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Trial registered on ANZCTR


Registration number
ACTRN12622000981729
Ethics application status
Approved
Date submitted
18/05/2021
Date registered
13/07/2022
Date last updated
13/07/2022
Date data sharing statement initially provided
13/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Refractory haEmorrhage Devices trial: Efficacy of uterine tamponade devices for management of refractory postpartum haemorrhage
Scientific title
Refractory haEmorrhage Devices trial: a multi-arm, multi-stage, multicentre randomized active controlled superiority trial to evaluate the efficacy of uterine tamponade devices for the management of refractory postpartum haemorrhage
Secondary ID [1] 304243 0
A66009
Universal Trial Number (UTN)
Trial acronym
RED
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory Postpartum haemorrhage 321944 0
Condition category
Condition code
Reproductive Health and Childbirth 319674 319674 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 1
• Three uterine tamponade devices (Ellavi® free-flow, Ellavi® fixed-volume, or Suction Tube Uterine Tamponade (STUT)) will be evaluated.

Arm 1: Ellavi® fixed-volume
The Ellavi® balloon, is a fully pre-assembled UBT device made of plastic that can be quickly filled up to 750 mL without expansion pressure.

Arm 2: Ellavi® free-flow
Although most purpose-designed UBTs work as fixed-volume systems, the Ellavi® balloon can also work with a free-flow mechanism, through an open gravidity-fed system.

Arm 3: STUT
The STUT device consists of a FG36 Levin stomach tube connected to suction apparatus or to an MVA device. It is an improvised device that uses vacuum force to collapse the uterus by mimicking physiologic uterine contractions.

Procedure
Women admitted to hospital in early labour will be informed about the trial and will be asked to provide informed consent. All women will receive a uterotonic drug for PPH prophylaxis and a plastic drape will be placed under their buttocks to measure ongoing postpartum blood loss as part of local standard practice. In cases of atonic PPH, treatment will be provided according to local policies including uterotonics, tranexamic acid and IV fluids. If bleeding cessation is not achieved at the judgement of the attending physician and she/he considers that further treatment is required, a research midwife will immediately randomize the consenting woman to one of the trial interventions. The physician in charge will insert the allocated device into the uterine cavity. The balloon is then inflated, or suction is switched on. The physician re-evaluates the bleeding every 5 minutes for the next quarter of an hour; if bleeding does not stop within 15 minutes, the device is removed and further treatment is provided according to local policies; if bleeding has stopped, the device stays in place for the next 6 hours without further action. After 6 hours the device will be removed; if bleeding resumes the device will be kept in place until 24 hours, when it will be definitely removed. All participants will receive prophylactic antibiotics according to local policies.

Selection of the best performing device
At the end of Stage I, an interim analysis will be conducted to identify the best performing device, based on the observed decrease in the incidence of the primary outcome. In case more than one device showed a positive effect on the composite primary outcome, compared with the control, the device with the most favourable profile in terms of acceptability and adherence to the protocol will be selected for stage 2. In case the effect size was larger than expected, the trial might be stopped early for loss of clinical equipoise. If none of the research devices showed a potential reduction of the primary outcome by at least 33% compared with the control arm, the trial would be stopped early for futility.

Stage 2
The best performing device identified in Stage 1 will progress to Stage 2 where it will be compared directly to the control device. Outcomes and procedures will be the same at both stages. This stage would start at the same hospitals three months after the completion of Stage 1. More hospitals and countries could join the study for Stage 2.
Intervention code [1] 320574 0
Treatment: Devices
Comparator / control treatment
The comparator will be the uterine tamponade device that the participant hospitals use in their routine practice to treat refractory postpartum haemorrhage. In the two hospitals in Vietnam they are currently using Foley catheter uterine balloon tamponades.
The procedure will be the same described for the experimental devices. The comparator will be the same for both trial stages.
Control group
Active

