Vaginal Progesterone for the Prevention of Preterm Birth in Women With Arrested Preterm Labor
Phase: NA
Conditions: Premature Birth, Obstetric Labor, Premature
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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PROTOCOL: 
 
VAGINAL PROGESTERONE FOR THE PREVENTION OF 
PRETERM BIRTH IN WOMEN WITH ARRESTED 
PRETERM LABOR (PAL) 
 
 
 
NCT01840228  
 
 
 
DOCUMENT DATE: MARCH 11, 2015 
 

 
 
 
 
 
 
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TABLE OF CONTENTS 
 
A 
INTRODUCTION ............................................................................................................................... 4 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 4 
A3 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 4 
B 
BACKGROUND .................................................................................................................................. 4 
B1 
PRIOR LITERATURE AND STUDIES .................................................................................................. 4 
B2 
RATIONALE FOR THIS STUDY ......................................................................................................... 5 
C 
STUDY OBJECTIVES........................................................................................................................ 5 
C1 
PRIMARY AIM ................................................................................................................................ 5 
C2 
SECONDARY AIM ........................................................................................................................... 5 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 5 
D 
INVESTIGATIONAL AGENT .......................................................................................................... 5 
D1 
PRECLINICAL DATA ....................................................................................................................... 5 
D2 
CLINICAL DATA TO DATE .............................................................................................................. 5 
D3 
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 6 
E 
STUDY DESIGN ................................................................................................................................. 6 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 6 
E2 
SUBJECT SELECTION AND WITHDRAWAL....................................................................................... 7 
2.a 
Inclusion Criteria ..................................................................................................................... 7 
2.a 
Exclusion Criteria ..................................................................................................................... 7 
2.b 
Ethical Considerations ............................................................................................................. 7 
2.c 
Subject Recruitment Plans and Consent Process ..................................................................... 7 
2.d 
Randomization Method and Blinding ....................................................................................... 8 
2.e 
Risks and Benefits ..................................................................................................................... 8 
2.f 
Early Withdrawal of Subjects ................................................................................................... 9 
2.g 
When and How to Withdraw Subjects ....................................................................................... 9 
2.h 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
E3 
STUDY DRUG ................................................................................................................................. 9 
3.a 
Description ............................................................................................................................... 9 
3.b 
Treatment Regimen ..................................................................................................................10 
3.c 
Method for Assigning Subjects to Treatment Groups ..............................................................10 
3.d 
Preparation and Administration of Study Drug .......................................................................10 
3.e 
Subject Compliance Monitoring ..............................................................................................10 
3.f 
Prior and Concomitant Therapy ..............................................................................................11 
3.g 
Packaging ................................................................................................................................11 
3.h 
Blinding of Study Drug ............................................................................................................11 
3.i 
Receiving, Storage, Dispensing and Return ............................................................................12 
F 
STUDY PROCEDURES ....................................................................................................................12 
F1 
SCREENING FOR ELIGIBILITY ........................................................................................................12 
F2 
SCHEDULE OF MEASUREMENTS ....................................................................................................13 
F3 
SAFETY AND ADVERSE EVENTS ....................................................................................................15 

 
 
 
 
 
 
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3.a 
Safety and Compliance Monitoring .........................................................................................15 
3.b 
Medical Monitoring .................................................................................................................16 
i 
Investigator only ..................................................................................................................................... 16 
ii 
Independent expert to monitor ................................................................................................................ 16 
iii 
Institutional Data and Safety Monitoring Board ..................................................................................... 16 
iv 
Independent Data and Safety Monitoring Board ..................................................................................... 16 
3.c 
Definitions of Adverse Events ..................................................................................................16 
3.d 
Classification of Events ...........................................................................................................16 
i 
Relationship ............................................................................................................................................ 16 
ii 
Severity ................................................................................................................................................... 16 
iii 
Expectedness .......................................................................................................................................... 17 
3.e 
Data Collection Procedures for Adverse Events .....................................................................17 
3.f 
Reporting Procedures ..............................................................................................................17 
3.g 
Adverse Event Reporting Period ..............................................................................................17 
3.h 
Post-study Adverse Event ........................................................................................................17 
F5 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ..........................................................17 
G 
STATISTICAL PLAN ........................................................................................................................18 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................................18 
G2 
INTERIM MONITORING AND EARLY STOPPING ..............................................................................18 
G3 
ANALYSIS PLAN............................................................................................................................18 
G4 
STATISTICAL METHODS ................................................................................................................18 
G5 
MISSING OUTCOME DATA ............................................................................................................19 
G6 
UNBLINDING PROCEDURES ...........................................................................................................19 
H 
DATA HANDLING AND RECORD KEEPING .............................................................................19 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................................19 
H2 
TRAINING......................................................................................................................................20 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................................................20 
H4 
RECORDS RETENTION ...................................................................................................................20 
H5 
PERFORMANCE MONITORING .......................................................................................................20 
I 
STUDY MONITORING, AUDITING, AND INSPECTING ..........................................................20 
I1 
STUDY MONITORING PLAN ...............................................................................................................20 
I2 
AUDITING AND INSPECTING ..............................................................................................................20 
J 
STUDY ADMINISTRATION ...........................................................................................................20 
J1 
ORGANIZATION AND PARTICIPATING CENTERS .................................................................................20 
J2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ..............................................................................20 
J3 
COMMITTEES .....................................................................................................................................20 
J4 
SUBJECT STIPENDS OR PAYMENTS ....................................................................................................21 
J5 
STUDY TIMETABLE ...........................................................................................................................21 
K 
PUBLICATION PLAN ......................................................................................................................21 
L 
ATTACHMENTS ...............................................................................................................................21 
L1 
TABLES .........................................................................................................................................21 
L2 
INFORMED CONSENT DOCUMENTS.................................................................................................21 
L3 
PATIENT EDUCATION BROCHURES.................................................................................................21 
L4 
SPECIAL PROCEDURES PROTOCOLS ...............................................................................................21 
L5 
QUESTIONNAIRES OR SURVEYS .....................................................................................................21 
M 
REFERENCES ...................................................................................................................................21 
 

 
 
 
 
 
 
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A Introduction 
 
A1 Study Abstract 
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. 
A2 Primary Hypothesis 
We hypothesize that administration of vaginal progesterone in women who present with 
preterm labor but remain undelivered 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. 
A3 Purpose of the Study Protocol 
This study protocol outlines the purposes and procedures of this randomized controlled 
trial. 
B Background 
 
B1 Prior Literature and Studies 
Approximately 12% of births in the United States (U.S.) are preterm, defined as 
occurring before 37 weeks’ gestation (Mathews 2012). Infants born preterm suffer from 
short- and long-term complications affecting multiple organ systems (Mathews 2012, 
McIntire 2008, Saigal 2008). In addition, approximately 67% of all deaths within the first 
year of life occur in infants born prematurely (Mathews 2012). Progesterone is the single 
most effective medical therapy in the primary prevention of preterm birth (Tita 2009); 
however, its use is limited to women with a history of prior preterm delivery and women 
found by transvaginal ultrasound to have a short cervix (Meis 2003, Fonseca 2007, 
Hassan 2011). An additional group of women at risk for preterm delivery is the 
approximately 5% of pregnant women (McPheeters 2006) who present with contractions 
and cervical change but have temporary arrest of preterm labor. Despite the initial arrest 
of labor progress, as many as 50-60% of these women will ultimately deliver preterm 
infants (ACOG 2012, Lyell 2008). A handful of studies, including a recent meta-analysis 
(Likis 2012), have found that the use of vaginally administered progesterone in women 
with arrested preterm labor is associated with a longer arrest-to-delivery interval and 
higher infant birth weight. However, concerns about the applicability of the findings to the 
U.S. healthcare system limit their ability to change the standard of care for this at-risk 
population; an adequately powered study providing Level I evidence for this practice is 
thus required. 

 
 
 
 
 
 
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B2 Rationale for this Study 
There is a direct correlation between gestational age at delivery and infant morbidity and 
mortality (Mathews 2012). Prolonging a pregnancy by even a few days or weeks can 
have a significant impact on a child’s health. Women with arrested preterm labor are an 
identifiable high-risk group whose children may benefit from long-term therapy to delay 
delivery. If our study confirms the findings of the meta-analysis by Likis (2012) that 
progesterone decreased by 38% the preterm birth rate in women with arrested preterm 
labor, we estimate (on the basis of recent birth data [Mathews, 2012]) that this therapy 
may prevent as many as 40,000 preterm births annually in the U.S. 
C Study Objectives 
 
C1 Primary Aim 
To evaluate the efficacy of vaginal progesterone in women with arrested preterm labor 
after 24 weeks’ gestation to reduce their risk of preterm birth before 37 weeks.  
 
C2 Secondary Aim 
None 
C3 Rationale for the Selection of Outcome Measures 
The primary outcome is delivery prior to 37 weeks’ gestation. This was selected as the 
primary outcome because the current definition of preterm birth is any delivery occurring 
prior to 37 weeks gestation. With advancing gestational age, the risks of adverse 
outcomes for the fetus are diminished. Infants born at term generally do not require 
additional therapeutic interventions and are discharged from the hospital at the time of 
maternal discharge without the sequelae of prematurity. 
D Investigational Agent  
 
D1 Preclinical Data 
 
See clinical data to date. 
D2 Clinical Data to Date  
 
Although not FDA approved, micronized vaginal progesterone is commonly used in 
practice for the prevention of preterm birth. Recently, the American College of 
Obstetricians and Gynecologists recommended that women with diagnosed short cervix 
(<20 mm on ultrasound) at 24 weeks gestation or earlier should receive vaginally 
administered progesterone supplementation which is routinely administered daily until 37 
weeks gestation. Multiple randomized controlled trials have demonstrated the safety and 
tolerability of this medical therapy. Fonseca et al. performed a randomized controlled 
trial utilizing micronized progesterone capsules 200 mg in 250 women with a short 

 
 
 
 
 
 
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cervix. None of the women reported any increase in the frequency or severity of side 
effects such as fatigue, headaches or genital irritation. Also, no new symptoms were 
reported by participants after starting treatment. Arikan et al. published a randomized 
trial evaluating the use of micronized progesterone in women with arrested preterm 
labor. In this non-blinded study, no complaints or adverse effects related to the treatment 
were reported by participants. In a large, international multicenter randomized controlled 
trial that include 458 women, micronized progesterone was administered as a gel rather 
than a tablet. No difference in adverse events were reported in women who received 
progesterone and those who received a placebo gel. The most commonly reported side 
effects in both groups included vaginal pruritus, vaginal discharge, vaginal yeast 
infection and nausea. No differences in rates of congenital anomalies were found in 
those fetuses of women who received progesterone and those who received the placebo 
(RR 0.32, 95% CI 0.03-3.02). Likewise, a study specifically evaluating the safety of 
progesterone exposure in pregnancy found no increased risk of fetal adverse effects 
(Northen 2007). 
D3 Dose Rationale and Risk/Benefits  
The progesterone that will be utilized is micronized vaginal progesterone 200 mg daily. 
This choice was selected because this is the dose and formulation that is routinely 
prescribed by Washington University/Barnes-Jewish Hospital obstetricians for the 
prevention of preterm birth in asymptomatic women with a short cervix diagnosed by 
routine ultrasound examination. In addition, this dose was also used by Fonseca et al. in 
their randomized controlled trial for the prevention of preterm in women with a 
sonographically short cervix and they reported no increase in side effects with this drug. 
We also believe that the use of a vaginally inserted suppository rather than a gel may be 
easier for women participating in the study. 
E Study Design  
 
E1 Overview or Design Summary 
 
Randomized, double-blinded, placebo controlled trial. Women enrolled in the study will 
be randomized to vaginal administration of micronized progesterone 200 mg or placebo 
daily from time of enrollment until 36 6/7 weeks gestation. Investigators, participants, 
and the obstetric providers will be blinded to the allocated intervention. 
 
