Relationship Between Plasma Concentration of Hydroxyprogesterone Caproate (17-OHPC) and Preterm Birth (PRO)

Steve N. Caritis, MD

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Preterm Birth

Treatments: Drug: 17-Hydroxyprogesterone caproate 250mg or 500 mg.; Drug: Safety study of 500 mg dose.

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03292731

PRO16110007

STUDY19020368 (Other Identifier)

U54HD047905-11 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

The study plans to determine the relationship between plasma concentrations of 17-OHPC hydroxyprogesterone caproate (17-OHPC) and the rate of preterm birth. The study is an open label study of pregnant women with one or more prior spontaneous preterm births who are receiving either 250mg of 500 mg of 17-OHPC as a weekly single injection. The safety of the 500 mg dose will also be assessed.

Full description

The study will determine the association between plasma concentrations of 17-OHPC (hydroxyprogesterone caproate) and the rate of preterm birth and will evaluate the impact of several potential covariates on plasma concentrations of 17-OHPC and its efficacy. 17-OHPC (hydroxyprogesterone caproate) administration has proven effective in reducing preterm births in high risk groups but the current dose of 250mg administered intramuscular (IM ) is thought to be an inadequate for a substantial portion of women receiving the therapy. The potential benefit of identifying a therapeutic concentration range and of optimizing the dosage of 17-OHPC are substantial.

One cohort of pregnant subjects with a history of a prior spontaneous preterm birth with be randomized to either the 250mg or 500mg weekly intramuscular injections. All subjects will have trough blood samples collected immediately prior to their second injection of the 17-OHPC, at 26-30 weeks (but only after a minimum of 7 injections have been administered) , 6-9 weeks later and at the time of delivery. Another tube of maternal blood will be collected during one of the scheduled blood samples for genotyping. A cord blood specimen will also be collected and with consent, a cord blood specimen will be collected for genetic studies of the infant. Investigators will also collect a small sample of the placenta after delivery.

In order to enhance sample size for this trial, investigators will also enroll a second cohort of subjects (ancillary cohort) who are not in the randomized clinical trial (RCT) described above. Women already receiving 250 mg 17-OHPC weekly from their healthcare provider as part of their standard of care will be approached prior to 26 weeks gestation. This will be an observational cohort and subjects enrolled in the ancillary cohort will not be randomized, as they are already receiving the 250 mg dose. Research staff will not administer the study drug to subjects enrolled in the ancillary cohort. These subjects will be asked to provide two blood samples: one at 26-30 weeks and one 6-9 weeks later, which will be utilized to address the primary objective of the study.

In response to the addition of the ancillary cohort, randomization for subjects in the RCT will be 2:1 for the 500 mg vs the 250 mg dose. The ancillary study will be implemented initially at the UPITT site only but may be expanded to other sites, as required.

Enrollment: 159 patients

Sex: Female

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

1. Randomized Clinical Trial Eligibility Criteria:

   Inclusion Criteria:

   • pregnant with a prior preterm birth 16 0/7-35 6/7 weeks from spontaneous labor or preterm premature rupture of membranes(PPROM),
   • current gestational age <22 weeks,
   • pregnant with one baby
   • age between 18-45 years
   • able to give consent and undergo study procedures

   Exclusion Criteria:

   • plans for cerclage at enrollment, plan for progesterone treatment other than study medications at enrollment
   • known fetal anomaly or chromosomal anomaly that could affect gestational age at delivery
   • malformation of the uterus or known cervical length <2.5cm
   • participation in another trial that may affect gestational age at delivery
   • planned delivery where outcome data cannot be collected
   • medical or obstetrical complication that may affect gestational age at delivery, such as active ulcerative colitis, liver tumors, liver disease/failure, renal disease/failure, undiagnosed vaginal bleeding unrelated to pregnancy, or hypertension requiring 2 or more agents
   • Current or history of thrombosis or thromboembolic disorders
   • known or suspected breast cancer, other hormone-sensitive cancer, or a history of these conditions
   • moderately severe depression (PHQ-9 score ≥ 15, EPDS score of >13, or suicidal ideation)

2. Ancillary Cohort Eligibility Criteria:

Inclusion Criteria:

• Pregnant female with documented prior birth between 16 0/7- 35 6/7 week gestation from spontaneous preterm labor or preterm premature rupture of membranes
• Receiving 250 mg 17-OHPC weekly- must be compliant with that treatment based on interview and reviewing the medical record
• Gestational age (GA) <26 weeks, based on study determined GA
• Singleton gestation
• Age between 18 - 45 years
• Able to give informed consent and undergo study procedures

Exclusion Criteria:

• Inclusion in the RCT of 250 vs 500 mg OPRC study
• Cerclage in place
• Plan for progesterone treatment other than study medication
• Known major fetal anomaly or chromosomal anomalies that might affect gestational age at delivery
• Malformation of uterus (uterine didelphus, septate uterus or bicornuate uterus) or known cervical length <2.5 cm
• Participation in another trial that may affect gestational age at delivery
• Planned delivery at other institution where pregnancy outcome data cannot be obtained
• Medical or obstetrical complication that might affect gestational age at delivery, such as active ulcerative colitis, liver tumors, liver disease/failure, renal disease/failure, undiagnosed vaginal bleeding unrelated to pregnancy, or hypertension requiring 2 or more agents
• Current or history of thrombosis or thromboembolic disorder.
• Known or suspected breast cancer, other hormone-sensitive cancer, or a history of these conditions.
• Moderately severe depression (PHQ-9 score ≥15, EPDS score of >13, or suicidal ideation)- based on criteria in the RCT

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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159 participants in 3 patient groups

hydroxyprogesterone caproate 500 mg

Experimental group

Description:

For safety assessment of the 500 mg dose, subjects will be randomized to the 500 mg dose of 17-OHPC.

Treatment:

Drug: Safety study of 500 mg dose.

hydroxyprogesterone caproate 250 mg

Active Comparator group

Description:

For safety assessment of the 500 mg dose, subjects will be randomized to the 250mg dose of 17-OHPC.

Treatment:

Drug: 17-Hydroxyprogesterone caproate 250mg or 500 mg.

Ancillary cohort 250 mg dose

Active Comparator group

Description:

Receiving 250 mg as part of routine care

Treatment:

Drug: 17-Hydroxyprogesterone caproate 250mg or 500 mg.