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

• Sponsor: Obstetrix Medical Group (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01119963
• Collaborator: (none)
• Enrollment: 152
• Locations: 15
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Preterm Delivery	Drug: 17-alpha-hydroxy-progesterone caproate, Makena®; Drug: Castor Oil (Placebo)	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 152 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• 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 Start Date: Oct 1, 2011
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

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: 17 alpha hydroxyprogesterone Caproate 17P 17Pc 17HP 170HP 170HPC Progesterone 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

Outcome Measures

Primary Outcome Measures

1. Gestational Age at Delivery [Measured from day of last menstrual cycle to day of birth and measured in weeks.]

   Gestational age is measured in weeks, from the first day of the woman's last menstrual cycle to the date the baby was born.

Secondary Outcome Measures

1. Duration of Latency Period [average number of days measured from day of study entry until day of delivery]

   Secondary Outcomes: - Duration of latency period (time from randomization to birth)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama Medical Center	Mobile	Alabama	United States	36617
2	Desert Good Samaritan Hospital	Mesa	Arizona	United States	85202
3	Banner Good Samaritan Hospital	Phoenix	Arizona	United States	85006
4	Tucson Medical Center	Tucson	Arizona	United States	85712
5	Long Beach Memorial Medical Center	Long Beach	California	United States	90801-1428
6	Good Samaritan Hospital	San Jose	California	United States	95124
7	OConnor Hospital	San Jose	California	United States	95128
8	Swedish Medical Center	Denver	Colorado	United States	80110
9	Presbyterian/St Luke's Hospital	Denver	Colorado	United States	80218
10	Norton Kosair Children's Hospital	Louisville	Kentucky	United States	40202
11	Spectrum Health Hospital	Grand Rapids	Michigan	United States	49503
12	Saint Luke's Hospital, Kansas City	Kansas City	Missouri	United States	64111
13	Sunrise Medical Center	Las Vegas	Nevada	United States	89109
14	University of Cincinnati	Cincinnati	Ohio	United States	45267-0526
15	Swedish Medical Center	Seattle	Washington	United States	98122-4307

Sponsors and Collaborators

• Obstetrix Medical Group

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

• ACOG Committee on Obstetric Practice. Antenatal corticosteroid therapy for fetal maturation. ACOG Committee Opinion 273: 1-3, American College of Obstetricians and Gynecologists, 2002.
• ACOG Committee on Practice Bulletins. Premature rupture of membranes. ACOG Practice Bulletin 80: 1-13, American College of Obstetricians and Gynecologists, 2007
• 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.
• 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.
• 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.
• 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.
• Beydoun SN, Yasin SY. Premature rupture of the membranes before 28 weeks: conservative management. Am J Obstet Gynecol. 1986 Sep;155(3):471-9.
• 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.

• Responsible Party: Obstetrix Medical Group
• ClinicalTrials.gov Identifier: NCT01119963
• Other Study ID Numbers: OBX0012
• First Posted: May 10, 2010
• Last Update Posted: Jun 28, 2018
• Last Verified: May 1, 2018

• Keywords provided by Obstetrix Medical Group: Preterm delivery
• Additional relevant MeSH terms: Premature Birth; Rupture; Castor Oil; Progesterone; 17 alpha-Hydroxyprogesterone Caproate; 11-hydroxyprogesterone

Study Results

Participant Flow

Recruitment Details	Participants between the Gestational age of 23w0d-30w6d were approach in the hospital setting following confirmation of rupture of membranes.
Pre-assignment Detail	We had two patient that consented to the study but were withdrawn prior to randomization because they began to go into labor

