Indomethacin PK and PD Therapy in Pregnancy

• ClinicalTrials.gov Identifier: NCT02451228
• Recruitment Status: Completed
• First Posted: May 21, 2015
• Last Update Posted: June 11, 2019
• Sponsor: The University of Texas Medical Branch, Galveston
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): The University of Texas Medical Branch, Galveston

Study Description

Brief 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.

Condition or disease	Intervention/treatment
Premature Labor; Pregnancy; Premature Birth	Other: Serial blood collection

Detailed 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.

Study Design

• Study Type: Observational
• Actual Enrollment: 62 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Pharmacokinetic and Pharmacogenomic Approach to Indomethacin Therapy in Pregnancy
• Study Start Date: May 2015
• Actual Primary Completion Date: December 31, 2018
• Actual Study Completion Date: December 31, 2018

Groups and Cohorts

Group/Cohort	Intervention/treatment
Single-group; Observational opportunistic pharmacokinetic study of 300 pregnant women receiving Indomethacin therapy as standard of care for risk of preterm birth. Receive serial blood collection from IV.	Other: Serial blood collection; Serial blood collection from IV for pharmacokinetic and pharmacodynamic analysis. No drug, device, or biologic intervention. Opportunistic.

Outcome Measures

Primary Outcome Measures :

1. Gestational age at delivery [ Time Frame: Enrollment until delivery of the participant ]
   Gestational age at delivery calculated from the first day of last menstrual period unless "unsure" and then it will be calculated from ultrasound measurements

Secondary Outcome Measures :

1. Maternal outcomes [ Time Frame: Enrollment until delivery and maternal discharge ]
   Diagnosed maternal outcomes including oligohydramnios, chorioamnionitis, preterm premature rupture of membranes, venous thromboembolism, pulmonary edema, postpartum hemorrhage, and maternal death
2. Neonatal outcomes [ Time Frame: The earlier of neonatal discharge or up to 120 days postnatal ]
   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
3. Neonatal admission to Neonatal intensive care unit (NICU) [ Time Frame: The earlier of neonatal discharge or up to 120 days postnatal ]
   Documentation of NICU admission [yes/no]
4. Length of stay in the Neonatal intensive care unit (NICU) [ Time Frame: The earlier of neonatal discharge or up to 120 days postnatal ]
   If admitted to the NICU, number of days in the NICU

Biospecimen Retention:   Samples With DNA

Maternal Venous Blood for serum Maternal Blood for DNA (for CYP2C9) Maternal Urine Cord Blood (Umbilical Vein and Artery) for serum

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

This is a multi-center study including 300 pregnant women between 12-32 weeks of gestation at risk of PTB (sPTL or shortened cervix with or without funneling membranes) or other conditions to whom indomethacin is prescribed.

Criteria

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama

Birmingham, Alabama, United States, 35233

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, New York

Columbia University

New York, New York, United States, 10032

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27705

United States, Texas

University of Texas Medical Branch, Dept of OB/GYN

Galveston, Texas, United States, 77555-0587

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

The University of Texas Medical Branch, Galveston

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Gary Hankins, MD; University of Texas
• Principal Investigator: Erik Rytting, PhD; University of Texas

More Information

• Responsible Party: The University of Texas Medical Branch, Galveston
• ClinicalTrials.gov Identifier: NCT02451228
• Other Study ID Numbers: 15-0067; 1R01HD083003-01 ( U.S. NIH Grant/Contract )
• First Posted: May 21, 2015
• Last Update Posted: June 11, 2019
• Last Verified: February 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Once published

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

Keywords provided by The University of Texas Medical Branch, Galveston:

Pharmacokinetics; Pharmacodynamics; Preterm labor; Preterm birth; Estradiol; Indomethacin; Pregnancy; Short Cervix; CYP2C9 Genotype

Additional relevant MeSH terms:

Premature Birth; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases