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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Short Cervical Length

Intervention / Treatment
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* Drug: Vaginal progesterone
* Drug: Placebo
* Device: Arabin Pessary


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Gestational age at randomization between 16 weeks 0 days and 23 weeks 6 days based on clinical information and evaluation of the earliest ultrasound. Cervical length on transvaginal examination of less than 30 mm within 10 days prior to randomization by a study certified sonographer. Exclusion Criteria: 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. Monoamniotic gestation, due to increased risk of adverse pregnancy outcome Twin-twin transfusion syndrome, due to increased risk of adverse pregnancy outcome Evidence of severe IUGR (intrauterine growth restriction) (<5th percentile for gestational age) in either fetus 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. Placenta previa, because of risk of bleeding and high potential for indicated preterm birth Active vaginal bleeding greater than spotting at the time of randomization, because of potential exacerbation due to pessary placement. Symptomatic, untreated vaginal or cervical infection, also because of potential exacerbation due to pessary placement. Patients may be treated and if subsequently asymptomatic, randomized. 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. 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 More than six contractions per hour reported or documented prior to randomization. It is not necessary to place the patient on a tocodynamometer 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 Any fetal/maternal condition which would require invasive in-utero assessment or treatment, for example significant red cell antigen sensitization or neonatal alloimmune thrombocytopenia 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. Planned cerclage or cerclage already in place since it would preclude placement of a pessary Planned indicated delivery prior to 35 weeks Planned or actual progesterone treatment of any type or form after 14 weeks 6 days during the current pregnancy Allergy to progesterone, silicone, or excipients in the study drug, including peanuts or peanut oil in the study drug or placebo Known, suspected or history of breast cancer because breast cancer is a contraindication to the active study medication. Known liver dysfunction or disease because liver disease is a contraindication to the active study medication. Participation in another interventional study that influences gestational age at delivery or neonatal morbidity or mortality 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. Prenatal care or delivery planned elsewhere unless the study visits can be made as scheduled and complete outcome information can be obtained
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Women will be randomly assigned to study drug (200 mg micronized progesterone daily), placebo study drug appearing identical to progesterone capsule, or Arabin pessary.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Progesterone<br>200mg micronized vaginal progesterone softgel capsule, daily from randomization to < 35 wks | Drug: Vaginal progesterone<br>* 200mg micronized vaginal progesterone softgel capsule, daily from randomization to < 35 wks<br>* Other names: Prometrium;|
| Placebo Comparator: Placebo<br>placebo softgel capsule, daily from randomization to < 35 wks | Drug: Placebo<br>* placebo softgel capsule, daily from randomization to < 35 wks<br>|
| Active Comparator: Arabin Pessary<br>placement management from randomization to < 35 wks | Device: Arabin Pessary<br>* Placement management from randomization to < 35 wks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delivery prior to 35 weeks or fetal loss | Delivery of the infant before 35 weeks gestation or loss of the fetus. | prior to 35 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Randomization to delivery interval | Randomization may begin at 16 weeks, and most patients will be delivered by 41 weeks | 16 to 42 weeks | 
| Gestational age at delivery |  | 16 to 42 weeks | 
| Neonatal morbidity and mortality |  | 16 to 42 weeks | 
| Lower genital tract or urinary tract infection |  | 16 to 42 weeks | 
| Physician interventions | Composite measure. Includes bedrest, cerclage, labor inhibition therapy. | 16 to 42 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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women, cervical length of less than 30 millimeters, carrying twins, short cervix