Postpartum Hemorrhage
Conditions
Keywords
tranexamic acid, postpartum hemorrhage
Brief summary
Postpartum hemorrhage is a significant contributor to maternal morbidity and mortality and is worldwide. TXA has recently been proven to reduce mortality when given to women in setting of diagnosed PPH. US obstetricians and anesthesiologists are hesitant to use TXA in the peripartum period especially for prevention of PPH due to uncertainty of an optimal dose and safety profile. The purpose of this study is to characterize the pharmacokinetics of TXA when given prophylactically at time of delivery. In addition investigators will determine the pharmacodynamics of TXA in the peripartum period.
Detailed description
Conduct a prospective, open-label, dose finding PK study in 30 pregnant 3rd trimester women scheduled for non-emergent cesarean section who are at risk for hemorrhage. Three doses of the drug will be administered in an escalating fashion by cohort with the lowest dose first. A maximum of 1 gram will be administered. TXA serum levels at several time points after delivery will be assayed. A PK model will be constructed for determining the optimal TXA dose administered at parturition.
Interventions
DRUGTranexamic Acid
Tranexamic acid dosage (5 mg/kg, 10 mg/kg and 15 mg/kg) administered in a dose escalating fashion by cohort with the lowest dose first.
Sponsors
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Advancing Translational Sciences (NCATS)
George Washington University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Three doses of Tranexamic acid (5 mg/kg, 10 mg/kg, and 15 mg/kg) will be used in a dose escalation fashion by cohort with the lowest dose first.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
* Women who are undergoing medically indicated cesarean section at greater than 34+0 weeks gestation or women undergoing elective cesarean section at 39+0 weeks gestation in accordance with recommendations from the American Congress of Obstetricians and Gynecologists * Pregnant women with normal serum creatinine (serum creatinine \< 0.9) * Women between the ages of 18 and 50 years old
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 * multiple gestations (Twin or triplet pregnancies) * Hypersensitivity to Tranexamic acid or anti-fibrinolytic therapy * History of liver dysfunction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Model Parameter Estimates | Different time points ranging from surgery (T0) to 1 day postpartum. | Data obtained from assays of TXA in blood, dose group and patient characteristics; parameter estimates in 2 compartment model includes the clearance of the drug (L/hr). |
| Pharmacodynamics of Tranexamic Acid | Different time points ranging from surgery (T0) to 1 day postpartum. | PD model parameters included concentration of TXA causing 50% of maximal fractional inhibition (IC50). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Blood Loss | During surgery | Intraoperative blood loss |
| Safety Parameters | During surgery, after surgery while in hospital, 2 weeks and 6 weeks postpartum | Safety parameters such as adverse events (including nausea/vomiting) and serious adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Dose of Tranexamic acid 5mg/kg will be administered.
Tranexamic Acid: Tranexamic acid dosage (5 mg/kg, 10 mg/kg and 15 mg/kg) administered in a dose escalating fashion by cohort with the lowest dose first. | 10 |
| Cohort 2 Dose of Tranexamic acid 10 mg/kg will be administered.
Tranexamic Acid: Tranexamic acid dosage (5 mg/kg, 10 mg/kg and 15 mg/kg) administered in a dose escalating fashion by cohort with the lowest dose first. | 10 |
| Cohort 3 Dose of Tranexamic acid 15 mg/kg will be administered.
Tranexamic Acid: Tranexamic acid dosage (5 mg/kg, 10 mg/kg and 15 mg/kg) administered in a dose escalating fashion by cohort with the lowest dose first. | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
| Age, Continuous | 34 years | 31 years | 33 years | 33 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 10 Participants | 10 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 5 Participants | 6 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 3 Participants | 12 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 9 / 10 | 8 / 10 | 6 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Pharmacodynamics of Tranexamic Acid
PD model parameters included concentration of TXA causing 50% of maximal fractional inhibition (IC50).
Time frame: Different time points ranging from surgery (T0) to 1 day postpartum.
Population: Groups are combined because in PKPD modeling the best model parameter estimates are determined from combination of individual participant data of the dose administered, patient characteristics, times of administration and measured ML levels in plasma.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 5mg/kg | Pharmacodynamics of Tranexamic Acid | 5.49 mg/L | Standard Deviation 2.35 |
| 10 mg/kg | Pharmacodynamics of Tranexamic Acid | 6.49 mg/L | Standard Deviation 2.88 |
| 15 mg/kg | Pharmacodynamics of Tranexamic Acid | 9.45 mg/L | Standard Deviation 3.55 |
Primary
PK Model Parameter Estimates
Data obtained from assays of TXA in blood, dose group and patient characteristics; parameter estimates in 2 compartment model includes the clearance of the drug (L/hr).
Time frame: Different time points ranging from surgery (T0) to 1 day postpartum.
Population: Groups are combined because in PKPD modeling the best model parameter estimates are determined from combination of individual participant data of the dose administered, patient characteristics, times of administration and drug level in plasma.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 5mg/kg | PK Model Parameter Estimates | 8.85 L/hr | Standard Deviation 2.24 |
| 10 mg/kg | PK Model Parameter Estimates | 10.39 L/hr | Standard Deviation 2.62 |
| 15 mg/kg | PK Model Parameter Estimates | 9.45 L/hr | Standard Deviation 2.37 |
Secondary
Estimated Blood Loss
Intraoperative blood loss
Time frame: During surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 5mg/kg | Estimated Blood Loss | 750 mL |
| 10 mg/kg | Estimated Blood Loss | 750 mL |
| 15 mg/kg | Estimated Blood Loss | 700 mL |
Secondary
Safety Parameters
Safety parameters such as adverse events (including nausea/vomiting) and serious adverse events
Time frame: During surgery, after surgery while in hospital, 2 weeks and 6 weeks postpartum
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5mg/kg | Safety Parameters | 9 events |
| 10 mg/kg | Safety Parameters | 8 events |
| 15 mg/kg | Safety Parameters | 6 events |