Trial of Progesterone in Twins and Triplets to Prevent Preterm Birth (STTARS)

Study Overview
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Brief Summary
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Women pregnant with twins or triplets are at high risk of preterm birth, yet no intervention or approach has served to reduce this risk. A recently completed trial by the NICHD sponsored Maternal Fetal Medicine Units (MFMU) Network has, for the first time, demonstrated a treatment that substantially reduces the rate of preterm birth in women at high risk for preterm delivery (i.e. progesterone therapy). Preterm birth was reduced by 35% among progesterone-treated women with a singleton pregnancy when compared with women receiving placebo. The current trial compares weekly treatment by injection of progesterone with placebo in women pregnant with twins or triplets.

Detailed Description
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Women with multifetal gestation face numerous risks in excess of those faced by women with singleton gestation. Preterm birth is by far the most common and the most significant of these problems, yet no intervention or approach has served to reduce this risk. The prevalence of preterm birth has risen dramatically in recent years, in large part due to Assisted Reproductive Technologies. Consequently, the problem of preterm birth has assumed an even greater role in contributing to perinatal morbidity and mortality. The recently completed trial by the NICHD sponsored Maternal Fetal Medicine Units (MFMU) Network has, for the first time, demonstrated a treatment (i.e. progesterone therapy) that substantially reduces the rate of preterm birth in women at high risk for preterm delivery because of a prior spontaneous preterm birth . Preterm birth was reduced by 35% among progesterone-treated women when compared with women receiving placebo. Given this dramatic benefit and the extremely high risk of preterm birth in women with multifetal gestation, a trial to evaluate the benefit of progesterone in women with multifetal pregnancy is appropriate and timely. This protocol outlines a randomized, double-masked clinical trial comparing weekly treatment by injection of 17 alpha-hydroxyprogesterone caproate (17P) with placebo in women with twin or triplet gestation. In an ancillary study, the pharmacokinetics and pharmacodynamics of 17P in multifetal gestation will be studied. This trial aims to enroll six hundred women with twin gestation and one hundred twenty women with triplet gestation between 16 weeks 0 days to 20 weeks 6 days. At the initial screening evaluation, and after signing the informed consent form, the patient will receive an injection of the placebo (1 ml inert castor oil). She will be asked to return after three days for randomization. During this compliance test period, an ultrasound exam will be scheduled, if not previously done. When the patient returns and if she still meets the inclusion criteria, she will be randomized to one of two treatments: 17 a-hydroxyprogesterone caproate: weekly 1 ml injections containing 250 mg of 17P Placebo: weekly injections of 1 ml placebo inert castor oil Treatment will be given through 34 weeks 6 days gestation or delivery. At the time of consent to the main study, the patient will also be asked to participate in an ancillary study. If she agrees, she will have 30 cc of blood drawn at 24-28 weeks and at 32-35 weeks gestation. A pelvic exam will be done at the same two times to collect vaginal specimens and to determine Bishop score.

Official Title
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A Randomized Trial of 17 Alpha-Hydroxyprogesterone Caproate for Prevention of Preterm Birth in Multifetal Gestation (STTARS)

Conditions
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Preterm Birth, Pregnancy, Multifetal

