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.

Condition	Treatment or Intervention	Phase
Preterm birth Pregnancy, multiple	Drug: 17 alpha-hydroxyprogesterone caproate	Phase III

Further Study Details: 

Primary Outcomes: Delivery prior to 35 weeks 0 days gestation
Secondary Outcomes: MATERNAL OUTCOMES:; *Randomization to delivery interval of first fetus; *pPROM – spontaneous rupture of the membranes at least one hour prior to the start of labor, regular contractions accompanied by cervical change; *Indicated preterm delivery; *Spontaneous preterm delivery; *Cesarean delivery; *Gestational age at delivery; *Placement of cervical cerclage; *Maternal hospital days; *Maternal complications such as preeclampsia, gestational diabetes, placental abruption, chorioamnionitis.; NEONATAL OUTCOMES:; *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; *Fetal and neonatal death; *Stillbirth; *Twin-twin transfusion syndrome; *Birth weight and degree of birth weight discordance; *Infant days in hospital, *Respiratory distress syndrome (RDS); *Transient tachypnea of the newborn (TTN); *Bronchopulmonary dysplasia (BPD)/chronic lung disease; *Persistent pulmonary hypertension of the newborn (PPHN; *Duration of ventilator support; *Duration of supplemental oxygen; *Periventricular leukomalacia (PVL); *Intraventricular hemorrhage (IVH); *Necrotizing enterocolitis (NEC); *Neonatal sepsis/meningitis/urinary tract infection/ pneumonia; *Seizures, as documented by the attending physician; *Retinopathy of prematurity (ROP); *Small for gestational age (<10th percentile).
Expected Total Enrollment:  720

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.

Genders Eligible for Study:  Female

Accepts Healthy Volunteers

Criteria

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.

Alabama
      University of Alabama - Birmingham, Birmingham,  Alabama,  35233,  United States; Recruiting
Illinois
      Northwestern University, Chicago,  Illinois,  60611,  United States; Recruiting
Michigan
      Wayne State University, Detroit,  Michigan,  48201,  United States; Recruiting
New York
      Columbia University, New York,  New York,  10032,  United States; Recruiting
North Carolina
      Wake Forest University School of Medicine, Winston Salem,  North Carolina,  27157,  United States; Recruiting
      University of North Carolina - Chapel Hill, Chapel Hill,  North Carolina,  27599,  United States; Recruiting
Ohio
      Ohio State University, Columbus,  Ohio,  43210,  United States; Recruiting
      Case Western University, Cleveland,  Ohio,  44109,  United States; Recruiting
Pennsylvania
      University of Pittsburgh Magee Womens Hospital, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
      Dexel University, Philadelphia,  Pennsylvania,  19107,  United States; Recruiting
Rhode Island
      Brown University, Providence,  Rhode Island,  02905,  United States; Recruiting
Texas
      University of Texas - Southwest, Dallas,  Texas,  75235,  United States; Recruiting
      University of Texas - Houston, Houston,  Texas,  77030,  United States; Recruiting
Utah
      University of Utah Medical Center, Salt Lake City,  Utah,  84132,  United States; Recruiting

Study chairs or principal investigators

Catherine Spong, MD,  Study Director,  National Institute of Child Health and Human Development (NICHD)   
Elizabeth A Thom, Ph.D.,  Principal Investigator,  George Washington University Biostatistics Center   
Dwight Rouse, MD,  Study Chair,  University of Alabama, Birmingham   
Steve N Caritis, MD,  Study Chair,  University of Pittsburgh - Magee Womens Hospital   

Study ID Numbers:  HD36801-STTARS; HD21410; HD27869; HD27917; HD27860; HD27915; HD34116; HD34208; HD34136; HD40500; HD40485; HD40544; HD40545; HD40560; HD40512; HD36801
Record last reviewed:  March 2005
Last Updated:  March 29, 2005
Record first received:  December 8, 2004
ClinicalTrials.gov Identifier:  NCT00099164
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08