Conditions: Preterm Birth
Keywords: 17P 17-HPC 17-OHPC 17-hydroxyprogesterone caproate progestogens preterm birth recurrent preterm birth spontaneous preterm birth
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1740
Healthy volunteers: no

Brief summary:
As part of the continuing effort to study the benefit and risks of 17P and preterm delivery, this study is designed as a multi-center, randomized, double-blind, vehicle-controlled clinical trial of 17P for the prevention of preterm birth prior to 35 weeks, 0 days of gestation in women with a singleton pregnancy, aged 18 years or older, with a previous singleton spontaneous preterm delivery. The study also includes a population pharmacokinetic (PK) substudy to assess the hydroxyprogesterone caproate (HPC) exposure-response relationship and the effect of body mass index (BMI) on the PK of 17P.

Detailed description:
One of the most significant risk factors for preterm birth is previous pregnancy history. Women who have had a prior preterm birth have a 2.5-fold greater risk than women with no prior history of preterm birth. Prophylactic methods for prevention of preterm birth, including tocolytic drugs, bed rest, and other interventions such as cerclage, have been shown in most studies to be ineffective. One of the preventive measures that has shown effectiveness in randomized trials is the use of progesterone agents.9,10 Progesterone has been shown to support gestation and to inhibit uterine activity.

Arms:
arm 1: Castor Oil arm 2: HPC 250 mg/mL in oil

Interventions: intervention 1: Hydroxyprogesterone Caproate Injection (HPC), 250mg/mL intervention 2: Vehicle
Intervention descriptions: intervention 1: 1 mL intramuscular injection every week until 36 weeks, 6 days of gestation or delivery, whichever occurs first. intervention 2: Weekly intramuscular injections of 1 mL vehicle inert oil until 36 weeks, 6 days of gestation or delivery, whichever occurs first.

Protocol document:
Prot_000.pdf: 
STUDY PROTOCOL 
IND NUMBER: 68,108 
A PHASE 3B, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND STUDY OF 
HYDROXYPROGESTERONE CAPROATE INJECTION, 250 MG/ML, VERSUS 
VEHICLE FOR THE PREVENTION OF PRETERM BIRTH IN WOMEN WITH A 
PREVIOUS SINGLETON SPONTANEOUS PRETERM DELIVERY 
PROTOCOL NUMBER: 17P-ES-003 
06 APRIL 2016
NCT01004029   


STUDY PROTOCOL 
IND NUMBER: 68,108 
A PHASE 3B, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND STUDY OF 
HYDROXYPROGESTERONE CAPROATE INJECTION, 250 MG/ML, VERSUS 
VEHICLE FOR THE PREVENTION OF PRETERM BIRTH IN WOMEN WITH A 
PREVIOUS SINGLETON SPONTANEOUS PRETERM DELIVERY 
Sponsor:
Sponsor Contact/
Project Manager:
Global Medical Monitor:
Version:
Date of Protocol:
Confidentiality Statement:
Ethics Statement:
PROTOCOL NUMBER: 17P-ES-003 
AMAG Phruma USA, Inc.
1100 Winter Street 
Waltham, MA 02451
-Affairs 
AMAG Phanna USA, Inc.
1100 Winter Street 
Waltham, MA 02451
Telephone:
E-mail: 
Version 6.0
06 April 2016
The info1mation contained in this document, especially unpublished data,
is the prope1ty of the sponsor and is therefore provided to you in
confidence as an investigator, potential investigator, or consultant. The
information may be reviewed by you, your staff, and your h1temal
Review Board/Ethics Committee. It is Ullderstood that this information
will not be disclosed to others without wiitten authorization from the
sponsor.
The study will be completed according to the guidelines of Good Clinical
Practice. Compliance with this standard provides public assurance that
the rights, safety, ru1d well-being of trial subjects are protected, consistent
with the principles that have their 01igin in the Declru·ation of Helsinki. 
CONFIDENTIAL 




 
 
TABLE OF CONTENTS 
Description 
Page 
Signature Page ..................................................................................................2 
Protocol Summary ...........................................................................................8 
Abbreviations .................................................................................................11 
1 Introduction ..............................................................................................13 
1.1 
Prevalence and Prevention of Preterm Birth .................................13 
1.2 
Hydroxyprogesterone Caproate (HPC) ..........................................13 
1.3 
Rationale for Clinical Trial ..............................................................14 
2 Study Objectives.......................................................................................15 
2.1 
Primary Objectives ...........................................................................15 
2.2 
Secondary Objectives .......................................................................15 
3 Study Plan .................................................................................................15 
3.1 
Overall Design ...................................................................................15 
3.2 
Efficacy Assessments ........................................................................18 
3.3 
Pharmacokinetic Assessments .........................................................18 
3.4 
Safety Assessments ............................................................................19 
3.5 
Primary and Secondary Outcomes .................................................19 
3.5.1 
Primary Outcomes ....................................................................19 
3.5.2 
Secondary Outcomes ................................................................20 
3.5.3 
Additional Outcomes ................................................................20 
4 Study Treatments .....................................................................................21 
4.1 
Study Drug .........................................................................................21 
4.1.1 Dosage and Administration ..............................................................21 
4.1.2 Study Drug Discontinuation .............................................................21 
4.2 
Prior/Concomitant Medications and Restrictions .........................22 
4.2.1 
Prior Medications......................................................................22 
4.2.2 
Concomitant Medications ........................................................22 
4.2.3 
Restrictions ................................................................................22 
4.3 
Measurement of Subject Compliance and Tolerability .................23 
4.4 
Study Drug Description ....................................................................23 
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4.5 
Study Drug Packaging and Storage ................................................23 
4.6 
Study Medication Accountability ....................................................24 
4.7 
Retention of Testing Samples ...........................................................24 
5 Subject Enrollment ..................................................................................24 
5.1 
Inclusion Criteria ..............................................................................24 
5.1.1 
Gestational Age Determination ...............................................25 
5.2 
Exclusion Criteria .............................................................................25 
5.3 
Randomization Procedures ..............................................................26 
5.4 
Blinding Procedures .........................................................................27 
5.5 
Breaking the Blind ............................................................................27 
5.6 
Subject Withdrawal ..........................................................................27 
5.6.1 
Subject Withdrawal from Study Drug ....................................27 
5.6.2 
Subject Withdrawal from Study..............................................28 
5.6.3 
Replacements .............................................................................28 
5.6.4 
Sponsor’s Termination of Study ..............................................28 
6 STUDY VISITS ........................................................................................28 
6.1 
Baseline (Visit 1) ................................................................................29 
6.2 
Active Treatment Period (Visit 2 to 366 Weeks of Gestation or 
Delivery) .............................................................................................30 
6.3 
Delivery and Hospitalization ............................................................31 
6.4 
Neonatal Hospitalization ..................................................................31 
6.5 
Neonate Follow-Up ...........................................................................31 
6.6 
End of Treatment Period Visit ........................................................32 
6.7 
Early Withdrawal Procedures .........................................................32 
7 Study Assessments ...................................................................................32 
7.1 
Demographic Data/Medical and Obstetrical History ....................32 
7.2 
Physical Examination .......................................................................32 
7.3 
Height and Weight Measurements ..................................................32 
7.4 
Prior and Concomitant Medication ................................................32 
7.5 
Ultrasound .........................................................................................33 
7.6 
Pharmacokinetic Testing ..................................................................33 
8 Reporting Adverse Events .......................................................................33 
8.1 
Definitions ..........................................................................................33 
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8.2 
Eliciting Adverse Event Information ..............................................35 
8.3 
Adverse Event Reporting .................................................................35 
8.4 
Assessment of Causality ...................................................................35 
8.5 
Assessment of Severity ......................................................................36 
8.6 
Serious Adverse Event Reporting ...................................................37 
8.7 
Investigating the Cause of Stillbirth/Fetal Death/In-Utero Fetal 
Loss .....................................................................................................38 
9 Statistical Methods ...................................................................................39 
9.1 
Sample Size ........................................................................................39 
9.2 
Populations to be Analyzed ..............................................................40 
9.3 
Statistical Methodology ....................................................................41 
9.3.1 
Subject Population and Characteristics..................................41 
9.4 
Efficacy Analysis ...............................................................................41 
9.4.1 
Primary Efficacy Outcome Measure .......................................41 
9.4.2 
Secondary Outcomes ................................................................42 
9.4.3 
Additional Analyses ..................................................................43 
9.5 
Pharmacokinetic/Pharmacodynamic Analysis ...............................43 
9.6 
Safety Analysis ..................................................................................44 
9.6.1 
Interim Analyses .......................................................................44 
10 Data Handling and Quality Assurance ..................................................44 
10.1 Electronic Case Report Forms .........................................................44 
10.2 Monitoring of the Study ...................................................................44 
10.3 Inspection of Records .......................................................................45 
10.4 Study Record Retention ...................................................................45 
11 Administrative Considerations ...............................................................45 
11.1 Confidentiality ...................................................................................45 
11.2 Institutional Review Board /Independent Ethics Committee 
Approval ............................................................................................46 
11.3 Modification of the Protocol ............................................................46 
11.4 Informed Consent .............................................................................46 
11.5 Protocol Deviations ...........................................................................47 
11.6 Study Reporting Requirements .......................................................47 
11.7 Financial Disclosure and Obligations .............................................48 
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11.8 Investigator Documentation .............................................................48 
11.9 Study Conduct ...................................................................................48 
11.10 Publications .......................................................................................49 
12 Investigator’s Statement ..........................................................................50 
13 Maternal complications and Neonatal Outcomes ..................................51 
13.1 Maternal Pregnancy Complications ................................................51 
13.2 Neonatal Outcomes ...........................................................................52 
14 List of drugs metabolized by Cyp1a2, cyp2a6, and cyp2b6 ..................55 
15 References ..................................................................................................56 
 
