Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery

NCT ID: NCT02797119

Last Updated: 2022-06-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 225 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-15
• Study Completion Date: 2021-04-15

Brief Summary

TRACES trial is a multicenter randomized double blind placebo control therapeutic and pharmaco-biological dose ranging study to measure the effect on blood loss reduction of a single intravenous infusion of two doses regimens (standard dose and low dose) of TA administered at the onset of an active PPH (>800mL) during elective or non-emergent CS and to correlate this clinical effect with the biological effect of fibrinolysis inhibition and the pharmacodynamic measure of TA uterine bleeding and venous blood concentration.

Detailed Description

Postpartum hemorrhage (PPH) is the leading cause of maternal death. Tranexamic acid (TA) (Exacyl® Sanofi France), an antifibrinolytic drug, reduces bleeding and transfusion need in major surgery and trauma (1). In ongoing PPH following vaginal delivery (2), a high dose of TA decreased the volume and duration of PPH, the transfusion need and the maternal morbidity, while early fibrinolysis was inhibited (3). Prophylactic use of TA limited the postoperative bleeding in elective non hemorrhagic caesarean section (CS). (1, 4) TA efficiency in the hemorrhagic caesarean context has not been previously published.

TA doses range vary from 2,5 to 100 mg/kg and side effects were observed with the largest doses.(1,4) Pharmacokinetics old data concerned non hemorrhagic patients.(1) WOMAN ongoing international trial using a one gram dose have a mortality reduction objective.(5) The optimal dose for ongoing caesarean PPH has to be determined.

Aim of the study:

The aim of the multicenter randomized double blind placebo control therapeutic and pharmaco-biological dose ranging study TRACES is to measure the effect on blood loss reduction of a single intravenous infusion of two doses regimens of TA administered at the onset of an active PPH (>800mL) during elective or non-emergent CS and to correlate this clinical effect with the biological effect of fibrinolysis inhibition and the pharmacodynamic measure of TA uterine bleeding and venous blood concentration.

Statistical method:

The sample size computation is based on the expected difference between the placebo group and the low dose. On the base of EXADELI trial results, the investigators calculated that a total of 342 subjects (114 per group) is required, For the main objective, the blood loss volume measured in each experimental group (low dose and high dose) will be compared to that of the placebo group by using an analysis of covariance adjusted for baseline blood loss volume. In cases of non-normal distribution, relative blood loss volume will be calculated and compared using a Mann-Whitney U test. Analyses will be done on an intention-to-treat basis and all statistical tests will be performed with a 2-tailed alpha risk of 0.05. The sample size computation for the pharmaco-biological substudy have been calculated regarding the inhibition of fibrinolysis (D Dimers increase between 30 and 120 minutes negative or null (EXADELI trial 11)). The NNS for this substudy is 48 patients in each of the 3 hemorrhagic groups and 48 patients in the reference non-hemorrhagic group for a total of 192 patients. These substudy hemorrhagic patients will be selected from the experimental groups as the first 144 patients for which the TA concentration and plasmin peak specific sampling will be completed regarding the blood collection and congelation organisation in each center.

Expected research benefit:

The project is aimed to answer for a current clinical practice question: Timing and dose of TA to reduce blood loss and maternal morbidity due to active hemorrhage during CS in order to determine the optimal and minimal TA dose to obtain the better efficacy and the limitations of side-effects.

Conditions

Pregnancy Complications; Hemorrhage

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

tranexamic acid 1 g (TA1)

To measure the efficacy of a standard 1g dose TA to reduce blood loss in ongoing hemorrhagic cesarean section.

To correlate this clinical effect with the fibrinolysis inhibition and the TA venous and uterine blood concentration

Group Type: EXPERIMENTAL

tranexamic acid 1 g (TA1)

Intervention Type: DRUG

1 g standard dose tranexamic acid, intravenous unique bolus over 1 minute

tranexamic acid 0.5 g (TA1/2)

To measure the efficacy of a low 0,5g dose TA to reduce blood loss in ongoing hemorrhagic cesarean section To correlate this clinical effect with the fibrinolysis inhibition and the TA venous and uterine blood concentration

Group Type: EXPERIMENTAL

tranexamic acid 0.5 g (TA1/2)

Intervention Type: DRUG

0.5 g standard dose tranexamic acid, intravenous unique bolus over 1 minute

Saline Solution (TA0)

To measure the evolution of blood loss without TA in ongoing hemorrhagic cesarean section To correlate this clinical evolution with fibrinolysis.

Group Type: PLACEBO_COMPARATOR

Saline Solution (TA0)

Intervention Type: DRUG

NH

To measure the reference fibrinolytic activity in non-hemorrhagic cesarean section

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

tranexamic acid 1 g (TA1)

1 g standard dose tranexamic acid, intravenous unique bolus over 1 minute

Intervention Type: DRUG

tranexamic acid 0.5 g (TA1/2)

0.5 g standard dose tranexamic acid, intravenous unique bolus over 1 minute

Intervention Type: DRUG

Saline Solution (TA0)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Experimental group: Each patient

• experiencing a bleeding volume of more than 800 mL
• due to surgery or to atony uterine
• during an elective or non-emergent caesarean section
• secondary post-partum haemorrhage after caesarean section, even if CS has been emergent
• after complete information and consent signature.
• covered by social security. Reference non-hemorrhagic group: Each patient
• experiencing a bleeding volume of strictly less than 800 mL
• during an elective or emergent caesarean section
• after complete information and consent signature.
• covered by social security.

