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

Study Description

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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	Not Applicable

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

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	120 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 2013
Estimated Primary Completion Date :	May 2018
Estimated Study Completion Date :	May 2018

Arms and Interventions

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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

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Primary Outcome Measures :

1. Delivery before 37 weeks [ Time Frame: Duration of current pregnancy, anticipated maximum 18 weeks ]

Secondary Outcome Measures :

1. Delivery before 34 weeks [ Time Frame: Duration of current pregnancy, anticipated maximum 18 weeks ]
   Evaluated in women enrolled prior to 32 weeks gestation
2. Delivery within 2 weeks of randomization [ Time Frame: 2 weeks ]
3. Number of days pregnancy prolongation [ Time Frame: Duration of current pregnancy, anticipated maximum 18 weeks ]
4. Infant birth weight [ Time Frame: Day of delivery in current pregnancy ]
5. Neonatal intensive care unit admission [ Time Frame: Followed for duration of neonatal hospital stay, estimated maximum 16 weeks ]
6. Chorioamnionitis [ Time Frame: Duration of current pregnancy, anticipated maximum 18 weeks ]
7. Composite neonatal outcome [ Time Frame: 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

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Ages Eligible for Study:	18 Years to 50 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Singleton of 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

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Molly J Stout, MD, MSCI	314-362-8895	stoutm@wudosis.wustl.edu
Contact: Emily Diveley, RN, BSN	314-362-4685	diveley@wustl.edu

Locations

United States, Missouri
Washington University School of Medicine/ Barnes-Jewish Hospital	Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Molly J Stout, MD, MSCI 314-362-8895 stoutm@wudosis.wustl.edu
Contact: Emily Diveley, RN, BSN 314-362-4685 diveley@wustl.edu
Principal Investigator: George A Macones, MD, MSCE
Principal Investigator: Alison G Cahill, MD, MSCI
Principal Investigator: Molly J Stout, MD, MSCI

Sponsors and Collaborators

Washington University School of Medicine

Thrasher Research Fund

Investigators

Study Chair:	George A Macones, MD, MSCE	Washington University School of Medicine

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

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):1221-6. doi: 10.1097/AOG.0b013e31818d8386.

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.

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.

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.

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.

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.

Responsible Party:	Washington University School of Medicine
ClinicalTrials.gov Identifier:	NCT01840228 History of Changes
Other Study ID Numbers:	201301148
First Posted:	April 25, 2013
Last Update Posted:	June 8, 2017
Last Verified:	June 2017

Keywords provided by Washington University School of Medicine:

Preterm; Progesterone

Additional relevant MeSH terms:

Premature Birth; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Progesterone	Progestins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs