RCT of Progesterone to Prevent Preterm Birth in Nulliparous Women With a Short Cervix

Study Overview
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Brief Summary
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The purpose of this study is to see if giving progesterone medication to pregnant women, who have never delivered a baby after 19 weeks of pregnancy and who have a short cervix, lowers the risk of early delivery and improves the health of their baby.

Detailed Description
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Preterm births, defined as the delivery of a baby less than 37 weeks of gestation, are responsible for the majority of neonatal mortality and morbidities. Studies have shown that a number of risk factors, including never having a baby before and having a short cervix are associated with early delivery. Recently the NICHD did a study in women who were pregnant again after having delivered preterm. It showed that giving 17 alpha-hydroxyprogesterone caproate (17P) medication during pregnancy decreased the chance of delivering another preterm baby by 34%. This placebo-controlled randomized clinical trial will address the primary research question: does treatment with 17P initiated before 23 weeks of gestation prevent delivery prior to 37 weeks in nulliparous women with a singleton gestation who have a short cervix?

Official Title
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A Randomized Trial of 17 Alpha-Hydroxyprogesterone Caproate for Prevention of Preterm Birth in Nulliparous Women With a Short Cervix

Conditions
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Preterm Delivery, Cervical Length

Intervention / Treatment
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* Drug: 17 alpha-hydroxyprogesterone caproate
* Other: Placebo Oil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Nulliparous Cervical length as measured on transvaginal examination < 30mm between gestational ages of 16 weeks 0 days to 22 weeks 3 days Gestational age 16 weeks 3 days to 22 weeks 6 days at time of randomization Exclusion Criteria: Multifetal gestation Progesterone treatment after 14 weeks 6 days during current pregnancy Vaginal bleeding, heavier than spotting, after 15 weeks 6 days Amniotic membranes prolapsed beyond external os Preterm rupture of membranes Fetal anomaly Pregnancy without a viable fetus Current or planned cervical cerclage Congenital Mullerian abnormality of the uterus Contraindication to intra-muscular injections Hypertension requiring medication Diabetes managed with insulin or oral hypoglycemic agents DES exposure Cervical surgery such as cold knife conization Planned indicated preterm delivery Participation in another interventional study that influences age at delivery Participation in this trial in a previous pregnancy Prenatal care or delivery planned outside a MFMU Network center
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment with 17 alpha-hydroxyprogesterone caproate via weekly injections of 250 mg of 17p until 37 weeks gestation or delivery vs. weekly injections of placebo oil until 37 weeks gestation or delivery.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 17 alpha-hydroxyprogesterone caproate<br>250 mg of 17 alpha-hydroxyprogesterone caproate given by weekly injection until 37 weeks gestation or delivery | Drug: 17 alpha-hydroxyprogesterone caproate<br>* Coded study medication is sterile solution containing 250 mg/mL of 17 alpha-hydroxyprogesterone caproate in castor oil with benzyl benzoate and benzyl alcohol as a preservative; placebo is same without the active ingredient. Study drug is administered as weekly 1 ml intramuscular injections until 36 week 6 days of gestation or delivery, whichever occurs first.<br>* Other names: 17 AHP;|
| Placebo Comparator: Placebo<br>Placebo oil given by weekly injection until 37 weeks gestation or delivery. | Other: Placebo Oil<br>* Placebo oil is a 250 mg/mL solution of castor oil with benzyl benzoate and benzyl alcohol as a preservative<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Delivering Before 37 Weeks Gestation | Number of participants delivering before 37 weeks gestation by indication | Delivery before 37 weeks gestation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Gestational Age at Delivery | Mean gestational age at delivery | Delivery | 
| Number of Participants With Preterm Premature Rupture of Membranes |  | <37 weeks | 
| Number of Participants Who Delivered Before 35 Weeks Gestation | Delivery before 35 weeks gestation | Delivery | 
| Number of Participants Who Delivered Before 32 Weeks Gestation | Delivery before 32 weeks gestation | Delivery | 
| Number of Participants Who Delivered Before 28 Weeks Gestation | Delivery before 28 weeks gestation | Delivery | 
| Number of Participants Who Visited the Hospital Due to Preterm Labor | Number of participants who visited the hospital due to preterm labor before 37 weeks gestation | Between randomization and 37 weeks gestation | 
| Number of Participants Who Underwent Tocolytic Therapy | Number of participants who underwent tocolytic therapy during pregnancy | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Who Underwent Corticosteroid Therapy | Number of participants who underwent corticosteroid therapy in pregnancy | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Who Had a Cerclage Placement | Number of participants who had a cerclage placement | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Experiencing Gestational Hypertension or Preeclampsia |  | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants With Gestational Diabetes Mellitus |  | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Experiencing Cholestasis |  | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Who Experienced Placental Abruption |  | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Who Experienced Chorioamnionitis |  | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Who Had Cesarean Delivery |  | delivery | 
| Number of Participants Who Reported Side Effects | Number of participants who reported any side effect, nausea, urticaria, and/or an issue at the injection site | Any time during pregnancy from randomization to delivery, a timeframe up to 20 weeks | 
| Number of Participants Meeting the Composite Adverse Perinatal Outcome and Components | comprised of fetal or infant death, respiratory distress syndrome, intraventricular hemorrhage (grades 3 and 4), periventricular leukomalacia, necrotizing enterocolitis (stage II and III), Bronchopulmonary dysplasia /chronic lung disease, retinopathy of prematurity (stage III or higher), early onset sepsis | within 72 hours of delivery | 
| Mean Birth Weight | Birth weight as measured in grams | Delivery | 
| Birth Weight by Count of Participants | Birth weight by count of participants < 2500 grams and < 1500 grams | Delivery | 
| Number of Neonates Who Measured Small for Gestational Age | Birth weight percentile and small for gestational age <10th percentile based on number of weeks and gender. | Delivery | 
| Number of Participants With Apgar Score of Less Than 7 at 5 Minutes | The Apgar score is a simple method of quickly assessing the health and vital signs of a newborn baby created by and named after Dr. Virginia Apgar. Apgar testing assesses Appearance, Pulse, Grimace and Activity in a newborn and is typically done at one and five minutes after a baby is born, and it may be repeated at 10, 15, and 20 minutes if the score is low. The five criteria are each scored as 0, 1, or 2 (two being the best), and the total score is calculated by then adding the five values obtained. Agar scores of 0-3 are critically low, 4-6 are below normal, and indicate that the baby likely requires medical intervention, scores of 7+ are considered normal. The lower the Apgar score, the more alert the medical team should be to the possibility of the baby requiring intervention. Some components of the Apgar score are subjective, and there are cases in which a baby requires urgent medical treatment despite having a high Apgar score. | 5 minutes post delivery | 
| Number of Neonates With a Major Congenital Anomaly | Presence of a major congenital anomaly at birth | Delivery | 
| Number of Neonates With Patent Ductus Arteriosus | Number of neonates diagnosed with the heart defect patent ductus arteriosus | Delivery through neonatal discharge | 
| Number of Neonates Experiencing Seizures | Number of neonates experiencing seizures from delivery to hospital discharge | Delivery through neonatal discharge | 
| Number of Neonates Admitted to NICU | Admission to the neonatal intensive care unit | Delivery through hospital discharge | 
| Median Length of NICU Stay | Median length of stay in the neonatal intensive care unit in days | NICU admission through NICU discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nulliparous, pregnancy, short cervix, progesterone