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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Preterm Birth

Intervention / Treatment
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* Drug: 17-Hydroxyprogesterone caproate 250mg or 500 mg.
* Drug: Safety study of 500 mg dose.


Participation Criteria
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Eligibility Criteria
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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) 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An open labelled rct for secondary analysis of safety of 500 mg dose. A pharmacodynamic study of 17-OHPC concentration and rate of sPTB
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hydroxyprogesterone caproate 500 mg<br>For safety assessment of the 500 mg dose, subjects will be randomized to the 500 mg dose of 17-OHPC. | Drug: Safety study of 500 mg dose.<br>* Subjects randomized to 250 mg or 500 mg dose<br>* Other names: safety;|
| Active Comparator: hydroxyprogesterone caproate 250 mg<br>For safety assessment of the 500 mg dose, subjects will be randomized to the 250mg dose of 17-OHPC. | Drug: 17-Hydroxyprogesterone caproate 250mg or 500 mg.<br>* For the pharmacodynamic study, subjects receiving either 250mg or 500 mg dose will be studied to relate the plasma concentration at 26-30 to the rate of sPTB. For the safety study, subjects will be randomized to either the 250mg or 500 mg dose.<br>* Other names: pharmacodynamic;|
| Active Comparator: Ancillary cohort 250 mg dose<br>Receiving 250 mg as part of routine care | Drug: 17-Hydroxyprogesterone caproate 250mg or 500 mg.<br>* For the pharmacodynamic study, subjects receiving either 250mg or 500 mg dose will be studied to relate the plasma concentration at 26-30 to the rate of sPTB. For the safety study, subjects will be randomized to either the 250mg or 500 mg dose.<br>* Other names: pharmacodynamic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship Between 17-OHPC Concentration and Spontaneous Preterm Birth - A Concentration-Response Analysis | relationship between the rate of spontaneous preterm birth ( delivery < 37 weeks) and drug concentration obtained at 26-30 weeks among those with a blood sample and adherent to study protocol (n=116) | 26-30 week blood sample after a minimum of 7 injections among those with a blood sample and compliant with protocol(n=116) | 
| Survival A | days from first injection to spontaneous preterm delivery | time in days from first injection to spontaneous preterm delivery | 
| Survival B | days from when the 26-30 week blood sample was obtained to the gestation at spontaneous preterm birth. All blood samples were obtained after at least 7 injections were give by which time steady state would have been achieved. This analysis was limited to those with a 26-30 week blood sample who were compliant with the protocol | days from blood sample time to spontaneous preterm delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Neonatal Outcome | Composite NN outcome (fetal death, neonatal death (NND), respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage 3 or 4, retinopathy of prematurity, hypoxic-ischemic encephalopathy, seizures.) and NICU admission | till discharge from nicu up to 30 days | 
| NICU Admission | Infants admitted to the NICU | any admission to the NICU from time of delivery to time of discharge from the hospital up to 30 days or transfer to another facility | 
| Comparison of Plasma Concentration of 17-OHPC According to Dose | Plasma concentrations of 17-OHPC after 250 or 500 mg dose. Subjects were compliant with protocol up to the 26-30 week blood draw and had a blood sample available . This included subjects with indicated preterm birth and was not limited to those with spontaneous PTB. Plasma concentration among those receiving the 250 mg dose are compared to those receiving 500 mg dose. Those receiving the 250 mg dose include both the RCT and ancillary groups. | Blood sample obtained at 26-30 weeks after a minimum of 7 injections and compliant with study protocol | 
| Preterm Birth by Dosing Group | rate of preterm birth according to dosing group. Subjects were the same cohort in spec aims 1 and 2 . They were compliant with protocol, had a 26-30 week blood sample and did not miss more than 2 injections. | from enrollment till preterm delivery |