Preterm Delivery, Short Cervix, Short Uterine Cervical Length
Conditions
Keywords
Preterm, Cervix
Brief summary
The purpose of this research study is to evaluate the usefulness of progesterone vaginal gel in decreasing the preterm birth rate in a population of pregnant women with short cervical length and at high risk for preterm birth.
Detailed description
A Short uterine cervical length in the mid-trimester is the most powerful predictor of preterm birth.
Interventions
DRUGprogesterone
8% vaginal gel, 1.125 Grams once daily, beginning at 19 0/7 to 23 6/7 weeks gestation through 36 6/7 weeks gestation
DRUGplacebo
vaginal gel, 1.125 Grams once daily, beginning at 19 0/7 to 23 6/7 weeks gestation through 36 6/7 weeks gestation
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Juniper Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
15 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. The subject has a short cervical length by transvaginal ultrasound (TVU) defined as 10-20mm. In cases of dynamic cervix, the shortest observed/documented cervical length by TVU is to be used as the cervical length for inclusion purposes. 2. Singleton gestation. 3. The pregnancy has an estimated gestational age between 19 0/7 weeks and 23 6/7 weeks. 4. Maternal age between 15 (or local age of majority/emancipation) and 45 years of age at the time of screening. An alternative age range can be accepted according to the standards and applicable regulations of the study centers. 5. The subject speaks either English or a common local language. 6. The subject has voluntarily signed the Informed Consent Form and associated forms after having the contents explained, and all her questions are answered to her satisfaction and understanding. 7. In the opinion of the investigator, the subject is able to understand the study and is able to give informed consent, as well as participate in it and adhere to study procedures.
Exclusion criteria
1. The subject has a cervical length \<10 or \>20mm. 2. The subject has a multifetal gestation. 3. The subject has or is scheduled to have a cervical cerclage prior to randomization. According to ACOG Practice Bulletin Number 48 (November 2003), cerclage can be considered in a subject with a history of 3 or more unexplained midtrimester pregnancy losses or preterm deliveries.228,229 4. Subjects diagnosed to have acute cervical insufficiency with bulging membranes passing the external os. 5. The subject has a previous history of an adverse reaction to progesterone or any component present in Prochieve® 8% vaginal gel. 6. The subject has been treated with a progestogen within the previous 4 weeks. 7. The subject is currently being treated for a seizure disorder, has an unstable psychiatric disorder, is taking antihypertensive therapy for chronic hypertension at the time of enrollment, has a history of congestive heart failure or chronic renal failure, or has uncontrolled diabetes mellitus (known end-organ dysfunction secondary to vascular disease). 8. The subject has active thrombophlebitis or a thromboembolic disorder, or a history of hormone-associated thrombophlebitis or thromboembolic disorders. 9. The subject has active liver dysfunction or disease. 10. The subject has known or suspected malignancy of the breast or genital organs. 11. The subject is currently participating in another interventional study or has participated in an interventional drug study within one month prior to screening for this study. 12. The subject's current pregnancy is complicated by a major fetal anomaly or known chromosomal abnormality. 13. The subject has a uterine anatomic malformation (bicornuate uterus, septate uterus) 14. The subject, in the judgment of the investigator, will be unable or unwilling to comply with study-related assessments and procedures. 15. The subject currently has preterm rupture of membranes, vaginal bleeding, known or suspected amnionitis, or signs or symptoms of preterm labor at the time of enrollment. 16. The subject is HIV positive with a CD4 count of \<350 cells/mm3 and is receiving more than one (1) medication to prevent the transfer of AIDS to the fetus. 17. Complete placenta previa.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Birth <=32 6/7 Weeks Gestation. | 9 to 13 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Delivery Hospitalization (1-212 days) | Each infant is scored based on the 7 morbidity and mortality events above: 0= no morbidity event 1. 1 morbidity event 2. 2 morbidity events 3. 3 or more morbidity events 4. mortality |
| Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation. | Gestational Age at Delivery | Number of participants at \<=27 6/7 , \<=34 6/7, and \<36 6/7. |
| Number of Neonates Who Died. | Delivery to 28 days | — |
| Number of Infants With a Birth Weight < 1500 Grams or < 2500 Grams | date of delivery | Assessment of birth weight \< 1500 grams or \< 2500 grams |
Countries
Belarus, Chile, Czechia, India, Israel, Italy, Russia, South Africa, Ukraine, United States
Participant flow
Recruitment details
March 2008 to June 2010
Participants by arm
| Arm | Count |
|---|---|
| Placebo placebo vaginal gel | 223 |
| Prochieve Progesterone 8% Vaginal Gel | 235 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 1 |
Baseline characteristics
| Characteristic | Placebo | Prochieve | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 223 Participants | 235 Participants | 458 Participants |
| Age Continuous | 26.2 years STANDARD_DEVIATION 5.1 | 26.5 years STANDARD_DEVIATION 5.8 | 26.4 years STANDARD_DEVIATION 5.5 |
| Region of Enrollment Belarus | 7 participants | 5 participants | 12 participants |
| Region of Enrollment Chile | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Czech Republic | 1 participants | 3 participants | 4 participants |
| Region of Enrollment India | 73 participants | 73 participants | 146 participants |
| Region of Enrollment Israel | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Italy | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Russian Federation | 0 participants | 1 participants | 1 participants |
| Region of Enrollment South Africa | 11 participants | 10 participants | 21 participants |
| Region of Enrollment Ukraine | 26 participants | 28 participants | 54 participants |
| Region of Enrollment United States | 100 participants | 107 participants | 207 participants |
| Sex: Female, Male Female | 223 Participants | 235 Participants | 458 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 | — / — | — / — |
| other Total, other adverse events | 24 / 223 | 30 / 235 |
| serious Total, serious adverse events | 98 / 224 | 97 / 235 |
Outcome results
Primary
Number of Participants With Birth <=32 6/7 Weeks Gestation.
