Clinical trial NCT02302456: Tranexamic Acid for Preventing Postpartum Haemorrhage Following a Vaginal Delivery
Official title: Tranexamic Acid for Preventing Postpartum Haemorrhage Following a Vaginal Delivery: a Multicenter Randomised Double Blind Placebo Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Immediate Postpartum Hemorrhage
Keywords: Immediate postpartum hemorrhage
tranexamic acid
prevention
Lead sponsor: University Hospital, Angers
Sponsor class: OTHER_GOV
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2014-11-27
Enrollment: 4079
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to assess whether the administration of a low dose of tranexamic acid just after vaginal delivery can reduce the incidence of immediate postpartum hemorrhage, in women who receive a prophylactic administration of oxytocin.

Detailed description: Postpartum hemorrhage (PPH) is a major cause of maternal mortality, accounting for one quarter of all maternal deaths worldwide. Its incidence estimates in the literature vary widely, from 3% to 15% of deliveries. Uterotonics after birth are the only intervention that has been shown to be effective for PPH prevention. Tranexamic acid (TXA), an antifibrinolytic agent, has therefore been investigated as a potentially useful complement to uterotonics for prevention because it has been proved to reduce blood loss in elective surgery, bleeding in trauma patients, and menstrual blood loss. Randomized controlled trials for PPH prevention after cesarean (n=10) and vaginal (n=2) deliveries showed that women who had received TXA had a significantly lesser amount of postpartum blood loss without any increase in severe maternal adverse effect. However, overall, the quality of these trials was poor, and they were not designed to test the effect of TXA on the reduction of PPH incidence, nor on the incidence of rare but severe adverse effects. Large, adequately powered multicenter randomized controlled trials are required before the widespread use of TXA for preventing PPH can be recommended.

The investigators propose a multicentre randomised, double-blind, placebo-controlled trial, with two parallel groups.

Individual information on the trial will be provided to women in late pregnancy during prenatal visits. This information will be repeated when the women arrive in the delivery room; the women then will confirm their participation and provide informed written consent before delivery, when, in the opinion of the investigator, the woman is likely to have a vaginal delivery with a minimum of 4 cm of cervix dilatation.

The intervention will be the intravenous administration of a 10-ml blinded ampoule of the study drug (either 1g TXA or placebo according to the randomisation order), slowly (over 30-60 seconds), within 2 minutes after birth and prophylactic oxytocin administration, and once the cord has been clamped.

All other aspects of management of the third stage will be identical in both arms:

* Routine prophylactic intravenous injection of 5 IU oxytocin at delivery of the anterior shoulder or within 2 minutes after birth
* Placement of a graduated (100 mL graduation) collector bag just after birth, left in place until the birth attendant judges that bleeding has stopped, and always at least for 15 minutes. When a woman is included in the trial, a bag will be prepared and ready to be put in place as soon as the baby is born and placed on the mother's belly; if needed, a second staff person will be present to help in managing both the baby and the bag. This will make it possible to collect and measure vaginal blood loss objectively during the immediate postpartum.
* Manual removal of the placenta at 30 minutes after birth if not expelled in absence of bleeding.
* Rapid suturing of the episiotomy, in accordance with good clinical practices
* Systematic use of uterotonic drugs after third stage of labor is not recommended.
* Controlled cord traction (CCT) will be left at the discretion of the practitioner.

If PPH occurs, standardised management will be provided according to the department's protocol. In particular, the use of TXA for the treatment of PPH will be allowed and left at the discretion of the practitioner according to the department's protocol.

The duration of the participation of each patient included in the trial will be from inclusion through 3 months postpartum.

