Vaginal Versus Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth
Phase: PHASE4
Conditions: Premature Birth
Sponsor: Thomas Jefferson University

VIP Trial 
Rupsa C. Boelig, MD (PI) 
1 
 
Version: 4 
Date: June 1, 2019 
 
Vaginal versus intramuscular progesterone for prevention of recurrent spontaneous preterm birth  
(VIP Trial) 
 
Aim: To determine if vaginal progesterone for the treatment of prior spontaneous preterm birth can 
reduce the occurrence of recurrent preterm birth over intramuscular progesterone 
Background: 
Preterm birth is one of the leading causes of neonatal morbidity and mortality.  One of the most significant 
risk factors for spontaneous preterm birth is a history of a prior spontaneous preterm birth.  This high risk 
population is thus an important target for intervention.  Intramuscular progesterone (17 
hydroxyprogesterone caproate) is the only FDA approved medication for the prevention of reccurent 
preterm birth in women with a prior spontaneous preterm birth.  It was studied in a randomized 
controlled trial (see reference Meis 2003 attached and ACOG practice bulletin number 130 attached). 
Vaginal progesterone is not FDA approved for the prevention of recurrent preterm birth, but has been 
found to beneficial in this regard.  Da Fonseca et al (2003) found that vaginal progesterone reduced the 
risk of both preterm birth (<37 weeks) and early preterm birth (<34 weeks) when compared to placebo in 
women with a prior spontaneous preterm birth (see attached reference de Fonseca 2007). In contrast, 
O’Brien et al (2007) did not find that vaginal progesterone significantly reduced the rate of recurrent 
preterm birth compared to placebo (see attached O’Brien 2007).  
A recent meta-analysis of three randomized trials comparing vaginal to intramuscular progesterone for 
the prevention of recurrent preterm birth in women with a prior spontaneous preterm birth found that 
vaginal progesterone was superior to intramuscular progesterone in prevention of preterm birth <34 
weeks and <32 weeks (see attached Saccone 2016). 
ACOG has provided a practice bulletin for the prevention of preterm birth. Given the data presented 
above, they recommend “progesterone supplementation starting at 16-24 weeks of gestation to reduce 
the risk of recurrent spontaneous preterm birth” but do not specify the dosage or route of progesterone 
administration.  Given the presence of trials demonstrating efficacy for both intramuscular and vaginal 
progesterone in the prevention of recurrent preterm birth they provide a table (See Table 1, relevant trials 
highlighted) with possible formulations of progesterone for the prevention of preterm birth in women 
with a prior preterm birth.     
 
Methods: 

VIP Trial 
Rupsa C. Boelig, MD (PI) 
2 
 
Version: 4 
Date: June 1, 2019 
 
This is a prospective randomized controlled trial comparing vaginal progesterone (200mg suppository 
daily) and intramuscular progesterone (250mg intramuscular weekly) for the prevention of recurrent 
spontaneous preterm birth in women with a history of prior spontaneous preterm birth. 
 
Patients: 
Pregnant women with singleton pregnancies are eligible to enroll in the trial if they were ≥18 years old 
with an estimated gestational age less than 24 weeks and had a prior spontaneous preterm birth of a 
singleton pregnancy between 16 0/7-36 6/7 weeks and have not already initiated progesterone therapy 
for preterm birth prevention (ie after 16 weeks gestation; first trimester use is not a contraindication).    
Patients are also required provide consent, demonstrate an understanding of the purpose of the study, 
and agree to the study protocol. 
Exclusion criteria include: a 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 
The patient may choose to withdraw from the study at any time. Treatment for prior preterm birth will 
continue with a progesterone agent as recommended by the patient’s primary obstetric provider.  
Participation in the interventional trial by the investigator may happen if the investigator deems that 
participation is detrimental to the health of the patient or the pregnancy. Patients who meet criteria but 
decline to participate in the trial will be verbally consented to have their outcomes followed in an 
observational cohort.  
 