Time frame: 9 to 13 weeks
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Birth <=32 6/7 Weeks Gestation. | 36 participants |
| Prochieve | Number of Participants With Birth <=32 6/7 Weeks Gestation. | 21 participants |
p-value: 0.0295% CI: [0.33, 0.92]Cochran-Mantel-Haenszel
Secondary
Number of Infants With a Birth Weight < 1500 Grams or < 2500 Grams
Assessment of birth weight \< 1500 grams or \< 2500 grams
Time frame: date of delivery
Population: Available birth weight.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Infants With a Birth Weight < 1500 Grams or < 2500 Grams | Birth weight < 1500 grams | 30 participants |
| Placebo | Number of Infants With a Birth Weight < 1500 Grams or < 2500 Grams | Birth weight < 2500 grams | 68 participants |
| Prochieve | Number of Infants With a Birth Weight < 1500 Grams or < 2500 Grams | Birth weight < 1500 grams | 15 participants |
| Prochieve | Number of Infants With a Birth Weight < 1500 Grams or < 2500 Grams | Birth weight < 2500 grams | 60 participants |
Comparison: Statistical analysis for birth weight \< 1500 grams data.p-value: 0.0195% CI: [0.26, 0.85]Cochran-Mantel-Haenszel
Comparison: Statistical analysis for birth weight \< 2500 grams data.p-value: 0.21395% CI: [0.62, 1.11]Cochran-Mantel-Haenszel
Secondary
Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC)
Each infant is scored based on the 7 morbidity and mortality events above: 0= no morbidity event 1. 1 morbidity event 2. 2 morbidity events 3. 3 or more morbidity events 4. mortality
Time frame: Delivery Hospitalization (1-212 days)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 0 | 192 participants |
| Placebo | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 1 | 11 participants |
| Placebo | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 2 | 8 participants |
| Placebo | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 3 | 0 participants |
| Placebo | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 4 | 11 participants |
| Placebo | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Infants with RDS | 17 participants |
| Prochieve | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 4 | 8 participants |
| Prochieve | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 0 | 217 participants |
| Prochieve | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 3 | 3 participants |
| Prochieve | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 1 | 5 participants |
| Prochieve | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Infants with RDS | 7 participants |
| Prochieve | Number of Infants With Neonatal Morbidities Such as Respiratory Distress Syndrome (RDS), Bronchopulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH), Proven Sepsis, and Necrotizing Enterocolitis (NEC) | Composite score 2 | 2 participants |
Comparison: Statistical analysis presented for composite score data.p-value: 0.048Cochran-Mantel-Haenszel
Comparison: Statistical analysis presented for RDS data.p-value: 0.02695% CI: [0.17, 0.92]Cochran-Mantel-Haenszel
Secondary
Number of Neonates Who Died.
Time frame: Delivery to 28 days
Population: All infants with a known delivery date and status.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Neonates Who Died. | 5 participants |
| Prochieve | Number of Neonates Who Died. | 3 participants |
p-value: 0.43195% CI: [0.14, 2.35]Cochran-Mantel-Haenszel
Secondary
Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation.
Number of participants at \<=27 6/7 , \<=34 6/7, and \<36 6/7.
Time frame: Gestational Age at Delivery
Population: Intent to Treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation. | Number of deliveries <= 27 6/7 weeks | 23 participants |
| Placebo | Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation. | Number of deliveries <= 34 6/7 weeks | 52 participants |
| Placebo | Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation. | Number of deliveries <= 36 weeks | 76 participants |
| Prochieve | Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation. | Number of deliveries <= 27 6/7 weeks | 12 participants |
| Prochieve | Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation. | Number of deliveries <= 34 6/7 weeks | 34 participants |
| Prochieve | Number of Subjects With Preterm Birth at ≤27 6/7, ≤34 6/7, and <36 6/7 Weeks Gestation. | Number of deliveries <= 36 weeks | 71 participants |
Comparison: Statistical analysis presented for births \<=27 6/7 weeks data.p-value: 0.03695% CI: [0.25, 0.97]Cochran-Mantel-Haenszel
Comparison: Statistical analysis presented for \<= 34 6/7 weeks data.p-value: 0.01695% CI: [0.42, 0.92]Cochran-Mantel-Haenszel
Comparison: Statistical analysis presented for \<36 weeks data.p-value: 0.37695% CI: [0.68, 1.16]Cochran-Mantel-Haenszel