Preterm Birth
Conditions
Keywords
17P, 17-HPC, 17-OHPC, 17-hydroxyprogesterone caproate, progestogens, preterm birth, recurrent preterm birth, spontaneous preterm birth
Brief summary
As part of the continuing effort to study the benefit and risks of 17P and preterm delivery, this study is designed as a multi-center, randomized, double-blind, vehicle-controlled clinical trial of 17P for the prevention of preterm birth prior to 35 weeks, 0 days of gestation in women with a singleton pregnancy, aged 18 years or older, with a previous singleton spontaneous preterm delivery. The study also includes a population pharmacokinetic (PK) substudy to assess the hydroxyprogesterone caproate (HPC) exposure-response relationship and the effect of body mass index (BMI) on the PK of 17P.
Detailed description
One of the most significant risk factors for preterm birth is previous pregnancy history. Women who have had a prior preterm birth have a 2.5-fold greater risk than women with no prior history of preterm birth. Prophylactic methods for prevention of preterm birth, including tocolytic drugs, bed rest, and other interventions such as cerclage, have been shown in most studies to be ineffective. One of the preventive measures that has shown effectiveness in randomized trials is the use of progesterone agents.9,10 Progesterone has been shown to support gestation and to inhibit uterine activity.
Interventions
DRUGHydroxyprogesterone Caproate Injection (HPC), 250mg/mL
1 mL intramuscular injection every week until 36 weeks, 6 days of gestation or delivery, whichever occurs first.
DRUGVehicle
Weekly intramuscular injections of 1 mL vehicle inert oil until 36 weeks, 6 days of gestation or delivery, whichever occurs first.
Sponsors
ResearchPoint Global
AMAG Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each subject must meet the following criteria to be enrolled in this study: 1. Age ≥ 18 years. 2. Singleton gestation. 3. Project gestational age 16 weeks 0 days of gestation or more and less than or equal to 20 weeks 6 days of gestation at the time of randomization, based on clinical information and evaluation of the first ultrasound. 4. Documented history of a previous singleton spontaneous preterm delivery. Spontaneous preterm birth is defined as delivery from 20 weeks 0 days to 36 weeks 6 days of gestation following spontaneous preterm labor or pPROM. Where possible, the gestational age of the previous preterm birth (referred to as the qualifying delivery) should be determined as described in Gestational Age Determination. If the gestational age at delivery is obtained directly from the medical record and more than one gestational age appears, the latest will be used. As a validation of the gestational age of the previous delivery, if the infant weighed more than 3300 grams (the birth weight 90th percentile for 36 weeks gestational age), this will not qualify as preterm. The previous preterm delivery cannot be an antepartum stillbirth.
Exclusion criteria
1. Multifetal gestation. 2. Known major fetal anomaly or fetal demise. An ultrasound examination between 14 weeks 0 days through 20 weeks 3 days of gestation must be performed to rule out fetal anomalies. 3. Progesterone treatment in any form (i.e., vaginal, oral, intramuscular) during current pregnancy, other than micronized progesterone delivered orally or vaginally provided it is stopped at least 4 weeks prior to the first dose of study medication. 4. Heparin therapy during current pregnancy or history of thromboembolic disease. 5. Maternal medical/obstetrical complications including: * Current or planned cerclage * Hypertension requiring medication * Seizure disorder 6. Subjects with a uterine anomaly (uterine didelphys or bicornate uterus). However, subjects with uterine fibroids are eligible for the study. 7. Unwillingness to comply with and complete the study. 8. A 14 weeks 0 days through 20 weeks 3 days of gestation ultrasound cannot be arranged before randomization. 9. Participation in an antenatal study in which the clinical status or intervention may influence gestational age at delivery. 10. Participation in this trial in a previous pregnancy. Women who were screened in a previous pregnancy, but not randomized, do not have to be excluded. 11. Known hypersensitivity to hydroxyprogesterone caproate or its components. 12. Have any significant medical disorder that, in the opinion of the investigator, would be a contraindication to the use of the drug including those listed in section 5.3.2 of the investigational brochure. Other examples to consider include uncontrolled diabetes, known HIV infection or renal dysfunction. 13. Have any significant medical disorder that, in the opinion of the investigator, would preclude accurate evaluation of the subject's condition or outcome in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Preterm Birth <35 Weeks Gestation | Up to 35 weeks | Determine if treatment with 17P reduces the rate of preterm birth \< 35 weeks, 0 days of gestation in women with a previous singleton spontaneous preterm delivery. |