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LIST OF IN-TEXT TABLES 
Table 1 
Schedule of Events ........................................................17 
Table 2 
Cut-offs for Using LMP to Determine Gestational 
Age ..................................................................................25 
Table 3 
Sample Size Calculation ...............................................40 
 
 
 
 
 
 
 
 
 
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PROTOCOL SUMMARY 
Protocol Number: 
17P-ES-003  
Title: 
A Phase 3B, Multi-Center, Randomized, Double-Blind Study of 
Hydroxyprogesterone Caproate Injection, 250 mg/mL, Versus Vehicle for the 
Prevention of Preterm Birth in Women with a Previous Singleton Spontaneous 
Preterm Delivery  
Study Phase: 
Phase 3B 
Study Sites: 
Sites will be recruited in the United States and other countries. 
Study Drug, Dosage 
and Route of 
Administration: 
Hydroxyprogesterone Caproate Injection, 250mg/mL (17P), weekly 1 mL 
intramuscular injections until 366 weeks of gestation or delivery, whichever occurs 
first. 
Control Drug, 
Dosage, and Route of 
Administration: 
Vehicle, weekly intramuscular injections of 1 mL vehicle (castor oil, benzyl 
benzoate and benzyl alcohol) until 366 weeks of gestation or delivery, whichever 
occurs first. 
Objectives: 
There are two co-primary objectives of this study  
1. Determine if treatment with 17P reduces the rate of preterm birth < 350 
weeks of gestation in women with a previous singleton spontaneous 
preterm delivery. 
2. Determine if 17P reduces the rate of neonatal mortality or morbidity. 
Neonatal mortality or morbidity is measured by a composite index 
comprised of: 
o Neonatal death. 
o Grade 3 or 4 intraventricular hemorrhage. 
o Respiratory distress syndrome. 
o Bronchopulmonary dysplasia. 
o Necrotizing enterocolitis. 
o Proven sepsis. 
The secondary objectives of this study are to: 
o Exclude a doubling of the risk of fetal/early infant death, defined as 
spontaneous abortion/miscarriage (delivery from 160 through 196 weeks of 
gestation) or neonatal death occurring in liveborns born at less than 24 
weeks gestation or stillbirth (antepartum or intrapartum death from 20 
weeks gestation through term), in the 17P group compared to the vehicle 
group. 
o Determine if 17P reduces the rate of preterm birth < 320 weeks of 
gestation. 
o Determine if 17P reduces the rate of preterm birth < 370 weeks of 
gestation. 
o Determine if 17P reduces the rate of stillbirth defined as all stillbirths/fetal 
deaths/in-utero fetal losses occurring from 20 weeks gestation until term. 
o Determine if 17P reduces the rate of neonatal death (from minutes after 
birth until 28 days of life) occurring in liveborns born at 24 weeks 
gestation or greater. 
o Evaluate the pharmacokinetics/pharmacodynamics (PK/PD) of 17P in a 
subset of pregnant women. 
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Subject Population:  
A total of 1707 women (1138 active and 569 vehicle) with a singleton pregnancy, 
aged 18 years or older, with a documented history of a previous singleton 
spontaneous preterm delivery. 
Study Design: 
This study is a multi-center, randomized, double-blind, vehicle-controlled clinical 
trial. Subjects will be assessed and receive weekly injections of study drug from 
randomization (160 through 206 weeks of gestation) until 366 weeks of gestation or 
delivery, whichever occurs first. 
Efficacy 
Assessments: 
All randomized subjects will be followed until delivery for efficacy assessments. 
The primary and secondary maternal outcome measures will be determined based 
on the date of delivery and the estimated date of confinement (EDC), which is 
evaluated in a standardized manner. Neonates born to randomized subjects will be 
followed until day 28 or the date of discharge from the NICU, whichever occurs 
later. Discharge from the NICU is defined as discharge to any of the following: 
home, a non-medical facility, a chronic-care facility, or a step-down unit.  The 
neonatal outcome measures will be determined from review of the neonatal 
medical record and will be based on standardized definitions of the morbidity 
measures. 
 
