Preterm Birth
Conditions
Brief summary
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
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.
Interventions
DRUG17-Hydroxyprogesterone caproate 250mg or 500 mg.
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.
DRUGSafety study of 500 mg dose.
Subjects randomized to 250 mg or 500 mg dose
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Steve N. Caritis, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention 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
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relationship Between 17-OHPC Concentration and Spontaneous Preterm Birth - A Concentration-Response Analysis | 26-30 week blood sample after a minimum of 7 injections among those with a blood sample and compliant with protocol(n=116) | 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) |
| Survival A | time in days from first injection to spontaneous preterm delivery | days from first injection to spontaneous preterm delivery |
| Survival B | days from blood sample time to spontaneous preterm delivery | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Neonatal Outcome | till discharge from nicu up to 30 days | 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 |
| Preterm Birth by Dosing Group | from enrollment till preterm delivery | 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. |
| NICU Admission | 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 | Infants admitted to the NICU |
| Comparison of Plasma Concentration of 17-OHPC According to Dose | Blood sample obtained at 26-30 weeks after a minimum of 7 injections and compliant with study protocol | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hydroxyprogesterone Caproate 250 mg RCT Cohort Pregnant subjects randomized to 250mg of hydroxyprogesterone caproate RCT cohort | 67 |
| Hydroxyprogesterone Caproate 500 mg RCT Cohort Pregnant subjects randomized to 500 mg of hydroxyprogesterone caproate RCT cohort | 76 |
| Hydroxyprogesterone Caproate 250 mg Ancillary Cohort Pregnant subjects receiving 250 mg of hydroxyprogesterone caproate Ancillary cohort | 16 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Protocol Violation | 4 | 11 | 1 |
Baseline characteristics
| Characteristic | Hydroxyprogesterone Caproate 500 mg RCT Cohort | Hydroxyprogesterone Caproate 250 mg Ancillary Cohort | Total | Hydroxyprogesterone Caproate 250 mg RCT Cohort |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 16 Participants | 159 Participants | 67 Participants |
| Age, Continuous | 30.5 years STANDARD_DEVIATION 5.4 | 32.7 years STANDARD_DEVIATION 3.3 | 30.8 years STANDARD_DEVIATION 5.3 | 30.8 years STANDARD_DEVIATION 5.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 0 Participants | 20 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 61 Participants | 16 Participants | 133 Participants | 56 Participants |
| Region of Enrollment United States | 76 Participants | 16 Participants | 159 Participants | 67 Participants |
| Sex: Female, Male Female | 76 Participants | 16 Participants | 159 Participants | 67 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 66 | 0 / 131 |
| other Total, other adverse events | 53 / 65 | 57 / 66 | 121 / 131 |
| serious Total, serious adverse events | 19 / 65 | 17 / 66 | 36 / 131 |
Outcome results
Primary
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)
Time frame: 26-30 week blood sample after a minimum of 7 injections among those with a blood sample and compliant with protocol(n=116)
Population: the primary outcome was pre-specified as only applying to those receiving either 250 mg or 500 mg dose and having a blood sample drawn according to protocol and having received at least 7 injections (n=116). The number of sPTBs is listed by group in the outcome table.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ancillary -250 mg | Relationship Between 17-OHPC Concentration and Spontaneous Preterm Birth - A Concentration-Response Analysis | 1 Participants |
| RCT Group 250 mg Dose | Relationship Between 17-OHPC Concentration and Spontaneous Preterm Birth - A Concentration-Response Analysis | 9 Participants |
| RCT Group -500 mg Dose | Relationship Between 17-OHPC Concentration and Spontaneous Preterm Birth - A Concentration-Response Analysis | 12 Participants |
| Summarized OHPC | Relationship Between 17-OHPC Concentration and Spontaneous Preterm Birth - A Concentration-Response Analysis | 22 Participants |
Comparison: logistic regression comparing drug concentration to the rate of sPTBp-value: 0.9695% CI: [0.93, 1.08]Regression, Logistic
Primary
Survival A
days from first injection to spontaneous preterm delivery
Time frame: time in days from first injection to spontaneous preterm delivery
Population: Subjects with a blood sample and no more than two missed injections
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ancillary -250 mg | Survival A | 150 days | Standard Deviation 37 |
| RCT Group 250 mg Dose | Survival A | 144 days | Standard Deviation 17 |
| RCT Group -500 mg Dose | Survival A | 145 days | Standard Deviation 19 |
| Summarized OHPC | Survival A | 145 days | Standard Deviation 21 |
p-value: 0.0595% CI: [0, 2.23]Regression, Linear
Primary
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
Time frame: days from blood sample time to spontaneous preterm delivery
Population: This analysis was limited to those 116 subjects with a 26-30 week blood sample who were compliant with the protocol regardless of group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ancillary -250 mg | Survival B | 74 days | Standard Deviation 15 |
| RCT Group 250 mg Dose | Survival B | 73 days | Standard Deviation 18 |
| RCT Group -500 mg Dose | Survival B | 73 days | Standard Deviation 19 |
| Summarized OHPC | Survival B | 73 days | Standard Deviation 18 |
p-value: 0.02295% CI: [0.25, 2.87]Regression, Linear
Secondary
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.
Time frame: Blood sample obtained at 26-30 weeks after a minimum of 7 injections and compliant with study protocol
Population: Subjects with available 26-30 week specimen (after 7 injections minimum) who were compliant with protocol up to the point of the blood draw. Included those with indicated preterm birth. . The subjects received either a 250 mg injection or a 500 mg injection and it is not relevant whether she was in the RCT or ancillary group. Those receiving the 250 mg dose include both the RCT and ancillary groups
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ancillary -250 mg | Comparison of Plasma Concentration of 17-OHPC According to Dose | 8.6 ng/ml |
| RCT Group 250 mg Dose | Comparison of Plasma Concentration of 17-OHPC According to Dose | 16.2 ng/ml |
Secondary
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
Time frame: till discharge from nicu up to 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ancillary -250 mg | Composite Neonatal Outcome | 3 Participants |
| RCT Group 250 mg Dose | Composite Neonatal Outcome | 10 Participants |
| RCT Group -500 mg Dose | Composite Neonatal Outcome | 12 Participants |
| Summarized OHPC | Composite Neonatal Outcome | 25 Participants |
Comparison: Only RCT subjects utilized in neonatal safety analysisp-value: 0.82Fisher Exact
Secondary
NICU Admission
Infants admitted to the NICU
Time frame: 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
Population: Only includes those neonates exposed to 17-OHPC who's mothers were randomized to either the 250 mg or 500 mg dose . Those in the ancillary study were excluded from this analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ancillary -250 mg | NICU Admission | 11 Participants |
| RCT Group 250 mg Dose | NICU Admission | 16 Participants |
| RCT Group -500 mg Dose | NICU Admission | 27 Participants |
Secondary
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.
Time frame: from enrollment till preterm delivery
Population: Those receiving the 250 mg dose include both the RCT and ancillary groups
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ancillary -250 mg | Preterm Birth by Dosing Group | 7 Participants |
| RCT Group 250 mg Dose | Preterm Birth by Dosing Group | 9 Participants |