World Maternal Antifibrinolytic Trial_2

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Intrapartum - Moderate and Severe Anaemia

Intervention / Treatment
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* Drug: Tranexamic Acid
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomised, double blind, placebo controlled trial among 15,000 women with moderate or severe anaemia having given birth vaginally.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tranexamic acid<br>One intravenous injection of tranexamic acid. Total dose 1 gram (10mL) | Drug: Tranexamic Acid<br>* Ampoules and packaging for both arms will be identical in appearance.<br>|
| Placebo Comparator: Placebo<br>One Injection of the placebo which is 10 mL Sodium Chloride (0.9%) | Other: Placebo<br>* Ampoules and packaging for both arms will be identical in appearance.<br>* Other names: (Sodium Chloride 0.9%);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postpartum blood loss | Clinical assessment | 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier | 
| Haemoglobin | Haemocue (Point of care test) | 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier | 
| Haemodynamic instability | Defined as per protocol | 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier | 
| Shock index | Heart rate/systolic blood pressure | 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier | 
| Quality of Life (maternal) | Defined as per protocol | Day 42 or discharge from hospital, whichever is earlier | 
| Expected side effects of trial medication | nausea, vomiting, diarrhoea | Day 42 or discharge from hospital, whichever is earlier | 
| Exercise tolerance | 6 minute walk test | Day 42 or discharge from hospital, whichever is earlier | 
| 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 | 
| Receipt of blood product transfusion | units and type | Day 42 or discharge of mother from hospital, whichever is earlier | 
| 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 | 
| Symptoms of anaemia | measured using Quality of life Questionnaire and walk test | Day 42 or discharge of mother from hospital, whichever is earlier | 
| Organ disfunction | Any of the following: Cardiovascular, Respiratory, Renal, Hepatic, Neurological, Coagulation/ haematologic dysfunction | Day 42 or discharge from hospital, whichever is earlier | 
| 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 | 
| In hospital death | Cause and time of death will be described | Day 42 | 
| Length of hospital stay. | Days | Day 42 or discharge from hospital, whichever is earlier | 
| 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 | 
| Status of baby/ies | alive or dead | Day 42 or discharge of mother from hospital, whichever is earlier | 
| Thromboembolic events in breastfed babies | as defined in protocol | Day 42 or discharge of mother from hospital, whichever is earlier | 
| Adverse events | Any untoward medical occurrence (other than expected complications) | Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prevention, postpartum haemorrhage, moderate anaemia, severe anaemia, antifibrinolytic, tranexamic acid, pregnancy