Prevention of Postpartum Hemorrhage With Tranexamic Acid (Phase 2)

Study Overview
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Brief Summary
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In part 1 of the study, the investigators conducted a prospective, open-label, dose finding pharmacokinetic (PK) study in 43 pregnant 3rd trimester women scheduled for non-emergent cesarean section. The investigators administered three doses of the drug (5 mg/kg, 10 mg/kg and 15 mg/kg) in an escalating fashion by cohort with the lowest dose first. The drug was administered intravenously at the time of umbilical cord clamping for a non-emergent cesarean section. A maximum of 1 gram was administered. TXA serum levels at several time points after delivery were assayed to see if they reach the target plasma concentration of 10 microg/mL. A PK model was constructed for determining the optimal TXA dose administered at parturition. In part 2 of the study, the investigators aim to compare PKPD endpoints using prophylactic TXA via IV and IM routes administered pre-cord clamp. The investigators will administer 1000 mg TXA within 10 minutes of skin incision via intravenous infusion (up to n=15), intravenous bolus < 2 minutes (up to n=15) and intramuscular injection (up to n=15). The investigators will target women undergoing scheduled cesarean delivery greater than 34 weeks gestation, women undergoing vaginal delivery > 34 weeks of gestation and morbidly obese women (BMI>50) undergoing either a vaginal or cesarean delivery. The investigators will use advanced modeling techniques to determine time to achieve PKPD targets and duration remaining at those targets. The goal will be to determine how the optimal dose may vary if route of administration is modified. The investigators plan to enroll 45 patients in addition to the 43 that were enrolled during part 1. Our goal is to 30 participants, but the investigators will enroll 45 to account for lost to follow-up. The investigatorsalso aim to enroll 30 patients undergoing vaginal delivery and 30 morbidly obese women (BMI > 50) undergoing either a vaginal or cesarean delivery but the investigators will enroll 45 patients for each of these groups to account for loss to follow up. In addition, the investigators will enroll 30 pregnant patients receiving no medication acting as the control group, but the investigators will enroll 45 to account for loss to follow up.

Detailed Description
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The study will enroll 45 additional third trimester pregnant women scheduled for nonemergent cesarean sections who are at high risk for hemorrhage. The investigators plan to enroll 30, but to account for lost to follow-up, the investigators will enroll 45. The investigatorswill also enroll 30 pregnant patients > 34 weeks of gestation undergoing vaginal delivery, and 30 morbidly obese (BMI > 50) pregnant patients undergoing either vaginal or cesarean delivery. However, the investigators will enroll 45 patients in each of these two groups to account for loss to follow up. The investigators will also enroll 45 patients as a control group that will not receive TXA. The total number of enrolled patients will thus be 223. A total of 1 gram of TXA will be administered to patients prior to fetal delivery via three different routes of administration: IV infusion, IV push, and IM injection. The subjects in each group will be divided into three subgroups: Group 1: Up to 15 subjects, TXA dose: 1 gram, Route: IV infusion over 10 minutes Group 2: Up to 15 subjects, TXA dose: 1 gram, Route: IV Push for <2 minutes Group 3: Up to 15 subjects, TXA dose: 1 gram, Route: IM Injection Plasma sampling: Timing of samples will be relative to the end of drug administration (t = 0) and include: Pre-drug administration, 5-10 minutes, 30-60 minutes, 60-90 minutes, 1.5-3 hours, 3-4 hours, 4-5 hours, 7-8 hours, and 10-18 hours. Each volume of blood draw will be approximately 7-9 mL. Actual times of plasma sampling will be documented. A second IV will be required for participating in the study. Citrated plasma samples will be centrifuged and supernatant will be stored at -70 degree Celsius. Breast milk sampling of no more than 2 mL per time point will occur at time points coinciding with maternal feedings. Procedure: Subject recruitment will take place in the GW MFA routine prenatal clinic among other prenatal patients. In addition, inpatient charting will utilize a screening tool developed for research projects at GW called 'Power Trials' to help screen eligibIe subjects admitted to L&D. Interested subjects will be consented by either a physican investigator or research coordinator as described below. The subjects serum creatinine levels will be obtained if indicated at the time of delivery. TXA administration will be given in cohort fashion as outlined in the chart above with up to15 subjects enrolled being placed in Group 1 (1g TXA via IV infusion over 10 mins), up to 15 subjects enrolled will be placed in Group 2 (1g TXA via IV push for < 2 mins), and up to 15 subjects enrolled will be placed in Group 3 (1g TXA via IM injection). Each patient will be assigned to either one of three cohorts. The participants are not randomly assigned to each cohort since the focus of this study is not efficacy, and randomization in pharmacodynamic-pharmacokinetic (PKPD) studies such as this one is not typically done.

Official Title
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OPTIMUM OB-TXA: Optimal Timing, Route and Dose of Tranexamic Acid Prior to UMbilical Cord Clamp for Postpartum Hemorrhage Prevention

Conditions
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Post Partum Hemorrhage

Intervention / Treatment
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* Drug: Tranexamic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women who are undergoing elective or non-urgent cesarean delivery greater than 34+0 weeks gestation Women at > 34 weeks of gestation undergoing vaginal delivery Morbidly obese women (BMI > 50) undergoing either a vaginal or cesarean delivery Women between the ages of 18 and 50 years old pregnant women with normal serum creatinine (serum creatinine < 0.9) Exclusion Criteria: Patients younger than 18 or older than 50 Women with active thrombotic or thromboembolic disease Women with a history of arterial or venous thromboembolic event Women with inherited thrombophilia or preexisting conditions that predisposes them to thromboembolic events (i.e. lupus, antiphospholipid syndrome) Women with a subarachnoid hemorrhage Women with acquired defective color vision history of seizure disorder known renal dysfunction (serum creatinine >2.0) multiple gestations (Twin or triplet pregnancies) Hypersensitivity to Tranexamic acid or anti-fibrinolytic therapy History of liver dysfunction

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cesarean Delivery<br> | Drug: Tranexamic acid<br>* IV 2 minutes, IV 10 minutes, IM<br>|
| Experimental: Vaginal Delivery<br> | Drug: Tranexamic acid<br>* IV 2 minutes, IV 10 minutes, IM<br>|
| Experimental: Morbidly Obese<br> | Drug: Tranexamic acid<br>* IV 2 minutes, IV 10 minutes, IM<br>|
| No Intervention: No TXA<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adequate timing and formulation of TXA in prevention of postpartum hemorrhage (PPH) so that maternal benefit is maximized | Comparing PKPD endpoints using prophylactic TXA via IV (mg) and IM (mg) routes pre-cord clamp. | 2 years |