Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery

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

Sponsors

Lead Sponsor: University Hospital, Lille

Collaborator: Ministry of Health, France
French Health Products Safety Agency

Source University Hospital, Lille
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.

Overall Status Recruiting
Start Date March 2016
Completion Date September 2021
Primary Completion Date September 2021
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
Bleeding between inclusion (T0) and 6 hours after inclusion (T360).
Secondary Outcome
Measure Time Frame
Postpartum anemia at day 2, at day 5
Postpartum blood loss at Day 2
number of patients presenting with maternal morbidity ie haemostatic interventions and organ failure and ICU admission At day 5, At day 42
Death at day 42
Biological fibrinolysis inhibition Between T0 (inclusion) and T360 (6hours later)
Urinary urea and Creatinuria on timed diuresis Between T0 (inclusion) and T360 (6hours later)
the number of patients developing an oliguria or a renal failure (RIFLE score more than 2) Between T0 (inclusion) and T360 (6hours later)
Deep vein thrombosis or pulmonary embolism Between T0 (inclusion) and Day 42
Seizures Between T0 (inclusion) and Day 42
Visual disturbances Between T0 (inclusion) and Day 42
Nausea Between T0 (inclusion) and Day 42
Peak Plasma Concentration (Cmax) in venous blood Between T0 (inclusion) and T360 (6hours after inclusion)
Area under the plasma concentration versus time curve (AUC) in venous blood Between T0 (inclusion) and T360 (6hours after inclusion)
Lagtime between thrombin and plasmin peaks (s) in venous blood Between T0 (inclusion) and T360 (6hours after inclusion)
Peak Plasma Concentration (Cmax) in uterine bleeding Between T0 (inclusion) and T360 (6hours after inclusion)
Area under the plasma concentration versus time curve (AUC) in uterine bleeding Between T0 (inclusion) and T360 (6hours after inclusion)
Lagtime between thrombin and plasmin peaks (s) in uterine bleeding Between T0 (inclusion) and T360 (6hours after inclusion)
Tranexamic acid plasma concentration Between T0 (inclusion) and T360 (6hours after inclusion)
Tranexamic acid concentration in uterine bleeding Between T0 (inclusion) and T360 (6hours after inclusion)
Tranexamic acid urinary excretion Between T0 (inclusion) and T360 (6hours after inclusion)
Enrollment 390
Condition
Intervention

Intervention Type: Drug

Intervention Name: tranexamic acid 1 g (TA1)

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

Arm Group Label: tranexamic acid 1 g (TA1)

Intervention Type: Drug

Intervention Name: tranexamic acid 0.5 g (TA1/2)

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

Arm Group Label: tranexamic acid 0.5 g (TA1/2)

Intervention Type: Drug

Intervention Name: Saline Solution (TA0)

Arm Group Label: Saline Solution (TA0)

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

Gender: Female

Gender Based: Yes

Minimum Age: 18 Years

Maximum Age: 60 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Anne-Sophie Ducloy-Bouthors, MD Principal Investigator University Hospital, Lille
Overall Contact

Last Name: Anne-Sophie Ducloy-Bouthors, MD

Email: [email protected]

Location
Facility: Status: Contact: Investigator:
Hôpital Jeanne de Flandre - CHRU de Lille | Lille, France Recruiting Anne-Sophie Ducloy-Bouthors, MD [email protected] Alexandre Turbelin, MD Principal Investigator
Hospices civils de Lyon CHU-Lyon Croix Rousse | Lyon, France Not yet recruiting Françoise Broisin, MD Principal Investigator
Assistance Publique Hôpitaux Paris Hôpital Louis Mourier | Paris, France Recruiting Hawa Keita-Meyer, MD Principal Investigator
Assistance Publique Hôpitaux Paris Hôpital Trousseau | Paris, France Recruiting Agnès Rigouzzo, MD Principal Investigator
Centre Hospitalier Maternité Monaco Valenciennes | Valenciennes, France Recruiting Laurent Chonow, MD Principal Investigator
Location Countries

France

Verification Date

September 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 4
Arm Group

Label: tranexamic acid 1 g (TA1)

Type: Experimental

Description: 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

Label: tranexamic acid 0.5 g (TA1/2)

Type: Experimental

Description: 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

Label: Saline Solution (TA0)

Type: Placebo Comparator

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

Label: NH

Type: No Intervention

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

Acronym TRACES
Patient Data Undecided
Study Design Info

Allocation: Randomized

Intervention Model: Factorial Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov