Clinical trial NCT03463993: Efficacy of Tranexamic Acid in Preventing Postpartum Haemorrhage After Elective Caesarean Section
Official title: Efficacy of Tranexamic Acid in Preventing Postpartum Haemorrhage After Elective Caesarean Section
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Post Partum Hemorrhage
Lead sponsor: University of Zimbabwe
Sponsor class: OTHER
First posted: 2018-03-13
Enrollment: 506
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized control trial with two arms. Participants receive either 10mg/kg of TXA 10 minutes prior to elective caesarean section with prophylactic oxytocin administration after delivery of the baby, versus prophylactic oxytocin alone after delivery of the baby.
Primary purpose: PREVENTION

Brief summary: Background Postpartum haemorrhage (PPH) is a major cause of maternal mortality worldwide accounting for 25% of maternal deaths. In Zimbabwe PPH is the second most common cause of death. Tranexamic acid (TXA) is widely used to reduce blood loss in elective surgery, bleeding trauma patients, and menorrhagia.

The investigators seek to determine the efficacy of TXA in reducing PPH during and after elective caesarean section.

Methods and Design The investigators intend to perform an open label randomized control study of 1,162 women who are undergoing elective caesarean section. The participants will be randomly selected to receive an intravenous infusion of TXA 10 minutes prior to skin incision or not to receive the intervention. Prophylactic oxytocin will be administered to all the women.

The primary outcome will be incidence of PPH defined by blood loss equal to or more than 1,000ml calculated by determining the difference in haematocrit values taken prior to and 48 hours after caesarean section.

Discussion In addition to prophylactic uterotonic administration, TXA is a complementary component acting on the haemostatic process that can be used in the third stage of labour to prevent PPH. It is a promising intervention that is cheap, easy to administer and would be easy to add to routine delivery protocols in hospitals. It would also help to conserve precious resources by reducing the need for blood products, and expensive surgical interventions to manage PPH.

This large adequately powered randomized study seeks to determine the efficacy of TXA to validate its routine use at caesarean section to prevent PPH.

Detailed description: RESEARCH QUESTION Does intravenous Tranexamic Acid (TXA) 10mg/kg plus Oxytocin 5 International Units (IU) result in a lower incidence of primary postpartum haemorrhage compared to Oxytocin alone after elective caesarean section.

RATIONALE FOR THE RESEARCH Postpartum haemorrhage (PPH) is a major cause of maternal mortality worldwide accounting for 25% of maternal deaths. In Zimbabwe, PPH is the second most common cause of death. Tranexamic acid (TXA) is widely used to reduce blood loss in elective surgery, bleeding trauma patients, and menorrhagia.

In addition to prophylactic uterotonic administration, TXA is a complementary component acting on the haemostatic process that can be used in the third stage of labour to prevent PPH. It is a promising intervention that is cheap, easy to administer and would be easy to add to routine delivery protocols in hospitals. It would also help to conserve precious resources by reducing the need for blood products, and expensive surgical interventions to manage PPH.

The investigators seek to determine the efficacy of TXA in reducing PPH during and after elective caesarean section.

RESEARCH OBJECTIVES

1. To assess the impact of TXA (10mg/kg) given 10 minutes prior to elective caesarean section on postpartum blood loss
2. To assess the potential adverse effects of TXA given 10 minutes prior to elective caesarean section Primary Outcome

   * Incidence of PPH defined by blood loss equal to or exceeding 1000ml following elective caesarean section Secondary Outcomes
   * Estimated blood loss during caesarean section
   * Need for blood transfusion
   * Use of additional uterotonics (such as oxytocin infusion or prostaglandins)
   * TXA side effects
   * Incidence of emergency surgery for PPH
   * Duration of mother's postnatal hospital stay
   * Neonatal outcome RESEARCH METHODOLOGY Research Design The aim of this study is to compare the effect of a low dose of TXA (10mg/kg) administered 10 minutes prior to elective caesarean section with prophylactic oxytocin administration, versus prophylactic oxytocin alone in an open label randomized clinical trial (RCT). An RCT is appropriate as it aims to reduce bias when testing this potentially new intervention.

Target Population Women undergoing elective caesarean sections at Harare and Parirenyatwa Hospitals based on set inclusion and exclusion criteria Inclusion criteria Pregnant woman with signed informed consent, who understand English and/or Shona, at estimated gestational age of 38 weeks or older, requiring Elective Caesarean Section, with a live intrauterine fetus.

Exclusion criteria Placental Abruption, emergency caesarean section, current or previous history of significant disease including heart disease, liver, renal disorders; known coagulopathy or history of deep venous thrombosis and/or pulmonary embolism, or arterial thrombosis (angina pectoris, myocardial infarction, stroke); history of epilepsy or seizures; autoimmune disease; sickle cell disease; severe haemorrhagic disease; intrauterine fetal demise; eclampsia/HELLP syndrome; administration of anticoagulants - clexane or antiplatelet agents in the week prior to delivery.

Sample Size A total sample size of 1,162 (581 per group) was calculated assuming a proportion of 2.1% PPH in the experimental group and 5.8% in the control group at 95% confidence interval and 90% power using Fleiss formula.

Subjects' state of physical health Healthy Intervention Participants receive either 10mg/kg of TXA 10 minutes prior to elective caesarean section with prophylactic oxytocin administration after delivery of the baby, versus prophylactic oxytocin alone after delivery of the baby.