Pharmacokinetic 
Assessments: 
Pharmacokinetic assessments will be made based on a sparse sampling of 
approximately 450 subjects (300 active and 150 vehicle) stratified according to 
body mass index (BMI) to analyze the dose-plasma concentration-time 
relationship of 17P. Three blood samples will be drawn: 
1. Before study drug dosing at either Visit 6 or 7 (i.e., Dose 5 or 6). 
2. Before study drug dosing at either Visit 8 or 9 (i.e., Dose 7 or 8). 
3. At a separate, non-dosing visit 1 to 6 days after Visit 9, 10, or 11 (i.e., 1 to 
6 days after Doses 8, 9, or 10). Subjects will be stratified 2:1 (17P: vehicle) 
such that an even distribution of samples will be drawn on day 1, day 2, 
day 3, day 4, or day 5/6 post-dose. This will result in approximately 60 
17P and 30 vehicle samples on each day interval. 
The dependence of apparent clearances and volumes on BMI will be examined as 
the primary covariate. Pharmacokinetic models to evaluate effects on concomitant 
medications that may affect the inhibition or induction of HPC will be evaluated 
and modeled as data permit. 
Safety Assessments: 
Safety assessments include but are not limited to determination of maternal 
adverse events, maternal pregnancy complications, and investigation of the cause 
of stillbirth/fetal death/in-utero fetal loss and will be based on standardized 
definitions. Maternal pregnancy complications include such events as gestational 
diabetes, oligohydramnios, significant antepartum bleeding or hemorrhage, 
preeclampsia, gestational hypertension, abruption, and chorioamnionitis.  
Statistical Methods: 
Using a 2:1 randomization, a total of 1665 live born infants are required to detect a 
reduction of 35% in the rate of the composite index (from 17% to 11%) with a 
power of 90% (assuming a two-sided type I error of 5%).  Assuming 2.5% of 
pregnancies will result in miscarriage or stillbirth, an additional 42 women need to 
be enrolled for a total of 1707 women (1138 active and 569 vehicle).  A total 
sample size of 1707 subjects provides 98% power to detect a reduction of 
approximately 30% in the rate of preterm birth < 350 weeks of gestation (from 
30% to 21%) using a two-sided type I error of 5%.  The effect size for the neonatal 
composite index as well as preterm birth < 350 weeks gestation was chosen to 
represent a clinically significant reduction.  
Significant differences between the 17P and vehicle group in the proportion of 
subjects who deliver prior to 350 weeks gestation will be determined using a 
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Cochran-Mantel-Haenszel test stratified by gestational age at randomization (160 
weeks - 176 weeks gestation and 180 weeks – 206 weeks gestation), where the 
effective sample sizes for each treatment group and stratum will be derived from 
Greenwood’s formula and a staggered entry Kaplan-Meier analysis using the time 
from randomization until delivery as the analysis variable.  Subjects with missing 
outcome data will be censored on the date last known pregnant. 
The number and percentage of liveborn infants with the neonatal composite index 
will be presented by gestational age at randomization and overall, for each 
treatment group.  Significant differences between the 17P and vehicle group will 
be determined using the Cochran-Mantel-Haenszel procedure stratified by 
gestational age at randomization.  
A two-sided 95% confidence interval (CI) for the relative risk of fetal/early infant 
death for 17P relative to vehicle will be calculated using the method of Cochran-
Mantel-Haenszel stratified by gestational age at randomization. If the upper bound 
of the CI is less than or equal to 2.0, a doubling in risk of fetal/early infant death 
can be ruled out. 
The percentage of subjects with a preterm birth <320 and <370 weeks of gestation 
will also be determined from the staggered entry Kaplan-Meier analysis and tested 
for statistical differences using the same analytic approach as for <350 weeks. 
Significant differences between the 17P and vehicle groups in stillbirths and 
neonatal deaths will be determined using the Cochran-Mantel-Haenszel test 
stratified by gestational age at randomization.  
  
