World maternal antifibrinolytic trial-2
| ISRCTN | ISRCTN62396133 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN62396133 |
| ClinicalTrials.gov number | NCT03475342 |
| Secondary identifying numbers | WOMAN-2 |
- Submission date
- 23/11/2017
- Registration date
- 07/12/2017
- Last edited
- 28/10/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Pregnancy and Childbirth
Plain English Summary
Background and study aims:
Postpartum haemorrhage (PPH) is characterised as a large amount of blood loss after giving birth. PPH is responsible for about 100,000 maternal deaths every year, almost all of which occur in low and middle income countries. When given within three hours of birth, tranexamic acid (a drug which helps in keeping blood clots firm) reduces deaths due to bleeding in women with PPH by almost one third. However, for many women, the use of tranexamic acid to treat PPH is too late to prevent death and severe health problems. Over one-third of pregnant women in the world are anaemic. The aim of this study is to progress the WOMAN-2 trial to see if giving tranexamic acid can prevent PPH and other severe outcomes in women with moderate and severe anaemia.
Who can participate?
Women with moderate or severe anaemia who are in the active stage of labour and plan to give birth vaginally are eligible (if their doctor believes there is no reason why the woman cannot receive the trial drug). Where a woman is less than 18 years old, unless she has an appropriate guardian available to witness the consent process, she cannot take part.
What does the study involve?
Women do not need to change their birth plans and they continue to receive all care and treatments which their doctor/midwife/nurse believe is required. Additionally, they are given a single injection of either tranexamic acid or a dummy drug (salty water) immediately the umbilical cord is cut or clamped and no later than 15 minutes after. Women are then be followed-up for a maximum 42 days. There is no special hospital visits required unless an adverse event occurs.
What are the possible benefits and risks of participating?
Women with anaemia have a higher risk of severe bleeding after childbirth and cannot afford to lose any blood. Tranexamic acid has been shown to reduce blood loss in surgery and can stop women dying from bleeding if they are treated as soon as possible. We do not know if giving tranexamic acid before bleeding develops will help reduce the risk of severe bleeding after childbirth and this trial will help us answer that question. Although there is a theoretical risk of forming clots where they are not wanted (e.g. deep vein thrombosis) with tranexamic acid, there is no evidence of this when available data is reviewed. Tranexamic acid can sometimes cause nausea, dizziness and diarrhoea.
Where is the study run from?
The trial will be coordinated by the Clinical Trials Unit at the London School of Hygiene and Tropical Medicine (UK) and supported by Regional Coordinating Centres in Pakistan (Rawalpindi Medical University), Nigeria (University College Hospital, Ibadan) and Tanzania (Muhimbili University of Health and Allied Sciences).
When is the study starting and how long is it expected to run for?
January 2018 to September 2023
Who is the main contact?
Ian Roberts, woman2@lshtm.ac.uk
Contact information
Scientific
Clinical Trials Unit - Global Health Trials Group
London School of Hygiene & Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom
 ORCID ID |
0000-0002-6511-109X |
|---|---|
| Phone | +44(0)20 7299 4684 |
| woman2@lshtm.ac.uk |
Public
Clinical Trials Unit - Global Health Trials Group
London School of Hygiene & Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom
| ORCID ID |
0009-0001-6066-3688 |
|---|---|
| woman2@lshtm.ac.uk |
Study information
| Study design | A multi centre randomised double blind placebo controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Tranexamic acid for the prevention of postpartum bleeding in Women with anaemia: an international, randomised, double-blind, placebo controlled trial |
| Study acronym | WOMAN-2 |
| Study hypothesis | Can tranexamic acid by intravenous injection prevent PPH and other severe outcomes in women with moderate and severe anaemia? |
| Ethics approval(s) | 1. Approved 10/05/2018, London School of Hygiene and Tropical Medicine Research Ethics Committee (Keppel Street, London, WC1E 7HT, United Kingdom; no phone number provided; ethics@lshtm.ac.uk), ref: 15194 2. Approved 29/09/2019, National Health Research Ethics Committee (Federal Ministry of Health, Federal Secretariat Complex Shehu Shagari Way, Garki, Abuja, Abuja, P.M.B. 083, Nigeria; no phone number provided; info@nhrec.net), ref: NHREC/01/01/2007-29/09/2019 3. Approved 27/11/2018, National Bioethics Committee (NIH (HRI), Shahrah-e-Jamhuriat, G-5/2 Islamabad, Pakistan, Islamabad, N/A, Pakistan; no phone number provided; nbcpakistan@nih.org.pk), ref: NBC-340 4. Approved 19/08/2021, National Institute of Medical Research (3 Barack Obama Drive, P.O. Box 9653, Dar-es-Salaam, 11101, Tanzania; no phone number provided; info@nimr.or.tz), ref: NIMR/HQ/R.8a/Vol.IX/3767 5. Approved 02/02/2019, University of Zambia Biomedical Research Ethics Committee (Ridgeway Campus, Lusaka, P.O. Box 50110, Zambia; no phone number provided; unzarec@unza.zm), ref: REF. 001-04-19 |
