Postpartum Hemorrhage Reduction With Oral Tranexamic Acid: a Clinical Trial (PROTECT)

Postpartum Hemorrhage Reduction With Oral Tranexamic Acid (PROTECT): a Multicenter Randomized Controlled Trial

This is a multicentre randomized placebo-controlled double-blinded phase IV study among 1000 women in Sweden and South Africa on the effect of oral tranexamic acid on PPH after vaginal delivery. The main purpose of the study is to evaluate the effect of orally administered tranexamic acid (TA) compared to placebo on rate of postpartum hemorrhage (PPH) after vaginal birth. Participants will be randomized to receive either 20 ml (2g) of the investigational medicinal product (TA100mg/ml) or 20ml of a placebo solution during labor. Our main endpoint, assessed at 24 hours after delivery is PPH defined as blood loss >=500ml and assessed both by weight and pre-postpartum hemoglobin (Hb) decrease >10 units difference in vaginal deliveries

Study Overview

• Status: Recruiting
• Conditions: PPH
• Intervention / Treatment: Drug: Tranexamic acid

Detailed Description

Background Severe PPH is the leading cause of maternal death worldwide especially in developing countries. Preventing PPH before onset is of key importance because once bleeding starts it is difficult to control.Tranexamic acid (TA) is a well-established medication for treatment and prevention of heavy bleeding. Oral forms of TA are available over the counter in many settings. The effect of oral treatment in vaginal deliveries has however been little studied and is a stated research priority by the WHO. Oral TA is low-cost, stable at room temperature and easy to administer which makes it especially applicable to both low resource delivery settings and home- births.To prevent PPH, a therapeutic serum concentration of TA should coincide with the period immediately after delivery of the child, when the risk of PPH is greatest, meaning that TA should optimally be administered during the latter part of active labor.

The premises of the RCT are the following:

1. The effect of oral prophylactic TA on rate of PPH is insufficiently known
2. If oral TA is effective in preventing PPH, routine administration could reduce maternal morbidity significantly at low expense.

Methods Study population and inclusion criteria The study will include 1000 women planned for vaginal delivery at three study sites in Sweden (n=500) and two study sites in South Africa (n=500) during the period September 2023 to December 2026. Enrolled women will be ≥18 years, ≥36 gestational weeks, and planned for vaginal delivery. Women with known bleeding disorders, known allergy to TA, ongoing treatment for venous thrombosis, or inability to make an informed consent will be ineligible.

Setting and duration: The study will take place between September 2023 and December 2026 at three study sites in Sweden as well as Mowbray Maternity Hospital and Khayelitsha District Hospital in South Africa.

Recruitment and randomization We will recruit women during a routine or planned antenatal visit after 35 gestational weeks, or after admission to the delivery ward during the latency phase of labor or the early stages of labor.

Randomization will occur after a woman has been admitted to the labor ward with spontaneous onset of labor. Participants will be randomized to receive either 20 ml of the investigational medicinal product (TA) or 20ml of a placebo solution. The randomization sequence will be computer-generated by KTA (Karolinska Clinical Trial Alliance) and flasks with the IMP/placebo will be marked according to this sequence. Randomization will be 1:1 in permuted blocks of 10 to allow for block-sized deliveries to study sites. The placebo will be developed and manufactured by Apotek Produktion och Laboratorier (APL), Sweden, who will also supply the TA. Placebo and IMP flasks, in their randomization sequence will be transported in a temperature-validated delivery to a central laboratory in Cape Town through World Courier who specialises in research related distributions.

Intervention Our intervention consists of the oral self-intake of either 20 ml (2g) of oral solution of TA, 20 ml of placebo equivalent in appearance, odor and taste to the IMP, when the cervix is fully dilated.

Primary endpoints Weight-estimated rate of PPH (≥500ml)

Secondary endpoints Pre-postpartum Hb difference (g/L) ≥10 units Weight-estimated rate of severe PPH (≥1000ml) Mean blood loss (ml) Mean pre-postpartum Hb decrease (units Rate of blood transfusion (%) Feasibility (adherence to protocol) Acceptability of the treatment among participants and providers Thromboembolism up to 6 weeks postpartum

Study procedures Participants will experience three study procedures that would not necessarily occur had they not taken part in the study but all of which form part of routine care.

1. A blood sample (hemoglobin, EVF, MCV, MCH, MCHC, LPC, TPC) taken at admission
2. The oral intake of 20 ml IMP/placebo at full cervical dilatation
3. Weighing of total blood loss (which is routine in many delivery settings)
4. A blood sample including (hemoglobin, EVF, MCV, MCH, MCHC, LPC, TPC) taken after 24 hours (or prior to discharge should discharge occur before 24 hours)

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Helena Paul; Email: helena.paul@regionstockholm.se
• Study Contact Backup: Name: Margit Endler, MD PhD; Phone Number: 0706747227; Email: margit.endler@ki.se

Study Locations

• Sweden
  • Stockholm, Sweden, 118 83
    • Recruiting
    • Södersjukhuset (South General Hospital)
    • Contact: Gita Strindfors; Email: gita.strindfors@regionstockholm.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Enrolled women will be ≥18 years, ≥36 gestational weeks, and planned for vaginal delivery. Women with known bleeding disorders, known allergy to TA, ongoing treatment for venous thrombosis, or inability to make an informed consent will be ineligible.

Exclusion Criteria:

Opposite of above

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tranexamic acid; Will receive 20ml of tranexamic acid 100mg/ml at a timepoint when the cervix is dilated 6 cn (for multipara) and 8 cm for primipara	Drug: Tranexamic acid; 20 ml of oral solution TA (100mg/ml); Other Names: Cyklokapron
Placebo Comparator: Placebo; Will receive 20ml of placebo solution, equivalent in appearance and taste to tranexamic acid solution but with no active ingredient, at a timepoint when the cervix is dilated 6 cn (for multipara) and 8 cm for primipara	Drug: Tranexamic acid; 20 ml of oral solution TA (100mg/ml); Other Names: Cyklokapron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PPH	Proportion of participants with weight-assessed blood loss after delivery >/= 500ml	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe PPH	Proportion of participants with blood loss after delivery >/= 1000ml	24 hours
Blood transfusion	Proportion of participants receiving blood transfusion after vaginal birth	72 hours
Mean blood loss	Mean blood loss after vaginal delivery (ml) among participants	24 hours
Mean pre-post partal hemoglobin	Mean pre-post partal hemoglobin difference (units) among participants	24 hours
Pre-post partal hemoglobin	Pre-post partal hemoglobin >/= 10 units among participants	24 hours
Thromboembolism	Proportion of participants with thromboembolic event postpartum	6 weeks after delivery
Feasibility of intervention	Proportion of participants taking TXA/placebo according to protocol	As specified in protocol
Acceptability for participants	Rate of no to minor discomfort upon administration of intervention (acceptability) among participants	Delivery and 24 hours after delivery
Acceptability for providers	Rate of no to minor disruption caused by administration of intervention (acceptability) experienced by providers	Delivery and 24 hours after delivery

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: University of Cape Town; Stockholm South General Hospital
• Investigators: Principal Investigator: Margit Endler, MD PhD, Associate Professor, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: August 29, 2023
• First Submitted That Met QC Criteria: August 29, 2023
• First Posted (Actual): September 6, 2023

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Pregnancy Complications; Obstetric Labor Complications; Puerperal Disorders; Uterine Hemorrhage; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hemorrhage; Postpartum Hemorrhage; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: 2022-00327

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Anonymized research data will be made available upon reasonable request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No