Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pregnancy Complications, Hemorrhage

Intervention / Treatment
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* Drug: tranexamic acid 1 g (TA1)
* Drug: tranexamic acid 0.5 g (TA1/2)
* Drug: Saline Solution (TA0)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tranexamic acid 1 g (TA1)<br>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 | Drug: tranexamic acid 1 g (TA1)<br>* 1 g standard dose tranexamic acid, intravenous unique bolus over 1 minute<br>|
| Experimental: tranexamic acid 0.5 g (TA1/2)<br>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 | Drug: tranexamic acid 0.5 g (TA1/2)<br>* 0.5 g standard dose tranexamic acid, intravenous unique bolus over 1 minute<br>|
| Placebo Comparator: Saline Solution (TA0)<br>To measure the evolution of blood loss without TA in ongoing hemorrhagic cesarean section To correlate this clinical evolution with fibrinolysis. | Drug: Saline Solution (TA0)<br> <br> |
| No Intervention: NH<br>To measure the reference fibrinolytic activity in non-hemorrhagic cesarean section | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding | Bleeding will be strictly measured (mL) in aspiration or cell salvage bags (substraction of the amniotic fluid if needed) and drapes weighting at each time point. | between inclusion (T0) and 6 hours after inclusion (T360). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | Percentage of patients for which D Dimers increase is blunted. | Between T0 (inclusion) and T360 (6hours later) | 
| Urinary urea and Creatinuria on timed diuresis | Urinary Urea (g/L) and creatinuria (mg/L) are measured on a timed urinary sample : collected from the bladder catheter, initial diuresis at the beginning of CS is thrown out at the time of inclusion. A strict measure of urinary volume is made at T120, a sample of one monovette of urines is done to get the concentration of urea, creatinuria and tranexamic acid and their ratio and then thrown out. The same process is done on the urinary volume collected between T120 and T360. | Between T0 (inclusion) and T360 (6hours later) | 
| the number of patients developing an oliguria or a renal failure (RIFLE score more than 2) | Diuresis is measured on a timed urinary sample : collected from the bladder catheter, initial diuresis at the beginning of CS is thrown out at the time of inclusion. A strict measure of urinary volume is made at T120 and T360. Oliguria is defined as a diuresis less than 180mL per 6 hours. Urea (g/L) and creatininemia (mg/L) are measured at T0 inclusion and T360, 6 hours later. the number of patients developping an oliguria or a renal failure (RIFLE score more than 2) is collected. | Between T0 (inclusion) and T360 (6hours later) | 
| Deep vein thrombosis or pulmonary embolism | Number of patient developing a deep vein thrombosis or pulmonary embolism clinically diagnosed and confirmed by echodoppler for DVT and angiosccanner for PE. Data collected from the clinical follow up since hospital discharge and a phone call at D42 +/- 10 days | Between T0 (inclusion) and Day 42 | 
| Seizures | Number of patient developing a seizure clinically diagnosed | Between T0 (inclusion) and Day 42 | 
| Visual disturbances | Number of patient developing a colours' visual disturbance clinically diagnosed. Data collected from the clinical follow up since hospital discharge and a phone call at D42 +/- 10 days. | Between T0 (inclusion) and Day 42 | 
| Nausea | Number of patient developing nausea clinically diagnosed and needing a treatment. Data collected from the clinical follow up since hospital discharge and a phone call at D42 +/- 10 days. | Between T0 (inclusion) and Day 42 | 
| Peak Plasma Concentration (Cmax) in venous blood | Venous blood sampled on a dedicated catheter. Biological assessment using Van Geffen method for thrombin and plasmin direct measurement in a weill. Plasmin inhibition. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Area under the plasma concentration versus time curve (AUC) in venous blood | Venous blood sampled on a dedicated catheter. Biological assessment using Van Geffen method for thrombin and plasmin direct measurement in a weill. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Lagtime between thrombin and plasmin peaks (s) in venous blood | Venous blood sampled on a dedicated catheter. Biological assessment using Van Geffen method for thrombin and plasmin direct measurement in a weill. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Peak Plasma Concentration (Cmax) in uterine bleeding | Uterine bleeding sampled by obstetrician in placental bed and after hysterotomy is closed, collected vaginally. Biological assessment using Van Geffen method for thrombin and plasmin direct measurement in a weill. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Area under the plasma concentration versus time curve (AUC) in uterine bleeding | Uterine bleeding sampled by obstetrician in placental bed and after hysterotomy is closed, collected vaginally. Biological assessment using Van Geffen method for thrombin and plasmin direct measurement in a weill. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Lagtime between thrombin and plasmin peaks (s) in uterine bleeding | Uterine bleeding sampled by obstetrician in placental bed and after hysterotomy is closed, collected vaginally. Biological assessment using Van Geffen method for thrombin and plasmin direct measurement in a weill. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Tranexamic acid plasma concentration | Venous blood sampled on a dedicated catheter. Biological assessment using direct plasma drug concentration (mg/L) measurement. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Tranexamic acid concentration in uterine bleeding | Uterine bleeding sampled by obstetrician in placental bed and after hysterotomy is closed, collected vaginally. Biological assessment using direct plasma drug concentration (mg/L) measurement. | Between T0 (inclusion) and T360 (6hours after inclusion) | 
| Tranexamic acid urinary excretion | Tranexamic acid concentration (mg/L) is measured parallely to urinary urea (g/L) and creatinuria (mg/L) on a timed urinary sample : collected from the bladder catheter, initial diuresis at the beginning of CS is thrown out at the time of inclusion. A strict measure of urinary volume is made at T120, a sample of one monovette of urines is done to get the concentration of urea, creatinuria and tranexamic acid and their ratio and then thrown out. The same process is done on the urinary volume collected between T120 and T360. | Between T0 (inclusion) and T360 (6hours after inclusion) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tranexamic acid, Fibrinolysis, Cesarean section, Pharmacokinetics, D dimers, Fibrinogen, Plasmin, Transfusion