The planned total duration of the trial will be 34 months including 23 months of patient inclusion

Eligibility criteria: Inclusion Criteria:

* Age≥ 18 years
* Planned vaginal delivery
* Term ≥ 35 weeks of gestation
* Singleton pregnancy
* Informed consent form signed

Exclusion Criteria:

* History of venous (deep vein thrombosis and/or pulmonary embolism) or arterial (angina pectoris, myocardial infarction, stroke) thrombosis.
* History of epilepsy or seizure
* Any known cardiovascular, renal, liver disorders
* Auto-immune disease
* Sickle cell disease
* Severe hemorrhagic disease
* Placenta previa
* Abnormally invasive placenta (placenta accreta/increta/percreta)
* Abruptio placentae
* Eclampsia; hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome
* Multiple pregnancy
* In utero foetal death
* Administration of Low-Molecular-Weight Heparin or antiplatelet agents seven days before delivery
* Poor understanding of the French language

Primary outcomes:
measure: Incidence of PPH
timeFrame: 24 hours after birth
Secondary outcomes:
measure: Mean blood loss at 15 minutes after birth
timeFrame: 15 minutes after birth
measure: Mean total blood loss
timeFrame: Up to 24 hours after birth
measure: Incidence of severe PPH
timeFrame: 24 hours after birth
measure: Need for supplementary uterotonic treatment
timeFrame: 24 hours after birth
measure: Postpartum transfusion
timeFrame: Duration of postpartum hospital stay, an expected average of 3 days
measure: Need for invasive second-line procedures for PPH
timeFrame: Duration of postpartum hospital stay, an expected average of 3 days
measure: Hemoglobin peripartum delta
timeFrame: 2 days postpartum
measure: Hematocrit peripartum delta
timeFrame: 2 days postpartum
measure: Hemodynamic tolerance
timeFrame: 15, 30, 45, 60 and 120 minutes after delivery
measure: Mild adverse effects
timeFrame: Stay in labor ward, an expected average of 2 hours
measure: Tolerance lab tests
timeFrame: Day 2 postpartum
measure: Severe adverse effects
timeFrame: Up to 12 weeks after delivery
Other outcomes:
measure: Women's satisfaction
timeFrame: Day 2 postpartum
measure: Psychological status
timeFrame: 2 months postpartum
Locations:
city: Angers
country: France
facility: Angers University Hospital
Study officials:
affiliation: Department of Obstetrics, Angers University Hospital Center
name: Loic SENTILHES, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Catherine DENEUX-THARAUX, MD PhD
role: STUDY_DIRECTOR
References:
citation: Novikova N, Hofmeyr GJ. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD007872. doi: 10.1002/14651858.CD007872.pub2.
citation: Peitsidis P, Kadir RA. Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum. Expert Opin Pharmacother. 2011 Mar;12(4):503-16. doi: 10.1517/14656566.2011.545818. Epub 2011 Feb 4.
citation: Sentilhes L, Daniel V, Darsonval A, Deruelle P, Vardon D, Perrotin F, Le Ray C, Senat MV, Winer N, Maillard F, Deneux-Tharaux C. Study protocol. TRAAP - TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery: a multicenter randomized, double-blind, placebo-controlled trial. BMC Pregnancy Childbirth. 2015 Jun 14;15:135. doi: 10.1186/s12884-015-0573-5.
citation: Sentilhes L, Lasocki S, Ducloy-Bouthors AS, Deruelle P, Dreyfus M, Perrotin F, Goffinet F, Deneux-Tharaux C. Tranexamic acid for the prevention and treatment of postpartum haemorrhage. Br J Anaesth. 2015 Apr;114(4):576-87. doi: 10.1093/bja/aeu448. Epub 2015 Jan 8.
citation: Sentilhes L, Winer N, Azria E, Senat MV, Le Ray C, Vardon D, Perrotin F, Desbriere R, Fuchs F, Kayem G, Ducarme G, Doret-Dion M, Huissoud C, Bohec C, Deruelle P, Darsonval A, Chretien JM, Seco A, Daniel V, Deneux-Tharaux C; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery. N Engl J Med. 2018 Aug 23;379(8):731-742. doi: 10.1056/NEJMoa1800942.