Confirmatory Study of 17P vs Vehicle for Prevention of Preterm Birth in Women w/ Previous Spontaneous Preterm Delivery

A Phase 3B, Multi-Center, Randomized, Double-Blind Study of Hydroxyprogesterone Caproate (HPC) Injection, 250 mg/mL, Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery

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.

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.

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.