Indomethacin PK and PD Therapy in Pregnancy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02451228
Recruitment Status : Recruiting
First Posted : May 21, 2015
Last Update Posted : June 13, 2018
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
The University of Texas Medical Branch, Galveston

Brief Summary:

This study will follow pregnant women who are taking indomethacin for preterm labor to find out the pharmacokinetics (what the body does to the drug) and pharmacodynamics (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
Premature Labor Pregnancy Premature Birth

Detailed Description:
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 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 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 Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Pharmacokinetic and Pharmacogenomic Approach to Indomethacin Therapy in Pregnancy
Study Start Date : May 2015
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : May 2019

Resource links provided by the National Library of Medicine

No intervention; Observational study of 300 pregnant women receiving Indomethacin therapy for risk of preterm birth

Primary Outcome Measures :
  1. Delivery <34 weeks gestation [ Time Frame: Delivery ]

Secondary Outcome Measures :
  1. Preterm delivery <37, 32, and 28 weeks gestation [ Time Frame: Delivery ]
  2. Prolongation of pregnancy by 48 hours after enrollment (for sPTL) [ Time Frame: Delivery ]
  3. Gestational age at delivery [ Time Frame: Delivery ]
  4. Chorioamnionitis [ Time Frame: Delivery ]
  5. Preterm premature rupture of membranes [ Time Frame: Delivery ]
  6. Oligohydramnios [ Time Frame: Delivery ]
  7. Mode of delivery [ Time Frame: Delivery ]
  8. Postpartum hemorrhage [ Time Frame: Delivery ]
  9. Venous thromboembolism [ Time Frame: Delivery ]
  10. Pulmonary edema [ Time Frame: Delivery ]
  11. Maternal Death [ Time Frame: Delivery ]
  12. Birth weight [ Time Frame: Delivery ]
  13. Apgar scores [ Time Frame: Delivery ]
  14. Fetal or neonatal death [ Time Frame: Delivery and up to 120 days ]
  15. Admission and length of stay in the NICU [ Time Frame: Delivery and up to 120 days ]
  16. Proven neonatal sepsis by culture [ Time Frame: Delivery and up to 120 days ]
  17. Respiratory distress syndrome [ Time Frame: Delivery and up to 120 days ]
  18. Patent ductus arteriosus [ Time Frame: Delivery and up to 120 days ]
  19. Necrotizing enterocolitis [ Time Frame: Delivery and up to 120 days ]
  20. Bronchopulmonary dysplasia [ Time Frame: Delivery and up to 120 days ]
  21. Periventricular leukomalacia [ Time Frame: Delivery and up to 120 days ]
  22. Intraventricular hemorrhage [ Time Frame: Delivery and up to 120 days ]

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

Information from the National Library of Medicine

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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.

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
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02451228

Contact: Holly A West, DHEd, PA-C 409-747-8234
Contact: Ashley Salazar, NP 409-772-0312

United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35233
Contact: Lisa Dimperio    205-934-3276   
Contact: Nancy Saxon, RN   
Sub-Investigator: Alan Tita, MD         
Principal Investigator: Amelia Sutton, MD         
United States, Mississippi
University of Mississippi Medical Center Recruiting
Jackson, Mississippi, United States, 39216
Contact: Tony Wen, MD   
Contact: Latasha Cox, MHSA    601-815-5018   
Principal Investigator: Tony Wen, MD         
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Caroline Torres    212-305-2158   
Principal Investigator: Kirsten Cleary, MD         
United States, North Carolina
Duke University Recruiting
Durham, North Carolina, United States, 27705
Contact: Kristin Weaver    919-681-0308   
Principal Investigator: Chad Grotegut, MD         
United States, Texas
University of Texas Medical Branch, Dept of OB/GYN Recruiting
Galveston, Texas, United States, 77555-0587
Contact: Holly West, DHEd, PA-C    409-747-8234   
Contact: Ashley Salazar, WHNP    409-772-0312   
Principal Investigator: Gary Hankins, MD         
Principal Investigator: Erik Rytting, PhD         
Sub-Investigator: Maged Costantine, MD         
Sub-Investigator: Shannon Clark, MD         
Sub-Investigator: Tatiana Nanovskaya, DDS, PhD         
Sub-Investigator: Michael Cohen-Wolkowiez, MD, PhD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Marie Gibson    801-213-2845   
Principal Investigator: Erin Clark, MD         
Sponsors and Collaborators
The University of Texas Medical Branch, Galveston
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Gary DV Hankins, MD University of Texas
Principal Investigator: Erik Rytting, PhD University of Texas

Responsible Party: The University of Texas Medical Branch, Galveston Identifier: NCT02451228     History of Changes
Other Study ID Numbers: 15-0067
1R01HD083003-01 ( U.S. NIH Grant/Contract )
First Posted: May 21, 2015    Key Record Dates
Last Update Posted: June 13, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Once published

Keywords provided by The University of Texas Medical Branch, Galveston:
Preterm labor
Preterm birth
Short Cervix
CYP2C9 Genotype

Additional relevant MeSH terms:
Premature Birth
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gout Suppressants
Tocolytic Agents
Reproductive Control Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action