As part of the study, participants have the option to provide a vaginal swab specimens 
for future studies evaluating the effect of vaginal progesterone on the vaginal 
microbiome. If the woman agrees to participant in this part of the study as well, then a 
swab will be collected by her obstetric care provider after enrollment but prior to study 
drug administration and an additional swab will be collected 2-6 weeks after 
randomization at a follow-up visit. 
 
 
 
 
 

 
 
 
 
 
 
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E2 Subject Selection and Withdrawal  
 
2.a 
Inclusion Criteria  
 
Singleton or twin gestation 
 
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 3) no 
further cervical change after 12 hours if no tocolytic is administered 
 
The participant’s cervix must be at least 1 cm dilated at the time of enrollment
2.a 
Exclusion Criteria  
 
non-English speaking, 
 
rupture of membranes, 
 
chorioamnionitis,  
 
non-reassuring fetal status,  
 
maternal indication for delivery 
(e.g., severe preeclampsia),  
 
placental abruption,  
 
intrauterine fetal demise, 
 
prenatally diagnosed major fetal 
anomalies,  
 
a 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 at the Barnes-Jewish Hospital Center for Outpatient Health or 
the Maternal-Fetal Medicine (MFM) practice at Washington University. Enrollees 
will not need to receive their pregnancy care at these locations but must meet with 
a study coordinator every two weeks. 
 
2.b 
Ethical Considerations  
All participants in the study will be consented. Information about potential maternal and 
fetal risks and benefits will be reviewed. There will be no coercion involved. Neither 
enrollment nor refusal to participate in the study will influence a woman’s obstetric care 
or the care of her fetus/neonate, besides the use of the allocated study drug and follow-
up after hospital discharge for women for women who agree to participate. 
 
2.c 
Subject Recruitment Plans and Consent Process 
A member of the research team will approach women with arrested preterm labor to 
discuss possible participation. Women may be approached prior to the completed 12 
hours after discontinuation of acute tocolytic therapy; however they will not be 
randomized until at least 12 hours after the discontinuation time unless they are 
considered eligible for discharge from the hospital prior to completion of the 12 hour time 
period. The research team member will review the goals of the study, use of the 
allocated study drug, plans for follow-up, and the entire consent process, and will 
provide the woman a copy of the consent form. The physicians and nurses caring for the 
patient will not be involved in the consent process, and the patient will be assured that 
her decision to participate in the study will not influence her care beyond the use of the 

 
 
 
 
 
 
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allocated study drug and follow-up if discharge from the hospital occurs before delivery. 
Each woman will have up to 24 hours to decide whether she would like to participate in 
the study. At the time of enrollment, release of records forms will also be signed by the 
participant to permit the investigators to obtain medical records for the participant and 
her infant from another institution or obstetric provider in the event that she delivers at a 
location other than Barnes-Jewish Hospital.  
 
A separate section of the consent form allows the participant to agree or decline 
participation in the vaginal sample collections for future studies. Woman will be able to 
participate in the randomized controlled trial without agreeing to specimen collection. 
2.d 
Randomization Method and Blinding 
Participants in the study will be randomized using a computer-generated randomization 
scheme with 1:1 allocation to receive progesterone or placebo. The randomization 
scheme will be set-up by a statistician within the department of Obstetrics and 
Gynecology at Washington University. Research assistants not otherwise involved in the 
study will place pieces of papers with letters "A" or "B" into envelopes labeled with 
participant study numbers based on the randomized assignment. This will be completed 
prior to the study commencement. The envelopes will then be provided to Katherine 
Vehe, phone: 314-362-3376, in the Barnes-Jewish Hospital pharmacy who will supervise 
the allocation of study drugs within the pharmacy. She will decide prior to the study start 
the assignment of "A" or "B" to the progesterone or placebo and this will be recorded. 
This allocation will remain consistent throughout the study and the other members of the 
research team, patient care providers, and participants will be blinded to this allocation. 
Once a participant is given a study number, the study coordinator will contact Katherine 
Vehe who will provide the appropriate drug based on the letter contained within the 
envelope that corresponds to the study number.  
 
 
2.e 
Risks and Benefits 
There are no emotional, psychological, or social risks to the participant beyond the stress 
of having an increased risk for preterm birth. The cost of the study drug will be covered, 
so there is no increased financial burden to the participant. Both progesterone and the 
placebo will be placed vaginally and there is a potential risk for vaginal discharge, irritation, 
yeast infection, and nausea with either drug. However, data from large randomized 
controlled trials performed with the same medication suggests that there is minimal to no 
increased risk of these potential side effects (Fonseca 2007, Hassan 2011). Every two 
weeks, a research nurse will discuss and record any side effects reported by the 
participant. The participant may discontinue use of the allocated study drug at any time 
and continue to participate in the study. A Data Safety and Monitoring Board, which will 
be created before the study begins, will review the blinded results, including reported side 
effects when 50% of planned enrollment is achieved (120 women) and provide 
recommendations to the investigator regarding the safety of continuing the study. There 
is a very small potential risk of loss of confidentiality; however, multiple mechanisms will 
be used to decrease this risk, including the storage of research information in a password-
protected database on a password-protected computer in a locked office, the use of 
research identification codes, and coding of data entered in the database. 
 

 
 
 
 
 
 
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There are no direct benefits that are expected for the participant. However, available 
data suggests a possible delay in delivery with the use of vaginal progesterone in this 
population of women. Survival increases and the risk of significant morbidity decreases 
with advancing gestational age. Even a few days or weeks of delaying preterm birth can 
be of significant benefit, as the fetus is developing every day. 
 