Intervention / Treatment
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* Drug: 17 alpha-hydroxyprogesterone caproate (17P)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Twin or triplet pregnancy. Quadruplets reduced to triplets may be included, but no other prior reductions. Gestational age between 16 weeks 0 days to 20 weeks 6 days based on clinical information and evaluation of the first ultrasound. Signed patient authorization and consent form. Exclusion Criteria: Prior elective fetal reduction in the current pregnancy, except in the case of a quadruplet gestation reduced to triplets. Planned fetal reduction or planned termination Monoamniotic gestation Twin-twin transfusion syndrome Fetal death or imminent fetal demise Major fetal anomaly (e.g., gastroschisis, spina bifida, serious karyotypic abnormalities). An ultrasound examination from 12 weeks 0 days to 20 weeks 6 days by project estimated date of confinement (EDC) must be performed to rule out fetal anomalies Discordance in fetal size, defined as a discrepancy of 3 or more weeks in gestational age by ultrasound between the largest and the smallest fetus. Diagnosis is based on measurements made at the ultrasound done between 12 weeks 0 days and 20 weeks 6 days gestation Progesterone treatment used or planned after 14 weeks gestation Heparin therapy at a dose ≥ 10,000 units per day of unfractionated heparin, or any low molecular weight heparin during the current pregnancy, or thromboembolic disease for which such heparin treatment is planned (because of contraindication to intra-muscular injections) Current or planned cervical cerclage Uterine anomaly (uterine didelphys, bicornate uterus) Contraindication to intra-muscular injections Maternal medical conditions, such as: known idiopathic thrombocytopenia purpura (ITP) or a known platelet count less than 100,000 per cubic millimeter (because of contraindication to intra-muscular injections), hypertension requiring medication, diabetes managed with insulin or oral hypoglycemic agents Inability to arrange a pre-randomization ultrasound between 12 weeks 0 days and 20 weeks 6 days gestation Participation in another interventional study that influences gestational age at delivery or neonatal morbidity or mortality Prenatal follow-up or delivery planned elsewhere (unless the study visits can be made as scheduled and complete outcome information can be obtained) Participation in this trial in a previous pregnancy.
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
Masking: Triple


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: 17 alpha-hydroxyprogesterone caproate (17P)|Study coded medication is 250 mg of 17P as a 1 ml intramuscular injection (or 1 ml of placebo inert oil). Patients are seen weekly to administer the study drug through 34 weeks 6 days gestation or delivery, whichever occurs first.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delivery prior to 35 weeks 0 days gestation |  | Delivery Date | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal randomization to delivery interval of first fetus |  | Delivery | 
| pPROM - spontaneous rupture of the membranes at least one hour prior to the start of labor, regular contractions accompanied by cervical change |  | Duration of pregnancy | 
| Indicated preterm delivery |  | Delivery | 
| Spontaneous preterm delivery |  | Delivery | 
| Cesarean delivery |  | Delivery | 
| Gestational age at delivery |  | Length of pregnancy | 
| Placement of cervical cerclage |  | During pregnancy | 
| Maternal hospital days |  | Delivery | 
| Maternal complications such as preeclampsia, gestational diabetes, placental abruption, chorioamnionitis. |  | Duration of pregnancy, delivery | 
| Composite neonatal outcome, comprised of fetal or infant death, RDS, IVH (grades 3 and 4), PVL, NEC (stage II and III), BPD/chronic lung disease, ROP (stage III or higher), early onset sepsis including meningitis |  | Early life | 
| Fetal and neonatal death |  | Delivery, Early life | 
| Stillbirth |  | Delivery | 
| Twin-twin transfusion syndrome |  | During pregnancy | 
| Birth weight and degree of birth weight discordance |  | Birth | 
| Infant days in hospital, *Respiratory distress syndrome (RDS) |  | Early life | 
| Transient tachypnea of the newborn (TTN) |  | Early life | 
| Bronchopulmonary dysplasia (BPD)/chronic lung disease |  | Early life | 
| Persistent pulmonary hypertension of the newborn (PPHN) |  | Early life | 
| Duration of ventilator support |  | Early life | 
| Duration of supplemental oxygen |  | Early life | 
| Periventricular leukomalacia (PVL) |  | Early life | 
| Intraventricular hemorrhage (IVH) |  | Early life | 
| Necrotizing enterocolitis (NEC) |  | Early life | 
| Neonatal sepsis/meningitis/urinary tract infection/ pneumonia |  | Early life | 
| Seizures, as documented by the attending physician |  | Early life | 
| Retinopathy of prematurity (ROP) |  | Early life | 
| Small for gestational age (<10th percentile). |  | Early life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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preterm birth, pregnancy, multifetal, Progesterone