| Neonatal Composite Index (NCI) | Until 28 days of life or discharge from the neonatal intensive care unit (NICU), whichever occurred later. | The composite index is defined as a liveborn neonate with any of the following occurring at any time during the birth hospitalization up through discharge from the NICU: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis or proven sepsis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preterm Birth Prior to 37 Weeks Gestation | Up to 37 weeks | — |
| Fetal/Early Infant Death | Delivery from 16 weeks 0 days through 19 weeks 6 days of gestation; or neonatal death occurring in liveborns born at less than 24 weeks gestation; or stillbirth (antepartum or intrapartum death) from 20 weeks gestation through term). | Defined as spontaneous abortion/miscarriage (delivery from 16 weeks 0 days through 19 weeks 6 days of gestation) or neonatal death occurring in liveborns born at less than 24 weeks gestation or stillbirth (antepartum or intrapartum death from 20 weeks gestation through term), in the 17P group compared to the vehicle group |
| Neonatal Deaths With ≥24 Weeks Gestational Age | Until 28 days of life or discharge from the NICU whichever occurred later. | Neonatal death (from minutes after birth until 28 days of life) occurring in liveborns born at 24 weeks gestation or greater |
| Stillbirths | 20 weeks gestation until term | Defined as all stillbirths/fetal deaths/in utero fetal losses occurring from 20 weeks gestation until term. |
| Preterm Birth Prior to 32 Weeks Gestation | Up to 32 weeks | — |
Countries
Bulgaria, Canada, Czechia, Hungary, Italy, Russia, Spain, Ukraine, United States
Participant flow
Pre-assignment details
1740 subjects enrolled (signed the informed consent form), but only 1708 were randomized to each group (10 subjects did not return for Visit 2, 8 subjects did not meet all eligibility requirements, 8 subjects withdrew consent, and 6 subjects discontinued for other reasons).
Participants by arm
| Arm | Count |
|---|---|
| Vehicle Castor Oil
Vehicle: Weekly intramuscular injections of 1 mL vehicle inert oil until 36 weeks, 6 days of gestation or delivery, whichever occurs first. | 578 |
| 17P (Hydroxyprogesterone Caproate Injection) HPC 250 mg/mL in oil
Hydroxyprogesterone Caproate Injection, 250mg/mL: 1 mL intramuscular injection every week until 36 weeks, 6 days of gestation or delivery, whichever occurs first. | 1,130 |
| Total | 1,708 |
Baseline characteristics
| Characteristic | Vehicle | 17P (Hydroxyprogesterone Caproate Injection) | Total |
|---|---|---|---|
| Age, Continuous | 29.9 years STANDARD_DEVIATION 5.22 | 30 years STANDARD_DEVIATION 5.17 | 30.0 years STANDARD_DEVIATION 5.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 54 Participants | 101 Participants | 155 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 524 Participants | 1029 Participants | 1553 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Pre-pregnancy BMI (kg/m2), n | 24.7 kg/m^2 STANDARD_DEVIATION 8.65 | 24.3 kg/m^2 STANDARD_DEVIATION 7.05 | 24.5 kg/m^2 STANDARD_DEVIATION 7.62 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 22 Participants | 23 Participants | 45 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants | 73 Participants | 114 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 8 Participants | 15 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 18 Participants | 22 Participants |
| Race (NIH/OMB) White | 504 Participants | 1004 Participants | 1508 Participants |
| Sex: Female, Male Female | 578 Participants | 1130 Participants | 1708 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 578 | 0 / 1,130 |
| other Total, other adverse events | 334 / 578 | 647 / 1,128 |
| serious Total, serious adverse events | 18 / 578 | 34 / 1,128 |
Outcome results
Primary
Neonatal Composite Index (NCI)
The composite index is defined as a liveborn neonate with any of the following occurring at any time during the birth hospitalization up through discharge from the NICU: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis or proven sepsis.