2.f 
Early Withdrawal of Subjects  
Participants may withdraw from the study at any time. Alternatively, participants who are 
unable to follow-up after discharge from the hospital or refuse to continue taking the 
study drug may remain in the study for the purpose of intention-to-treat analysis. 
2.g 
When and How to Withdraw Subjects  
Participants may withdraw from the study at any time. Participants may do this by 
contacting the study team or sending in a withdrawal letter. 
 
In addition, the study coordinator will contact a participant who does not return to 
Barnes-Jewish Hospital/Washington University for study drug pick-up as scheduled to 
discuss further participation. She will call the participant at the phone number that she 
provided at the beginning of the study. 
 
If a participant withdraws from the study, a member of the research team should 
discuss the following options: 
1) Complete withdrawal from the study without the use of data collected as part of the 
study in analysis. 
2) Continued study participation with no further follow-up visits and discontinuation of 
the study drug, but with the collection of information following delivery regarding the 
delivery timing and neonatal outcomes. This will allow intention-to-treat analysis. 
 
Participants who withdraw from the study will also be asked to provide a reason for 
study withdrawal. 
 
2.h 
Data Collection and Follow-up for Withdrawn Subjects  
Even if the participant discontinues the study drug, she may continue to participate in the 
study and outcome data regarding delivery timing and neonatal outcomes will be 
collected with her permission (option 2 above).  
 
 
E3 Study Drug  
 
3.a 
Description  
 
Women in the study will be randomized to receive vaginal micronized progesterone or a 
similar appearing placebo.  

 
 
 
 
 
 
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3.b 
Treatment Regimen  
A single suppository of the allocated drug will be placed vaginally each day.  
3.c 
Method for Assigning Subjects to Treatment Groups  
Participants in the study will be randomized using a computer-generated randomization 
scheme with 1:1 allocation to receive progesterone or placebo. The randomization 
scheme will be set-up by a statistician within the department of Obstetrics and 
Gynecology at Washington University. Research assistants not otherwise involved in the 
study will place pieces of papers with letters "A" or "B" into envelopes labeled with 
participant study numbers based on the randomized assignment. This will be completed 
prior to the study commencement. The envelopes will then be provided to Katherine 
Vehe, phone: 314-362-3376, in the Barnes-Jewish Hospital pharmacy who will supervise 
the allocation of study drugs within the pharmacy. She will decide prior to the study start 
the assignment of "A" or "B" to the progesterone or placebo and this will be recorded. 
This allocation will remain consistent throughout the study and the other members of the 
research team, patient care providers, and participants will be blinded to this allocation. 
Once a participant is given a study number, the study coordinator will contact Katherine 
Vehe who will provide the appropriate drug based on the letter contained within the 
envelope that corresponds to the study number.  
3.d 
Preparation and Administration of Study Drug  
Both the study drug and placebo will be compounded in the Barnes-Jewish Hospital 
pharmacy. The placebo will contain polyethylene glycol (PegBlend, Fagron 
Pharmaceuticals) a compound commonly used in the manufacturing of suppositories. 
The progesterone suppositories will contain micronized progesterone 200 mg and 
polyethylene glycol. These products will be contained within an opaque suppository 
capsule which can be placed vaginally. The drugs will be refrigerated prior to use. 
3.e 
Subject Compliance Monitoring  
Every two weeks regardless of whether the patient remains inpatient or outpatient the 
study coordinator will meet with the participant. Women who were discharged from the 
hospital will be instructed to bring their study drug containers to this visit and the number 
of remaining suppositories will be counted and the number of missed doses calculated.  
During these visits, compliance and side effects will be discussed. Prior to the start of 
the visit the participant will be asked to fill out a one-page questionnaire:  
 
 
1) Have you been admitted to the hospital since our last meeting? 
 
A. Yes 
B. No 
 
If yes, reason(s) and date(s): ___________________________________ 
 
 
 
 
 
         ____________________________________ 
 
 
2) Have you started any new medications since our last meeting? 
 
A. Yes 

 
 
 
 
 
 
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B. No 
 
If yes, please list them: ___________________________________________ 
 
 
 
3) How many does of the study drug have you missed or forgotten to take since our 
last meeting? 
 
A. Missed 10 or more 
B. Missed 5 – 10 
C. Missed less than 5 
D. Missed none 
 
 
4) Have you noticed any new symptoms since our last meeting? 
 
A. Yes 
B. No 
 
If yes:   Symptom(s): ______________________________________________ 
              Start and End Date(s): ______________________________________ 
              Frequency: _______________________________________________ 
              Severity: _________________________________________________ 
 
3.f 
Prior and Concomitant Therapy 
Prior use of any form of progesterone during the current pregnancy other than that 
provided during the study is an exclusion criterion for study enrollment. Another criterion 
for enrollment is that the participant must have discontinued acute tocolytic therapy for 
12 hours prior to enrollment and remained clinically stable. An exception to this is that if 
the participant begins to labor in the future (any time prior to 32 weeks’ gestation) while 
enrolled in the study, magnesium sulfate may be administered for the purpose of fetal 
neuroprotection while the threat of preterm delivery persists. Magnesium is used for 
acute tocolytic therapy, but it use in this circumstance is not tocolysis but rather to 
decrease the risk of cerebral palsy in the offspring. Other therapy for medical or 
pregnancy-related indications may be prescribed by the participant’s physician and be 
taken concomitantly.  
3.g 
Packaging  
Either the progesterone and placebo suppositories will be distributed to the patient’s 
nurse (while inpatient) or study coordinator (outpatient) in a UV light protected, USP tight 
medicine bottle. 
3.h 
Blinding of Study Drug  
The research team, obstetric providers, and participant will be blinded to the study drug. 
The pharmacist will not be blinded to the drug and will distribute the proper allocated 
drug to the study coordinator and nursing staff. The placebo and micronized 
progesterone will be contained within identical appearing suppository capsules. Care will 
be taken not to include information regarding the specific drug on the medicine bottle. 