 
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ABBREVIATIONS 
ABBREVIATION 
TERM 
17P 
Hydroxyprogesterone Caproate Injection, 250 mg/mL 
AE 
Adverse event 
BMI 
Body mass index 
BPD 
Bronchopulmonary dysplasia 
BV 
Bacterial vaginosis 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CV 
Curriculum vitae 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic case report form 
EDC 
Estimated date of confinement 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice Guidelines 
HELLP  
Hemolytic anemia elevated liver enzymes and low platelet count  
HPC 
Hydroxyprogesterone caproate 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IVH 
Intraventricular hemorrhage  
IVRS 
LMP 
Interactive voice response system 
Last menstrual period 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified intent to treat  
NEC 
Necrotizing enterocolitis 
NDA 
New Drug Application 
NICHD 
National Institute of Child Health and Human Development 
NICU 
Neonatal intensive care unit 
NONMEM 
Nonlinear mixed effects modeling 
OTC 
Over-the-counter 
PD 
Pharmacodynamic 
PDA 
Patent ductus arteriosus 
PE 
Physical examination 
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ABBREVIATION 
TERM 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/pharmacodynamic 
POME 
Pulmonary oil microemboli 
PP 
Per-protocol population 
pPROM 
Preterm premature rupture of membranes 
RDS 
Respiratory distress syndrome 
ROP 
Retinopathy of prematurity 
SAE 
Serious adverse event 
TEAE 
Treatment emergent adverse events 
US 
United States 
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1 INTRODUCTION 
1.1 
Prevalence and Prevention of Preterm Birth 
Preterm birth, defined as birth before the 37th week of gestation, is a very serious health 
concern, and is recognized as the leading cause of neonatal mortality and morbidity in the US.1  
Despite advances in perinatal care, the incidence of preterm birth remains high in the US. 
According to the Centers for Disease Control and Prevention, it peaked in 2006 when 12.8% 
of the 4.3 million births occurred preterm, which represented a 21% increase since 1990 and a 
33% increase from 1981 to 2004.2,3  Since 2006, the rate has fallen slightly to a rate of 11.99% 
in 2010.4   At its current rate, 1 preterm birth occurs nearly every minute in the US.  
One of the most significant risk factors for preterm birth is previous pregnancy history. Women 
who have had a prior preterm birth have a 2.5-fold greater risk than women with no prior 
history of preterm birth.5,6  Prophylactic methods for prevention of preterm birth, including 
tocolytic drugs, bed rest, and other interventions such as cerclage, have been shown in most 
studies to be ineffective.7,8  One of the preventive measures that has shown effectiveness in 
randomized trials is the use of progesterone agents.9,10  Progesterone has been shown to support 
gestation and to inhibit uterine activity.   
Hydroxyprogesterone caproate (HPC) has a long history of use in pregnant women dating back 
numerous decades when it was marketed as Delalutin® (E.R. Squibb & Sons, Inc.) for habitual 
and recurrent abortion, threatened abortion, and post-partum after pains.  In addition a number 
of studies support the use of HPC for prevention of preterm births.11-15 
1.2 
Hydroxyprogesterone Caproate (HPC) 
In a large, controlled clinical study conducted by the National Institute of Child Health and 
Human Development (NICHD), 17P was shown to significantly reduce the rate of recurrent 
preterm birth among women at high-risk for preterm birth.15 This multi-center, randomized, 
double-blind, placebo-controlled study enrolled a high-risk population of pregnant women 
between 160 and 206 weeks of gestation with a history of previous singleton spontaneous 
preterm delivery. A total of 463 subjects were randomized in a 2:1 ratio to receive weekly 
injections of either 17P (310 subjects) or placebo (153 subjects) through 366 weeks of gestation 
or delivery, whichever occurred first. 
The results from this study confirmed earlier reports of the efficacy of HPC in preventing 
preterm birth. Treatment with 17P significantly reduced the incidence of preterm birth less than 
370 weeks of gestation compared with placebo (P < 0.001). The 17P treatment also significantly 
reduced the incidence of preterm births when defined as < 350 (P = 0.0263) or < 320 
(P = 0.0273) weeks of gestation and prolonged the duration of pregnancy from time of 
enrollment (P = 0.0024). 
Treatment with 17P also led to significantly (P < 0.05) lower rates of low birth weight infants 
(< 2500 g), neonates with necrotizing enterocolitis (NEC), neonates having any grade 3 or 4 
intraventricular hemorrhage (IVH), neonates requiring supplemental oxygen, and neonates 
requiring admission to the neonatal intensive care unit (NICU). Although the differences did 
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not reach statistical significance, rates of respiratory distress syndrome (RDS), ventilator 
support, and patent ductus arteriosus (PDA) were also reduced following 17P treatment. 
The effectiveness of 17P treatment in the NICHD study was accompanied by a favorable safety 
profile. Weekly intramuscular injections of 17P were well tolerated by pregnant women, with 
injection site reactions being the most commonly reported adverse event (AE). Treatment with 
17P did not lead to increased rates of pregnancy complications or pregnancy-related 
procedures. The most common pregnancy complications (those reported by > 5% of subjects) 
were preeclampsia or gestational hypertension and gestational diabetes, which occurred at 
comparable rates in the 17P and placebo groups. The total incidence of miscarriages, stillbirths, 
and neonatal deaths during the study was not different between the 2 treatment groups: 6.2% 
in the 17P group and 7.2% in the placebo group (P = 0.6887). The incidence of miscarriages 
and stillbirths was slightly higher in the 17P group (3.5% vs. 1.3%); while the incidence of 
neonatal deaths was 2-fold lower in the 17P group (2.7% vs. 6.0%). Neither of these between-
group differences was statistically significant. Moreover, the rates of congenital anomalies 
identified at birth in the NICHD study were similar between treatment groups and were 
consistent with those reported in general population surveys. 
In the follow-up study of children born to mothers who participated in the NICHD 17P study, 
the authors reported that they did not detect differences in developmental delays, safety 
concerns related to overall health or physical development, or genital or reproductive 
anomalies between children with in-utero exposure to placebo and in-utero exposure to 17P. 
The results of the NICHD 17P study led to a recommendation from the American College of 
Obstetricians and Gynecologists Committee on Obstetric Practice that progesterone be used to 
prevent recurrent preterm birth.15,16-18  
1.3 
Rationale for Clinical Trial 
The FDA-approved indication for 17P (Makena, Hydroxyprogesterone Caproate Injection) 
states that it is a progestin indicated to reduce the risk of preterm birth in women with a 
singleton pregnancy who have a history of singleton spontaneous preterm birth.  However, 
since this is a subpart-H approval the following caveat is added: “The effectiveness of 
Hydroxyprogesterone Caproate Injection is based on improvement in the proportion of women 
who delivered < 37 weeks of gestation.  There are no controlled trials demonstrating a direct 
clinical benefit, such as improvement in neonatal mortality and morbidity.” 
Study 17P-ES-003 is a multi-center, randomized, double-blind, vehicle-controlled clinical trial 
of 17P designed to have sufficient size and power to evaluate both a reduction in the risk of 
preterm birth < 350 weeks of gestation and an improvement in neonatal mortality and morbidity 
if one exists.  The study will include women with a singleton pregnancy, aged 18 years or 
older, with a previous singleton spontaneous preterm delivery, and includes a population 
pharmacokinetic (PK) substudy to assess the HPC exposure-response relationship and the 
effect of BMI on the PK of 17P. The effects of concomitant medications on 17P 
pharmacodynamics will also be investigated. 
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2 STUDY OBJECTIVES 
2.1 
Primary Objectives 
The two co-primary objectives of this study are to:  
• Determine if treatment with 17P reduces the rate of preterm birth < 350 weeks of gestation 
in women with a singleton pregnancy, aged 18 years or older, with a previous singleton 
spontaneous preterm delivery. 
• Determine if 17P reduces the rate of neonatal mortality or morbidity.   Neonatal mortality 
or morbidity is measured by a composite index comprised of (See Section 13.2 for 
definitions): 
– 
Neonatal death. 
– 
Grade 3 or 4 intraventricular hemorrhage. 
– 
Respiratory distress syndrome. 
– 
Bronchopulmonary dysplasia. 
– 
Necrotizing enterocolitis. 
– 
Proven sepsis. 
 
2.2 
Secondary Objectives 
The secondary objectives of this study are to: 
 
• Exclude a doubling of the risk of fetal/early infant death, defined as spontaneous 
abortion/miscarriage (delivery from 160 through 196 weeks of gestation) or neonatal death 
occurring in liveborns born at less than 24 weeks gestation or stillbirth (antepartum or 
intrapartum death from 20 weeks gestation through term), in the 17P group compared to 
the vehicle group. 
• Determine if 17P reduces the rate of preterm birth < 320 weeks of gestation. 
• Determine if 17P reduces the rate of preterm birth < 370 weeks of gestation. 
• Determine if 17P reduces the rate of stillbirth defined as all stillbirths/fetal deaths/in-utero 
fetal losses occurring from 20 weeks gestation until term. 
• Determine if 17P reduces the rate of neonatal death (from minutes after birth until 28 days 
of life) occurring in liveborns born at 24 weeks gestation or greater. 
• Evaluate the PK/PD of 17P in a subset of pregnant women. 
3 STUDY PLAN 
3.1 
Overall Design 
This study is a multi-center, randomized, double-blind, vehicle-controlled clinical trial in 
women with a singleton pregnancy, aged 18 years or older, with a history of a previous 
singleton spontaneous preterm delivery. A total of 1707 subjects will be randomized in a 
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2:1 ratio to receive either 17P or vehicle, respectively. Subjects will receive weekly injections 
of study drug from randomization (160 through 206 weeks of gestation) until 366 weeks of 
gestation or delivery, whichever occurs first. Pharmacokinetic assessments will be made based 
on a sparse sampling of approximately 450 subjects (300 active and 150 vehicle), stratified 
according to BMI to analyze the dose-plasma concentration-time relationship of 17P. 
Randomized subjects will be followed for efficacy outcomes through the date of delivery and 
for adverse events up to the End of Treatment Period Visit defined as 35 ± 7 days after the last 
dose of study drug.  If the End of Treatment Period Visit is prior to the date of delivery, 
maternal and fetal deaths should be reported until delivery. Neonates of randomized subjects 
will be followed until day 28 or the date of discharge from the NICU or equivalent, whichever 
occurs later.   Discharge from the NICU is defined as discharge to any of the following: home, 
a non-medical facility, a chronic-care facility, or a step-down unit. At centers participating in 
the 17P-FU-004 study, every effort will be made to obtain informed consent for the 17P-FU-
004 study from all randomized subjects while they are pregnant.  If it is not possible to obtain 
consent during the pregnancy, consent may be obtained up to the point that their child reaches 
one year of age. 
 