Exclusion Criteria

Patient unable to consent (<18 years old or incapable people and specially protected mentioned in the article L1121-5 to L1121-8) RCP medical contraindication to tranexamic acid such as

• Hypersensibility to the product or excipient,
• Previous or ongoing arterial or venous thrombosis,
• Coagulopathy, except DIC associated with a predominant fibrinolytic profile,
• Renal failure,
• Previous seizures,
• intrathecal or intraventricular administration. Obstetrical contraindication to TA
• Severe HELLP syndrome (platelet count <50 000/m3 or renal failure prior to the caesarean (RIFLE score>2) Protocol related contraindication to inclusion
• Administration of TA before inclusion-Inherited haemorrhagic diseases and low molecular weight heparin within 24 hours before inclusion
• Patients who participated in a study on the efficacy of an experimental drug in the two month preceding the caesarean section
• Inherited haemorrhagic diseases or low molecular weight heparin within 24 hours before inclusion
• Previous inclusion in an interventional trial since the 2 months before CS

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Ministry of Health, France

OTHER_GOV

Sponsor Role: collaborator

French Health Products Safety Agency

OTHER_GOV

Sponsor Role: collaborator

University Hospital, Lille

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anne-Sophie Ducloy-Bouthors, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Lille

Locations

Hôpital Jeanne de Flandre - CHRU de Lille

Lille, , France

Hospices civils de Lyon CHU-Lyon Croix Rousse

Lyon, , France

Assistance Publique Hôpitaux Paris Hôpital Louis Mourier

Paris, , France

Assistance Publique Hôpitaux Paris Hôpital Trousseau

Paris, , France

Centre Hospitalier Maternité Monaco Valenciennes

Valenciennes, , France

Countries

France

References

van Geffen M, Loof A, Lap P, Boezeman J, Laros-van Gorkom BA, Brons P, Verbruggen B, van Kraaij M, van Heerde WL. A novel hemostasis assay for the simultaneous measurement of coagulation and fibrinolysis. Hematology. 2011 Nov;16(6):327-36. doi: 10.1179/102453311X13085644680348.

Reference Type: BACKGROUND

PMID: 22183066 (View on PubMed)

Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-Meyer H, Mandelbrot L, Tillouche N, Fontaine S, Le Goueff F, Depret-Mosser S, Vallet B; EXADELI Study Group; Susen S. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care. 2011;15(2):R117. doi: 10.1186/cc10143. Epub 2011 Apr 15.

Reference Type: RESULT

PMID: 21496253 (View on PubMed)

Anne-Sophie Ducloy-Bouthors, Alain Duhamel, Antoine Tournoys, Annabelle, Gisele Debize, Edith Peneau, Brigitte Jude, Benoit Vallet, Dominique De Prost, Cyril Huissoud, Sophie Susen., Hyperfibrinolysis and post-partum haemorrhage induced coagulopathy. 2013, Thrombosis research Volume 131, Supplement S88-89. Accepted BJA-2014-00923.

Reference Type: RESULT

Goobie SM, Meier PM, Sethna NF, Soriano SG, Zurakowski D, Samant S, Pereira LM. Population pharmacokinetics of tranexamic acid in paediatric patients undergoing craniosynostosis surgery. Clin Pharmacokinet. 2013 Apr;52(4):267-76. doi: 10.1007/s40262-013-0033-1.

Reference Type: RESULT

PMID: 23371895 (View on PubMed)

Rozen L, Faraoni D, Sanchez Torres C, Willems A, Noubouossie DC, Barglazan D, Van der Linden P, Demulder A. Effective tranexamic acid concentration for 95% inhibition of tissue-type plasminogen activator induced hyperfibrinolysis in children with congenital heart disease: A prospective, controlled, in-vitro study. Eur J Anaesthesiol. 2015 Dec;32(12):844-50. doi: 10.1097/EJA.0000000000000316.

Reference Type: RESULT

PMID: 26258658 (View on PubMed)

Ducloy-Bouthors AS, Gilliot S, Kyheng M, Faraoni D, Turbelin A, Keita-Meyer H, Rigouzzo A, Moyanotidou G, Constant B, Broisin F, Gouez AL, Favier R, Peynaud E, Ghesquiere L, Lebuffe G, Duhamel A, Allorge D, Susen S, Hennart B, Jeanpierre E, Odou P; TRACES working group. Tranexamic acid dose-response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study. Br J Anaesth. 2022 Dec;129(6):937-945. doi: 10.1016/j.bja.2022.08.033. Epub 2022 Oct 13.

Reference Type: DERIVED

PMID: 36243576 (View on PubMed)

Ducloy-Bouthors AS, Jeanpierre E, Saidi I, Baptiste AS, Simon E, Lannoy D, Duhamel A, Allorge D, Susen S, Hennart B. TRAnexamic acid in hemorrhagic CESarean section (TRACES) randomized placebo controlled dose-ranging pharmacobiological ancillary trial: study protocol for a randomized controlled trial. Trials. 2018 Mar 1;19(1):149. doi: 10.1186/s13063-017-2421-6.

Reference Type: DERIVED

PMID: 29490690 (View on PubMed)

Bouthors AS, Hennart B, Jeanpierre E, Baptiste AS, Saidi I, Simon E, Lannoy D, Duhamel A, Allorge D, Susen S. 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. Trials. 2018 Mar 1;19(1):148. doi: 10.1186/s13063-017-2420-7.

Reference Type: DERIVED

PMID: 29490682 (View on PubMed)

Other Identifiers

2015-002499-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PHRC_2014_0032

Identifier Type: OTHER

Identifier Source: secondary_id

2015_13

Identifier Type: -

Identifier Source: org_study_id