 
 
 
 
 
 
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3.i 
Receiving, Storage, Dispensing and Return  
While the participant is an inpatient in Barnes-Jewish Hospital, the study coordinator will 
notify pharmacy of the new participant and the study drug will be distributed from 
pharmacy to the nursing staff on labor and delivery or the antepartum unit on a daily 
basis. The drug will be stored in the medication refrigerator on the unit until it is 
administered to the patient. Upon discharge from the hospital, the study coordinator will 
obtain a 21-day supply of the study drug from the pharmacy which will be distributed to 
the participant. The participant will be instructed to store the medication in a refrigerator 
prior to use. She will follow-up every two weeks with the study coordinator at 
Washington University or Barnes-Jewish Hospital outpatient offices and will be provided 
with the next two week supply of study drug and will bring back any leftover pills from her 
previous supply of drugs. 
 
 
F Study Procedures  
 
F1 Screening for Eligibility 
Obstetric care providers including physicians and nurses will notify the study coordinator 
if a potential participant is identified. Prior to approaching the individual for possible 
enrollment, the study coordinator will review the patient’s records to determine eligibility 
for the study based on the prior outlined inclusion and exclusion criteria. We will keep 
track of the total number of women screened, but will not record any personal 
information regarding women who do not meet eligibility criteria. 
 
If the woman meets eligibility criteria, then the study coordinator will approach her for 
enrollment in the study. The goals of the study, the use of the allocated study drug, plans 
for follow-up and the entire consent will be reviewed in person with each woman and she 
will be provided a copy of the consent form. This discussion will occur in the woman's 
private hospital room. The physicians and nurses caring for the patient will not be 
involved in the consent process and the patient will be assured that her decision to 
participate in the study will not influence her care beyond the use of the allocated study 
drug and follow-up if discharge from the hospital occurs prior to delivery. The study 
coordinator may approach women prior to the completed 12 hours after discontinuation 
of acute tocolytic therapy to discuss the study and gauge interest in participation, but the 
woman will not be randomized until at least 12 hours after the discontinuation time 
unless the patient is eligible for discharge prior to the 12 hour time period based on 
attending physician judgement. Each woman will have up to 24 hours to decide whether 
she would like to participate in the study. 
 
Questions that the study coordinator will specifically ask of the individual prior to 
enrollment in the study include: 
 
 
Are you currently taking any form of progesterone therapy?  
 
Have you in the past had any adverse reaction to taking a progesterone drug?  
 
Would you be willing and able to return to Barnes-Jewish Hospital/Washington 
University every two weeks for a study visit and to receive a refill on the study 

 
 
 
 
 
 
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drug if your physician determines that you are able to be discharged from the 
hospital prior to delivery? 
 
The name and birth date of each individual invited to participate in the study will be 
recorded in a password protected spreadsheet stored in the password protected 
computer of the study coordinator along with information about whether the participant 
agreed to participate in the study or not. This information will ensure that the same 
woman is not approached for the study more than once. 
 
We will also ask the potential participant to provide a reason for not wanting to 
participate in the study. Basic demographic information including maternal age, race, 
parity, history of prior preterm birth, and gestational age and cervical dilation at the time 
she was approached for study participation will be recorded from the medical record. 
Women who decline participation will be notified that we would plan to collect the 
information above and the purpose of collecting that information. 
 
As a trial that is evaluating the use of a preventive medication in a population that is not 
normally offered this type of therapy, it is critical that the acceptability of the therapy 
within this population is assessed as part of the trial. In addition, the basic demographic 
data that is collected will allow the research team to assess for a possible selection bias 
among women who agree to participate and those who do not. This information will be 
stored in a secure document on the password protected computer of the investigator. All 
PHI data will be deleted at the completion of the study and publications resulting from 
this study will contain no personally identifiable information about these individuals. 
However, we will use this information to create a flow diagram for the study. 
 
F2 Schedule of Measurements 
 
I. Procedures following enrollment: 
 
Randomization: Once the participant agrees to participate in the study, the study 
coordinator will contact the pharmacy with the participant’s study identification 
number. The pharmacist or pharmacy technician will use the study randomization 
scheme to determine whether the participant will receive progesterone or 
placebo. This will be recorded by the pharmacist in a randomization log which will 
link the study number with the allocated drug. This log will not be seen by the 
participant, obstetric provider or any member of the research team unless 
requested by the Data Safety and Monitoring Board or at the completion of the 
study. 
 
Vaginal specimen swab: If the participant agrees to provide vaginal specimens, 
then the first specimen will be collected by her obstetric care provider in the 
hospital with a speculum examination prior to beginning the study drug. This 
specimen will be stored for future vaginal microbiome research. The swabs will 
be stored as part of the Women and Infants' Health Specimen Consortium. 
 
Data collection: Initial data collection will begin following enrollment. Information 
will be recorded from the participants medical record and will include: 
o Participant demographic data: age, race/ethnicity, weight, height, smoking 
status, drug use, marital status 
o Past medical and surgical history data 

 
 
 
 
 
 
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o Prior pregnancy history data: number of prior pregnancies and prior 
pregnancy outcomes including gestational age at delivery 
o Current pregnancy data: date of first prenatal visit, use of medications 
during the pregnancy, infections, date of first ultrasound examination, any 
pregnancy complications other preterm labor, cervical length if performed 
as part of routine screening earlier in pregnancy 
o Care during current hospitalization for preterm labor: gestational age at 
time of admission, medications administered including tocolytics and 
antenatal corticosteroids, cervical examination on admission, most recent 
cervical examination, complications of pregnancy diagnosed during the 
hospitalization, estimated fetal weight at time of admission  
 
Study drug distribution: While the participant remains hospitalized at Barnes-
Jewish Hospital the study drug will be dispensed on a daily basis by the 
pharmacy to the nursing staff in the unit in which the participant is staying. The 
participant will be provided the drug every 24 hours and will be asked to place 
the drug herself with nursing instruction. 
 