Table 1 provides the schedule of events for the study. 
 
 
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Table 1 
Schedule of Events 
Procedures 
Baselinea  
Treatment Periodb 
Delivery and 
Hospitalization 
Neonate 
Follow-Upc 
End of 
Treatment 
Period 
Visitd 
Visit 1 
Visits 2 to 366 
Weeks of Gestation 
or Delivery 
Informed consente 
X 
 
 
 
 
Medical records releasef 
X 
 
 
 
 
Medical/obstetrical history 
X 
 
 
 
 
Demographic information/social 
history 
X 
 
 
 
 
Ultrasound (140 through 203) 
Xg 
 
 
 
 
Document previous preterm 
delivery 
X 
 
 
 
 
Brief physical examinationh 
Xh 
Xh 
 
 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
 
 
 
Prior medicationsi 
X 
X 
 
 
 
Concomitant medicationsj 
 
X 
X 
 
X 
Determine project gestational 
age and estimated date of 
confinement 
X 
 
 
 
 
Schedule randomization visit 
X 
 
 
 
 
Trial injection 
X 
 
 
 
 
Randomizationk 
 
X 
 
 
 
Collect blood sample for 
pharmacokinetic analysis 
 
Xl 
 
 
 
Study drug administration 
 
Xm 
 
 
 
Record adverse events (AEs)d 
Xn 
X 
X 
 
X 
Record presence or absence of 
POME symptoms 
X 
X 
 
 
 
Record pregnancy complications 
 
X 
X 
 
 
Record additional risk factors of 
miscarriage 
X 
 
X 
 
 
Maternal delivery information 
 
 
X 
 
 
Neonatal informationc 
 
 
X 
X 
 
a Visit will occur wherever possible within 7 days before randomization. 
b Subject will report to the clinical site weekly for study drug administration until 366 weeks of gestation or delivery, whichever 
occurs first. 
c Neonates born to randomized subjects will be followed through 28 days of life or discharge from the NICU whichever is later. 
Therefore, the status of all neonates (alive or dead), regardless of when they are delivered and discharged from the hospital 
will be obtained at least 28 days after delivery (this contact may occur at later than 28 days after delivery as long as the status 
of the infant on Day 28 after delivery is determined). If the neonate has been discharged from the birth hospitalization, the 
subject may be contacted by telephone to obtain the neonate’s status.  If the infant is still in the NICU or equivalent 28 days 
after delivery, then their status (alive or dead) will be determined upon discharge from the NICU or equivalent.  This status 
may be obtained after the infant is discharged as long as the status of the infant on the day of discharge is determined. 
d All randomized subjects, regardless of when they deliver, should be contacted for an End of Treatment Period Visit to obtain 
AE information including medications to treat AE(s). The contact can be either in person or by telephone and should occur 
35 ± 7 days after the last dose of study drug. 
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e To be completed before performing any baseline procedures.  Informed consent may be obtained at a gestational age of 10 
weeks or greater to facilitate obtaining records from the qualifying delivery.  At centers participating in the 17P-FU-004 study, 
every effort will be made to obtain informed consent for the 17P-FU-004 study from all randomized subjects while they are 
pregnant.  If it is not possible to obtain consent during the pregnancy, consent may be obtained up to the point that their child 
reaches one year of age. 
f Must be signed by subject in order to obtain medical records of previous deliveries.   
g If a 140 to 203 weeks of gestation ultrasound to rule out fetal anomalies has not been performed as part of standard prenatal 
care; one must be performed prior to randomization. 
h Conduct a brief physical examination including a brief head-to-toe visual inspection at either Baseline (Visit 1) or Visit 2 only. 
i Prior medications include all medications taken since the start of this pregnancy, defined as 40 weeks before the project EDC 
and before the study drug is randomly assigned.  Prior medications collection ends at Visit 2. 
j Concomitant medications must be recorded in the electronic case report form through the End of Treatment Period Visit. 
k Between 160 and 206 weeks of gestation. 
l Three blood samples will be drawn from the PK population at the following times: (1) Before study drug dosing at either Visit 
6 or 7 (i.e., dose 5 or 6). (2) Before dosing at either Visit 8 or 9 (i.e., Dose 7 or 8). (3) At a separate, non-dosing visit 1 to 
6 days after Visit 9, 10, or 11 (i.e., 1 to 6 days after Doses 8, 9, or 10). Subjects will be stratified 2:1 (17P: vehicle) such that 
an even distribution of samples will be drawn on day 1, day 2, day 3, day 4 or day 5/6 post-dose.  
m Subjects will receive one injection for each week they are pregnant from randomization through 366 weeks gestation or 
delivery, whichever occurs first.  As much as possible injections should be given on the same day each week.   However, if a 
schedule change is required, in general injections should be at least 5 days apart and no more than 10 days apart. 
n AEs are recorded from administration of the trial injection through the End of Treatment Period Visit including medications 
to treat the AE. Preterm birth is an anticipated outcome and is not considered an AE.  Maternal or fetal deaths will be recorded 
through delivery.  
 
3.2 
Efficacy Assessments 
All randomized subjects will be followed until delivery for efficacy assessments. The primary 
and secondary maternal outcome measures will be determined based on the date of delivery 
and the estimated date of confinement (EDC), which is evaluated in a standardized manner. 
Neonates born to randomized subjects will be followed until day 28 or the date of discharge 
from the NICU, whichever occurs later. Discharge from the NICU is defined as discharge to 
any of the following: home, a non-medical facility, a chronic-care facility, or a step-down unit.  
The neonatal outcome measures will be determined from review of the neonatal medical record 
and will be based on standardized definitions of the morbidity measures. 
3.3 
Pharmacokinetic Assessments 
Subjects may be offered the opportunity to participate in a pharmacokinetic sub-study until 
approximately 450 subjects (300 active and 150 vehicle) have been enrolled.  Pharmacokinetic 
assessments will be made based on a sparse sampling stratified according to pre-pregnancy 
BMI to analyze the dose-plasma concentration-time relationship of HPC.  
Three blood samples will be drawn: 
1. Before study drug dosing at either Visit 6 or 7 (i.e., Dose 5 or 6). 
2. Before study drug dosing at either Visit 8 or 9 (i.e., Dose 7 or 8). 
3. At a separate, non-dosing visit 1 to 6 days after Visit 9, 10, or 11(i.e., 1 to 6 days after 
Doses 8, 9, or 10). Subjects will be stratified 2:1 (17P: vehicle) such that an even 
distribution of samples will be drawn on day 1, day 2, day 3, day 4 or day 5/6 post-dose. 
This will result in approximately 60 17P and 30 vehicle samples on each day interval. 
Study sites should follow the procedure outlined in the study manual.   
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The dependence of apparent clearances and volumes on BMI will be examined as the primary 
covariate. Pharmacokinetic models to evaluate effects on concomitant medications that may 
affect the inhibition or induction of HPC will be evaluated and modeled as data permit.  
3.4 
Safety Assessments 
Safety assessments include determination of maternal AE(s) and maternal pregnancy 
complications. Maternal pregnancy complications include, but are not limited to, the 
following: 
• Gestational diabetes  
• Oligohydramnios 
• Significant antepartum bleeding or hemorrhage 
• Preeclampsia 
• Eclampsia  
• HELLP syndrome 
• Gestational hypertension 
• Abruption 
• Chorioamnionitis  
Definitions of these maternal pregnancy complications are given in Section 13.1. 
3.5 
Primary and Secondary Outcomes 
3.5.1 
Primary Outcomes 
There are two co-primary outcomes: 
• Preterm birth prior to 350 weeks of gestation (as determined by project gestational age). 
All deliveries occurring from randomization until 350 weeks of gestation, including 
miscarriages occurring from 160 through 196 weeks of gestation and elective abortions, will 
be included. 
• Composite neonatal morbidity and mortality index. The composite index includes the 
following: 
– 
Neonatal death 
– 
Grade 3 or 4 IVH 
– 
RDS 
– 
BPD 
– 
NEC 
– 
Proven sepsis 
Definitions of neonatal outcomes are given in Section 13.2. 
 