Outcomes
Primary outcome [1] 327553 0
The proportion of women with the composite outcome of mortality related to post partum haemorrhage (PPH) or invasive surgical procedures (i.e. laparotomy for compressive sutures, uterine artery ligation, hysterectomy). An Endpoint Review Committee (ERC) will access collected data from the medical records relevant to the primary composite outcome to confirm whether any postpartum invasive surgery was performed for bleeding and any maternal death should be attributed to haemorrhage. The primary outcome will be the same for Stage 1 and Stage 2
Timepoint [1] 327553 0
Outcomes will be measured for all enrolled women at Day 3 postpartum,
Secondary outcome [1] 395639 0
Severe PPH-related morbidity, defined as any organ failure or dysfunction diagnosed by management or clinical criteria based on the WHO near miss approach. The outcome data will be extracted from the medical records. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [1] 395639 0
At Day 3 postpartum.
Secondary outcome [2] 404438 0
Additional post randomization blood loss of 500 mL or more. Blood loss will be measured by collecting blood in plastic drapes (at the delivery ward) or underpads (at the postpartum ward); drapes and underpads will be weighted and the result converted in ml. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [2] 404438 0
At 6 hours post randomization
Secondary outcome [3] 404439 0
Severe maternal uterine infection, defined as: pyrexia (greater than or equal to 38 degrees Celsius), use of therapeutic parenteral antibiotics, and suspected uterine source with no other extra-genital infection (e.g. mastitis). The outcome data will be extracted from the medical records. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [3] 404439 0
at 3 days postpartum
Secondary outcome [4] 404440 0
Maternal death. The outcome data will be extracted from the medical records. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [4] 404440 0
at 3 days postpartum
Secondary outcome [5] 404441 0
Blood loss in mL Blood loss will be measured by collecting blood in plastic drapes (at the delivery ward) or underpads (at the postpartum ward); drapes and underpads will be weighted and the result converted in ml. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [5] 404441 0
at 1 hour and 6 hours post randomization
Secondary outcome [6] 404442 0
Shock Index. Blood pressure and heart rate measures to compute the shock index will be extracted from the medical records. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [6] 404442 0
Measured at least twice within the first 15 minutes after insertion of the device.
Secondary outcome [7] 404443 0
Provider’s acceptability of the intervention, Measured through a specifically designed questionnaire. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [7] 404443 0
within 3 days postpartum
Secondary outcome [8] 404444 0
Acceptability of the intervention according to mother’s views. Measured through a specifically designed questionnaire. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [8] 404444 0
at 3 days postpartum
Secondary outcome [9] 406228 0
Maternal side effects (e.g. nausea, vomiting, abdominal pain). The outcome data will be extracted from the medical records. This outcome will be measured for both Stage 1 and Stage 2
Timepoint [9] 406228 0
at 6 hs post randomization

Eligibility
Key inclusion criteria
Women will be eligible for the trial if they provide consent, have a vaginal birth and experience PPH likely to be caused by uterine atony, not responding to first-line treatment with uterotonic drugs, and therefore require further treatment to control the bleeding according to the birth attendant’s opinion. These criteria apply for both Stage 1 and Stage 2.
Minimum age
16 Years
Maximum age
49 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Eligible women will not be randomized either if the clinical condition or the severity of the bleeding imply performing an invasive surgical procedure without delay at the judgment of the birth attendant in charge, or they present a clinical chorioamnionitis or in utero foetal death, they have been diagnosed with cervical cancer during pregnancy, have known uterine anomalies, or have allergy to trial device material . These criteria apply for both Stage 1 and Stage 2.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An application specifically designed will be installed in tablets used by study research midwives. Once the birth attendant confirms that the woman is not responding to first-line treatment with uterotonic drugs, the research midwife will enter the patient screening number into the application and the system will allocate the woman to any of the study arms. The research midwife will inform the provider about the allocation and will provide the corresponding device. This application will be used for both Stage 1 and Stage 2. For Stage 2 only two interventions will be allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization sequence will be computer-generated centrally at WHO by the study statistician, in permuted blocks and stratified by study site, For Stage 1 the sequence will include four interventions; for Stage 2, two interventions.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features

Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This is a randomized controlled trial using an adaptive MAMS design to first select a promising device, and second to test a superiority hypothesis with an one-sided Family wise type I error rate of 0.025. Stage 1 will enrol N=170 participants into each of the 4 arms, total N=680. Stage 2 will include the N=170 control participants and N=170 participants randomised to the device that was identified as best performing that will continue to be tested in the second stage. An additional N=1,966 (N=983 in each of the control and intervention arms) participants will be enrolled into Stage 2, equating to an overall sample size of 2,306.
A detailed statistical analysis plan (SAP), providing a more comprehensive description of the planned statistical analyses, will be developed and reviewed by the WHO trial coordinating Unit prior to database lock for interim analysis. A brief outline of trial analyses is given below. All analyses will be by intention to treat, which means that all participating women will be analysed according to their randomly assigned allocation, irrespectively of any protocol deviations. In general, participant and clinical characteristics will be described according to the appropriate summary statistics (e.g. proportions for categorical data; means, standard error, and IQR for continuous data; median for time-to-event data).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2022
Actual
Date of last participant enrolment
Anticipated
13/02/2026
Actual
Date of last data collection
Anticipated
16/02/2026
Actual
Sample size
Target
2306
Accrual to date
Final
Recruitment outside Australia
Country [1] 23710 0
Viet Nam
State/province [1] 23710 0
Ho Chi Minh city

Funding & Sponsors
Funding source category [1] 308619 0
Other
Name [1] 308619 0
UNDP-UNFPA-UNICEF-WHO-WORLD BANK special programme of research, development and research training in human reproduction (HRP). World Health Organization
Country [1] 308619 0
Switzerland
Primary sponsor type
Other
Name
UNDP-UNFPA-UNICEF-WHO-WORLD BANK special programme of research, development and research training in human reproduction (HRP). World Health Organization
Address
Avenue Appia 20 - 1211 Geneva
Country
Switzerland
Secondary sponsor category [1] 309488 0
None
Name [1] 309488 0
Address [1] 309488 0
Country [1] 309488 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308551 0
WHO Ethics Review Committee (ERC)
Ethics committee address [1] 308551 0
Avenue Appia 20, 1202 Geneva
Ethics committee country [1] 308551 0
Switzerland
Date submitted for ethics approval [1] 308551 0
13/11/2020
Approval date [1] 308551 0
09/03/2021
Ethics approval number [1] 308551 0

Summary
Brief summary
This will be an adaptive, hospital-based, multicentre, multi-arm, multi-stage (MAMS), individually randomized active-controlled superiority trial. Stage I will identify the most promising device, and Stage II will test that device against the control device.
Women admitted to hospital in early labour will be informed about the trial and will be asked to provide informed consent. All women will receive a uterotonic drug for PPH prophylaxis and a plastic drape will be placed under their buttocks to measure ongoing postpartum blood loss as part of local standard practice. In cases of atonic PPH, treatment will be provided according to local policies including uterotonics, tranexamic acid and IV fluids. If bleeding cessation is not achieved at the judgement of the attending physician and she/he considers that further treatment is required, a research midwife will immediately randomize the consenting woman to one of the trial interventions. The physician in charge will insert the allocated device into the uterine cavity. The balloon is then inflated, or suction is switched on. The physician re-evaluates the bleeding every 5 minutes for the next quarter of an hour; if bleeding does not stop within 15 minutes, the device is removed and further treatment is provided according to local policies; if bleeding has stopped, the device stays in place for the next 6 hours without further action. After 6 hours the device will be removed; if bleeding resumes the device will be kept in place until 24 hours, when it will be definitely removed. All participants will receive prophylactic antibiotics according to local policies. The primary outcome will be measured at 72 h postpartum or at hospital discharge if this occurs before the 72 h.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111106 0
Mrs Mariana Widmer
Address 111106 0
World Health Organization. Avenue Appia 20 - 1211 Geneva
Country 111106 0
Switzerland
Phone 111106 0
+41227914323
Fax 111106 0
Email 111106 0
[email protected]
Contact person for public queries
Name 111107 0
Mariana Widmer
Address 111107 0
World Health Organization. Avenue appia 20 - 1211 Geneva
Country 111107 0
Switzerland
Phone 111107 0
+41227914323
Fax 111107 0
Email 111107 0
[email protected]
Contact person for scientific queries
Name 111108 0
Mariana Widmer
Address 111108 0
World Health Organization. Avenue appia 20 - 1211 Geneva
Country 111108 0
Switzerland
Phone 111108 0
+41227914323
Fax 111108 0
Email 111108 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This has to be discussed as it has to follow WHO rules.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11689Study protocol    The study protocol will be published in a peer rev... [More Details]
11690Informed consent form  [email protected] Upon request to Mrs Mariana Widmer



Results publications and other study-related documents

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