Randomization and treatment groups 
Patients will be randomized in a 1:1 scheme.  Patients, obstetric care providers, and study investigators 
will not be blinded as to allocation.  The vaginal progesterone group will be prescribed 200mg vaginal 
progesterone suppositories to be taken daily starting at 16 0/7 – 23 6/7 weeks, and continued daily until 
36 6/7 weeks’ gestation or delivery.   The intramuscular progesterone group will be prescribed 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 therapies 
17 hydroxyprogesterone caproate 250mg weekly intramuscular from 16 weeks -36 weeks 

VIP Trial 
Rupsa C. Boelig, MD (PI) 
3 
 
Version: 4 
Date: June 1, 2019 
 
This medication is FDA approved for the purpose of prevention of recurrent preterm birth.  Common side 
effects include irritation at injection site, urticaria, pruritis, nausea, increased appetite, changes in mood. 
Micronized progesterone 200mg vaginal suppository daily from 16weeks- 36 weeks 
This medication is not FDA approved for the purpose of prevention of recurrent preterm birth and meets 
all the criteria for IND exemption by the FDA: 
_X_ The drug product is lawfully marketed in the United States. 
_X_ It is not intended to be reported to FDA in support of a new indication for use or to support any 
other significant change in the labeling for the drug;  
_X_ It is not intended to support a significant change in the advertising for the product;  
_X_ It does not involve a route of administration or dosage level, use in a subject population, or other 
factor that significantly increases the risks (or decreases the acceptability of the risks) associated 
with the use of the drug product;  
_X_ It is conducted in compliance with the requirements for IRB review and informed consent [21 CFR 
parts 56 and 50, respectively]; and 
_X_ It is conducted in compliance with the requirements concerning the promotion and sale of drugs 
[21 CFR 312.7]. 
Common side effects include: vaginal discharge, irritation, breast pain, constipation, cramping, emotional 
lability, nausea/vomiting, fatigue, headache, decreased libido, increased appetite, abdominal 
distension, arthralgia, dyspareunia 
Study Protocol 
Screening and Enrollment 
Patients with a prior spontaneous preterm birth of a singleton pregnancy between 16 0/7-36 6/7 weeks 
will be screened at gestational age less than 24 weeks.  Gestational age is as determined by last 
menstrual period and ultrasound biometry before 24 weeks.  Aside from route of progesterone therapy, 
patients will otherwise be managed as is standard of care including the recommendation for cervical 
length screening between 16 0/7- 23 6/7 weeks.   Patients with a cerclage for any indication will remain 
in the study.    
Patients meeting criteria are screened and enrolled by study personnel and investigators (coordinators, 
nurse practitioners, residents, fellows, or attendings) during prenatal care at the institution during 
regularly scheduled visits, consultation with Maternal Fetal Medicine, or obstetric ultrasound visit, prior 

VIP Trial 
Rupsa C. Boelig, MD (PI) 
4 
 
Version: 4 
Date: June 1, 2019 
 
to 24 weeks.  If desired, the patient may take the consent home to review it with family/friend, discuss 
the trial with their primary obstetrician/nurse practitioner/ midwife, and return at a later date to sign 
the consent with study personnel. The time limit for consenting will be up to 24 weeks gestation or 
starting another progesterone agent, whichever occurs first. Patients who consent will then be 
randomized after 12 weeks to receive either vaginal progesterone or intramuscular progesterone to be 
started between 16 0/7-23 6/7 weeks.  Treatment will be continued until 36 6/7 weeks or delivery, 
whichever occurs first.   
Children are not included as they are not significantly impacted by a prior preterm birth history and does 
not warrant additional risk if they are pregnant and <18 years of age.  Imprisoned women and women 
with cognitive impairment will not be approached.  Students or employees may be approached for the 
study.  To reduce any possible coercion, the consent will be reviewed, and encouraged to take home 
with and review with someone else prior to consenting.  Whenever possible, the consent will be signed 
with study personnel not directly related to the teaching, performance, or medical care of the patient. 
The patient may sign on the same day if she chooses to.   
Subject fees 
There is no reimbursement schedule associated with the study.  Travel and medication costs will not be 
reimbursed, as they are part of standard treatment for routine prenatal care and prior spontaneous 
preterm birth.  The patient’s insurance company will be billed for the cost of the progesterone 
treatment, and both treatment methods (intramuscular and vaginal progesterone) are recommended 
modalities by ACOG. The patient will be responsible for any co-pays associated with medications.  If 
insurance declines to cover the medication, though unlikely given recent experience, or the patient does 
not have insurance, she will be responsible for the cost of the medication. There are no additional 
tests/examinations that are being done solely for research purposes that would be billed to the 
insurance company. 
Interim Contacts 
Each patient will be interviewed using a predefined questionnaire every 4 weeks during routine prenatal 
visit or by phone call to assess medication compliance and adverse effects/events by a trained study 
personnel or investigator. 
Preterm Labor or Preterm Premature Rupture of Membranes 
If a patient develops preterm labor during the study period, she will be managed per the primary 
obstetric provider with the recommendation being to continue study medication until delivery.  If a 
patient is diagnosed with preterm premature rupture of membranes, study medication will be 
discontinued. 
Data Collection 