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3.5.2 
Secondary Outcomes 
The secondary outcomes include: 
 
• Fetal/early infant death. Spontaneous abortion/miscarriage (delivery from 160 through 
196 weeks of gestation) or neonatal death occurring in liveborns born at less than 24 weeks 
gestation or stillbirth (antepartum or intrapartum death) from 20 weeks gestation through 
term. 
• Preterm birth prior to 320 weeks of gestation (as determined by project gestational age). 
All deliveries occurring from randomization until 320 weeks of gestation, including 
miscarriages occurring from 160 through 196 weeks of gestation and elective abortions, will 
be included. 
• Preterm birth prior to 370 weeks of gestation (as determined by project gestational age). 
All deliveries occurring from randomization until 370 weeks of gestation, including 
miscarriages occurring from 160 through 196 weeks of gestation and elective abortions, will 
be included. 
• Stillbirth: All stillbirths/fetal deaths/in-utero fetal losses occurring from 20 weeks gestation 
until term. 
• Neonatal death (from minutes after birth until 28 days of life) occurring in liveborns born 
at 24 weeks gestation or greater. 
• Dose-plasma concentration-time data of HPC analyzed using a nonlinear mixed effects 
modeling (NONMEM) of a population approach and the NONMEM software 
 
 The dependence of apparent clearances and 
volumes on BMI examined as the primary covariate through its formal inclusion in the 
NONMEM models.  
• Pharmacokinetic models to evaluate effects on concomitant medications that may affect 
the inhibition or induction of HPC will be evaluated and modeled as data permit. 
3.5.3 
Additional Outcomes 
Additional maternal outcomes that will be measured include: 
• Spontaneous preterm birth prior to 370 and prior to 350 weeks of gestation. Spontaneous 
delivery is defined as following preterm premature rupture of membranes (pPROM) or 
spontaneous labor from 200-370 and 200-350 weeks of gestation or miscarriage from 160 
through 196 weeks of gestation. 
• Indicated preterm birth prior to 370 weeks of gestation. Elective abortions will be defined 
as indicated preterm births. 
• Gestational age at delivery as determined by project gestational age. 
• Miscarriage (delivery from 160 through 196 weeks of gestation). 
Additional neonatal outcomes that will be measured include (See Section 13.2 for definitions): 
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• The following individual components of the neonatal index: 
– 
IVH 
– 
RDS 
– 
BPD 
– 
NEC 
– 
Proven sepsis 
 
• Birth weight 
• Seizures 
• Retinopathy of prematurity (ROP) 
• PDA 
• Infant hospital days: Time from birth to hospital discharge. 
• Number of days of neonatal respiratory therapy: Defined as the number of days on 
ventilator support and/or oxygen therapy. 
• Transient tachypnea 
• Persistent pulmonary hypertension 
4 STUDY TREATMENTS 
4.1 
Study Drug  
4.1.1 Dosage and Administration 
The study drug is 250 mg /mL of 17P given by the study site personnel as a 1 mL intramuscular 
injection (or 1 mL of vehicle (castor oil, benzyl benzoate and benzyl alcohol)) in the upper 
outer quadrant of the gluteus maximus.  Slow injection (over one minute or longer) is 
recommended.  The study drug will be dispensed by authorized site personnel and stored as 
multiple-dose vials containing 17P or vehicle.  If required by institutional policy or the medical 
condition of the subject the injection may be given at an alternative location in the same 
muscle.  Do not use product 5 weeks or more after first use.  Vials and packaging should be 
handled according to protocol instruction. 
4.1.2 Study Drug Discontinuation 
The study drug should be discontinued if any of the following events occur: 
• Arterial or deep venous thrombotic or thromboembolic event 
• Recurrent clinical depression in subjects with a history of clinical depression 
 
Subjects should be carefully monitored and the risk/benefit of continuing the drug should be 
evaluated if any of the following events occur  
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• Allergic reactions including urticaria, pruritis and angioedema 
• Jaundice 
• Hypertension 
 
4.2 
Prior/Concomitant Medications and Restrictions  
4.2.1 
Prior Medications 
Prior medications, defined as all medications taken since the start of this pregnancy, defined as 
40 weeks before the project EDC and before study drug is randomly assigned, will be recorded 
in the subject’s electronic case report form (eCRF) at Baseline (Visit 1), and Randomization 
Visit (Visit 2). This will include all prescription drugs, herbal products, vitamins (including 
prenatal vitamins), minerals, and other over-the-counter (OTC) medications. 
4.2.2 
Concomitant Medications 
All concomitant medications will be recorded in the subject’s eCRF from the time the subject 
is randomly assigned at Visit 2 through the End of Treatment Period Visit. This will include 
all prescription drugs, herbal products, vitamins (including prenatal vitamins), minerals, and 
OTC medications. Any changes in concomitant medications will also be recorded in the 
subject’s eCRF. 
Since hydroxyprogesterone caproate caused acceleration of the metabolic reactions catalyzed 
by CYP2A6, 2B6 and 1A2, a list of medicines using these metabolic pathways is included in 
Section 14. 
During the current pregnancy, a subject may have received an oral or intravaginal progestin 
other than hydroxyprogesterone caproate providing it is stopped at least 4 weeks prior to 
starting study medication. Any other concomitant medication deemed necessary for the welfare 
of the subject during the study may be given at the discretion of the investigator.   
 
