Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery

Hemorrhage Clinical Trial

— TRACES  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02797119
• Other study ID #: 2015_13
• Secondary ID: 2015-002499-26PH
• Status: Terminated
• Phase: Phase 4
• Start date: March 15, 2016
• Est. completion date: April 15, 2021

Study information

• Verified date: June 2022
• Source: University Hospital, Lille
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 225
• Est. completion date: April 15, 2021
• Est. primary completion date: April 15, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Hemorrhage
• Pregnancy Complications

Intervention

Drug:
• tranexamic acid 1 g (TA1)
1 g standard dose tranexamic acid, intravenous unique bolus over 1 minute
• tranexamic acid 0.5 g (TA1/2)
0.5 g standard dose tranexamic acid, intravenous unique bolus over 1 minute
• Saline Solution (TA0)

Locations

Country	Name	City	State
France	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

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Lille	French Health Products Safety Agency, Ministry of Health, France

Country where clinical trial is conducted

France, 

References & Publications (5)

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

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 haemorrhag — View 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/s40262-013-0 — View 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 congenit — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Postpartum anemia		at day 2, at day 5
Secondary	Postpartum blood loss		at Day 2
Secondary	number of patients presenting with maternal morbidity ie haemostatic interventions and organ failure and ICU admission		At day 5, At day 42
Secondary	Death		at day 42
Secondary	Biological fibrinolysis inhibition	Percentage of patients for which D Dimers increase is blunted.	Between T0 (inclusion) and T360 (6hours later)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	Seizures	Number of patient developing a seizure clinically diagnosed	Between T0 (inclusion) and Day 42
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)