The participant’s care will not be altered based on her enrollment in the study 
except for taking the study drug. Decisions regarding clinical management will be 
determined by the obstetric care providers caring for the participant during her 
hospitalization. Other than collection of the vaginal swab at enrollment, no 
additional procedures will be performed as part of the study. 
 
II. Follow-up procedures:  
 
Follow-up procedures will depend on whether the participant remains 
hospitalized until delivery or she is discharged home, which will be determined by 
her obstetric care providers and will not be influenced by her participation in the 
study. 
 
Inpatient:  
o The study drug will continue to be provided by the pharmacy on a daily 
basis and distributed to the participant by nursing staff.  
o During the follow-up visit, the study coordinator will discuss compliance 
with the study drug and possible side effects. The participant will fill out a 
one-page questionnaire form that asks questions about compliance and 
side effects. This information will be recorded and provided to the DSMB 
at the midpoint review. 
o For women enrolled in the vaginal specimen collection portion of the 
study, a repeat vaginal swab will be collected by the obstetric care 
provider 2-6 weeks after enrollment. 
 
Outpatient: 
o At the time of discharge from the hospital, the participant will be provided 
with a 21-day supply of study drug. 
o The participant’s follow-up prenatal care will be determined by 
obstetricians caring for her during the hospitalization. Continued prenatal 
care by a primary obstetrician not affiliated with Washington 
University/Barnes-Jewish Hospital is not an exclusion criterion for the 
study. 
o The participant will be asked to return to Washington University/Barnes-
Jewish Hospital for a follow-up study visit every two weeks. At that time, a 
clinical visit in the High-Risk Obstetric Clinic at the Center of Outpatient 
Health or with a Maternal-Fetal Medicine specialist at the Center for 

 
 
 
 
 
 
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Advanced Medicine will be offered to those women not receiving primary 
obstetric care at Washington University/Barnes-Jewish Hospital, but this 
will be optional for the participant if she is receiving care at a different 
location with an obstetric care provider. The date and time of study visits 
will be coordinated with the study coordinator. 
o At each study visit, the next two week supply of study drug will be 
provided to the participant by the study coordinator. The participant will 
bring back any leftover pills. The study coordinator will obtain the study 
drug from the pharmacy at Barnes-Jewish hospital where the 
compounding is occurring prior to each study visit. 
o During the follow-up visit, the study coordinator will discuss compliance 
with the study drug and possible side effects. The participant will fill out a 
one-page questionnaire form that asks questions about compliance and 
side effects. This information will be recorded and provided to the DSMB 
at the midpoint review. 
o For women enrolled in the vaginal specimen collection portion of the 
study, a repeat vaginal swab will be collected by an on-site obstetric care 
provider or PI 2-6 weeks after enrollment. 
 
III. Delivery follow-up 
 
The following data will be collected following delivery: 
o Delivery data: gestational age at delivery, indications for delivery, mode of 
delivery, maternal complications antepartum or postpartum including 
placental abruption, rupture of membranes, infection, other  
o Infant outcomes: birth weight, sex, Apgar scores, cord gas results if 
performed, type of nursery admission, respiratory distress, intraventricular 
hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, and 
discharge status 
 
Collected infant data will be limited to the hospitalization at the 
time of birth. 
 
F3 Safety and Adverse Events  
3.a 
Safety and Compliance Monitoring 
Every two weeks, a study coordinator will discuss and record any side effects reported 
by the participant. The participant may discontinue use of the allocated study drug at any 
time and continue to participate in the study. A Data Safety and Monitoring Board will be 
created prior to the study. The Data Safety and Monitoring Board (DSMB) will meet and 
be provided interim results and data regarding reported adverse events after 50% of 
planned enrollment is achieved (120 women enrolled). The data will be presented in a 
blinded fashion with regards to the drug exposure of each group. At the request of the 
DSMB, the study will be unblinded for further review. It is at the discretion of the DSMB 
to request early cessation of the trial. During conduct of the study, any severe adverse 
events will be immediately reported to the DSMB and Human Research Protection Office 
at Washington University. 

 
 
 
 
 
 
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3.b 
Medical Monitoring  
i 
Investigator only- N/A 
ii 
Independent expert to monitor- N/A 
iii 
Institutional Data and Safety Monitoring Board 
The Data Safety and Monitoring Board (DSMB) will meet and be provided interim results 
and data regarding reported adverse events after 50% of planned enrollment is achieved 
(120 women enrolled). Members of the DSMB include: Jeffrey Peipert, MD, PhD; Emily 
Jungheim, MD, MSCI; Jenifer Allsworth, PhD. 
iv 
Independent Data and Safety Monitoring Board- N/A 
3.c 
Definitions of Adverse Events 
 
An adverse event will be defined as any undesirable experience which occurs while 
taking the study drug, whether or not the event is attributable to taking the drug. 
3.d 
Classification of Events 
All adverse events reported by the participant or her physicians will be recorded as part 
of the study. They will be further investigated if necessary and categorized by their 
relationship to the study drug, severity, and expectedness. 
i 
Relationship 
Unlikely to be related to the study drug: These include events that have not been 
previously described to be associated with the study drug; events that have a temporal 
relationship with study drug administration which makes causation highly unlikely; known 
biological mechanisms for the event suggest that the likelihood that the study drug 
caused the event is low. 
 
Possibly related to the study drug: These events are not previously reported to be 
associated with the study drug, but the temporal relationship between study drug 
administration and the event and a plausible biological mechanism suggest that there is 
a possible relationship between the study drug and the event. 
 
Likely to be related to the study drug: These events have been previously reported in 
prior studies evaluating the use of vaginal progesterone (vaginal irritation, vaginal 
discharge, vaginal infection, headache, nausea). Of note, however, the side effects 
recorded in prior studies have not significantly differed among those women who 
received progesterone and those who received placebo. 
ii 
Severity 
Mild: Vaginal irritation, infection or discharge; headache, nausea 
 
Severe: Allergic reaction, congenital anomaly, maternal or fetal death, a life-threatening 
event or disability 
 

 
 
 
 
 
 
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iii 
Expectedness 
Common: A common event occurring in pregnancy regardless of the probability of its 
relationship with the study drug (i.e.; vaginal irritation, infection, or discharge; headache, 
nausea, vomiting). 
 
Rare: A rare event in pregnancy regardless of the probability of its relationship with study 
drug (i.e.; allergic reaction, congenital anomaly, death or disability). 
 
3.e 
Data Collection Procedures for Adverse Events 
Every two weeks, a study coordinator will discuss and record any side effects reported 
by the participant. In addition, the participant will fill out one-page questionnaire form 
with questions regarding study drug compliance and possible side effects.  
3.f 
Reporting Procedures 
All adverse events will be reviewed by the Data Safety and Monitoring Board (DSMB) at 
the midpoint meeting. Any severe event will be reported the Human Research Protection 
Office at Washington University and the DSMB immediately. 
3.g 
Adverse Event Reporting Period 
All severe adverse events will be reported to the Human Research Protection Office and 
the DSMB members immediately for review. Any other adverse event will be reviewed 
by the DSMB at the midpoint of the study (50% enrollment). Participants can report 
adverse events at any time during enrollment in the study and up to six weeks 
postpartum. 
3.h 
Post-study Adverse Event 
Adverse events can be reported by participants up to six weeks postpartum. It is highly 
unlikely that any new events after that time period are related to participation in the 
study. 
F4 Study Outcome Measurements and Ascertainment 
 
Primary Outcome: Delivery before 37 weeks’ gestation 
 
Secondary Outcomes: 
 
Delivery prior to 34 weeks’ (evaluated among women enrolled ≤ 31 6/7 weeks’ 
gestation)  
 
Delivery within two weeks of randomization 
 
Total number of days of pregnancy prolongation 
 
Infant birth weight 
 
Neonatal intensive care unit admission 
 
Chorioamnionitis 
 
A composite neonatal outcome comprising neonatal death, respiratory distress 
syndrome, bronchopulmonary dysplasia, severe (grade III/IV) interventricular 
hemorrhage, necrotizing enterocolitis, and sepsis. 
 

 
 
 
 
 
 
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The outcomes of interest will be ascertained from the participant’s medical record and 
her infant’s medical record during the hospitalization at the time of birth. 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
We 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, assuming an alpha of 0.05, 80% power, and a baseline risk of preterm 
birth of 60% in the population of women with arrested preterm labor (Lyell 2008). A 
recent query of admissions to Barnes-Jewish Hospital revealed that 730 women were 
evaluated for threatened preterm labor each year during the last 3 years. Although we 
suspect that <50% of women will meet inclusion criteria, we estimate that the study will 
be completed within 2 years. 
G2  Interim Monitoring and Early Stopping 
The Data Safety and Monitoring Board (DSMB) will be provided interim results and data 
regarding reported adverse events after 50% of planned enrollment is achieved (120 
women enrolled). The data will be presented in a blinded fashion with regards to the 
drug exposure of each group. At the request of the DSMB, the study will be unblinded for 
further review. It is at the discretion of the DSMB to request early cessation of the trial. 
During conduct of the study, any severe adverse events will be immediately reported to 
the DSMB and HRPO. 
G3  Analysis Plan 
All analyses will be performed using the intention-to-treat principle. Outcomes will be 
compared among women allocated to progesterone therapy and women who received 
placebo. 
G4  Statistical Methods  
Baseline characteristics of women randomized to progesterone will be compared with 
those of women randomized to placebo. Rates of delivery before 37 weeks’ gestation 
will be compared among the groups using the Chi-square test. A secondary analysis of 
women enrolled ≤31 6/7 weeks’ gestation will evaluate rates of delivery before 34 weeks. 
Additional outcomes that will be evaluated (by using Chi-square test for binary outcomes 
and the Student t-test for continuous outcomes) include delivery within two weeks of 
randomization, total number of days of pregnancy prolongation, infant birth weight, 
neonatal intensive care unit admission, chorioamnionitis, and a composite adverse 
neonatal outcome comprising neonatal death, respiratory distress syndrome, 
bronchopulmonary dysplasia, severe (grade III/IV) interventricular hemorrhage, 
necrotizing enterocolitis, and sepsis. 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. 
 
Microbial sequencing will be performed on the vaginal swabs using well established 16s 
RNA sequencing procedures at the Genome Institute at Washington University. 

 
 
 
 
 
 
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Sequenced data will be processed to compare the vaginal microbiome in those who 
received the placebo to those who received vaginal progesterone. 
 
We will use a multivariate model of species abundance distribution (SAD) or ranked 
abundance distribution (RAD) of vaginal microbiomes obtained from taxonomical 
assignment of 16S rRNA genes samples, with Dirichlet-Multinomial (DM) distribution and 
its generalizations. SAD/RAD is classified as a multivariate community descriptor of 
intermediate level of complexity providing more information than univariate community 
descriptors such as species richness, Shannon evenness, and Simpson diversity. To 
compare case and control groups we will apply the two sample RAD-mean test 
comparison. We will also apply a logistic regression model to predict PTB as a function 
of the vaginal microbiome. 
G5  Missing Outcome Data 
Women with missing primary outcome data, delivery before 37 weeks’ gestation, will be 
excluded from analysis. However, information regarding missing data will be reported in 
the manuscript. 
G6  Unblinding Procedures  
After the final participant in the study has delivered, the study will be closed. At that time, 
the randomization log maintained by the pharmacists during the study which links the 
participant identification number to the allocated study drug will be released to the 
research team. The study drug information for each participant will be added to the study 
database for analytic purposes. 
 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
 
All conversations with participants regarding enrollment in the study and the 
consent process will occur in a private hospital room. Follow-up visits as an 
outpatient will be conducted within the privacy of an office or examination room.  
 
All data collected on participants for the purpose of the study will be stored in a 
password-protected database on the password-protected computer in an 
investigator's locked office. Information stored in the database will be coded and 
the key for the code will be stored in a separate location. 
 
Research identification codes will be utilized in this study to link participant 
information in the study database. These research identification codes will be 
unrelated to participant name, date of birth, medical record number, or any other 
form of personally identifiable information. The spreadsheet linking the participant 
name with her research identification code will stored in a separate database on 
a password protected computer. This spreadsheet will be destroyed at the 
completion of the study. 
 
Vaginal swabs collected from women who agree to provide these biospecimens 
for future research will be labeled using the study research code so that the 
sample is de-identified. The swabs will be stored as part of the Women and 
Infants' Health Specimen Consortium. 

 
 
 
 
 
 
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H2 Training  
A thorough review of study procedures will be reviewed with the study coordinator prior 
to beginning enrollment in the study. 
H3 Case Report Forms and Source Documents 
N/A 
H4 Records Retention 
The de-identified database will be maintained for future research. Only women who 
consent to the collection of vaginal swab specimens will have biospecimens stored for 
future research. Data regarding whether a specimen was collected from a particular 
woman will be recorded in the study database. 
H5 Performance Monitoring  
N/A 
 
I Study Monitoring, Auditing, and Inspecting  
 
I1 
Study Monitoring Plan  
The Data Safety and Monitoring Board will evaluate interim results and reported adverse 
events. The members will meet at the midpoint of the study when 50% enrollment has 
been achieved (120 women). 
I2 
Auditing and Inspecting  
Study records including databases will be well-maintained and organized. If auditing or 
inspection of the study is requested by organizations with the appropriate authority, the 
required information will be provided. 
J Study Administration 
 
J1 Organization and Participating Centers 
Washington University School of Medicine & Barnes-Jewish Hospital 
J2 Funding Source and Conflicts of Interest 
 
Thrasher Early Career Award (PI: Heather Frey, MD) 
J3 Committees 
Data Safety and Monitoring Board 

 
 
 
 
 
 
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J4 Subject Stipends or Payments  
None 
J5  Study Timetable 
Start date: 4/1/13 
End date: 5/7/18 
 
K Publication Plan  
 
Following completion of the trial and data analysis, a manuscript will be submitted for 
publication in a peer-reviewed journal. 
 
L  Attachments  
 
L1  Tables- N/A 
 
L2  Informed consent documents 
See attached 
L3  Patient education brochures- N/A 
 
L4  Special procedures protocols- N/A 
 
L5  Questionnaires or surveys 
See attached. 
 
 
M References 
 
1. Mathews TJ, MacDorman MF. Infant mortality statistics from the 2008 period linked 
birth/infant death data set. National Vital Statistics Reports 2012; 60(5): 1-27. 
2. McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births 
compared with births at term. Obstet Gynecol 2008; 111(1): 35-41. 
3. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from 
infancy to adulthood. Lancet 2008; 371: 261-9. 
4. Tita A, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. 
Amer J Obstet Gynecol 2009; 200(3): 219-24. 

 
 
 
 
 
 
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5. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17-
alphahydroxyprogesterone acetate. NEJM 2003; 349(13): 2379-85. 
6. Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among 
women with a short cervix. NEJM 2008; 357: 462-9. 
7. Hassan SS, Romero R, Vidyadhari D, et al. 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; 38: 18-31. 
8. Management of preterm labor. Practice Bulletin No. 127. American College of 
Obstetricians and Gynecologists. Obstet Gynecol 2012; 119:1308–17. 
9. Lyell DJ, Pullen KM, Mannan J, et al. Maintenance nifedipine tocolysis compared with 
placebo. Obstet Gynecol 2008; 112(6): 1221-6. 
10. Likis FE, Velez Edwards DR, Andrews JC, et al. Progestogens for preterm birth 
prevention: a systematic review and meta-analysis. Obstet Gynecol 2012; 120(4): 897-
907. 
11. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants 
from the NICHD neonatal research network. Pediatrics 2010; 126: 443-56. 
12. Institute of Medicine Committee on Understanding Preterm Birth and Assuring 
Healthy Outcomes. Preterm birth: Causes, consequences, and prevention. Behrman RE, 
Butler AS, editors. Washington (DC): National Academies Press (US); 2007. 
13. Goepfert AR, Goldenberg RL, Andrews WW, et al. The preterm prediction study: 
association between cervical interleukin-6 and spontaneous preterm birth. Am J Obstet 
Gynecol 2001; 184(3): 483-8. 
14. Iams JD, Goldenbery RL, Meis PJ, et al. The length of the cervix and their risk of 
spontaneous premature delivery. NEJM 1996; 334(9): 567-72. 
15. Prediction and prevention of preterm birth. Practice Bulletin No. 130. American 
College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:964–73. 
16. Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened 
preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2008; 48: 58-
63. 
17. 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: 269-73. 
18. Sharami SH, Zahiri Z, Shakiba M, Milani R. Maintenance therapy by vaginal 
progesterone after threatened idiopathic preterm labor: a randomized placebo-controlled 
double-blind trial. Inter J Fert Sterility 2010; 4(2): 45-50. 
19. Northen AT, Norman SG, Anderson K, Moseley L, et al. Follow-up of children 
exposed in utero to 17 alpha-hydroxyprogesterone caporate compared with placebo. 
Obstet Gynecol 2007; 110: 865-872.