Arm/Group Title	17-alpha Hydroxyprogesterone Caproate, Makena®	Placebo
Arm/Group Description	250 mg of 17P, Makena® intramuscular (IM) weekly. 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)intramuscular (IM) weekly 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.
Period Title: Overall Study
STARTED	74	78
COMPLETED	73	77
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	17-alpha Hydroxyprogesterone Caproate, Makena®	Placebo	Total
Arm/Group Description	250 mg of 17P, Makena® intramuscular (IM) weekly. 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)intramuscular (IM) weekly 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.	Total of all reporting groups
Overall Participants	74	78	152
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.9 (5.8)	29.5 (5.7)	29.7 (5.8)
Sex: Female, Male (Count of Participants)
Female	74 100%	78 100%	152 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	21 28.4%	16 20.5%	37 24.3%
Not Hispanic or Latino	53 71.6%	61 78.2%	114 75%
Unknown or Not Reported	0 0%	1 1.3%	1 0.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 4.1%	4 5.1%	7 4.6%
Asian	4 5.4%	1 1.3%	5 3.3%
Native Hawaiian or Other Pacific Islander	1 1.4%	0 0%	1 0.7%
Black or African American	8 10.8%	14 17.9%	22 14.5%
White	37 50%	42 53.8%	79 52%
More than one race	0 0%	1 1.3%	1 0.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	74 100%	78 100%	152 100%
Marital Status (Count of Participants)
Married/Living with partner	44 59.5%	46 59%	90 59.2%
Single/Widowed	27 36.5%	30 38.5%	57 37.5%
Divorced/Separated	3 4.1%	0 0%	3 2%
Other (Unknown)	0 0%	2 2.6%	2 1.3%
Education (Count of Participants)
< HS graduate	6 8.1%	10 12.8%	16 10.5%
HS Graduate or equivalent	11 14.9%	18 23.1%	29 19.1%
Some College	22 29.7%	15 19.2%	37 24.3%
College Graduate	17 23%	15 19.2%	32 21.1%
Not Reported	18 24.3%	20 25.6%	38 25%
Tobacco Use (Count of Participants)
Count of Participants [Participants]	4 5.4%	5 6.4%	9 5.9%
Illicit Drug Use (Count of Participants)
Count of Participants [Participants]	7 9.5%	14 17.9%	21 13.8%
Gestational Age at Membrane Rupture (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	25.9 (3.0)	26.6 (2.9)	26.2 (3.0)
Gestational Age at time of randomization (wks) (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	26.7 (2.5)	27.1 (2.4)	26.9 (2.5)
Gestational Age Stratum at randomization (wks) (Count of Participants)
23w0d-25w6d	31 41.9%	28 35.9%	59 38.8%
26w0d - 28w6d	24 32.4%	27 34.6%	51 33.6%
29w0d-30w6d	19 25.7%	23 29.5%	42 27.6%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to treat population (included all participants who were randomized, whether they received study medication or not).

Arm/Group Title	17-alpha Hydroxyprogesterone Caproate, Makena®	Placebo
Arm/Group Description	250 mg of 17P, Makena® intramuscular (IM) weekly. 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)intramuscular (IM) weekly 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.
Measure Participants	73	77
Mean (Standard Deviation) [weeks.]	29.2 (2.72)	29.5 (2.74)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent to treat population (included all participants who were randomized, whether they received study medication or not).

Arm/Group Title	17-alpha Hydroxyprogesterone Caproate, Makena®	Placebo
Arm/Group Description	250 mg of 17P, Makena® intramuscular (IM) weekly. 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)intramuscular (IM) weekly 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.
Measure Participants	73	77
Mean (Standard Deviation) [days]	17.1 (16.08)	17.0 (15.77)

Adverse Events

Time Frame	Up to 60 days post delivery or discharge which ever comes first
Arm/Group Title	Neonate: 17-alpha Hydroxyprogesterone Caproate, Makena®		Neonate: Placebo		17-alpha Hydroxyprogesterone Caproate, Makena®		Placebo
Arm/Group Description	Neonate: 250 mg of 17P, Makena® intramuscular (IM) weekly. 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.		Neonate: Castor Oil (Placebo)intramuscular (IM) weekly 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.		250 mg of 17P, Makena® intramuscular (IM) weekly. 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)intramuscular (IM) weekly 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.
All Cause Mortality
	Neonate: 17-alpha Hydroxyprogesterone Caproate, Makena®		Neonate: Placebo		17-alpha Hydroxyprogesterone Caproate, Makena®		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/73 (4.1%)		2/77 (2.6%)		0/73 (0%)		0/77 (0%)
Serious Adverse Events
	Neonate: 17-alpha Hydroxyprogesterone Caproate, Makena®		Neonate: Placebo		17-alpha Hydroxyprogesterone Caproate, Makena®		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/73 (4.1%)		2/77 (2.6%)		0/73 (0%)		0/77 (0%)
Cardiac disorders
Suspected Pulmonary Hypertension	0/73 (0%)	0	1/77 (1.3%)	1	0/73 (0%)	0	0/77 (0%)	0
Congenital, familial and genetic disorders
Congenital Diaphragmatic Hernia	1/73 (1.4%)	1	0/77 (0%)	0	0/73 (0%)	0	0/77 (0%)	0
Infections and infestations
Respiratory Failure, Sepsis	1/73 (1.4%)	1	0/77 (0%)	0	0/73 (0%)	0	0/77 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	1/73 (1.4%)	1	0/77 (0%)	0	0/73 (0%)	0	0/77 (0%)	0
Atypical Pulmonary Infection	0/73 (0%)	0	1/77 (1.3%)	1	0/73 (0%)	0	0/77 (0%)	0
Other (Not Including Serious) Adverse Events
	Neonate: 17-alpha Hydroxyprogesterone Caproate, Makena®		Neonate: Placebo		17-alpha Hydroxyprogesterone Caproate, Makena®		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/73 (0%)		0/77 (0%)		0/73 (0%)		0/77 (0%)

Limitations/Caveats

One limitation is that we only studied one dose of 17OHPc (250mg) and only one frequency (once a week) however we did this to coincide with the study that showed benefits of 17OHPc in women with intact membranes with a history of preterm birth.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.