Clinical trial NCT03475342: World Maternal Antifibrinolytic Trial_2
Official title: Tranexamic Acid for the Prevention of Postpartum Bleeding in Women With Anaemia: an International, Randomised, Double-blind, Placebo Controlled Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Intrapartum - Moderate and Severe Anaemia
Keywords: prevention, postpartum haemorrhage
moderate anaemia
severe anaemia
antifibrinolytic
tranexamic acid
pregnancy
pain
episiotomy
Lead sponsor: London School of Hygiene and Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Wellcome Trust
name: Bill and Melinda Gates Foundation
First posted: 2018-03-23
Enrollment: 15068
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomised, double blind, placebo controlled trial among 15,000 women with moderate or severe anaemia having given birth vaginally.
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Postpartum Haemorrhage (cause will be described)
timeFrame: 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Secondary outcomes:
measure: Postpartum blood loss
timeFrame: 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
measure: Haemoglobin
timeFrame: 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
measure: Haemodynamic instability
timeFrame: 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
measure: Shock index
timeFrame: 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
measure: Quality of Life (maternal)
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Expected side effects of trial medication
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Exercise tolerance
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Interventions to control primary postpartum haemorrhage (medical and surgical)
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Receipt of blood product transfusion
timeFrame: Day 42 or discharge of mother from hospital, whichever is earlier
measure: Vascular occlusive events
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Symptoms of anaemia
timeFrame: Day 42 or discharge of mother from hospital, whichever is earlier
measure: Organ disfunction
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Sepsis
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: In hospital death
timeFrame: Day 42
measure: Length of hospital stay.
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Admission to and time spent in higher level facility
timeFrame: Day 42 or discharge from hospital, whichever is earlier
measure: Status of baby/ies
timeFrame: Day 42 or discharge of mother from hospital, whichever is earlier
measure: Thromboembolic events in breastfed babies
timeFrame: Day 42 or discharge of mother from hospital, whichever is earlier
measure: Adverse events
timeFrame: Day 42
Other outcomes:
Locations:
city: Akure
country: Nigeria
facility: Mother & Child Hospital
city: Akure
country: Nigeria
facility: University of Medical Sciences Teaching Hospital
city: Ibadan
country: Nigeria
facility: Adeoyo Maternity Hospital
city: Ilorin
country: Nigeria
facility: Ilorin General Hospital
city: Kano
country: Nigeria
facility: Muhammad Abdullahi Wase Specialist Hospital
city: Ogbomoso
country: Nigeria
facility: Ladoke Akintola University of Technology Teaching Hospital
city: Oyo
country: Nigeria
facility: State Hospital
city: Abbottabad
country: Pakistan
facility: Ayub Teaching Hospital (Unit A)
city: Abbottabad
country: Pakistan
facility: Ayub Teaching Hospital (Unit C)
city: Abbottabad
country: Pakistan
facility: Ayub Teaching Hospital Unit B
city: Bahawalpur
country: Pakistan
facility: Bahawalpur Victoria Hospital
city: Gujrat
country: Pakistan
facility: Aziz Bhatti Teaching Hospital
city: Islamabad
country: Pakistan
facility: MCH PIMS
city: Islamabad
country: Pakistan
facility: Military Hospital
city: Karachi
country: Pakistan
facility: Civil Hospital
city: Karachi
country: Pakistan
facility: Jinnah Postgraduate Medical Centre
city: Karachi
country: Pakistan
facility: Koohi Goth Hospital
city: Lahore
country: Pakistan
facility: Jinnah Hospital
city: Lahore
country: Pakistan
facility: Services Hospital
city: Lahore
country: Pakistan
facility: Sir Ganga Ram Hospital Unit 1
city: Lahore
country: Pakistan
facility: Sir Ganga Ram Hospital Unit 2
city: Lahore
country: Pakistan
facility: Sir Ganga Ram Hospital Unit 3
city: Lahore
country: Pakistan
facility: Sir Ganga Ram Hospital Unit 4
city: Larkana
country: Pakistan
facility: Chandka SMBBMU Sheikh Zaid Woman Hospital Unit 1
city: Lārkāna
country: Pakistan
facility: Chandka SMBBMU Sheikh Zaid Woman Hospital Units 2 & 3
city: Multan
country: Pakistan
facility: Nishtar Hospital Unit 1
city: Multān
country: Pakistan
facility: Nishtar Hospital Unit 2
city: Multān
country: Pakistan
facility: Nishtar Hospital Unit 3
city: Quetta
country: Pakistan
facility: Bolan Medical Centre
city: Rawalpindi
country: Pakistan
facility: Benazir Bhutto Shaheed Hospital
city: Rawalpindi
country: Pakistan
facility: Federal Government Polyclinic
city: Rawalpindi
country: Pakistan
facility: Holy Family Hospital
city: Arusha
country: Tanzania
facility: Mount Meru Regional Referral Hospital
city: Dar Es Salaam
country: Tanzania
facility: Amana Regional Referral Hospital,
city: Dar Es Salaam
country: Tanzania
facility: Muhimbili National Hospital
city: Dar Es Salaam
country: Tanzania
facility: Temeke Regional Referral Hospital
city: Dodoma
country: Tanzania
facility: Dodoma Regional Referral Hospital
city: Kibaha
country: Tanzania
facility: Tumbi Regional Referral Hospital, Kibaha
city: Kinondoni
country: Tanzania
facility: Mwananyamala Regional Referral Hospital
city: Mbeya
country: Tanzania
facility: Mbeya Zonal Referral Hospital
city: Lusaka
country: Zambia
facility: Women and Newborn Hospital
Study officials:
affiliation: Clinical Trials Unit, London School of Hygiene and Tropical Medicine
name: Ian Roberts
role: STUDY_CHAIR
affiliation: Clinical Trials Unit, London School of Hygiene and Tropical Medicine
name: Haleema Shakur-Still
role: STUDY_CHAIR
affiliation: National Coordinating Investigator, Shifa Tameer-e-Millat University, Pakistan
name: Rizwana Chaudhri
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinating Investigator, College of Medicine, University of Ibadan, Nigeria
name: Folasade A Bello
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinating Investigator, University of Zambia School of Medicine, Zambia
name: Bellington Vwalika
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinating Investigator, Muhimbili University of Health and Allied Sciences, Tanzania
name: Projestine Muganyizi
role: PRINCIPAL_INVESTIGATOR
affiliation: National Coordinating Investigator, College of Medicine, University of Ibadan, Nigeria
name: Oladapo Olayemi
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.