 
4.2.3 
Restrictions 
No attempt will be made to alter or mandate clinical management of the subjects. However, 
the use of other prophylactic tocolytic drugs is discouraged. If complications of the pregnancy 
arise, such as the following: 
• Need for a cervical cerclage, or 
• Fetal anomaly or trisomy, or 
• Hospitalization for any reason including preterm labor, 
continuation of treatment will be at the discretion of the clinician managing the subject. These 
complications are not necessarily indications for stopping treatment. Thus, if a subject is 
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hospitalized, administration of the study drug should continue during hospitalization, if 
possible, as well as following discharge. 
4.3 
Measurement of Subject Compliance and Tolerability 
Subjects’ ability to comply with the study protocol and procedures will be assessed at Baseline 
(Visit 1). The subject will receive an injection (referred to as the trial injection) of the vehicle 
(1 mL of castor oil, benzyl benzoate and benzyl alcohol). The subject will be told that this 
injection does not contain the active drug but is a test for compliance with the treatment 
regimen and for any unusual reactions to the injection. Subjects may return 3 or more days 
after the trial injection as long as randomization occurs from 160 through 206 weeks of 
gestation.  If a subject can only receive the trial injection at a gestational age of 204 – 205 weeks 
and an ultrasound to screen for congenital anomalies was performed at or prior to a gestational 
age of 203 weeks, the patient may be randomized 24 hours or more following the trial injection 
provided that gestational age is <=206 weeks and in the opinion of the investigator the patient 
is experiencing no adverse reactions to the trial injection that would preclude their participation 
in the trial. 
Overall subject compliance with study treatment will be assessed by determining the 
proportion of expected injections actually received. The date of each injection will be recorded 
in the subject’s eCRF. 
4.4 
Study Drug Description 
The following drug supplies will be used in the study:  
Product 
Supplied as: 
17P  
250 mg/mL HPC in multidose vials 
Vehicle 
Castor oil, benzyl benzoate and benzyl alcohol in 
multidose vials 
The 17P drug product will be supplied as a sterile solution containing HPC 250 mg/mL, benzyl 
benzoate, castor oil, and benzyl alcohol. 
Vehicle will be supplied as a sterile solution containing benzyl benzoate, castor oil, and benzyl 
alcohol and is matched in color and appearance compared with 17P. 
4.5 
Study Drug Packaging and Storage 
The 17P and matching vehicle are contained in glass vials individually packaged in a cardboard 
box and shipped. Each vial will contain a sufficient volume to be able to withdraw five 1-mL 
doses. 
Vials of study drug will be stored at room temperature, between 59-86ºF (15-30ºC), away from 
light. Store vial in the vial carton provided. Store vial upright.  
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4.6 
Study Medication Accountability 
Study sites will receive instructions on accounting for receipt of study medication, storing 
subject’s empty vials and vials containing unused medication, and returning study medication. 
The investigator will maintain accurate records of receipt, return or destruction of all study 
medication, including the dates of receipt and return. In addition, accurate records will be kept 
regarding when and how much study medication is dispensed and used by each subject in the 
study, including the number of unused doses remaining in an open multidose vial. Reasons for 
departure from the expected dispensing regimen must also be recorded. At the completion of 
the study, to satisfy regulatory requirements regarding drug accountability, all study 
medication will be reconciled and retained or destroyed according to applicable local and 
national regulations. 
4.7 
Retention of Testing Samples 
Pharmacokinetic assessments will be made on three blood samples collected from the PK 
Population. At the request of the Food and Drug Administration (FDA), a separate aliquot of 
each PK blood sample will be retained for potential future analysis of any important 
metabolites that may be identified through ongoing PK analyses, outside of this study. 
5 SUBJECT ENROLLMENT 
Approximately 1707 subjects will be enrolled and randomized at approximately 90 sites.   Sites 
will be recruited in the United States and other countries. 
A subject is considered enrolled in the study if she receives the trial injection. Each subject will 
be assigned to a randomized study treatment only if she meets all of the inclusion criteria and 
none of the exclusion criteria. 
5.1 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Age ≥ 18 years. 
2. Singleton gestation. 
3. Project gestational age 160 weeks of gestation or more and less than or equal to 206 weeks 
of gestation at the time of randomization, based on clinical information and evaluation of 
the first ultrasound, as described in “Gestational Age Determination” below. 
4. Documented history of a previous singleton spontaneous preterm delivery. Spontaneous 
preterm birth is defined as delivery from 200 to 366 weeks of gestation following 
spontaneous preterm labor or pPROM. Where possible, the gestational age of the previous 
preterm birth (referred to as the qualifying delivery) should be determined as described in 
“Gestational Age Determination” below. If the gestational age at delivery is obtained 
directly from the medical record and more than one gestational age appears, the latest will 
be used. As a validation of the gestational age of the previous delivery, if the infant weighed 
more than 3300 grams19 (the birth weight 90th percentile for 36 weeks gestational age), this 
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will not qualify as preterm. The previous preterm delivery cannot be an antepartum 
stillbirth. 
5.1.1 
Gestational Age Determination 
Gestational age is determined in the following manner and is denoted ‘project gestational age’. 
The ‘project EDC’ will be determined by the combination of a reliable menstrual history and 
measurements obtained at the subject’s first ultrasound examination. The project EDC is based 
on the project gestational age and cannot be revised once a determination has been made. 
Because the project EDC depends on information from the earliest dating ultrasound, if no 
ultrasound has been performed previously, one must be performed before the subject can be 
randomized. 
1. The first day of the last menstrual period (LMP) is determined and a judgment made as to 
whether or not the subject has a ‘sure’ LMP date. 
2. If the LMP date is unsure, the ultrasound measurements obtained at the subject’s first 
ultrasound examination will be used to determine the project gestational age, by the 
standard method of ultrasound gestational age determination at that institution. 
3. If the date of her LMP is sure, and the ultrasound confirms this gestational age within the 
number of days specified in ‘Cut-offs for Using LMP to Determine Gestational Age’ (Table 
2), the LMP derived gestational age will be used to determine the project gestational age. 
4. If the ultrasound-determined gestational age does not confirm the LMP generated 
gestational age within the number of days specified in Table 2 below, the ultrasound is 
used to determine the project gestational age. 
Table 2 
Cut-offs for Using LMP to Determine Gestational Age 
Gestational age at first ultrasound by LMP 
Ultrasound agreement with LMP 
Up through 196 weeks of gestation 
±7 days 
200 through 206 weeks of gestation 
±14 days 
5.2 
Exclusion Criteria 
1. Multifetal gestation. 
2. Known major fetal anomaly or fetal demise. An ultrasound examination between 
140 through 203 weeks of gestation must be performed to rule out fetal anomalies. 
3. Subjects who have received a progestin during the current pregnancy AND meet one of the 
following criteria are excluded.   
3.1. The progestin was administered in the 4 weeks preceding the first dose of study 
medication 
3.2. Subjects received hydroxyprogesterone caproate 
3.3. The progestin was administered by a route other than oral or intra-vaginal. 
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4. Heparin therapy during current pregnancy or history of thromboembolic disease. 
5. Maternal medical/obstetrical complications including: 
– 
Current or planned cerclage 
– 
Hypertension requiring medication 
– 
Seizure disorder 
 
