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

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.

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.