Indomethacin PK and PD Therapy in Pregnancy

Pregnancy Clinical Trial

Official title:

Pharmacokinetic and Pharmacogenomic Approach to Indomethacin Therapy in Pregnancy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02451228
• Other study ID #: 15-0067
• Secondary ID: 1R01HD083003-01
• Status: Completed
• 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
• 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

Related Conditions & MeSH terms

• Obstetric Labor, Premature
• Pregnancy
• Premature Birth
• Premature Labor

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