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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02451228
Other study ID # 15-0067
Secondary ID 1R01HD083003-01
Status Completed
Phase
First received
Last updated
Start date May 2015
Est. completion date December 31, 2018

Study information

Verified date February 2018
Source The University of Texas Medical Branch, Galveston
Contact n/a
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

This study will follow pregnant women who are taking indomethacin as Standard of Care (SOC) for the indications of preterm labor (PTL), short cervix, or other indications, to evaluate the pharmacokinetics (PK), what the body does to the drug, and pharmacodynamics (PD), effectiveness of the drug in treating the specific intended disease process of this medication. This will help us develop more information for medication dosing specific to pregnant women experiencing preterm labor.

Indomethacin is often prescribed to pregnant women presenting with preterm labor or shortened cervix, which places them at risk for preterm labor and delivery. Indomethacin has been used since the 1970s to prolong pregnancy by decreasing uterine contractions. However, despite the widespread use of indomethacin in pregnancy, there is limited information available to help physicians determine how much indomethacin to prescribe and how often to prescribe it.


Description:

Opportunistic study of indomethacin prescribed to patients per standard of care. Determine the pharmacokinetics, pharmacodynamics and pharmacogenomics of Indomethacin in pregnant patients with the hypothesis that that estradiol levels during pregnancy (12-32 weeks of gestation) and CYP2C9 polymorphisms affect the PK of indomethacin, and subsequently, the response to indomethacin therapy in patients at risk of Preterm birth (PTB). This hypothesis will be tested with the following specific aims: (1) Determine the PK of indomethacin in pregnant women at risk of PTB and its PD effects on reducing the rate of PTB before 34 weeks of gestation, as well as any associations between the PK and secondary maternal/neonatal clinical outcomes; (2) Determine the effects of maternal levels of estradiol in mid-pregnancy and CYP2C9 polymorphisms on indomethacin biotransformation to O-desmethylindomethacin in pregnant patients; (3) Construct a population PK/PD model of indomethacin in patients at risk of PTB (12-32 weeks of gestation) in order to optimize the dose and the dosing frequency for indomethacin prescribed to each individual based on covariates such as race/ethnicity, CYP2C9 genotype, gestational age, estradiol levels, smoking status, and body mass index (BMI). The investigators will enroll 300 subjects with spontaneous preterm labor (sPTL) or shortened cervix in a prospective opportunistic PK study designed to correlate the PK of indomethacin, patient genotype, and clinical outcomes. The investigators will merge dosing, sampling, demographic, and clinical information with the drug concentration data and use population PK methodologies to analyze the data using nonlinear mixed effect modeling. Quantification of the differences within and between individuals allows for identification of covariates (e.g., CYP2C9 genotype, estradiol levels, BMI, etc.) that can explain variability and affect drug exposure. These covariates, if significant, can then be used in the future to optimize dosing in individual patients at risk for PTB. Achieving this goal of individualized indomethacin therapy could have a significant impact on clinical practice and improve maternal and neonatal outcomes.


Recruitment information / eligibility

Status Completed
Enrollment 62
Est. completion date December 31, 2018
Est. primary completion date December 31, 2018
Accepts healthy volunteers No
Gender Female
Age group 18 Years and older
Eligibility Inclusion Criteria:

To be enrolled in the study, patients must meet all of the following criteria:

1. Age at least 18 years

2. Singleton gestation

3. 12 0/7 to 32 0/7 weeks gestation (see Gestational Age Determination section 3.2.1.1)

4. Patient receiving indomethacin for any of the following diagnoses:

1. Preterm labor: regular uterine contractions with documented cervical change or dilatation = 2 cm and 80% effacement

2. Cervical shortening (< 2.5 cm documented on transvaginal ultrasound) with or without funneling membranes

3. Planned cervical cerclage or emergent cerclage

4. Other condition whereby Indomethacin is indicated

5. Maternal and fetal condition allows anticipated delay of delivery for more than 24 hours -

Exclusion Criteria:

- Exclusion criteria include:

1. Contraindications to indomethacin use (history of maternal bleeding disorder, thrombocytopenia, maternal hepatic, gastrointestinal ulcerative, or renal dysfunction, asthma)

2. Known fetal abnormality, genetic syndrome, or intrauterine fetal demise

3. Anticipated delivery in less than 24 hours, cervical dilatation > 6 cm

4. Preterm premature rupture of membranes

5. Suspected chorioamnionitis

6. Oligohydramnios (DVP < 2 cm)

7. Congenital Uterine anomaly

8. Vaginal bleeding due to suspected placental abruption or placenta previa

9. Planned preterm delivery for maternal/fetal indications

10. Non-reassuring fetal status

11. Planned delivery outside UTMB or participation in another intervention trial which may affect maternal or neonatal outcomes

12. Unsure gestational age due to possibility of intrauterine growth restriction

13. Hematocrit <28% (as determined by most recent result within 1 month of enrollment)

14. Prisoners

Study Design


Intervention

Other:
Serial blood collection
Serial blood collection from IV for pharmacokinetic and pharmacodynamic analysis. No drug, device, or biologic intervention. Opportunistic.

Locations

Country Name City State
United States University of Alabama Birmingham Alabama
United States Duke University Durham North Carolina
United States University of Texas Medical Branch, Dept of OB/GYN Galveston Texas
United States University of Mississippi Medical Center Jackson Mississippi
United States Columbia University New York New York
United States University of Utah Salt Lake City Utah

Sponsors (2)

Lead Sponsor Collaborator
The University of Texas Medical Branch, Galveston Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Gestational age at delivery Gestational age at delivery calculated from the first day of last menstrual period unless "unsure" and then it will be calculated from ultrasound measurements Enrollment until delivery of the participant
Secondary Maternal outcomes Diagnosed maternal outcomes including oligohydramnios, chorioamnionitis, preterm premature rupture of membranes, venous thromboembolism, pulmonary edema, postpartum hemorrhage, and maternal death Enrollment until delivery and maternal discharge
Secondary Neonatal outcomes Diagnosed neonatal outcomes including birth weight, APGAR scores, neonatal sepsis, respiratory distress syndrome, patent ductus arteriosis, necrotizing enterocolitis, broncopulmonary dysplasia, paraventricular leukomalacia, intraventricular hemorrhage, fetal, or neonatal death The earlier of neonatal discharge or up to 120 days postnatal
Secondary Neonatal admission to Neonatal intensive care unit (NICU) Documentation of NICU admission [yes/no] The earlier of neonatal discharge or up to 120 days postnatal
Secondary Length of stay in the Neonatal intensive care unit (NICU) If admitted to the NICU, number of days in the NICU The earlier of neonatal discharge or up to 120 days postnatal
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