Assessment Questionnaire (attached). Vital signs (heart rate, blood pressure, respiratory rate) noted before surgery, immediately after placental delivery, and 1 to 2 hours after birth Full blood count (FBC), Urea \& electrolytes (u\&e) and liver function tests (LFTs) performed a day before delivery (routinely performed) U\&e, LFTs and FBC assessed 48 hours after delivery. Estimated blood loss (EBL) using the difference in hematocrit values taken prior to and 48 hours after caesarean delivery.

The investigators will also note the standard EBL based on estimates made by the anaesthetist after assessment of patient's linen and abdominal swabs.

RISKS AND BENEFITS The common adverse effects include headaches (50.4 - 60.4%), backaches (20.7 - 31.4%), nasal sinus problem (25.4%), abdominal pain (12 - 19.8%), diarrhea (12.2%), fatigue (5.2%) and anaemia (5.6%).

The WOMAN Trial collaborators found that TXA actually reduces mortality due to bleeding in women with PPH with no adverse effects.

Tranexamic acid potentiates the blood clotting system and is used to treat and prevent bleeding. Use of TXA could potentially prevent PPH due to factors other than uterine atony, where uterotonics will not be effective.

COSTS AND COMPENSATION Study participants will not receive any compensation. The cost of TXA shall not be incurred by the study participants. They will bear their usual admission and caesarean section costs that they would otherwise have borne had they not participated in the study.

INFORMED CONSENT All subjects or legally authorized representatives for minors are expected to be give informed consent.

CONFIDENTIALITY ASSURANCES Information collected from the participants shall be confidential, will be assigned a code and no personal identifiers will be used. Information collected will be stored in a secure place only accessible to the researcher and assistants, as well as on a password-protected laptop computer. Consent forms will be kept for three years after the completion of the investigation unless stipulated otherwise by the Medical Research Council of Zimbabwe.

CONFLICTS OF INTERESTS The study is being carried out in partial fulfillment of the degree of Masters of Medicine in Obstetrics and Gynaecology. No other gains are to be obtained from carrying out the study.

COLLABORATIVE AGREEMENTS N/A INTENDED USE OF RESULTS The results of the study will be submitted to the College of Health Sciences as part of the requirements for completion of the degree of Masters of Medicine in Obstetrics and Gynaecology, and may be considered for publications to add to the current body of knowledge on the use of TXA.

Eligibility criteria: Inclusion Criteria:

* Pregnant woman with signed informed consent\*\*\*
* Understand English and/or Shona
* Estimated gestational age of 38 weeks or older
* Requiring Elective Caesarean Section defined as caesarean section performed before onset of labour
* Live intrauterine fetus

  * The study will enrol participants who are Pregnant and who have a signed informed Consent form. Some of the pregnant women may be minors as they are occasionally included in patients planned for elective caesarean section for varying indications. Their inclusion also will make the results of the trial generalizable to elective caesarean section patients attended to at the two study hospitals. Consent will be sought from a legally authorized representative such as the parent or guardian.

Exclusion Criteria:

* Placental Abruption
* Emergency caesarean section
* Current or previous history of significant disease including heart disease, liver, renal disorders
* Known coagulopathy or history of deep venous thrombosis and/or pulmonary embolism, or arterial thrombosis (angina pectoris, myocardial infarction, stroke)
* History of epilepsy or seizures
* Autoimmune disease
* Sickle cell disease
* Severe haemorrhagic disease
* Intrauterine fetal demise
* Eclampsia/HELLP syndrome
* Administration of anticoagulants - clexane or antiplatelet agents in the week prior to delivery

Primary outcomes:
measure: Number of Participants With Postpartum Haemorrhage (PPH)
timeFrame: Up to 48 hours post-caesarean section
Secondary outcomes:
measure: Estimated Blood Loss
timeFrame: At caesarean section
measure: Amount of Blood Transfused
timeFrame: At caesarean section up to 48 hours post-caesarean section
measure: Number of Participants With Use of Additional Uterotonics
timeFrame: At caesarean section up to 48 hours post-caesarean section
measure: Number of Participants With Tranexamic Acid Side Effects
timeFrame: From intravenous infusion of the drug up to 48 hours post-caesarean section
measure: Number of Participants Requiring Emergency Surgery for PPH
timeFrame: At caesarean section up to 48 hours post-caesarean section
measure: Number of Days of Participants' Hospital Stay
timeFrame: From date of randomization until the day 2 post-caesarean section (date of discharge from hospital) or date of death whichever comes earlier
measure: Neonatal Outcome - Weight
timeFrame: From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier
measure: Neonatal Outcome - APGAR Score of the Neonates at 1 Minute and 5 Minutes After Delivery
timeFrame: Scores at 1 minute from time of delivery and at 5 minutes after delivery
measure: Neonatal Outcome - Number of Neonates Admitted to the Neonatal Unit
timeFrame: From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier
measure: Neonatal Outcome - Number of Neonates Diagnosed With Jaundice
timeFrame: From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier
measure: Neonatal Outcome - Thromboembolic Event
timeFrame: From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier
measure: Neonatal Outcome - Death
timeFrame: From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier
Other outcomes:
Locations:
city: Harare
country: Zimbabwe
facility: Harare Central Hospital
city: Harare
country: Zimbabwe
facility: Parirenyatwa Group of Hospitals
Study officials:
affiliation: Professor of Obstetrics and Gynaecology
name: Tsungai Chipato, MBChB FRCOG
role: STUDY_CHAIR
affiliation: Lecturer and Consultant
name: Taazadza Nhemachena, MBChB MMED
role: STUDY_CHAIR
affiliation: Registrar
name: Chipo Gwanzura, MBChB
role: PRINCIPAL_INVESTIGATOR
References: