E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036594 |
E.1.2 | Term | Premature birth |
E.1.2 | System Organ Class | 100000004868 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
There are two co-primary objectives of this study 1. Determine if treatment with 17P reduces the rate of preterm birth < 35 weeks of gestation in women with a singleton pregnancy, aged 18 years or older, with a previous singleton spontaneous preterm delivery. 2. Determine if 17P reduces the rate of neonatal mortality or morbidity. 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. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to: • Exclude a doubling of the risk of fetal/early infant death, defined as spontaneous abortion/miscarriage (delivery from 16 through 19 weeks 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. •Determine if 17P reduces the rate of preterm birth < 32 weeks of gestation. •Determine if 17P reduces the rate of preterm birth < 37 weeks of gestation. •Determine if 17P reduces the rate of stillbirth defined as all stillbirths/fetal deaths/in-utero fetal losses occurring from 20 weeks gestation until term. •Determine if 17P reduces the rate of neonatal death (from minutes after birth until 28 days of life) occurring in liveborns born at 24 weeks gestation or greater. •Evaluate the PK/PD of 17P in a subset of pregnant women. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The main protocol (17P-ES-003) includes a PK sub-study. Title" Evaluation of pharmacokinetic of 17p in subgroup of pregnant women" Subjects may be offered the opportunity to participate in a pharmacokinetic sub-study until approximately 450 subjects (300 active and 150 vehicle) have been enrolled.
Pharmacokinetic assessments will be made based on a sparse sampling stratified according to pre-pregnancy BMI to analyze the dose-plasma concentration-time relationship of HPC. |
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E.3 | Principal 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 of gestation or more and less than or equal to 20 weeks of gestation at the time of randomization, based on clinical information and evaluation of the first ultrasound, as described in “Gestational Age Determination” below. 4. Documented history of a previous singleton spontaneous preterm delivery. Spontaneous preterm birth is defined as delivery from 20 to 36 weeks 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” below. 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. |
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E.4 | Principal exclusion criteria |
1. Multifetal gestation. 2. Known major fetal anomaly or fetal demise. An ultrasound examination between 14 through 20 weeks of gestation must be performed to rule out fetal anomalies. 3. Subjects who have received a progestin during the current pregnancy AND meet one of the following criteria are excluded. 3.1. The progestin was administered in the 4 weeks preceding the first dose of study medication 3.2. Subjects received hydroxyprogesterone caproate 3.3. The progestin was administered by a route other than oral or intra-vaginal. 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 through 20 weeks 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 injection 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 the following list from section 5.3.2 of the investigational brochure: •Current or history of thrombosis or thromboembolic disorders •Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions • Undiagnosed abnormal vaginal bleeding unrelated to pregnancy • Cholestatic jaundice of pregnancy •Liver tumors, benign or malignant, or active liver disease •Uncontrolled hypertension 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 subjects condition or outcome or compromise the subjects safety in the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
There are two primary outcomes: •Preterm birth prior to 35 weeks of gestation •Composite neonatal morbidity and mortality index. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Date of delivery and estimated date of confinement [EDC] 2. 28 days post delivery date or date of discharge from Neonatal Intensive care [NICU], whichever is the later |
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E.5.2 | Secondary end point(s) |
The secondary outcomes include: •Fetal/early infant death. Spontaneous abortion/miscarriage or neonatal death. •Preterm birth prior to 32 weeks of gestation (as determined by project gestational age). • Preterm birth prior to 37 weeks of gestation (as determined by project gestational age). •Neonatal death. •Dose-plasma concentration-time data according to timepoint. •Pharmacokinetic models to evaluate effects on concomitant medications. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Date of delivery or spontaneous abortion/miscarriage 2. 28 days post delivery date or date of discharge from Neonatal Intensive care [NICU], whichever is the later |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Canada |
Czech Republic |
Hungary |
Italy |
Mexico |
Romania |
Russian Federation |
Serbia |
Spain |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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As stated in the Protocol |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |