Therapeutic and pharmaco-biological, dose-ranging multicentre trial to determine the optimal dose of TRAnexamic acid to reduce blood loss in haemorrhagic CESarean delivery (TRACES): study protocol for a randomised, double-blind, placebo-controlled trial

Anne-Sophie Bouthors, Benjamin Hennart, Emmanuelle Jeanpierre, Anne-Sophie Baptiste, Imen Saidi, Elodie Simon, Damien Lannoy, Alain Duhamel, Delphine Allorge, Sophie Susen, Anne-Sophie Bouthors, Benjamin Hennart, Emmanuelle Jeanpierre, Anne-Sophie Baptiste, Imen Saidi, Elodie Simon, Damien Lannoy, Alain Duhamel, Delphine Allorge, Sophie Susen

Abstract

Background: Postpartum haemorrhage (PPH) is the leading cause of maternal death worldwide. Tranexamic acid (TA), an antifibrinolytic drug, reduces bleeding and transfusion need in major surgery and trauma. In ongoing PPH following vaginal delivery, a high dose of TA decreases PPH volume and duration, as well as maternal morbidity, while early fibrinolysis is inhibited. In a large international trial, a TA single dose reduced mortality due to bleeding but not the hysterectomy rate. TA therapeutic dosages vary from 2.5 to 100 mg/kg and seizures, visual disturbances and nausea are observed with the highest dosages. TA efficiency and optimal dosage in haemorrhagic caesarean section (CS) has not been yet determined. We hypothesise large variations in fibrinolytic activity during haemorrhagic caesarean section needing targeted TA doses for clinical and biological efficacy.

Methods/design: The current study proposal is a blinded, randomised controlled trial with the primary objective of determining superiority of either 1 g of TXA or 0.5 g of TXA, in comparison to placebo, in terms of 30% blood-loss reduction at 6 h after non-emergency haemorrhagic caesarean delivery (active PPH > 800 mL) and to correlate this clinical effect in a pharmacokinetics model with fibrinolysis inhibition measured by an innovative direct plasmin measurement regarding plasmatic TA concentration. A sample size of 342 subjects (114 per group) was calculated, based on the expected difference of 30% reduction of blood loss between the placebo group and the low-dose group, out of which 144 patients will be included blindly in the pharmaco-biological substudy. A non-haemorrhagic reference group will include 48 patients in order to give a reference for peak plasmin level.

Discussion: TRACES trial is expected to give the first pharmacokinetics data to determinate the optimal dose of tranexamic acid to reduce blood loss and inhibit fibrinolysis in hemorrhagic cesarean section.

Trial registration: ClinicalTrials.gov, ID: NCT02797119 . Registered on 13 June 2016.

Keywords: Caesarean section; D-dimers; Fibrinolysis; Pharmacokinetics; Plasmin; Postpartum haemorrhage; Tranexamic acid.

Conflict of interest statement

Ethics approval and consent to participate

The TRACES trial obtained approval from the competent national authorities (ANSM 201500249926) and the Ethics Committee (CPP 15/50 020216) before beginning the study, in accordance with article L1121-4 of the Public Healthcare Code. This trial has been declared on the clinical trials registration on 13 June 2016 under the number CT 02797119. Registration will be performed in accordance with decree dated 14 November 2006 about gathering data in the national register of individuals participating in biomedical research.

Consent for publication

Authors and sponsors have given their consent and defined the publication rules.

Competing interests

The authors declare that they have no competing interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Global view of the TRACES trial conception
Fig. 2
Fig. 2
Reduction of postpartum haemorrhage duration in the high-dose-tranexamic-acid-treated group vs the untreated control group
Fig. 3
Fig. 3
Inhibition of the natural hyperfibrinolysis by a high dose of tranexamic acid administered at the early stage of postpartum haemorrhage. ††p < 0.05. Panel a (circles) : hemorrhagic non treated group, Panel b (triangles): hemorrhagic TA treated group
Fig. 4
Fig. 4
Study design
Fig. 5
Fig. 5
Study protocol. CS caesarean section, ETP-EPP thrombin and plasmin generation potential in a well
Fig. 6
Fig. 6
Schedule of enrolment, interventions, and assessments adapted from the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure
Fig. 7
Fig. 7
Ancillary pharmaco-biological substudy flow chart

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