World Maternal Antifibrinolytic Trial_2

NCT ID: NCT03475342

Last Updated: 2024-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 15068 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-24
• Study Completion Date: 2023-10-29

Brief Summary

Postpartum haemorrhage (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 reduces deaths due to bleeding in women with PPH by almost one third. However, for many women, treatment of PPH is too late to prevent death and severe morbidities. Over one-third of pregnant women in the world are anaemic and many are severely anaemic. We now want to do the WOMAN-2 trial to see if giving tranexamic acid can prevent PPH and other severe outcomes in women with moderate and severe anaemia.

Detailed Description

Anaemia is a cause and consequence of PPH. A cohort study in Assam, India found that women with moderate or severe anaemia had a greatly increased risk of PPH. Women with moderate anaemia had a 50% increased risk, whereas those with severe anaemia had a ten-fold increased risk of PPH. Anaemic women may be more susceptible to uterine atony due to impaired oxygen transport to the uterus. Anaemic women experience worse outcomes after PPH. An international survey of 275,000 women found that severe maternal outcomes after PPH were nearly three times more common in anaemic than in non-anaemic women. Even moderate bleeding can be life threatening in anaemic women. Excessive bleeding after childbirth worsens maternal anaemia, resulting in a vicious circle of bleeding and adverse outcomes. Fatigue due to anaemia severely limits a mothers' wellbeing and her ability to care for her children. Despite efforts to prevent anaemia, many women labour with perilously low haemoglobin levels

Tranexamic acid (TXA) inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. TXA reduces surgical bleeding and death due to bleeding in trauma patients. The WOMAN trial assessed the effects of TXA in 20,060 women with PPH. When given within three hours of birth, TXA reduced death due to bleeding by nearly one-third (RR=0.69, 95% CI 0.52 to 0.91, p=0.008). However, for many women, treatment is too late to prevent death from PPH. Most PPH deaths occur in the first hours after giving birth and women with anaemia are at greatly increased risk. Whilst there have been some trials of TXA for the prevention of PPH, most have serious flaws and none collected data on maternal health and wellbeing. There is currently no reliable evidence about the effectiveness and safety of TXA for preventing PPH.

The WOMAN-2 trial will determine reliably the effects of TXA in anaemic women who give birth vaginally.

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.

Conditions

Intrapartum - Moderate and Severe Anaemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Tranexamic acid

One intravenous injection of tranexamic acid. Total dose 1 gram (10mL)

Group Type: ACTIVE_COMPARATOR

Tranexamic Acid

Intervention Type: DRUG

Ampoules and packaging for both arms will be identical in appearance.

Placebo

One Injection of the placebo which is 10 mL Sodium Chloride (0.9%)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Ampoules and packaging for both arms will be identical in appearance.

Interventions

Tranexamic Acid

Ampoules and packaging for both arms will be identical in appearance.

Intervention Type: DRUG

Placebo

Ampoules and packaging for both arms will be identical in appearance.

Intervention Type: OTHER

Other Intervention Names

(Sodium Chloride 0.9%)

Eligibility Criteria

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 TXA

Exclusion Criteria

• Women who are not legally adult (<18 years) and not accompanied by a guardian
• Women with a known allergy to tranexamic acid or its excipients
• Women who experience postpartum haemorrhage before the umbilical cord is cut or clamped.

• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Wellcome Trust

OTHER

Sponsor Role: collaborator

Bill and Melinda Gates Foundation

OTHER

Sponsor Role: collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ian Roberts

Role: STUDY_CHAIR

Clinical Trials Unit, London School of Hygiene and Tropical Medicine

Haleema Shakur-Still

Role: STUDY_CHAIR

Clinical Trials Unit, London School of Hygiene and Tropical Medicine

Rizwana Chaudhri

Role: PRINCIPAL_INVESTIGATOR

National Coordinating Investigator, Shifa Tameer-e-Millat University, Pakistan

Folasade A Bello

Role: PRINCIPAL_INVESTIGATOR

National Coordinating Investigator, College of Medicine, University of Ibadan, Nigeria

Bellington Vwalika

Role: PRINCIPAL_INVESTIGATOR

National Coordinating Investigator, University of Zambia School of Medicine, Zambia

Projestine Muganyizi

Role: PRINCIPAL_INVESTIGATOR

National Coordinating Investigator, Muhimbili University of Health and Allied Sciences, Tanzania

Oladapo Olayemi

Role: PRINCIPAL_INVESTIGATOR

National Coordinating Investigator, College of Medicine, University of Ibadan, Nigeria

Locations

Mother & Child Hospital

Akure, , Nigeria

University of Medical Sciences Teaching Hospital

Akure, , Nigeria

Adeoyo Maternity Hospital

Ibadan, , Nigeria

Ilorin General Hospital

Ilorin, , Nigeria

Muhammad Abdullahi Wase Specialist Hospital

Kano, , Nigeria

Ladoke Akintola University of Technology Teaching Hospital

Ogbomoso, , Nigeria

State Hospital

Oyo, , Nigeria

Ayub Teaching Hospital (Unit A)