VIP Trial 
Rupsa C. Boelig, MD (PI) 
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Version: 4 
Date: June 1, 2019 
 
Data to be collected from each patient include demographic characteristics, BMI, smoking status, 
substance abuse history, obstetric history (including number and timing of prior spontaneous preterm 
births, and number of prior full term deliveries), antenatal complications (including hypertensive 
disorder of pregnancy, gestational diabetes, preexisting hypertension or diabetes, intrauterine growth 
restriction), delivery outcomes (gestational age, mode of delivery), neonatal outcomes (Apgar scores, 
birth weight, admission to neonatal intensive care unit, neonatal morbidity), and medication 
satisfaction, adherence,  and side effects. Demographic data will be collected through a combination of 
interview with the patient and the medical record.  Delivery and neonatal outcomes will be assessed 
through the paper or medical record. Compliance will be assessed through a  questionnaire. 
 
Observational Cohort 
Women who do not consent to participate in the study will be asked for verbal consent to collect data 
only in order to make sure their characteristics are similar to the study cohort.  Collected data will include 
demographic information, obstetric history, medical, social, and gynecological history, and current 
pregnancy outcomes.  150 women will be verbally consented to be in the observational cohort, 50 at 
Thomas Jefferson University Hospital, 50 at Baystate Medical Center and 50 women at George 
Washington University Hospital. 
Risk/Benefit Assessment 
The risks associated with participation in the interventional trial are thought to be minimal, as both 
intramuscular and vaginal progesterone are both in use for the treatment of prior spontaneous preterm 
birth.  Potential side effects/adverse events of each drug will be reviewed with the patient during the 
consent process.  The patient will be instructed that progesterone treatment would be started 
regardless of participating in the trial or not, and she would receive the same care if declining 
participation.  There may be not benefit from trial participation, but may identify a superior method to 
administer progesterone in future pregnant women, leading to a societal benefit.  
 
The risk of loss of confidentiality exists in both the interventional and observational cohort.  This risk is 
minimized by storing data on a secure online database (REDCap), using non-identifiable Study ID at the 
primary data collection site, and keeping all identifiable information (hard copy consents) in locked 
cabinets in locked offices.   
Outcome Measures 
Primary outcome is the incidence of preterm birth <37 weeks.   
Secondary outcomes  

VIP Trial 
Rupsa C. Boelig, MD (PI) 
6 
 
Version: 4 
Date: June 1, 2019 
 
 
Maternal outcomes: 
o Incidence of preterm birth <34 weeks and <28 weeks 
o Gestational age at delivery  
o Incidence of short TVU CL <25mm  
o Mode of delivery  
o Maternal mortality 
 
Neonatal outcomes:  
o 5 minute APGAR score,  
o Intensive care unit admission,  
o Birthweight 
o Perinatal mortality up to 28 days of life 
o 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)  
 
Medication related outcomes: 
o Medication side effects  
o Satisfaction with medication (5 point Likert scale) 
o Medication adherence defined as: 
 
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 
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 CL<25mm versus CL≥25mm, with a history indicated 
cerclage vs not,  and for those started on progesterone 16-20 weeks versus 20-24 weeks. 
Statistical Analysis 
Based on a two sided significance of 5% and a power of 80% for the primary outcome, as well as 
incidence of recurrent PTB 36% with IM progesterone (Meis 2003), and 50% decrease with vaginal 
progesterone, power calculation estimated at least 95 patients in each arm.   Assuming a 15% loss to 
follow up, 112 patients are needed in each group; if there is an additional ~5% loss due to exclusions 
that come up or other inability to randomize after consent, a total of 230 women will need to be 
consented to reach goal randomization.  
Randomization and data collection will be done using REDCap (see section below).  
Statistical analysis will be performed with SPSS 23.0   

