Clinical trial NCT00099164: Trial of Progesterone in Twins and Triplets to Prevent Preterm Birth (STTARS)
Official title: A Randomized Trial of 17 Alpha-Hydroxyprogesterone Caproate for Prevention of Preterm Birth in Multifetal Gestation (STTARS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Preterm Birth
Pregnancy
Multifetal
Keywords: preterm birth
pregnancy
multifetal
Progesterone
Lead sponsor: The George Washington University Biostatistics Center
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2004-12-09
Enrollment: 795
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility 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.

Primary outcomes:
measure: Delivery prior to 35 weeks 0 days gestation
timeFrame: Delivery Date
Secondary outcomes:
measure: Maternal randomization to delivery interval of first fetus
timeFrame: Delivery
measure: pPROM - spontaneous rupture of the membranes at least one hour prior to the start of labor, regular contractions accompanied by cervical change
timeFrame: Duration of pregnancy
measure: Indicated preterm delivery
timeFrame: Delivery
measure: Spontaneous preterm delivery
timeFrame: Delivery
measure: Cesarean delivery
timeFrame: Delivery
measure: Gestational age at delivery
timeFrame: Length of pregnancy
measure: Placement of cervical cerclage
timeFrame: During pregnancy
measure: Maternal hospital days
timeFrame: Delivery
measure: Maternal complications such as preeclampsia, gestational diabetes, placental abruption, chorioamnionitis.
timeFrame: Duration of pregnancy, delivery
measure: 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
timeFrame: Early life
measure: Fetal and neonatal death
timeFrame: Delivery, Early life
measure: Stillbirth
timeFrame: Delivery
measure: Twin-twin transfusion syndrome
timeFrame: During pregnancy
measure: Birth weight and degree of birth weight discordance
timeFrame: Birth
measure: Infant days in hospital, *Respiratory distress syndrome (RDS)
timeFrame: Early life
measure: Transient tachypnea of the newborn (TTN)
timeFrame: Early life
measure: Bronchopulmonary dysplasia (BPD)/chronic lung disease
timeFrame: Early life
measure: Persistent pulmonary hypertension of the newborn (PPHN)
timeFrame: Early life
measure: Duration of ventilator support
timeFrame: Early life
measure: Duration of supplemental oxygen
timeFrame: Early life
measure: Periventricular leukomalacia (PVL)
timeFrame: Early life
measure: Intraventricular hemorrhage (IVH)
timeFrame: Early life
measure: Necrotizing enterocolitis (NEC)
timeFrame: Early life
measure: Neonatal sepsis/meningitis/urinary tract infection/ pneumonia
timeFrame: Early life
measure: Seizures, as documented by the attending physician
timeFrame: Early life
measure: Retinopathy of prematurity (ROP)
timeFrame: Early life
measure: Small for gestational age (<10th percentile).
timeFrame: Early life
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University School of Medicine
state: North Carolina
city: Cleveland
country: United States
facility: Case Western University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Dexel University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Magee Womens Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas - Southwest
state: Texas
city: Houston
country: United States
facility: University of Texas - Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Medical Center
state: Utah
Study officials:
affiliation: NICHD Project Scientist
name: Menachem Miodovnik, M.D.
role: STUDY_DIRECTOR
affiliation: George Washington University Biostatistics Center
name: Elizabeth A Thom, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Dwight Rouse, MD
role: STUDY_CHAIR
affiliation: University of Pittsburgh - Magee Womens Hospital
name: Steve N Caritis, MD
role: STUDY_CHAIR
References:
citation: Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12;348(24):2379-85. doi: 10.1056/NEJMoa035140.
citation: Kogan MD, Alexander GR, Kotelchuck M, MacDorman MF, Buekens P, Papiernik E. A comparison of risk factors for twin preterm birth in the United States between 1981-82 and 1996-97. Matern Child Health J. 2002 Mar;6(1):29-35. doi: 10.1023/a:1014312132443.
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citation: Min SJ, Luke B, Gillespie B, Min L, Newman RB, Mauldin JG, Witter FR, Salman FA, O'sullivan MJ. Birth weight references for twins. Am J Obstet Gynecol. 2000 May;182(5):1250-7. doi: 10.1067/mob.2000.104923.
citation: Lynch A, McDuffie R, Stephens J, Murphy J, Faber K, Orleans M. The contribution of assisted conception, chorionicity and other risk factors to very low birthweight in a twin cohort. BJOG. 2003 Apr;110(4):405-10.
citation: Goldenberg RL, Iams JD, Miodovnik M, Van Dorsten JP, Thurnau G, Bottoms S, Mercer BM, Meis PJ, Moawad AH, Das A, Caritis SN, McNellis D. The preterm prediction study: risk factors in twin gestations. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol. 1996 Oct;175(4 Pt 1):1047-53. doi: 10.1016/s0002-9378(96)80051-2.
citation: Caritis SN, Rouse DJ, Peaceman AM, Sciscione A, Momirova V, Spong CY, Iams JD, Wapner RJ, Varner M, Carpenter M, Lo J, Thorp J, Mercer BM, Sorokin Y, Harper M, Ramin S, Anderson G; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Maternal-Fetal Medicine Units Network (MFMU). Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Obstet Gynecol. 2009 Feb;113(2 Pt 1):285-92. doi: 10.1097/AOG.0b013e318193c677.
citation: Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA, Spong CY, Varner M, Malone F, Iams JD, Mercer BM, Thorp J, Sorokin Y, Carpenter M, Lo J, Ramin S, Harper M, Anderson G; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med. 2007 Aug 2;357(5):454-61. doi: 10.1056/NEJMoa070641.
citation: Gyamfi C, Horton AL, Momirova V, Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Meis PJ, Spong CY, Dombrowski M, Sibai B, Varner MW, Iams JD, Mercer BM, Carpenter MW, Lo J, Ramin SM, O'Sullivan MJ, Miodovnik M, Conway D; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The effect of 17-alpha hydroxyprogesterone caproate on the risk of gestational diabetes in singleton or twin pregnancies. Am J Obstet Gynecol. 2009 Oct;201(4):392.e1-5. doi: 10.1016/j.ajog.2009.06.036. Epub 2009 Aug 29.
citation: Blumenfeld YJ, Momirova V, Rouse DJ, Caritis SN, Sciscione A, Peaceman AM, Reddy UM, Varner MW, Malone FD, Iams JD, Mercer BM, Thorp JM Jr, Sorokin Y, Carpenter MW, Lo J, Ramin SM, Harper M; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Accuracy of sonographic chorionicity classification in twin gestations. J Ultrasound Med. 2014 Dec;33(12):2187-92. doi: 10.7863/ultra.33.12.2187.
citation: Caritis SN, Sharma S, Venkataramanan R, Rouse DJ, Peaceman AM, Sciscione A, Spong CY, Varner MW, Malone FD, Iams JD, Mercer BM, Thorp JM Jr, Sorokin Y, Carpenter M, Lo J, Ramin S, Harper M; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation. Am J Obstet Gynecol. 2011 Jul;205(1):40.e1-8. doi: 10.1016/j.ajog.2011.03.028. Epub 2011 Mar 22.