A Trial of Pessary and Progesterone for Preterm Prevention in Twin Gestation With a Short Cervix

This protocol outlines a randomized trial of 630 women evaluating the use of micronized
vaginal progesterone or pessary versus control (placebo) to prevent early preterm birth in
women carrying twins and with a cervical length of less than 30 millimeters.

Multiple gestation increases the risk of preterm delivery. Babies born preterm have increased
rates of neonatal mortality and long-term neurodevelopmental morbidities. Short cervical
length is known to be an important risk factor for spontaneous preterm birth and to occur
more frequently in women with a twin gestation. Although there is no evidence that
progesterone reduces the risk of preterm birth in multifetal gestation, there is evidence
that progesterone reduces the risk of prematurity in singleton gestations complicated with a
short cervix. The Arabin pessary has also been shown to reduce the risk of preterm birth
among singletons with a short cervix, and in a secondary subgroup analysis of a recent study
of the use of pessary in multiple gestations, women with a cervical length < 25th percentile
had a significantly reduced risk of the primary composite neonatal adverse outcome. Secondary
analysis of studies of vaginal progesterone in multiple gestation with a short cervix also
suggest a possible beneficial effect on preterm delivery.

Inclusion Criteria:

1. Twin gestation with cardiac activity in both fetuses. Higher order multifetal
gestations reduced to twins, either spontaneously or therapeutically, are not eligible
unless the reduction occurred by 13 weeks 6 days project gestational age.

2. Gestational age at randomization between 16 weeks 0 days and 23 weeks 6 days based on
clinical information and evaluation of the earliest ultrasound.

3. Cervical length on transvaginal examination of less than 30 mm within 10 days prior to
randomization by a study certified sonographer.

Exclusion Criteria:

1. Cervical dilation (internal os) 3 cm or greater on digital examination or evidence of
prolapsed membranes beyond the external cervical os either at the time of the
qualifying cervical ultrasound examination or at a cervical exam immediately before
randomization. There is no lower threshold of cervical length measurement threshold on
ultrasound that is an exclusion criterion.

2. Monoamniotic gestation, due to increased risk of adverse pregnancy outcome

3. Twin-twin transfusion syndrome, due to increased risk of adverse pregnancy outcome

4. Evidence of severe IUGR (intrauterine growth restriction) (<5th percentile for
gestational age) in either fetus

5. Fetal anomaly in either twin or imminent fetal demise. This includes lethal anomalies,
or anomalies that may lead to early delivery or increased risk of neonatal death e.g.,
gastroschisis, spina bifida, serious karyotypic abnormalities). An ultrasound
examination from 14 weeks 0 days to 23 weeks 6 days by project EDC (estimated date of
conception) must be performed prior to randomization to evaluate the fetuses for
anomalies.

6. Placenta previa, because of risk of bleeding and high potential for indicated preterm
birth

7. Active vaginal bleeding greater than spotting at the time of randomization, because of
potential exacerbation due to pessary placement.

8. Symptomatic, untreated vaginal or cervical infection, also because of potential
exacerbation due to pessary placement. Patients may be treated and if subsequently
asymptomatic, randomized.

9. Active, unhealed herpetic lesion on labia minora, vagina, or cervix due to the
potential for significant patient discomfort or increasing genital tract viral spread.
Once lesion(s) heal and the patient is asymptomatic, she may be randomized. History of
herpes is not an exclusion.

10. Rupture of membranes due to likelihood of pregnancy loss and preterm delivery as well
as the risk of ascending infection which could be increased with pessary placement

11. More than six contractions per hour reported or documented prior to randomization. It
is not necessary to place the patient on a tocodynamometer

12. Known major Mullerian anomaly of the uterus (specifically bicornuate, unicornuate, or
uterine septum not resected) due to increased risk of preterm delivery which is
unlikely to be affected by progesterone

13. Any fetal/maternal condition which would require invasive in-utero assessment or
treatment, for example significant red cell antigen sensitization or neonatal
alloimmune thrombocytopenia

14. Major maternal medical illness associated with increased risk for adverse pregnancy
outcome or indicated preterm birth (treated hypertension requiring more than one
agent, pre-gestational treatment for diabetes prior to pregnancy, chronic renal
insufficiency failure defined by creatinine >1.4 mg/dL, carcinoma of the breast,
conditions treated with chronic oral glucocorticoid therapy. Specifically, patients
with seizure disorders, HIV, and other medical conditions not specifically associated
with an increased risk of indicated preterm birth are not excluded. Prior cervical
cone/LOOP/LEEP is not an exclusion criterion.

15. Planned cerclage or cerclage already in place since it would preclude placement of a
pessary

16. Planned indicated delivery prior to 35 weeks

17. Planned or actual progesterone treatment of any type or form after 14 weeks 6 days
during the current pregnancy

18. Allergy to progesterone, silicone, or excipients in the study drug, including peanuts
or peanut oil in the study drug or placebo

19. Known, suspected or history of breast cancer because breast cancer is a
contraindication to the active study medication.

20. Known liver dysfunction or disease because liver disease is a contraindication to the
active study medication.

21. Participation in another interventional study that influences gestational age at
delivery or neonatal morbidity or mortality

22. Participation in this trial in a previous pregnancy. Patients who were screened in a
previous pregnancy, but not randomized, do not have to be excluded.

23. Prenatal care or delivery planned elsewhere unless the study visits can be made as
scheduled and complete outcome information can be obtained