Clinical trial NCT02797119: Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery
Official title: Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery: a Multicenter Randomized Double Blind Placebo Controlled Therapeutic and Pharmaco-biological Dose Ranging Study (TRACES) for Its Optimal Benefit/Risk
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Pregnancy Complications
Hemorrhage
Keywords: Tranexamic acid
Fibrinolysis
Cesarean section
Pharmacokinetics
D dimers
Fibrinogen
Plasmin
Transfusion
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
name: French Health Products Safety Agency
First posted: 2016-06-13
Enrollment: 225
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Bleeding
timeFrame: between inclusion (T0) and 6 hours after inclusion (T360).
Secondary outcomes:
measure: Postpartum anemia
timeFrame: at day 2, at day 5
measure: Postpartum blood loss
timeFrame: at Day 2
measure: number of patients presenting with maternal morbidity ie haemostatic interventions and organ failure and ICU admission
timeFrame: At day 5, At day 42
measure: Death
timeFrame: at day 42
measure: Biological fibrinolysis inhibition
timeFrame: Between T0 (inclusion) and T360 (6hours later)
measure: Urinary urea and Creatinuria on timed diuresis
timeFrame: Between T0 (inclusion) and T360 (6hours later)
measure: the number of patients developing an oliguria or a renal failure (RIFLE score more than 2)
timeFrame: Between T0 (inclusion) and T360 (6hours later)
measure: Deep vein thrombosis or pulmonary embolism
timeFrame: Between T0 (inclusion) and Day 42
measure: Seizures
timeFrame: Between T0 (inclusion) and Day 42
measure: Visual disturbances
timeFrame: Between T0 (inclusion) and Day 42
measure: Nausea
timeFrame: Between T0 (inclusion) and Day 42
measure: Peak Plasma Concentration (Cmax) in venous blood
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Area under the plasma concentration versus time curve (AUC) in venous blood
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Lagtime between thrombin and plasmin peaks (s) in venous blood
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Peak Plasma Concentration (Cmax) in uterine bleeding
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Area under the plasma concentration versus time curve (AUC) in uterine bleeding
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Lagtime between thrombin and plasmin peaks (s) in uterine bleeding
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Tranexamic acid plasma concentration
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Tranexamic acid concentration in uterine bleeding
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
measure: Tranexamic acid urinary excretion
timeFrame: Between T0 (inclusion) and T360 (6hours after inclusion)
Other outcomes:
Locations:
city: Lille
country: France
facility: Hôpital Jeanne de Flandre - CHRU de Lille
city: Lyon
country: France
facility: Hospices civils de Lyon CHU-Lyon Croix Rousse
city: Paris
country: France
facility: Assistance Publique Hôpitaux Paris Hôpital Louis Mourier
city: Paris
country: France
facility: Assistance Publique Hôpitaux Paris Hôpital Trousseau
city: Valenciennes
country: France
facility: Centre Hospitalier Maternité Monaco Valenciennes
Study officials:
affiliation: University Hospital, Lille
name: Anne-Sophie Ducloy-Bouthors, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.