Confirmatory Study of 17P Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery (PROLONG)

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Preterm Birth	Drug: Hydroxyprogesterone Caproate Injection, 250mg/mL; Drug: Vehicle	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1710 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	A Phase 3B, Multi-Center, Randomized, Double-Blind Study of Hydroxyprogesterone Caproate Injection, 250 mg/mL, Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery
Study Start Date :	October 2009
Estimated Primary Completion Date :	October 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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Arm	Intervention/treatment
Placebo Comparator: Vehicle; Castor Oil	Drug: Vehicle; Weekly intramuscular injections of 1 mL vehicle inert oil until 36 weeks, 6 days of gestation or delivery, whichever occurs first.; Other Name: Placebo
Active Comparator: Hydroxyprogesterone Caproate Injection, 250 mg/mL; HPC 250 mg/mL in oil	Drug: Hydroxyprogesterone Caproate Injection, 250mg/mL; 1 mL intramuscular injection every week until 36 weeks, 6 days of gestation or delivery, whichever occurs first.; Other Names: Makena; 17P

Outcome Measures

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Primary Outcome Measures :

1. 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: Delivery ]
   Co-primary endpoint #1
2. Determine if 17P reduces the rate of neonatal mortality or morbidity [ Time Frame: 28 days of life or discharge from the NICU ]
   Co-primary endpoint #2 Neonatal mortality or morbidity is measured by a composite index comprised of: Neonatal death, Grade 3 or 4 intraventricular hemorrhage, Respiratory distress syndrome, Bronchopulmonary dysplasia, Necrotizing enterocolitis, Proven sepsis

Secondary Outcome Measures :

1. Exclude a doubling of the risk of fetal/early infant death [ Time Frame: Delivery ]
   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
2. Preterm birth prior to 32 weeks 0 days of gestation [ Time Frame: Delivery ]
3. Preterm birth prior to 37 weeks 0 days of gestation [ Time Frame: Delivery ]
4. Neonatal death (from minutes after birth until 28 days of life) occurring in liveborns born at 24 weeks gestation or greater [ Time Frame: 28 days of life or discharge from the NICU ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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Sponsors and Collaborators

AMAG Pharmaceuticals, Inc.

ResearchPoint Global

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	AMAG Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT01004029 History of Changes
Other Study ID Numbers:	17P-ES-003
First Posted:	October 29, 2009
Last Update Posted:	April 9, 2018
Last Verified:	April 2018

Keywords provided by AMAG Pharmaceuticals, Inc.:

17P; hydroxyprogesterone caproate; preterm birth; progesterone; women with a singleton pregnancy aged 18 years or older with a history of a previous singleton spontaneous preterm delivery

Additional relevant MeSH terms:

Premature Birth; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; 17-alpha-hydroxy-progesterone caproate; 11-hydroxyprogesterone	Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Progestins; Hormones