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

Preterm Delivery Clinical Trial

— 17PinPROM  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01119963
• Other study ID #: OBX0012
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: October 2011
• Est. completion date: October 2014

Study information

• Verified date: May 2018
• Source: Mednax Center for Research, Education, Quality and Safety
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 152
• Est. completion date: October 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Premature Birth
• Preterm Delivery
• Rupture

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Cincinnati	Cincinnati	Ohio
United States	Presbyterian/St Luke's Hospital	Denver	Colorado
United States	Swedish Medical Center	Denver	Colorado
United States	Spectrum Health Hospital	Grand Rapids	Michigan
United States	Saint Luke's Hospital, Kansas City	Kansas City	Missouri
United States	Sunrise Medical Center	Las Vegas	Nevada
United States	Long Beach Memorial Medical Center	Long Beach	California
United States	Norton Kosair Children's Hospital	Louisville	Kentucky
United States	Desert Good Samaritan Hospital	Mesa	Arizona
United States	University of South Alabama Medical Center	Mobile	Alabama
United States	Banner Good Samaritan Hospital	Phoenix	Arizona
United States	Good Samaritan Hospital	San Jose	California
United States	OConnor Hospital	San Jose	California
United States	Swedish Medical Center	Seattle	Washington
United States	Tucson Medical Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Obstetrix Medical Group

Country where clinical trial is conducted

United States, 

References & Publications (11)

ACOG Committee on Obstetric Practice. Use of progesterone to reduce preterm birth. ACOG Committee Opinion 291: 1-2, American College of Obstetricians and Gynecologists, 2003

ACOG Committee on Practice Bulletins. Premature rupture of membranes. ACOG Practice Bulletin 80: 1-13, American College of Obstetricians and Gynecologists, 2007

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. — View Citation

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. — View Citation

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. — View Citation

Beydoun SN, Yasin SY. Premature rupture of the membranes before 28 weeks: conservative management. Am J Obstet Gynecol. 1986 Sep;155(3):471-9. — View 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. — View Citation

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. — View 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. — View Citation

Committee on Obstetric Practice. ACOG committee opinion. Antenatal corticosteroid therapy for fetal maturation. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2002 Jul;78(1):95-7. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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