Progesterone (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM) (17PinPROM)

17-alpha-Hydroxyprogesterone Caproate (17P, Makena®) for Prolongation of Pregnancy in Women With Preterm Rupture of the Membranes (PROM), Double-blinded Randomized Clinical Trial

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.

Study Overview

• Status: Completed
• Conditions: Preterm Delivery
• Intervention / Treatment: Drug: 17-alpha-hydroxy-progesterone caproate, Makena®; Drug: Castor Oil (Placebo)

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.

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36617
      • University of South Alabama Medical Center
  • Arizona
    • Mesa, Arizona, United States, 85202
      • Desert Good Samaritan Hospital
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan Hospital
    • Tucson, Arizona, United States, 85712
      • Tucson Medical Center
  • California
    • Long Beach, California, United States, 90801-1428
      • Long Beach Memorial Medical Center
    • San Jose, California, United States, 95124
      • Good Samaritan Hospital
    • San Jose, California, United States, 95128
      • OConnor Hospital
  • Colorado
    • Denver, Colorado, United States, 80110
      • Swedish Medical Center
    • Denver, Colorado, United States, 80218
      • Presbyterian/St Luke's Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Kosair Children's Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital, Kansas City
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Sunrise Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0526
      • University of Cincinnati
  • Washington
    • Seattle, Washington, United States, 98122-4307
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 17-alpha hydroxyprogesterone caproate, Makena®; 250 mg of 17P, Makena® intramuscular (IM) weekly.	Drug: 17-alpha-hydroxy-progesterone caproate, Makena®; Intramuscular (IM) injection of 17P,Makena® (250mg) beginning as early as 23w0d administered weekly until 34w0d, documented fetal lung maturity at 32w0d - 33w6d, or delivery which ever comes first.; Other Names: Progesterone; 17 alpha hydroxyprogesterone Caproate; 17P; 17Pc; 17HP; 170HP; 170HPC; Makena®
Placebo Comparator: Placebo; Castor Oil (Placebo)intramuscular (IM) weekly	Drug: Castor Oil (Placebo); IM injections of Placebo (castor oil) beginning as early as 23w0d administered weekly until 34w0d, documented fetal lung maturity at 32w0d - 33w6d, or delivery which ever comes first.; Other Names: Placebo; Castor Oil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational Age at Delivery	Gestational age is measured in weeks, from the first day of the woman's last menstrual cycle to the date the baby was born.	Measured from day of last menstrual cycle to day of birth and measured in weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Latency Period	Secondary Outcomes: - Duration of latency period (time from randomization to birth)	average number of days measured from day of study entry until day of delivery

Collaborators and Investigators

• Sponsor: Obstetrix Medical Group
• Investigators: Principal Investigator: Andrew Combs, MD, Obstetrix Medical Group

Publications and helpful links

General Publications

• Beydoun SN, Yasin SY. Premature rupture of the membranes before 28 weeks: conservative management. Am J Obstet Gynecol. 1986 Sep;155(3):471-9. doi: 10.1016/0002-9378(86)90257-7.
• Amon E, Lewis SV, Sibai BM, Villar MA, Arheart KL. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. Am J Obstet Gynecol. 1988 Sep;159(3):539-43. doi: 10.1016/s0002-9378(88)80002-4.
• ACOG Committee on Obstetric Practice. Antenatal corticosteroid therapy for fetal maturation. ACOG Committee Opinion 273: 1-3, American College of Obstetricians and Gynecologists, 2002.
• American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Use of progesterone to reduce preterm birth. Obstet Gynecol. 2003 Nov;102(5 Pt 1):1115-6.
• ACOG Committee on Practice Bulletins. Premature rupture of membranes. ACOG Practice Bulletin 80: 1-13, American College of Obstetricians and Gynecologists, 2007
• Ananth CV, Savitz DA, Williams MA. Placental abruption and its association with hypertension and prolonged rupture of membranes: a methodologic review and meta-analysis. Obstet Gynecol. 1996 Aug;88(2):309-18. doi: 10.1016/0029-7844(96)00088-9.
• Armstrong J, Nageotte M for the Society for Maternal-Fetal Medicine. Can progesterone prevent preterm birth? Contemp Obstet Gynecol 2005 (Oct);30-43
• Bengtson JM, VanMarter LJ, Barss VA, Greene MF, Tuomala RE, Epstein MF. Pregnancy outcome after premature rupture of the membranes at or before 26 weeks' gestation. Obstet Gynecol. 1989 Jun;73(6):921-7. doi: 10.1097/00006250-198906000-00002.
• 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.
• Caughey AB, Robinson JN, Norwitz ER. Contemporary diagnosis and management of preterm premature rupture of membranes. Rev Obstet Gynecol. 2008 Winter;1(1):11-22.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: February 16, 2010
• First Submitted That Met QC Criteria: May 6, 2010
• First Posted (Estimate): May 10, 2010

Study Record Updates

• Last Update Posted (Actual): June 28, 2018
• Last Update Submitted That Met QC Criteria: May 29, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Preterm delivery
• Additional Relevant MeSH Terms: Wounds and Injuries; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Rupture; Premature Birth; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Estrogen Antagonists; Cathartics; Progestins; Progesterone; 17 alpha-Hydroxyprogesterone Caproate; 11-hydroxyprogesterone; Castor Oil
• Other Study ID Numbers: OBX0012