PAL: Vaginal Progesterone for the Prevention of Preterm Birth in Women With Arrested Preterm Labor

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01840228
• Collaborator: Thrasher Research Fund (Other)
• Enrollment: 38
• Location: 1
• Arms: 2
• Duration (Months): 60.2
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Preterm birth, defined as birth before 37 weeks' gestation, is a leading cause of infant death and disease. Progesterone is the single most effective intervention in the prevention of preterm birth. However, current use of this therapy is limited to certain high-risk groups including women with a history of preterm birth and women with a short cervix. This study seeks to evaluate the efficacy of this preventive therapy in another high-risk group: women with arrested preterm labor. The investigators hypothesize that administration of vaginal progesterone in women who present with preterm labor but remain undelivered 12 hours after cessation of short-term therapy to inhibit contractions will result in lower rates of preterm birth before 37 weeks' than will administration of placebo.

Condition or Disease	Intervention/Treatment	Phase
Premature Birth; Obstetric Labor, Premature	Drug: Micronized progesterone suppository	N/A

Detailed Description

RESEARCH DESIGN AND METHODS

The investigators will perform a randomized, blinded, placebo-controlled trial to evaluate the use of vaginal progesterone in women with arrested preterm labor after 24 weeks' gestation to reduce the risk of preterm birth before 37 weeks' gestation. Women enrolled in the study will be randomized to daily vaginal administration of progesterone (200 mg) or placebo from time of enrollment until 36 6/7 weeks' gestation. Women will be eligible if they have a singleton or twin gestation between 24 0/7 and 33 6/7 weeks' gestation and initially present with regular uterine contractions and a clinical diagnosis of preterm labor but remain undelivered without further cervical change 12 hours after discontinuation of acute tocolytic therapy. Women may also participate if it has been less than if they are considered eligible for discharge based on attending physician judgement prior to the 12 hour period of time.

Randomization and Blinding- Participants in the study will be randomized using a computer-generated randomization scheme with 1:1 allocation to receive progesterone or placebo. Investigators and research team members, participants, and the obstetric providers will be blinded to the allocated intervention.

Procedures-

• Data collection- Information will be recorded from the participant's medical record. Additional study information not included in the medical record will be obtained directly from the participant in an interview with the research team member.

• Follow-up- Regardless of whether the participant remains hospitalized or is discharged prior to delivery, she will meet with a study coordinator every 2 weeks. During the follow-up visit, a study team member will discuss compliance with the study drug and possible side effects. The participant will fill out a 1-page questionnaire that asks questions about compliance and side effects. This information will be recorded and provided to the Data Safety and Monitoring Board at the midpoint review.

SAMPLE SIZE ESTIMATION

The investigators plan to enroll 120 patients, with a 1:1 allocation to treatment and placebo. This sample size is adequate to detect a one-half reduction in the primary outcome, delivery before 37 weeks.

STATISTICAL ANALYSIS

Baseline characteristics of women randomized to progesterone will be compared with women randomized to placebo. Rates of delivery before 37 weeks' gestation will be compared among the groups using the Chi-square test. Secondary outcomes will be evaluated using the Chi-square test for binary outcomes and the Student t-test for continuous outcomes. Length of time from enrollment to delivery will be analyzed using Kaplan-Meier curves and the Cox proportional hazards model. All analyses will be performed using the intention-to-treat principle.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Vaginal Progesterone for the Prevention of Preterm Birth in Women With Arrested Preterm Labor
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: May 7, 2018
• Actual Study Completion Date: May 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Micronized progesterone suppository Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation.	Drug: Micronized progesterone suppository
Placebo Comparator: Placebo suppository One placebo suppository vaginally daily until 36 6/7 weeks' gestation.	Drug: Micronized progesterone suppository

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Delivered Before 37 Weeks' [Duration of current pregnancy, anticipated maximum 18 weeks]

Secondary Outcome Measures

1. Number of Participants Who Delivered Before 34 Weeks' [Duration of current pregnancy, anticipated maximum 18 weeks]

   Evaluated in women enrolled prior to 32 weeks gestation

2. Delivery Within 2 Weeks of Randomization [2 weeks]

3. Number of Weeks Pregnancy Prolongation [Duration of current pregnancy, anticipated maximum 18 weeks]

4. Infant Birth Weight [Day of delivery in current pregnancy]

5. Neonatal Intensive Care Unit Admission [Followed for duration of neonatal hospital stay, estimated maximum 16 weeks]

6. Number of Participants With Chorioamnionitis [Duration of current pregnancy, anticipated maximum 18 weeks]

7. Composite Neonatal Outcome [Followed for duration of neonatal hospital stay, estimated maximum 16 weeks]

   A composite neonatal outcome comprising neonatal death, respiratory distress syndrome, bronchopulmonary dysplasia, severe (grade III/IV) interventricular hemorrhage, necrotizing enterocolitis, and sepsis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Singleton or twin gestation

• Estimated gestational age between 24 0/7 and 33 6/7 weeks' gestation

• Initially present with regular contractions and clinical diagnosis of preterm labor but remain undelivered with 1) no further cervical change 12 hours after discontinuation of acute tocolytic therapy; or 2) be considered eligible for discharge based on attending physician judgment prior to the 12 hour period of time

• The participant's cervix must be at least 1 cm at the time of enrollment

Exclusion Criteria:

• Non-English speaking

• Rupture of membranes

• Chorioamnionitis

• Non-reassuring fetal status

• Maternal indication for delivery

• Placental abruption

• Intrauterine fetal demise

• Prenatally diagnosed major fetal anomaly

• Cervical cerclage in place

• Previous administration of progesterone during the current pregnancy for a history of preterm birth or short cervix

• Participant is either unwilling or unable to attend follow-up study visits following hospital discharge

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine/ Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• Thrasher Research Fund

Investigators

• Study Chair: George A Macones, MD, MSCE, Washington University School of Medicine
• Principal Investigator: Heather A Frey, MD, MSCI, Ohio State University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 11, 2015

More Information

Publications

• Arikan I, Barut A, Harma M, Harma IM. Effect of progesterone as a tocolytic and in maintenance therapy during preterm labor. Gynecol Obstet Invest. 2011;72(4):269-73. doi: 10.1159/000328719. Epub 2011 Nov 12.
• Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol. 2008 Feb;48(1):58-63. doi: 10.1111/j.1479-828X.2007.00803.x.
• Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007 Aug 2;357(5):462-9.
• Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011 Jul;38(1):18-31. doi: 10.1002/uog.9017. Epub 2011 Jun 15.
• Likis FE, Edwards DR, Andrews JC, Woodworth AL, Jerome RN, Fonnesbeck CJ, McKoy JN, Hartmann KE. Progestogens for preterm birth prevention: a systematic review and meta-analysis. Obstet Gynecol. 2012 Oct;120(4):897-907. Review.
• Lyell DJ, Pullen KM, Mannan J, Chitkara U, Druzin ML, Caughey AB, El-Sayed YY. Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial. Obstet Gynecol. 2008 Dec;112(6):1221-1226. doi: 10.1097/AOG.0b013e31818d8386.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01840228
• Other Study ID Numbers: 201301148
• First Posted: Apr 25, 2013
• Last Update Posted: Jun 18, 2019
• Last Verified: May 1, 2019

• Keywords provided by Washington University School of Medicine: Preterm; Progesterone
• Additional relevant MeSH terms: Premature Birth; Obstetric Labor, Premature; Progesterone

Study Results

Participant Flow

Arm/Group Title	Micronized Progesterone Suppository	Placebo Suppository
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository
Period Title: Overall Study
STARTED	19	19
COMPLETED	18	18
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Micronized Progesterone Suppository	Placebo Suppository	Total
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	Total of all reporting groups
Overall Participants	19	19	38
Age (Count of Participants)
<=18 years	1 5.3%	0 0%	1 2.6%
Between 18 and 65 years	18 94.7%	19 100%	37 97.4%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.8 (5.5)	26.3 (4.6)	26.0 (5.0)
Sex: Female, Male (Count of Participants)
Female	19 100%	19 100%	38 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 10.5%	1 5.3%	3 7.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	11 57.9%	10 52.6%	21 55.3%
White	6 31.6%	7 36.8%	13 34.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 5.3%	1 2.6%
Region of Enrollment (participants) [Number]
United States	19 100%	19 100%	38 100%
Parity (births) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [births]	1	1	1
Body mass index (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	25.3 (7.9)	25.4 (8.3)	25.3 (8.0)
Prior preterm birth (Count of Participants)
Count of Participants [Participants]	6 31.6%	8 42.1%	14 36.8%
Twin gestation (Count of Participants)
Count of Participants [Participants]	4 21.1%	4 21.1%	8 21.1%
Marital status (Count of Participants)
Single	13 68.4%	11 57.9%	24 63.2%
Married	6 31.6%	6 31.6%	12 31.6%
Divorced	0 0%	1 5.3%	1 2.6%
Unknown	0 0%	1 5.3%	1 2.6%
Insurance use (Count of Participants)
Public insurance	14 73.7%	11 57.9%	25 65.8%
Private insurance	3 15.8%	7 36.8%	10 26.3%
Other	2 10.5%	1 5.3%	3 7.9%
Gestational age at enrollment (weeks) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [weeks]	30.6	30.4	30.5
Cervical dilation at admission (cm) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cm]	1.5	1	1.25
Cervical dilation at enrollment (cm) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cm]	3	2.5	2.75
Tobacco use (Count of Participants)
Count of Participants [Participants]	3 15.8%	4 21.1%	7 18.4%
Prior use of progesterone (17OHP-C) (Count of Participants)
Count of Participants [Participants]	0 0%	3 15.8%	3 7.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Delivered Before 37 Weeks'
Time Frame	Duration of current pregnancy, anticipated maximum 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository	Placebo Suppository
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository
Measure Participants	18	18
Count of Participants [Participants]	11 57.9%	10 52.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Micronized Progesterone Suppository, Placebo Suppository
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Who Delivered Before 34 Weeks'
Description	Evaluated in women enrolled prior to 32 weeks gestation
Time Frame	Duration of current pregnancy, anticipated maximum 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository	Placebo Suppository
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository
Measure Participants	14	12
Count of Participants [Participants]	3 15.8%	6 31.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Micronized Progesterone Suppository, Placebo Suppository
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95%; 0.14 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Delivery Within 2 Weeks of Randomization
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository	Placebo Suppository
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository
Measure Participants	18	18
Count of Participants [Participants]	6 31.6%	4 21.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Micronized Progesterone Suppository, Placebo Suppository
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.51 to 4.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Weeks Pregnancy Prolongation
Time Frame	Duration of current pregnancy, anticipated maximum 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository	Placebo Suppository
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository
Measure Participants	18	18
Median (Inter-Quartile Range) [weeks]	5.3	5.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Micronized Progesterone Suppository, Placebo Suppository
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Infant Birth Weight
Time Frame	Day of delivery in current pregnancy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository - SINGLETON	Placebo Suppository - SINGLETON	Micronized Progesterone Suppository - TWINS	Placebo Suppository - TWINS
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation in singleton subgroup. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation in singleton subgroup Micronized progesterone suppository	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation in twin subgroup. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation in twin subgroup Micronized progesterone suppository
Measure Participants	14	14	8	8
Mean (Standard Deviation) [grams]	2454.9 (659.4)	2523.1 (748.5)	2164.4 (215.9)	1974.1 (252.8)