| Condition | Prevention of postpartum haemorrhage in women with moderate or severe anaemia having given birth vaginally |
| Intervention | Current intervention as of 21/12/2023 Participants are randomly allocated to one of two groups. The randomisation list is generated by computer. Active Comparator: Tranexamic acid, one intravenous injection of tranexamic acid. Total dose 1 g (10 mL). Placebo Comparator: One Injection of 10 mL Sodium Chloride (0.9%). Women receive clinically indicated care for the prevention and treatment of postpartum haemorrhage. We will also conduct a pre-planned cohort analysis of data from the WOMAN-2 trial to assess the effect of pain control and episiotomy on the risk of post-partum haemorrhage. Adrenaline is a potent stimulus for fibrinolysis. Adrenaline causes the release of tissue plasminogen activator (TPA) from the endothelium. In trauma victims, high adrenaline levels are associated with increased fibrinolysis, decreased clot strength and increased deaths due to bleeding. Childbirth is intensely painful and maternal adrenaline levels are two to six times higher during labour. Maternal adrenaline concentrations peak in the second and third stages of labour but then rapidly return to normal after birth. Pain control can reduce the maternal catecholamine response. We hypothesize that painful procedures such as episiotomy will significantly increase the risk of postpartum haemorrhage and that pain control will reduce the risk of PPH. The exposures of interest are the presence or absence of pain control during labour and delivery and whether episiotomy was conducted prior to birth. Pain control will be categorised as present or absent but the type of pain control administered during labour will also be described and examined. The types of pain control recorded in the study are epidural, opioids, ‘other’, or a combination of opioids and other pain control. For the multivariable regression analysis, the pain control variable was converted into a binary variable indicating whether a participant received any pain control or not. Episiotomy will be categorised as present or absent according to the CRF. The main outcome variable will be a clinical diagnosis of PPH (binary: yes/no), defined as an estimated blood loss of more than 500 mL or any blood loss sufficient to compromise haemodynamic stability within 24 hours. Potential confounding factors will include maternal age, BMI, anaemia, history of PPH, antepartum hemorrhage, hypertensive disease, multiple gestation, parity, prophylactic uterotonics, duration of labor, induction and augmentation of labor, assisted delivery, gestational age, birth canal trauma, placental abruption, and macrosomia. We will use multivariable logistic regression to examine the association between pain control and episiotomy and the risk of PPH after adjusting for confounding factors. We will describe our causal assumptions using a directed acyclic graph. We will examine the association between the exposures of interest and PPH with odds ratios and 95% confidence intervals. We will estimate odds ratios and 95% CI for the crude association between the exposures of interest and PPH and after controlling for confounding factors. We will check for collinearity using variance inflation factors. Finally, we will examine whether the effect of pain control and episiotomy on the risk of PPH is modified by tranexamic acid treatment. To do this we will conduct stratified analysis and calculate a p-value for heterogeneity using a likelihood ratio test. _____ Previous intervention as of 08/08/2018: Participants are randomly allocated to one of two groups. The randomisation list is generated by computer. Active Comparator: Tranexamic acid, one intravenous injection of tranexamic acid. Total dose 1 gram (10mL). Placebo Comparator: One Injection of 10 mL Sodium Chloride (0.9%). Women receive clinically indicated care for the prevention and treatment of postpartum haemorrhage. _____ Previous intervention: Participants are randomly allocated to one of two groups. The randomisation list is generated by computer. Active Comparator: Tranexamic acid, one intravenous injection of tranexamic acid. Total dose 1 gram (10mL). Placebo Comparator: One Injection of 10 mL Sodium Chloride (0.9%). Women receive clinically indicated care for the prevention of postpartum haemorrhage. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Tranexamic Acid |