Abbottabad, , Pakistan

Ayub Teaching Hospital (Unit C)

Abbottabad, , Pakistan

Ayub Teaching Hospital Unit B

Abbottabad, , Pakistan

Bahawalpur Victoria Hospital

Bahawalpur, , Pakistan

Aziz Bhatti Teaching Hospital

Gujrat, , Pakistan

MCH PIMS

Islamabad, , Pakistan

Military Hospital

Islamabad, , Pakistan

Civil Hospital

Karachi, , Pakistan

Jinnah Postgraduate Medical Centre

Karachi, , Pakistan

Koohi Goth Hospital

Karachi, , Pakistan

Jinnah Hospital

Lahore, , Pakistan

Services Hospital

Lahore, , Pakistan

Sir Ganga Ram Hospital Unit 1

Lahore, , Pakistan

Sir Ganga Ram Hospital Unit 2

Lahore, , Pakistan

Sir Ganga Ram Hospital Unit 3

Lahore, , Pakistan

Sir Ganga Ram Hospital Unit 4

Lahore, , Pakistan

Chandka SMBBMU Sheikh Zaid Woman Hospital Unit 1

Larkana, , Pakistan

Chandka SMBBMU Sheikh Zaid Woman Hospital Units 2 & 3

Lārkāna, , Pakistan

Nishtar Hospital Unit 1

Multan, , Pakistan

Nishtar Hospital Unit 2

Multan Khurd, , Pakistan

Nishtar Hospital Unit 3

Multan Khurd, , Pakistan

Bolan Medical Centre

Quetta, , Pakistan

Benazir Bhutto Shaheed Hospital

Rawalpindi, , Pakistan

Federal Government Polyclinic

Rawalpindi, , Pakistan

Holy Family Hospital

Rawalpindi, , Pakistan

Mount Meru Regional Referral Hospital

Arusha, , Tanzania

Amana Regional Referral Hospital,

Dar es Salaam, , Tanzania

Muhimbili National Hospital

Dar es Salaam, , Tanzania

Temeke Regional Referral Hospital

Dar es Salaam, , Tanzania

Dodoma Regional Referral Hospital

Dodoma, , Tanzania

Tumbi Regional Referral Hospital, Kibaha

Kibaha, , Tanzania

Mwananyamala Regional Referral Hospital

Kinondoni, , Tanzania

Mbeya Zonal Referral Hospital

Mbeya, , Tanzania

Women and Newborn Hospital

Lusaka, , Zambia

Countries

Nigeria; Pakistan; Tanzania; Zambia

References

WOMAN-2 Trial Collaborators. The effect of tranexamic acid on postpartum bleeding in women with moderate and severe anaemia (WOMAN-2): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2024 Oct 26;404(10463):1645-1656. doi: 10.1016/S0140-6736(24)01749-5.

Reference Type: DERIVED

PMID: 39461792 (View on PubMed)

Larson NJ, Mergoum AM, Dries DJ, Cook A, Blondeau B, Rogers FB. THE ROLE OF TRANEXAMIC ACID IN POSTPARTUM HEMORRHAGE: A NARRATIVE REVIEW. Shock. 2024 Nov 1;62(5):620-627. doi: 10.1097/SHK.0000000000002455. Epub 2024 Aug 20.

Reference Type: DERIVED

PMID: 39162220 (View on PubMed)

Collier T, Shakur-Still H, Roberts I, Balogun E, Olayemi O, Bello FA, Chaudhri R, Muganyizi P; WOMAN-2 Trial Collaborators. Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: Statistical analysis plan for the WOMAN-2 trial: an international, randomised, placebo-controlled trial. Gates Open Res. 2023 Aug 3;7:69. doi: 10.12688/gatesopenres.14529.2. eCollection 2023.

Reference Type: DERIVED

PMID: 37664793 (View on PubMed)

Brenner A, Roberts I, Balogun E, Bello FA, Chaudhri R, Fleming C, Javaid K, Kayani A, Lubeya MK, Mansukhani R, Olayemi O, Prowse D, Vwalika B, Shakur-Still H. Postpartum haemorrhage in anaemic women: assessing outcome measures for clinical trials. Trials. 2022 Mar 18;23(1):220. doi: 10.1186/s13063-022-06140-z.

Reference Type: DERIVED

PMID: 35303924 (View on PubMed)

Ker K, Roberts I, Chaudhri R, Fawole B, Beaumont D, Balogun E, Prowse D, Pepple T, Javaid K, Kayani A, Arulkumaran S, Bates I, Shakur-Still H; WOMAN-2 trial collaborators. Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial. Trials. 2018 Dec 29;19(1):712. doi: 10.1186/s13063-018-3081-x.

Reference Type: DERIVED

PMID: 30594227 (View on PubMed)

Other Identifiers

03475342

Identifier Type: OTHER

Identifier Source: secondary_id

WOMAN_2

Identifier Type: -

Identifier Source: org_study_id