Clinical trial NCT01119963: Progesterone (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM)
Official title: 17-alpha-Hydroxyprogesterone Caproate (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM), Double-blinded Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Preterm Delivery
Keywords: Preterm delivery
Lead sponsor: Pediatrix
Sponsor class: OTHER
First posted: 2010-05-10
Enrollment: 152
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The objective of the study is to determine if a weekly dose of 17 hydroxyprogesterone caproate (17P, Makena®) given to women with preterm rupture of the membranes will:

1. increase the probability of continuing the pregnancy until a favorable gestational age.
2. increase the interval between randomization and delivery.
3. decrease neonatal morbidity.

Detailed description: Preterm rupture of the membranes (PROM) is the leading identifiable cause of prematurity and accounts for about one-third of all preterm deliveries and 18-20% of perinatal deaths in the USA. When PROM occurs at very early gestational ages, the clinician must make a decision whether to attempt to prolong the pregnancy or whether to recommend prompt delivery. Both approaches carry substantial risk. The strategy of continuing the pregnancy is commonly called "expectant management." During expectant management, gestational age steadily increases, and the balance naturally shifts toward favoring delivery. Once the gestational age reaches 34 weeks, the risk of lethal or permanent sequelae of prematurity or minimal, so most clinicians agree that delivery is warranted. Despite an attempt at expectant management, the majority of patients with PROM will be delivered within the first week or so. Unfortunately, no intervention other than antibiotic prophylaxis or corticosteroids have been shown to prolong latency or reduce neonatal morbidity after PROM. Recent evidence suggests that prophylactic administration of progesterone medications may reduce the risk of preterm delivery in women with certain risk factors, notably those with a history of a prior preterm delivery and those with a shortened cervix discovered by ultrasound examination. Clearly, women with PROM are at very high risk of preterm delivery, so there is a pressing need to study whether 17 hydroxyprogesterone caproate (17P) is effective after PROM. Progesterone might be beneficial after PROM both because it tends to promote uterine quiescence by suppressing the formation of myometrial gap junctions and because it has anti-inflammatory properties, suppressing the production of inflammatory cytokines and thereby inhibiting cervical ripening. Inflammation is a major pathway leading to preterm labor, cervical dilation \& preterm delivery. 17P would seem to be like an ideal candidate for prolongation of pregnancy after PROM.

This is a double-blinded, placebo-controlled, multicenter, randomized clinical trial of 17P versus placebo. The primary outcome measure will be the percentage of each group reaching either a gestational age of 34w0d or documentation of fetal lung maturity at 32w0d to 33w6d. Secondary outcomes will include the latency period for each group and the percentage of newborns in each group who have major neonatal morbidity or death.

Eligibility criteria: Inclusion Criteria:

1. Participant is 18 years old or older
2. Gestational Age (GA) 23w0d and 30w6d @ time of enrollment
3. Singleton pregnancy
4. PROM defined as either (a) or (b) or (c) below (a) Documentation of vaginal leakage of indigo carmine dye instilled via amniocentesis (b) Positive Amnisure® test (c) Two or more of (i) through (iv): i. Nitrazine test with pH of 7 or more ii. Positive fern test iii. Gross pooling of clear fluid iv. US exam showing oligohydramnios

Exclusion Criteria:

1. Any contraindication to expectant management
2. Any fetal condition likely to cause serious neonatal morbidity independent of gestational age
3. History of allergy to 17P
4. Any contraindications to 17P use (e.g. Thrombosis, Breast CA, abnormal vaginal bleeding unrelated to pregnancy, jaundice, liver disease, uncontrolled HTN)
5. Any medical condition currently treated with systemic steroid medications
6. Cervical cerclage present at the time of PROM
7. Informed consent not obtained.

Primary outcomes:
measure: Gestational Age at Delivery
timeFrame: Measured from day of last menstrual cycle to day of birth and measured in weeks.
Secondary outcomes:
measure: Duration of Latency Period
timeFrame: average number of days measured from day of study entry until day of delivery
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama Medical Center
state: Alabama
city: Mesa
country: United States
facility: Desert Good Samaritan Hospital
state: Arizona
city: Phoenix
country: United States
facility: Banner Good Samaritan Hospital
state: Arizona
city: Tucson
country: United States
facility: Tucson Medical Center
state: Arizona
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: San Jose
country: United States
facility: Good Samaritan Hospital
state: California
city: San Jose
country: United States
facility: OConnor Hospital
state: California
city: Denver
country: United States
facility: Swedish Medical Center
state: Colorado
city: Denver
country: United States
facility: Presbyterian/St Luke's Hospital
state: Colorado
city: Louisville
country: United States
facility: Norton Kosair Children's Hospital
state: Kentucky
city: Grand Rapids
country: United States
facility: Spectrum Health Hospital
state: Michigan
city: Kansas City
country: United States
facility: Saint Luke's Hospital, Kansas City
state: Missouri
city: Las Vegas
country: United States
facility: Sunrise Medical Center
state: Nevada
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
Study officials:
affiliation: Obstetrix Medical Group
name: Andrew Combs, MD
role: PRINCIPAL_INVESTIGATOR
References:
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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.
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citation: Combs CA, McCune M, Clark R, Fishman A. Aggressive tocolysis does not prolong pregnancy or reduce neonatal morbidity after preterm premature rupture of the membranes. Am J Obstet Gynecol. 2004 Jun;190(6):1723-8; discussion 1728-31. doi: 10.1016/j.ajog.2004.02.042.
citation: Combs CA, Garite TJ, Maurel K, Mallory K, Edwards RK, Lu G, Porreco R, Das A; Obstetrix Collaborative Research Network. 17-Hydroxyprogesterone caproate to prolong pregnancy after preterm rupture of the membranes: early termination of a double-blind, randomized clinical trial. BMC Res Notes. 2011 Dec 29;4:568. doi: 10.1186/1756-0500-4-568.