| Primary outcome measure | Current primary outcome measure as of 08/08/2018: Postpartum haemorrhage is measured using a clinical assessment (estimated blood loss of more than 500 mL or any blood loss sufficient to compromise haemodynamic stability) within 24 hours after administration of trial medication or discharge from hospital (whichever is earlier). The cause of postpartum haemorrhage will be described. Previous primary outcome measure: Postpartum haemorrhage is measured using a clinical assessment (estimated blood loss of more than 500 mL or any blood loss sufficient to compromise haemodynamic stability) within 24 hours after administration of trial medication or discharge from discharge hospital whichever is earlier. |
| Secondary outcome measures | Current secondary outcome measures as of 08/08/2018: 1. Postpartum blood loss is measured using a clinical assessment at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 2. Haemoglobin is measured using Haemacue (Point of care test) at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 3. Haemodynamic instability is measured based on clinical signs e.g. low blood pressure, tachycardia, reduced urine output requiring intervention e.g. intravenous fluid at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 4. Shock index is measured using lowest recorded heart rate/systolic blood pressure at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 5. Symptoms of anaemia is measured using a questionnaire developed specifically for this trial at 42 days or discharge from hospital whichever is earlier (please move this to number 5 if possible) 6. Quality of life, including overall wellbeing, ability to care for herself and her baby, breastfeeding (time to first feed, ability to sustain breastfeeding at discharge is measured using questionnaire at day 42 or discharge from hospital whichever is earlier (questionnaire specifically developed for this trial) 7. Expected side effects of trial medication is measured using patient self reports and medical records of nausea, vomiting, and diarrhoea at day 42 or discharge from hospital whichever is earlier 8. Exercise tolerance is measured using the 6 minute walk test at day 42 or discharge from hospital whichever is earlier (standardised test) 9. Interventions to control primary postpartum haemorrhage (including uterotonics, removal of placenta/placenta fragments, intrauterine balloon tamponade, bimanual uterine compression, external aortic compression, non-pneumatic anti-shock garments, uterine artery embolisation, uterine compression suture, hysterectomy and laparotomy to control bleeding) is measured using medical records at day 42 or discharge from hospital whichever is earlier 10. Vascular occlusive events including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke and myocardial infarction (MI) are measured using from medical records at day 42 or discharge from hospital whichever is earlier 11. Organ dysfunction (cardiovascular, respiratory, renal, coagulation / haemotological, hepatic, neurological) is measured using medical records at day 42 or discharge from hospital whichever is earlier 12. Sepsis is measured using medical records at day 42 or discharge from hospital whichever is earlier 13. In hospital death (with cause described) is measured using medical records at day 42 or discharge from hospital whichever is earlier 14. Length of hospital stay is measured using medical records at day 42 or discharge from hospital whichever is earlier 15. Admission to and time spent in higher level facility is measured using medical records at day 42 or discharge from hospital whichever is earlier 16. Status of baby/babies (alive/dead) is measured using medical records at day 42 or discharge from hospital whichever is earlier 17. Thromboembolic events in breastfed babies are measured using medical records at 42 days or discharge from hospital whichever is earlier 18. Adverse events are measured as any untoward medical occurrences from medical records, patient self-report or report by any treating clinician up to day 42 19. Receipt of blood transfusion Previous secondary outcome measure: 1. Postpartum blood loss is measured using a clinical assessment at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 2. Haemoglobin is measured using Haemacue (Point of care test) at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 3. Haemodynamic instability is measured based on clinical signs e.g. low blood pressure, tachycardia, reduced urine output requiring intervention e.g. intravenous fluid at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 4. Shock index is measured using lowest recorded heart rate/systolic blood pressure at 24 hours after administration of the trial medication or at discharge from hospital whichever is earlier 5. Symptoms of anaemia is measured using