World Maternal Antifibrinolytic Trial_2

Intrapartum - Moderate and Severe Anaemia Clinical Trial

— WOMAN-2  

Official title:

Tranexamic Acid for the Prevention of Postpartum Bleeding in Women With Anaemia: an International, Randomised, Double-blind, Placebo Controlled Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03475342
• Other study ID #: WOMAN_2
• Secondary ID: 03475342
• Status: Completed
• Phase: Phase 3
• Start date: August 24, 2019
• Est. completion date: October 29, 2023

Study information

• Verified date: April 2023
• Source: London School of Hygiene and Tropical Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15068
• Est. completion date: October 29, 2023
• Est. primary completion date: September 20, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Anemia
• Intrapartum - Moderate and Severe Anaemia

Intervention

Drug:
• Tranexamic Acid
Ampoules and packaging for both arms will be identical in appearance.

Other:
• Placebo
Ampoules and packaging for both arms will be identical in appearance.

Locations

Country	Name	City	State
Nigeria	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
Pakistan	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	Larkana
Pakistan	Nishtar Hospital Unit 1	Multan
Pakistan	Nishtar Hospital Unit 2	Multan
Pakistan	Nishtar Hospital Unit 3	Multan
Pakistan	Bolan Medical Centre	Quetta
Pakistan	Benazir Bhutto Shaheed Hospital	Rawalpindi
Pakistan	Federal Government Polyclinic	Rawalpindi
Pakistan	Holy Family Hospital	Rawalpindi
Tanzania	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
Zambia	Women and Newborn Hospital	Lusaka

Sponsors (3)

Lead Sponsor	Collaborator
London School of Hygiene and Tropical Medicine	Bill and Melinda Gates Foundation, Wellcome Trust

Countries where clinical trial is conducted

Nigeria,  Pakistan,  Tanzania,  Zambia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postpartum Haemorrhage (cause will be described)	Clinical assessment: This may be an estimated blood loss of more than 500 mL or any blood loss sufficient to compromise haemodynamic stability within 24 hours of delivery. Haemodynamic instability is based on clinical judgement and assessed using clinical signs (low systolic blood pressure, tachycardia, reduced urine output).	24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Secondary	Postpartum blood loss	Clinical assessment	24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Secondary	Haemoglobin	Haemocue (Point of care test)	24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Secondary	Haemodynamic instability	Defined as per protocol	24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
Secondary	Shock index	Heart rate/systolic blood pressure	24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
Secondary	Quality of Life (maternal)	Defined as per protocol	Day 42 or discharge from hospital, whichever is earlier
Secondary	Expected side effects of trial medication	nausea, vomiting, diarrhoea	Day 42 or discharge from hospital, whichever is earlier
Secondary	Exercise tolerance	6 minute walk test	Day 42 or discharge from hospital, whichever is earlier
Secondary	Interventions to control primary postpartum haemorrhage (medical and surgical)	Any of the following: 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	Day 42 or discharge from hospital, whichever is earlier
Secondary	Receipt of blood product transfusion	units and type	Day 42 or discharge of mother from hospital, whichever is earlier
Secondary	Vascular occlusive events	Any of the following:pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, myocardial infarction	Day 42 or discharge from hospital, whichever is earlier
Secondary	Symptoms of anaemia	measured using Quality of life Questionnaire and walk test	Day 42 or discharge of mother from hospital, whichever is earlier
Secondary	Organ disfunction	Any of the following: Cardiovascular, Respiratory, Renal, Hepatic, Neurological, Coagulation/ haematologic dysfunction	Day 42 or discharge from hospital, whichever is earlier
Secondary	Sepsis	diagnosis is based on the presence of both infection and a systemic inflammatory response syndrome (SIRS). SIRS requires two or more of the following: a) temperature <36°C or >38°C (b) heart rate >90 beats/min (c) respiratory rate >20 breaths/min (d) white blood cell count <4x109/L (<4000/mm³) or >12x109/L (>12,000/mm³)	Day 42 or discharge from hospital, whichever is earlier
Secondary	In hospital death	Cause and time of death will be described	Day 42
Secondary	Length of hospital stay.	Days	Day 42 or discharge from hospital, whichever is earlier
Secondary	Admission to and time spent in higher level facility	High Dependency and/or Intensive Care Units	Day 42 or discharge from hospital, whichever is earlier
Secondary	Status of baby/ies	alive or dead	Day 42 or discharge of mother from hospital, whichever is earlier
Secondary	Thromboembolic events in breastfed babies	as defined in protocol	Day 42 or discharge of mother from hospital, whichever is earlier
Secondary	Adverse events	Any untoward medical occurrence (other than expected complications)	Day 42