6. Secondary Outcome

Title	Neonatal Intensive Care Unit Admission
Time Frame	Followed for duration of neonatal hospital stay, estimated maximum 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository - SINGLETON	Placebo Suppository - SINGLETON	Micronized Progesterone Suppository - TWINS	Placebo Suppository - TWINS
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation in singleton subgroup. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation in singleton subgroup Micronized progesterone suppository	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation in twin subgroup. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation in twin subgroup Micronized progesterone suppository
Measure Participants	14	14	8	8
Count of Participants [Participants]	2 10.5%	2 10.5%	0 0%	1 NaN

7. Secondary Outcome

Title	Number of Participants With Chorioamnionitis
Time Frame	Duration of current pregnancy, anticipated maximum 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository	Placebo Suppository
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository
Measure Participants	18	18
Count of Participants [Participants]	0 0%	0 0%

8. Secondary Outcome

Title	Composite Neonatal Outcome
Description	A composite neonatal outcome comprising neonatal death, respiratory distress syndrome, bronchopulmonary dysplasia, severe (grade III/IV) interventricular hemorrhage, necrotizing enterocolitis, and sepsis.
Time Frame	Followed for duration of neonatal hospital stay, estimated maximum 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Micronized Progesterone Suppository - SINGLETON	Placebo Suppository - SINGLETON	Micronized Progesterone Suppository - TWINS	Placebo Suppository - TWINS
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation in singleton subgroup. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation in singleton subgroup Micronized progesterone suppository	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation in twin subgroup. Micronized progesterone suppository	One placebo suppository vaginally daily until 36 6/7 weeks' gestation in twin subgroup Micronized progesterone suppository
Measure Participants	14	14	8	8
Count of Participants [Participants]	5 26.3%	5 26.3%	3 7.9%	7 NaN

Adverse Events

Time Frame	Information about adverse events was collected from time of enrollment until discharge from the hospital after delivery for all participants, which is generally < 1 week after delivery
Arm/Group Title	Micronized Progesterone Suppository		Placebo Suppository
Arm/Group Description	Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository		One placebo suppository vaginally daily until 36 6/7 weeks' gestation. Micronized progesterone suppository
All Cause Mortality
	Micronized Progesterone Suppository		Placebo Suppository
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)
Serious Adverse Events
	Micronized Progesterone Suppository		Placebo Suppository
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Micronized Progesterone Suppository		Placebo Suppository
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/18 (22.2%)		5/18 (27.8%)
General disorders
Other	0/18 (0%)	0	3/18 (16.7%)	3
Reproductive system and breast disorders
Vaginal discharge	3/18 (16.7%)	3	5/18 (27.8%)	5
Vaginal irritation	3/18 (16.7%)	3	0/18 (0%)	0

Limitations/Caveats

[Not Specified]

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.