a questionnaire developed specifically for this trial at 42 days or discharge from hospital whichever is earlier (please move this to number 5 if possible) 6. Quality of life, including overall wellbeing, ability to care for herself and her baby, breastfeeding (time to first feed, ability to sustain breastfeeding at discharge is measured using questionnaire at day 42 or discharge from hospital whichever is earlier (questionnaire specifically developed for this trial) 7. Expected side effects of trial medication is measured using patient self reports and medical records of nausea, vomiting, and diarrhoea at day 42 or discharge from hospital whichever is earlier 8. Exercise tolerance is measured using the 6 minute walk test at day 42 or discharge from hospital whichever is earlier (standardised test) 9. Interventions to control primary postpartum haemorrhage (including uterotonics, removal of placenta/placenta fragments, intrauterine balloon tamponade, bimanual uterine compression, external aortic compression, non-pneumatic anti-shock garments, uterine artery embolisation, uterine compression suture, hysterectomy and laparotomy to control bleeding) is measured using medical records at day 42 or discharge from hospital whichever is earlier 10. Vascular occlusive events including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke and myocardial infarction (MI) are measured using from medical records at day 42 or discharge from hospital whichever is earlier 11. Organ dysfunction (cardiovascular, respiratory, renal, coagulation / haemotological, hepatic, neurological) is measured using medical records at day 42 or discharge from hospital whichever is earlier 12. Sepsis is measured using medical records at day 42 or discharge from hospital whichever is earlier 13. In hospital death (with cause described) is measured using medical records at day 42 or discharge from hospital whichever is earlier 14. Length of hospital stay is measured using medical records at day 42 or discharge from hospital whichever is earlier 15. Admission to and time spent in higher level facility is measured using medical records at day 42 or discharge from hospital whichever is earlier 16. Status of baby/babies is measured using medical records definition at day 42 or discharge from hospital whichever is earlier 17. Thromboembolic events in breastfed babies are measured using medical records at 42 days or discharge from hospital whichever is earlier 18. Adverse events are measured as any untoward medical occurrences from medical records, patient self-report or report by any treating clinician up to day 42 |
| Overall study start date | 01/11/2017 |
| Overall study end date | 20/09/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Female |
| Target number of participants | 15,000 |
| Total final enrolment | 15068 |
| Participant inclusion criteria | Women with moderate or severe anaemia (haemoglobin level <100 g/ L or packed cell volume <30%) after giving birth vaginally where the responsible clinician is substantially uncertain whether to use tranexamic acid. |
| Participant exclusion criteria | 1. Women who are not legally adult (<18 years) and not accompanied by a guardian 2. Women with a known allergy to tranexamic acid or its excipients 3. Women who develop postpartum haemorrhage before randomisation |
| Recruitment start date | 01/10/2018 |
| Recruitment end date | 19/09/2023 |
Locations
Countries of recruitment
- Nigeria
- Pakistan
- Tanzania
- Zambia
Study participating centres
Akure
-
Nigeria
Akure
-
Nigeria
Ibadan
-
Nigeria
Ilorin
-
Nigeria
Kano
-
Nigeria
Ogbomoso
-
Nigeria
Oyo
-
Nigeria
Abbottabad
-
Pakistan
Bahawalpur
-
Pakistan
Islamabad
-
Pakistan
Islamabad
-
Pakistan
Karachi
-
Pakistan
Karachi
-
Pakistan
Karachi
-
Pakistan
Lahore
-
Pakistan
Lahore
-
Pakistan
Lahore
-
Pakistan
Larkana
-
Pakistan
Multan
-
Pakistan
Quetta
-
Pakistan
Rawalpindi
-
Pakistan
Rawalpindi
-
Pakistan
Rawalpindi
-
Pakistan
Arusha
-
Tanzania
Dar Es Salaam
-
Tanzania
Dar Es Salaam
-
Tanzania
Dar Es Salaam
-
Tanzania
Dodoma
-
Tanzania
Kibaha
-
Tanzania
Kinondoni
-
Tanzania
Mbeya
-
Tanzania
Lusaka
-
Zambia
Sponsor information
University/education
Keppel Street
London
WC1E 7HT
England
United Kingdom
"ROR" |
https://ror.org/00a0jsq62 |
|---|
Funders
Funder type
Charity
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Wellcome, WT
- Location
- United Kingdom
No information available
Results and Publications
| Intention to publish date | 31/10/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 29/12/2018 | Yes | No | |
| Statistical Analysis Plan | 03/08/2023 | 04/09/2023 | No | No | |
| Other publications | Cohort analysis of association between pre-birth anaemia and postpartum haemorrhage | 01/08/2023 | 21/12/2023 | Yes | No |
| Results article | 26/10/2024 | 28/10/2024 | Yes | No |
Editorial Notes
28/10/2024: Publication reference added.
