TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery (TRAAP2)

• ClinicalTrials.gov Identifier: NCT03431805
• Recruitment Status: Completed
• First Posted: February 13, 2018
• Last Update Posted: April 29, 2020
• Sponsor: University Hospital, Bordeaux
• Collaborator: Ministry of Health, France
• Information provided by (Responsible Party): University Hospital, Bordeaux

Tracking Information

• First Submitted Date: January 30, 2018
• First Posted Date: February 13, 2018
• Last Update Posted Date: April 29, 2020
• Actual Study Start Date: March 3, 2018
• Actual Primary Completion Date: January 14, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 10, 2019)

postpartum hemorrhage [ Time Frame: day 2 ]

Incidence of PPH defined by a calculated blood loss > 1000mL [Calculated estimated blood loss = estimated blood volume × (preoperative Ht - postoperative Ht)/preoperative Ht (where estimated blood volume (mL) = weight (Kg) × 85)] or red blood cell transfusion up to day 2 postpartum. Preoperative Ht will be the most recent Ht within one week before delivery. Postoperative Ht will be measured at D2

Original Primary Outcome Measures (submitted: February 12, 2018)

postpartum hemorrhage [ Time Frame: day 2 ]

Incidence of PPH defined by a calculated blood loss > 1000mL [Calculated estimated blood loss = estimated blood volume × (preoperative Ht - postoperative Ht)/preoperative Ht (where estimated blood volume (mL) = weight (Kg) × 85)] or red blood cell transfusion before day 2 postpartum. Preoperative Ht will be the most recent Ht within one week before delivery. Postoperative Ht will be measured at D2

Current Secondary Outcome Measures (submitted: May 10, 2019)

• mean calculated blood loss > 500mL [ Time Frame: day 2 ]
• mean calculated blood loss > 1500mL [ Time Frame: day 2 ]
• total mean calculated blood loss [ Time Frame: day 2 ]
• mean gravimetrically estimated blood loss [ Time Frame: 6 hours ]
  by measuring the suction volume and swab weight; proportion of women requiring supplementary uterotonic treatment including sulprostone
• incidence of postpartum transfusion [ Time Frame: day 2 ]
• Mean or median number of units of red blood cells transfused [ Time Frame: day 2 ]
• incidence of arterial embolisation or emergency surgery for PPH [ Time Frame: 3 months ]
• mean peripartum change in haemoglobin [ Time Frame: day 2 ]
  difference between the most recent Hb within one week before delivery and at day 2 postpartum
• mean peripartum change in hematocrit [ Time Frame: day 2 ]
  difference between the most recent Ht within one week before delivery and at day 2 postpartum
• heart rate [ Time Frame: 15, 30, 45, 60 and 120 minutes after delivery ]
  bpm
• diastolic blood pressure [ Time Frame: 15, 30, 45, 60 and 120 minutes after delivery ]
  mmHg
• systolic blood pressure [ Time Frame: 15, 30, 45, 60 and 120 minutes after delivery ]
  mmHg
• number of participants with nausea reported by caregivers [ Time Frame: 6 hours ]
• number of participants with vomiting reported by caregivers [ Time Frame: 6 hours ]
• number of participants with phosphenes reported by caregivers [ Time Frame: 6 hours ]
• number of participants with dizziness reported by caregivers [ Time Frame: 6 hours ]
• creatinemia [ Time Frame: day 2 ]
  micromol/L
• urea [ Time Frame: day 2 ]
  g/L
• prothrombin time (PT) [ Time Frame: day 2 ]
• aspartate transaminase [ Time Frame: day 2 ]
  IU/L
• alanine transaminase [ Time Frame: day 2 ]
  IU/L
• total bilirubin [ Time Frame: day 2 ]
  micromol/L
• total fibrinogen [ Time Frame: day 2 ]
  g/L
• number of participants with deep venous thrombosis confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• number of participants with pulmonary embolism confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• number of participants with myocardial infarction confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• number of participants with any thrombotic event confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• seizure [ Time Frame: within twelve weeks after the delivery ]
• renal failure [ Time Frame: within twelve weeks after the delivery ]
  defined by the need for dialysis
• women's satisfaction [ Time Frame: day 2 and weeks 8 postpartum ]
  assessed by a self-administered questionnaire
• Provider-assessed clinically significant PPH [ Time Frame: day 2 ]
• Hb drop > 2g/DL [ Time Frame: day 2 ]
• Active prothrombin time (aPTT) [ Time Frame: day 2 ]
• aspartate transaminase > 2N [ Time Frame: day 2 ]
• alanine transaminase > 2N (day 2) [ Time Frame: day 2 ]
• gravimetrically estimated blood loss > 500mL [ Time Frame: day 2 ]
• gravimetrically estimated blood loss > 1000 mL [ Time Frame: day 2 ]
• Shock [ Time Frame: day 2 ]
• Transfer to Intensive Care Unit [ Time Frame: twelve weeks after delivery ]
• Death from any cause [ Time Frame: 42 days postpartum ]
• supplementary uterotonic treatment [ Time Frame: day 2 ]
  proportion of women requiring supplementary uterotonic treatment
• iron sucrose perfusion [ Time Frame: discharge from hospital ]
  incidence of iron sucrose perfusion
• mean gravimetrically estimated blood loss [ Time Frame: at the end of the cesarean delivery ]