VIP Trial 
Rupsa C. Boelig, MD (PI) 
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Version: 4 
Date: June 1, 2019 
 
Baseline characteristics and outcome measures will be compared using student t-test for continuous 
variables, chi-square test for categorical variables, and Kaplan Meier survival curve for gestational age of 
delivery. P<0.05 is considered significant. 
Sites 
This will be a multi-center trial with the primary site being Thomas Jefferson University Hospital, and the 
other sites being Baystate Medical Center,George Washington University, Virginia Commonwealth 
University, and Ohio State University.  We anticipate that 80 women will be consented from Thomas 
Jefferson, 80 women from Baystate, 10 women from George Washington, 50 from Ohio State University, 
and 10 from Virginia Commonwealth University.  It is possible additional sites will be added as the trial 
progresses.  We anticipate 5 years for completion of trial including data analysis.  
Thomas Jefferson University 
PI: Rupsa C. Boelig 
Contact: Rupsa.boelig@jefferson.edu 
Baystate Medical Center 
PI: Corina Schoen 
Contact: Corina.SchoenMD@baystatehealth.org 
George Washington University 
PI: Alexis Gimovsky 
Contact: agimovsky@mfa.gwu.edu 
Virginia Commonwealth University 
PI: Edward Springel 
Contact: edwspringel@gmail.com 
Ohio State University 
PI: Heather Frey 
Contact: heather.frey@osumc.edu 
Interim Analysis/Data Safety Monitoring Board 
Interim analysis will be performed after the first 112 women (50% recruitment) randomized women 
deliver to assess for maternal mortality and neonatal mortality as part of data and safety monitoring.  

VIP Trial 
Rupsa C. Boelig, MD (PI) 
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Version: 4 
Date: June 1, 2019 
 
Chi square analysis will be performed with a p< .001 considered significant.   Interim analysis will be 
under the oversight of the Data Safety Monitoring Board which includes a neonatologist (Dr. Dave 
Carola), Maternal Fetal Medicine Dr. Stuart Weiner), from Thomas Jefferson University. Interim safety 
analysis statistics will be conducted by Jordan Levine (Alexendria Health LLC, 678-907-7730, Email: 
Jordan@alexandria.health). The following deidentified information will be used for interim safety 
analysis: Study ID, randomization group number (1 or 2), Maternal mortality (Y or N) and Perinatal 
mortality (Y or N).  None of the participants have any relation with the ongoing trial design or eventual 
analysis.   
Adverse events, protocol deviations, and unanticipated events will be reported within 48 hours to the 
principle study investigator at each site who will then report them to the study PI Rupsa Boelig within 48 
hours.  Serious adverse events will be reported to the IRB. Participating sites will be notified if any 
protocol changes must be made due to unexpected AE’s or SAEs within 7 business days. Monthly 
contact by phone or email between the primary site (Thomas Jefferson) and other sites will occur to 
discuss study progress, recruitment, study protocol and any of potential trial issues.  If new data 
becomes available during the course of the trial that may affect current or past trial participants, a study 
investigator or coordinator will contact the patient. This will be documented in the REDCap database via 
Thomas Jefferson University.   
In addition to an interim analysis for maternal and neonatal mortality, we will also review adverse 
events, protocol deviations, unanticipated events, and enrollment progress at each site and collectively 
every 6 months.   
 
Data Collection and Security 
Data collection will be done using REDCap database hosted by Thomas Jefferson University.  Only 
individuals who are included as investigators or study personnel will be granted access to the database.  
The REDCap database will NOT include any protected health information; patients will be identified by 
a unique Study ID.  There will be a separate secure database at each site linking Study ID with patient 
identification.  User access will be granted only by the PI Rupsa Boelig.  Investigators and research 
personnel will only have access to data entered by their respective sites, with the exception of study PI 
Rupsa Boelig who will have access to all the data.  When study personnel/investigators are no longer 
part of the institution or study, Rupsa Boelig will be notified and their access to the database will be 
immediately discontinued.