21/12/2023: The following changes have been made:
1. The recruitment end date has been changed from 31/01/2024 to 19/09/2023.
2. The overall study end date has been changed from 31/10/2024 to 20/09/2023 and the plain English summary updated accordingly.
3. The ethics approval information has been added.
4. The intervention has been changed.
5. The final enrolment number has been added.
6. Uganda has been removed from the countries of recruitment and Tanzania and Zambia added.
7. Rawalpindi Medical University, University College Hospital (Ibadan) and Makerere University have been removed from the study participating centres and Mother & Child Hospital (Akure), University of Medical Sciences Teaching Hospital (Akure), Adeoyo Maternity Hospital, Ilorin General Hospital, Muhammad Abdullahi Wase Specialist Hospital, Ladoke Akintola University of Technology Teaching Hospital, Oyo State Hospital, Ayub Teaching Hospital, Bahawalpur Victoria Hospital, MCH PIMS, Islamabad Military Hospital, Karachi Civil Hospital, Jinnah Postgraduate Medical Centre, Koohi Goth Hospital, Jinnah Hospital, Lahore Services Hospital, Sir Ganga Ram Hospital, Chandka SMBBMU Sheikh Zaid Woman Hospital, Nishtar Hospital, Bolan Medical Centre, Benazir Bhutto Shaheed Hospital, Federal Government Polyclinic, Holy Family Hospital, Mount Meru Regional Referral Hospital, Muhimbili National Hospital, Amana Regional Referral Hospital, Temeke Regional Referral Hospital, Dodoma Regional Referral Hospital, Tumbi Regional Referral Hospital, Mwananyamala Regional Referral Hospital, Mbeya Zonal Referral Hospital and Women and Newborn Hospital have been added.
8. The intention to publish date has been changed from 31/10/2025 to 31/10/2024.
9. The plain English summary has been updated to reflect the change of contact name and where the study is run from.
10. The previous public contact has been changed to a scientific contact and another public contact added.
11. Publication reference added.
04/09/2023: Publication reference added.
04/01/2023: The following changes were made to the trial record:
1. The overall end date was changed from 31/01/2023 to 31/10/2024.
2. The intention to publish date was changed from 31/01/2024 to 31/10/2025.
3. The plain English summary was updated to reflect these changes.
4. The target number of participants was changed from 10,000 to 15,000.
5. The recruitment end date was changed from 31/01/2021 to 31/01/2024.
04/01/2019: Publication reference added.
08/08/2018: The following changes have been made to the trial record:
1. The clinicaltrials.gov number was added
2. The interventions have been updated
3. The primary outcome measure has been updated
4. The secondary outcome measures have been updated
5. The trial website was added
6. The recruitment start date has been changed from 01/04/2018 to 01/10/2018
7. The recruitment end date has been changed from 31/01/2023 to 31/01/2021
8. Uganda was added as a country of recruitment
9. Dr Sam Ononge was added as a trial participating centre
