Vaginal Versus Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth (VIP)

The purpose of this study is to evaluate the two suggested therapies for prevention of recurrent preterm birth (PTB) in women with a prior spontaneous preterm birth, vaginal and intramuscular progesterone to determine whether vaginal progesterone is superior to intramuscular progesterone in the prevention of recurrent preterm birth.

Study Overview

• Status: Completed
• Conditions: Premature Birth
• Intervention / Treatment: Drug: Vaginal Progesterone; Drug: Intramuscular Progesterone (17 alpha hydroxprogesterone caproate)

Detailed Description

Preterm birth is one of the leading causes of neonatal morbidity and mortality. One of the greatest predictors of preterm birth is a history of prior spontaneous preterm birth. Presently 17 hydroxyprogesterone caproate (intramuscular) is the only FDA approved product for the prevention of recurrent preterm birth, however recent studies suggest that vaginal progesterone may be used for this purpose, and may even be superior. The American College of Obstetrics and Gynecology does not specify the optimal route of progesterone administration for the prevention of recurrent preterm birth. It is our intention to compare vaginal and intramuscular progesterone to see if one is superior.

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States
      • George Washington University
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital

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:

• Pregnant women with singleton pregnancies
• ≥18 years old
• Estimated gestational age less than 24 0/7 weeks
• Prior spontaneous preterm birth of a singleton pregnancy between 16 0/7-36 6/7 weeks.
• Patients are also required provide consent, demonstrate an understanding of the purpose of the study, and agree to the study protocol.

Exclusion Criteria:

• History of an adverse reaction to progesterone;
• A contraindication to progesterone treatment;
• Placenta previa or accreta;
• Major fetal anomaly diagnosed on ultrasound or known chromosomal disorder;
• Multifetal gestation;
• Preterm labor, premature rupture of membranes, or clinical chorioamnionitis, at the time of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vaginal Progesterone; 200mg micronized progesterone vaginally, to be taken daily starting at 16 0/7 - 23 6/7 weeks, and continued daily until 36 6/7 weeks' gestation or delivery	Drug: Vaginal Progesterone; Other Names: micronized progesterone
Active Comparator: Intramuscular Progesterone; 250mg intramuscular progesterone to be administered weekly starting at 16 0/7 - 23 6/7 weeks, and continued weekly until 36 6/7 weeks' or delivery.	Drug: Intramuscular Progesterone (17 alpha hydroxprogesterone caproate); Other Names: Makena

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preterm birth <37 weeks	Incidence of gestational age of delivery less than 37 weeks	up to 9 months (delivery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational age of delivery		up to 9 months (delivery)
Preterm birth <34 weeks and <28 weeks		up to 9 months (delivery)
Second trimester cervical length <25mm		2 months
Mode of delivery	Delivery mode- vaginal, cesarean, operative vaginal	up to 9 months (delivery)
Maternal mortality		up to 9 months (delivery)
5 minute Apgar score		up to 9 months (delivery)
Neonatal intensive care unit admission		up to 9 months (delivery)
Composite neonatal morbidity	(respiratory distress syndrome, grade III or IV intraventricular hemorrhage, culture proven sepsis, neonatal enterocolitis, and perinatal mortality up to 28 days of life)	up to 9 months (delivery)
Birthweight		up to 9 months (delivery)
Perinatal mortality up to 28 days of life		up to 10 months (4 weeks after delivery)
Medication side effects		up to 9 months (delivery)
Satisfaction with medication (5 point Likert scale)		up to 9 months (delivery)
Medication adherence	Vaginal progesterone: Overall adherence: #days used/#days of treatment x 100; Non-adherent: ≥4 days between doses Intramuscular progesterone: Overall adherence: #weeks used/#weeks of treatment x 100; Non-adherent: ≥10 days between doses	up to 9 months (delivery)
Planned subgroup analysis for the outcome preterm birth <37 weeks, <34 weeks, <28 weeks	Planned subgroup analysis for the primary outcome as well as the secondary outcomes of preterm birth <34 weeks and <28 weeks of patients with a cervical length <25mm versus ≥25mm, history-indicated cerclage versus not, and for those started on progesterone 16-20 weeks versus 20-24 weeks.	up to 9 months (delivery)

Collaborators and Investigators

• Sponsor: Thomas Jefferson University
• Collaborators: Ohio State University; George Washington University; Baystate Medical Center; Vriginia Commonwealth University
• Investigators: Principal Investigator: Rupsa C Boelig, MD, Thomas Jefferson University Hospital; Sidney Kimmel Medical College

Publications and helpful links

General Publications

• Committee on Practice Bulletins-Obstetrics, The American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012 Oct;120(4):964-73. doi: 10.1097/AOG.0b013e3182723b1b. No abstract available.
• Saccone G, Khalifeh A, Elimian A, Bahrami E, Chaman-Ara K, Bahrami MA, Berghella V. Vaginal progesterone vs intramuscular 17alpha-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2017 Mar;49(3):315-321. doi: 10.1002/uog.17245. Epub 2017 Feb 6.
• Boelig RC, Schoen CN, Frey H, Gimovsky AC, Springel E, Backley S, Berghella V. Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial. Am J Obstet Gynecol. 2022 May;226(5):722.e1-722.e12. doi: 10.1016/j.ajog.2022.02.012. Epub 2022 Feb 19.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2016
• Primary Completion (Actual): August 1, 2021
• Study Completion (Actual): September 1, 2021

Study Registration Dates

• First Submitted: September 22, 2016
• First Submitted That Met QC Criteria: September 22, 2016
• First Posted (Estimate): September 23, 2016

Study Record Updates

• Last Update Posted (Actual): October 13, 2021
• Last Update Submitted That Met QC Criteria: October 5, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Progesterone; Prevention of preterm birth
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: 16D.542

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Results will be available, individual participant data may not be