Original Secondary Outcome Measures (submitted: February 12, 2018)

• mean calculated blood loss > 500mL [ Time Frame: day 2 ]
• mean calculated blood loss > 1500mL [ Time Frame: day 2 ]
• total mean calculated blood loss [ Time Frame: day 2 ]
• mean gravimetrically estimated blood loss [ Time Frame: 6 hours ]
  by measuring the suction volume and swab weight; proportion of women requiring supplementary uterotonic treatment including sulprostone
• incidence of postpartum transfusion [ Time Frame: day 2 ]
• Mean or median number of units of red blood cells transfused [ Time Frame: day 2 ]
• incidence of arterial embolisation or emergency surgery for PPH [ Time Frame: 3 months ]
• mean peripartum change in haemoglobin [ Time Frame: day 2 ]
  difference between the most recent Hb within one week before delivery and at day 2 postpartum
• mean peripartum change in hematocrit [ Time Frame: day 2 ]
  difference between the most recent Ht within one week before delivery and at day 2 postpartum
• heart rate [ Time Frame: 15, 30, 45, 60 and 120 minutes after delivery ]
  bpm
• diastolic blood pressure [ Time Frame: 15, 30, 45, 60 and 120 minutes after delivery ]
  mmHg
• systolic blood pressure [ Time Frame: 15, 30, 45, 60 and 120 minutes after delivery ]
  mmHg
• number of participants with nausea reported by caregivers [ Time Frame: 6 hours ]
• number of participants with vomiting reported by caregivers [ Time Frame: 6 hours ]
• number of participants with phosphenes reported by caregivers [ Time Frame: 6 hours ]
• number of participants with dizziness reported by caregivers [ Time Frame: 6 hours ]
• creatinemia [ Time Frame: day 2 ]
  micromol/L
• urea [ Time Frame: day 2 ]
  g/L
• prothrombin time (PT) [ Time Frame: day 2 ]
• aspartate transaminase [ Time Frame: day 2 ]
  IU/L
• alanine transaminase [ Time Frame: day 2 ]
  IU/L
• total bilirubin [ Time Frame: day 2 ]
  micromol/L
• total fibrinogen [ Time Frame: day 2 ]
  g/L
• number of participants with deep venous thrombosis confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• number of participants with pulmonary embolism confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• number of participants with myocardial infarction confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• number of participants with any thrombotic event confirmed by paraclinical exams [ Time Frame: within twelve weeks after the delivery ]
• seizure [ Time Frame: within twelve weeks after the delivery ]
• renal failure [ Time Frame: within twelve weeks after the delivery ]
  defined by the need for dialysis
• women's satisfaction [ Time Frame: day 2 and weeks 8 postpartum ]
  assessed by a self-administered questionnaire
• Provider-assessed clinically significant PPH [ Time Frame: day 2 ]
• Hb drop > 2g/DL [ Time Frame: day 2 ]
• Active prothrombin time (aPTT) [ Time Frame: day 2 ]
• aspartate transaminase > 2N [ Time Frame: day 2 ]
• alanine transaminase > 2N (day 2) [ Time Frame: day 2 ]
• gravimetrically estimated blood loss > 500mL [ Time Frame: day 2 ]
• gravimetrically estimated blood loss > 1000 mL [ Time Frame: day 2 ]
• Shock [ Time Frame: day 2 ]
• Transfer to Intensive Care Unit [ Time Frame: twelve weeks after delivery ]
• Death from any cause [ Time Frame: 42 days postpartum ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery
• Official Title: TRAnexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery :a Multicenter Randomised, Double Blind Placebo Controlled Trial (TRAAP2)
• Brief Summary: The aim is to assess the impact of tranexamic acid (TXA) for preventing postpartum hemorrhage (PPH) following a cesarean section (CS).

Detailed Description

Regarding the prevention of PPH, recent randomized controlled trials (RCTs) of unclear quality have suggested that TXA may reduce blood loss and maternal morbidity, while a Cochrane Collaboration review has concluded, that "TXA (in addition to uterotonic medications) decreases postpartum blood loss and prevents PPH and blood transfusions following vaginal birth and CS in women at low risk of PPH based on studies of mixed quality. Further investigations are needed on efficacy and safety of this regimen for preventing PPH.

