Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery
Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Caesarean Delivery
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.
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.
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