from each other. Pre-existing implementation of early detection or bundled approach are exclusion criteria

Research participants: All healthcare providers attending vaginal births at the study facilities.

Patients: All verified vaginal births in the study facilities

Primary outcomes:
measure: The Primary Outcome is a Composite of the Following Three Clinical Outcomes: 1) Severe PPH Defined as Blood Loss ≥1000 ml or; 2) Postpartum Laparotomy for Bleeding or; 3) Postpartum Maternal Death From Bleeding. Please See Below for Further Details.
timeFrame: Postpartum until discharge from the health facility (up to 42 days)
Secondary outcomes:
measure: PPH Detection
timeFrame: Up to 24 hours postpartum
measure: Compliance With MOTIVE Bundle
timeFrame: Up to 24 hours postpartum
measure: Number of Women With Laparotomy Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days)
measure: Number of Women With Laparotomy With Compression Sutures Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women With Laparotomy With Arterial Ligation Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the healthcare facility (up to 42 days).
measure: Number of Women With Hysterectomy Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women With Hysterectomy for Bleeding Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Rate of All Cause Maternal Mortality Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Amount of Blood Loss (as a Continuous Variable)
timeFrame: Up to 24 hours postpartum
measure: Number of Women With Primary PPH Defined as Blood Loss ≥500 ml
timeFrame: Up to 24 hours postpartum
measure: Duration of Hospitalisation Postpartum
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Duration of ICU Hospitalisation Postpartum
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women Transferred to a Higher-level Facility Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Rate of All Cause Neonatal Mortality Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women Receiving Non-pneumatic Anti-shock Garment (NASG) Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women Receiving Uterine Balloon Tamponade Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women Receiving a Blood Transfusion Postpartum Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women Receiving Blood Transfusion for Postpartum Haemorrhage Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women Admitted to Intensive Care Unit (ICU) Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Number of Women With Primary Severe PPH (Defined as Blood Loss ≥1000 ml) Following a Vaginal Birth in the Facility Measured up to 2 Hours Postpartum
timeFrame: Up to 2 hours postpartum
measure: Postpartum Laparotomy for Bleeding Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: Postpartum Maternal Death From Bleeding Until Discharge From the Health Facility
timeFrame: Postpartum until discharge from the health facility (up to 42 days).
measure: PPH Treatment by Healthcare Provider up to 2 Hours Postpartum (or up to 24 Hours if Bleeding Continues)
timeFrame: Up to 2 hours postpartum (or up to 24 hours if bleeding continues)
measure: Bundle Usage up to 2 Hours Postpartum (or up to 24 Hours if Bleeding Continues)
timeFrame: Up to 2 hours postpartum (or up to 24 hours if bleeding continues)
measure: Bundle Usage for PPH up to 2 Hours Postpartum (or up to 24 Hours if Bleeding Continues)
timeFrame: Up to 2 hours postpartum (or up to 24 hours if bleeding continues)
measure: Number of Women Receiving Uterine Massage for PPH
timeFrame: Up to 24 hours postpartum
measure: Number of Women Receiving Oxytocin for PPH
timeFrame: Up to 24 hours postpartum
measure: Number of Women Receiving Misoprostol for PPH
timeFrame: Up to 24 hours postpartum
measure: Number of Women Receiving TXA for PPH
timeFrame: Up to 24 hours postpartum
measure: Number of Women Receiving Intravenous Fluids (IV) for PPH
timeFrame: Up to 24 hours postpartum
measure: Number of Women Receiving Examination of the Genital Tract
timeFrame: Up to 24 hours postpartum
measure: Number of Women Receiving Any Treatment Uterotonic for PPH
timeFrame: Up to 24 hours postpartum
measure: Number of Women Requiring Additional Treatment Interventions (Not Responding to the MOTIVE Bundle).
timeFrame: Up to 24 hours postpartum
Other outcomes:
Locations:
city: Nairobi
country: Kenya
facility: University of Nairobi
city: Kano
country: Nigeria
facility: Bayero University
city: Karachi
country: Pakistan
facility: Aga Khan University
city: Cape Town
country: South Africa
facility: University of Cape Town
city: Johannesburg
country: South Africa
facility: University of the Witwatersrand
city: Dar Es Salaam
country: Tanzania
facility: Muhimbili University of Health and Allied Sciences
Study officials:
affiliation: University of Birmingham
name: Arri Coomarasamy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gallos I, Devall A, Martin J, Middleton L, Beeson L, Galadanci H, Alwy Al-Beity F, Qureshi Z, Hofmeyr GJ, Moran N, Fawcus S, Sheikh L, Gwako G, Osoti A, Aswat A, Mammoliti KM, Sindhu KN, Podesek M, Horne I, Timms R, Yunas I, Okore J, Singata-Madliki M, Arends E, Wakili AA, Mwampashi A, Nausheen S, Muhammad S, Latthe P, Evans C, Akter S, Forbes G, Lissauer D, Meher S, Weeks A, Shennan A, Ammerdorffer A, Williams E, Roberts T, Widmer M, Oladapo OT, Lorencatto F, Bohren MA, Miller S, Althabe F, Gulmezoglu M, Smith JM, Hemming K, Coomarasamy A. Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage. N Engl J Med. 2023 Jul 6;389(1):11-21. doi: 10.1056/NEJMoa2303966. Epub 2023 May 9.
citation: Bohren MA, Lorencatto F, Coomarasamy A, Althabe F, Devall AJ, Evans C, Oladapo OT, Lissauer D, Akter S, Forbes G, Thomas E, Galadanci H, Qureshi Z, Fawcus S, Hofmeyr GJ, Al-Beity FA, Kasturiratne A, Kumarendran B, Mammoliti KM, Vogel JP, Gallos I, Miller S. Formative research to design an implementation strategy for a postpartum hemorrhage initial response treatment bundle (E-MOTIVE): study protocol. Reprod Health. 2021 Jul 14;18(1):149. doi: 10.1186/s12978-021-01162-3.