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

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.

Study Type: Interventional

Study Design: Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: August 2006

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.

Intervention(s) in this Clinical Trial

• 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.

Primary Measures

• Delivery prior to 35 weeks 0 days gestation
  • Time Frame: Delivery Date
    Safety Issue?: No

Secondary Measures

• Maternal randomization to delivery interval of first fetus
  • Time Frame: Delivery
    Safety Issue?: No
• pPROM - spontaneous rupture of the membranes at least one hour prior to the start of labor, regular contractions accompanied by cervical change
  • Time Frame: Duration of pregnancy
    Safety Issue?: No
• Indicated preterm delivery
  • Time Frame: Delivery
    Safety Issue?: No
• Spontaneous preterm delivery
  • Time Frame: Delivery
    Safety Issue?: No
• Cesarean delivery
  • Time Frame: Delivery
    Safety Issue?: No
• Gestational age at delivery
  • Time Frame: Length of pregnancy
    Safety Issue?: No
• Placement of cervical cerclage
  • Time Frame: During pregnancy
    Safety Issue?: No
• Maternal hospital days
  • Time Frame: Delivery
    Safety Issue?: No
• Maternal complications such as preeclampsia, gestational diabetes, placental abruption, chorioamnionitis.
  • Time Frame: Duration of pregnancy, delivery
    Safety Issue?: No
• 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
  • Time Frame: Early life
    Safety Issue?: No
• Fetal and neonatal death
• Stillbirth
• Twin-twin transfusion syndrome
  • Time Frame: During pregnancy
    Safety Issue?: No
• Birth weight and degree of birth weight discordance
  • Time Frame: Birth
    Safety Issue?: No
• Infant days in hospital, *Respiratory distress syndrome (RDS)
  • Time Frame: Early life
    Safety Issue?: No
• Transient tachypnea of the newborn (TTN)
  • Time Frame: Early life
    Safety Issue?: No
• Bronchopulmonary dysplasia (BPD)/chronic lung disease
  • Time Frame: Early life
    Safety Issue?: No
• Persistent pulmonary hypertension of the newborn (PPHN)
  • Time Frame: Early life
    Safety Issue?: No
• Duration of ventilator support
  • Time Frame: Early life
    Safety Issue?: No
• Duration of supplemental oxygen
  • Time Frame: Early life
    Safety Issue?: No
• Periventricular leukomalacia (PVL)
  • Time Frame: Early life
    Safety Issue?: No
• Intraventricular hemorrhage (IVH)
  • Time Frame: Early life
    Safety Issue?: No
• Necrotizing enterocolitis (NEC)
  • Time Frame: Early life
    Safety Issue?: No
• Neonatal sepsis/meningitis/urinary tract infection/ pneumonia
  • Time Frame: Early life
    Safety Issue?: No
• Seizures, as documented by the attending physician
  • Time Frame: Early life
    Safety Issue?: No
• Retinopathy of prematurity (ROP)
  • Time Frame: Early life
    Safety Issue?: No
• Small for gestational age (<10th percentile).
  • Time Frame: Early life
    Safety Issue?: No

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.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: National Institute of Child Health and Human Development (NICHD)

Overall Clinical Trial Officials and Contacts

Catherine Spong, MD Study Director National Institute of Child Health and Human Development (NICHD)  

Information obtained from ClinicalTrials.gov on August 21, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00099164

Study ID Number: HD36801-STTARS

ClinicalTrials.gov Identifier: NCT00099164

Health Authority: United States: Federal Government

The public website of the NICHD Maternal Fetal Medicine Units (MFMU) Network