Treatment, that is a 10-mL blinded vial of the study drug (either 1g TXA or placebo according to the randomization sequence), will be administered intravenously to the participant women during the third stage of labor of cesarean delivery.

The follow-up visit will take place in the postpartum ward of the maternity unit, on D2 postpartum. This stage will include a venous blood sample to measure plasma concentrations of Hb and Ht, urea and creatinemia, prothrombin time (PT), active prothrombin time (aPTT), aspartate and alanine transaminase, total bilirubin and fibrinogen, and the completion of a self-questionnaire about satisfaction by the women, as well as the assessment of the adverse events.

At 8 weeks postpartum, a self-questionnaire assessing psychological status and well-being will be sent to the women. At 12 weeks postpartum, all participants will be contacted by phone to assess the incidence of thrombotic and any other significant events.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:

Double blind

Primary Purpose: Prevention

• Condition: Postpartum Hemorrhage

Intervention

• Drug: Tranexamic Acid Injectable Solution
  After the routine and prophylactic administration of a uterotonic , the intervention will be the IV administration of a 10-ml blinded ampoule of the study drug (either TXA or placebo according to the randomisation sequence) to the woman within 3 minutes after birth, slowly (over 30-60 seconds), once the cord has been clamped.
• Drug: Sodium Chloride 0.9%
  After a routine and prophylactic administration of a uterotonic , the intervention will be the IV administration of a 10-ml blinded ampoule of the study drug (either TXA or placebo according to the randomisation sequence) to the patient within 3 minutes afterbirth), slowly (over 30-60 seconds), once the cord has been clamped.

Study Arms

• Experimental: Tranexamic acid
  intravenous administration of 10-mL of tranexamic acid (EXACYL® 1 g/10 ml I.V., solution injectable)
  Intervention: Drug: Tranexamic Acid Injectable Solution
• Placebo Comparator: Chloride solution
  sodium intravenous administration of 10-mL of chloride solution (0.9% -10mL).
  Intervention: Drug: Sodium Chloride 0.9%

Publications *

• Sentilhes L, Senat MV, Le Lous M, Winer N, Rozenberg P, Kayem G, Verspyck E, Fuchs F, Azria E, Gallot D, Korb D, Desbriere R, Le Ray C, Chauleur C, de Marcillac F, Perrotin F, Parant O, Salomon LJ, Gauchotte E, Bretelle F, Sananes N, Bohec C, Mottet N, Legendre G, Letouzey V, Haddad B, Vardon D, Madar H, Mattuizzi A, Daniel V, Regueme S, Roussillon C, Benard A, Georget A, Darsonval A, Deneux-Tharaux C; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery. N Engl J Med. 2021 Apr 29;384(17):1623-1634. doi: 10.1056/NEJMoa2028788.
• Sentilhes L, Daniel V, Deneux-Tharaux C; TRAAP2 Study Group and the Groupe de Recherche en Obstetrique et Gynecologie (GROG). TRAAP2 - TRAnexamic Acid for Preventing postpartum hemorrhage after cesarean delivery: a multicenter randomized, doubleblind, placebo- controlled trial - a study protocol. BMC Pregnancy Childbirth. 2020 Jan 31;20(1):63. doi: 10.1186/s12884-019-2718-4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 28, 2020): 4574
• Original Estimated Enrollment (submitted: February 12, 2018): 4524
• Actual Study Completion Date: April 8, 2020
• Actual Primary Completion Date: January 14, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• : adult women admitted for a cesarean delivery before or during labor, at a term ≥ 34 weeks,
• hemoglobin level at the last blood sample >9g/dl,
• available blood test for Hb and Ht within one week before caesarean delivery,
• informed signed consent

Exclusion Criteria:

• previous thrombotic event or preexisting pro-thrombotic disease,
• epileptic state or history of seizures,
• presence of any chronic or active cardiovascular disease outside hypertension,
• any chronic or active renal disease and chronic or active liver disease at risk thrombotic or hemorrhagic, autoimmune disease,
• sickle cell disease,
• placenta praevia,
• placenta accreta/increta/percreta,
• abruption placentae,
• eclampsia,
• HELLP syndrome,
• significant hemorrhage before cesarean section
• in utero fetal death,
• administration of low-molecular-weight heparin or antiplatelet agents during the week before delivery,
• planned general anesthesia,
• hypersensitivity to tranexamic acid or concentrated hydrochloric acid,
• instrumental extraction failure,
• multiple pregnancy with vaginal delivery of the first child,
• poor understanding of the French language.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 64 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT03431805
• Other Study ID Numbers: CHUBX 2015/41
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: University Hospital, Bordeaux
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Bordeaux
• Original Study Sponsor: Same as current
• Collaborators: Ministry of Health, France
• Investigators: Not Provided
• PRS Account: University Hospital, Bordeaux
• Verification Date: April 2020