Time frame: Until 28 days of life or discharge from the neonatal intensive care unit (NICU), whichever occurred later.
Population: Liveborn Neonatal Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle | Neonatal Composite Index (NCI) | 28 Participants |
| 17P (Hydroxyprogesterone Caproate Injection) | Neonatal Composite Index (NCI) | 61 Participants |
Primary
Preterm Birth <35 Weeks Gestation
Determine if treatment with 17P reduces the rate of preterm birth \< 35 weeks, 0 days of gestation in women with a previous singleton spontaneous preterm delivery.
Time frame: Up to 35 weeks
Population: Number of ITT (intent to treat) subjects with non-missing delivery data or who were known to still be pregnant at 35 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle | Preterm Birth <35 Weeks Gestation | 66 Participants |
| 17P (Hydroxyprogesterone Caproate Injection) | Preterm Birth <35 Weeks Gestation | 122 Participants |
Secondary
Fetal/Early Infant Death
Defined as spontaneous abortion/miscarriage (delivery from 16 weeks 0 days through 19 weeks 6 days of gestation) or neonatal death occurring in liveborns born at less than 24 weeks gestation or stillbirth (antepartum or intrapartum death from 20 weeks gestation through term), in the 17P group compared to the vehicle group
Time frame: Delivery from 16 weeks 0 days through 19 weeks 6 days of gestation; or neonatal death occurring in liveborns born at less than 24 weeks gestation; or stillbirth (antepartum or intrapartum death) from 20 weeks gestation through term).
Population: Intent to Treat (ITT) Population - all randomized subjects regardless of whether they received study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle | Fetal/Early Infant Death | 11 Participants |
| 17P (Hydroxyprogesterone Caproate Injection) | Fetal/Early Infant Death | 19 Participants |
Secondary
Neonatal Deaths With ≥24 Weeks Gestational Age
Neonatal death (from minutes after birth until 28 days of life) occurring in liveborns born at 24 weeks gestation or greater
Time frame: Until 28 days of life or discharge from the NICU whichever occurred later.
Population: Liveborn Neonatal Population - all babies of randomized women who were liveborn and have morbidity data available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle | Neonatal Deaths With ≥24 Weeks Gestational Age | 2 Participants |
| 17P (Hydroxyprogesterone Caproate Injection) | Neonatal Deaths With ≥24 Weeks Gestational Age | 3 Participants |
Secondary
Preterm Birth Prior to 32 Weeks Gestation
Time frame: Up to 32 weeks
Population: Intent to Treat (ITT) Population - all randomized subjects regardless of whether they received study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle | Preterm Birth Prior to 32 Weeks Gestation | 30 Participants |
| 17P (Hydroxyprogesterone Caproate Injection) | Preterm Birth Prior to 32 Weeks Gestation | 54 Participants |
Secondary
Preterm Birth Prior to 37 Weeks Gestation
Time frame: Up to 37 weeks
Population: Intent to Treat (ITT) Population - all randomized subjects regardless of whether they received study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle | Preterm Birth Prior to 37 Weeks Gestation | 125 Participants |
| 17P (Hydroxyprogesterone Caproate Injection) | Preterm Birth Prior to 37 Weeks Gestation | 257 Participants |
Secondary
Stillbirths
Defined as all stillbirths/fetal deaths/in utero fetal losses occurring from 20 weeks gestation until term.
Time frame: 20 weeks gestation until term
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vehicle | Stillbirths | 3 Participants |
| 17P (Hydroxyprogesterone Caproate Injection) | Stillbirths | 12 Participants |