6. Subjects with a uterine anomaly (uterine didelphys or bicornuate uterus).  However, 
subjects with uterine fibroids are eligible for the study. 
7. Unwillingness to comply with and complete the study. 
8. A 140 through 203 weeks of gestation ultrasound cannot be arranged before randomization. 
9. Participation in an antenatal study in which the clinical status or intervention may influence 
gestational age at delivery.  
10. Participation in this trial in a previous pregnancy. Women who were screened in a previous 
pregnancy, but not randomized, do not have to be excluded. 
11. Known hypersensitivity to hydroxyprogesterone caproate injection or its components. 
12. Have any significant medical disorder that, in the opinion of the investigator, would be a 
contraindication to the use of the drug including the following list from section 5.3.2 of the 
investigational brochure:  
• 
Current or history of thrombosis or thromboembolic disorders 
• 
Known or suspected breast cancer, other hormone-sensitive cancer, or history 
of these conditions 
• 
Undiagnosed abnormal vaginal bleeding unrelated to pregnancy 
• 
Cholestatic jaundice of pregnancy 
• 
Liver tumors, benign or malignant, or active liver disease  
• 
Uncontrolled hypertension 
Other examples to consider include uncontrolled diabetes, known HIV infection or renal 
dysfunction. 
13. Have any significant medical disorder that, in the opinion of the investigator, would 
preclude accurate evaluation of the subject’s condition or outcome or compromise the 
subject’s safety in the study. 
5.3 
Randomization Procedures 
Subjects will be randomly assigned in a 2:1 ratio to 17P  or vehicle treatment (two 17P  to 
1 vehicle subject) using a blocked randomization sequence stratified by study site and 
gestational age randomization (160 weeks - 176 weeks gestation and 180 weeks – 206 weeks 
gestation). Randomization is stratified by study site to ensure balance between the 2 treatment 
groups with respect to anticipated differences in the clinic population and possible site-to-site 
differences in subject management. The rationale for 2:1 randomization is that since the study 
involves weekly injections, subjects may be more willing to participate if they know that they 
have a 2 to 1 chance of receiving active medication. Randomization occurs when a 
randomization number has been assigned to a subject.  
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If a subject does not attend her randomization visit, the investigator should attempt to contact 
the subject and reschedule the randomization visit. If the coordinator cannot contact the subject 
or the randomization visit cannot be rescheduled ≤ 206 weeks of gestation, the subject cannot 
be randomized.  Randomization will occur through the use of an interactive voice response 
system (IVRS). 
5.4 
Blinding Procedures 
This will be a double-blind study. The subjects, clinical site staff, and sponsor will not be aware 
of the treatment assignment. A Data and Safety Monitoring Board (DSMB) will review 
summary safety data (see Section 9.6.1) and the DSMB Charter will provide the option for the 
DSMB to request unblinded review of the data. 
5.5 
Breaking the Blind 
With the exception of the DSMB data review, the study blind will not be broken until all 
subjects have completed the study and the database is locked. Upon request, the subject will 
be advised of her treatment assignment after her infant has completed the follow-up study, if 
applicable. Only in the case of an emergency, when knowledge of the study drug is essential 
for the immediate clinical management or welfare of a specific subject, may the investigator 
unblind a subject’s treatment assignment. 
Prior to any unblinding, the investigator is strongly advised to discuss options with the Medical 
Monitor or appropriate sponsor study personnel. As soon as possible, and without revealing 
the subject’s study treatment assignment (unless important to the safety of subjects remaining 
in the study), the investigator must notify the sponsor if the blind is broken for any reason and 
the investigator was unable to contact the sponsor prior to unblinding. The investigator will 
record in source documentation the date and reason for revealing the blinded treatment 
assignment for that subject. 
5.6 
Subject Withdrawal  
Subjects may prematurely discontinue study drug or withdraw consent to participate in this 
study at any time without penalty or loss of benefits to which the subjects are otherwise 
entitled. 
5.6.1 
Subject Withdrawal from Study Drug 
Subjects will be considered withdrawn from study drug if they are prematurely discontinued 
from administration of study drug (i.e., prior to the anticipated full course of study drug therapy 
for a reason other than delivery). If possible the subject should remain on study and at a 
minimum, delivery data will be obtained. Reasons for subject withdrawal from study drug are 
recorded in the appropriate page(s) of the eCRF and may include, but are not limited to: 
• Withdrawal of consent.  
• At request of the investigator due to the occurrence of an AE that, in the opinion of the 
investigator, warrants the subject’s permanent discontinuation from study drug therapy. In 
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the event of discontinuation from study drug therapy due to the occurrence of an AE, the 
study site should notify the Medical Monitor as soon as possible (see Section 8.6). At the 
time of withdrawal, the site staff should attempt to obtain end-of-study information from 
the subject. 
• Significant subject noncompliance, defined as unwillingness or inability to adhere to the 
prescribed dosing regimen. 
5.6.2 
Subject Withdrawal from Study 
A subject is considered withdrawn from the study if the subject delivery data are not obtained 
(i.e., the subject is lost to follow-up). The investigator should make reasonable attempts to 
contact the subject including at least 2 phone calls followed by a registered letter, receipt 
requested. If the subject is determined to be lost to follow-up, the last known date pregnant 
should be recorded in the appropriate page of the eCRF. 
5.6.3 
Replacements 
Randomized subjects who are withdrawn from the study or lost to follow-up will not be 
replaced. 
5.6.4 
Sponsor’s Termination of Study 
The sponsor reserves the right to terminate an investigational site or this clinical study at any 
time. Reasons for termination may include, but are not limited to, the following: 
• The incidence or severity of AEs in this study indicates a potential health hazard to subjects. 
• Serious or persistent noncompliance by the investigator with the protocol, clinical research 
agreement, US FDA Form FDA 1572, GCP, or other applicable regulatory guidelines in 
conducting the study. 
• IRB/IEC decision to terminate or suspend approval for the investigation or the investigator. 
• Investigator request to withdraw from participation. 
• Subject enrollment is unsatisfactory. 
 
6 STUDY VISITS 
Each subject will be seen for weekly study visits to administer intramuscular injections of study 
drug. Subjects will receive one injection for each week they are pregnant from randomization 
through 366 weeks gestation or delivery, whichever occurs first.  As much as possible, 
injections should be given on the same day each week.   However, if a schedule change is 
required, in general injections should be at least 5 days apart and no more than 10 days apart. 
 
Three blood samples will be collected from approximately 450 subjects (300 active and 150 
vehicle) for the population PK analysis at specified visits during the trial. If the treatment is 
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interrupted for any reason, the subject will be encouraged to resume treatment with their study 
drug and continue until 366 weeks of gestation or delivery, whichever occurs first. 
At each post randomization study visit, the subject will be asked about possible AE(s) 
experienced since the last injection, the use of concomitant medications, and information 
related to additional risk factors for miscarriage will be collected. 
6.1 
Baseline (Visit 1) 
The Baseline (Visit 1) will occur wherever possible within 7 days before randomization and 
administration of study medication. Prior to performing baseline procedures, each potential 
subject (or legal guardian of the potential subject) will sign an informed consent form (ICF). 
All subjects who present for prenatal care after 150 weeks of gestation and before 203 weeks 
gestational age are eligible for screening.  The latest gestational age for randomization is 206 
weeks of gestation. 
The potential subject/legal guardian will be asked to sign a medical records release so that the 
medical records of her previous delivery(ies) may be obtained. Documentation of the subject’s 
previous delivery(ies) will be reviewed to ensure the subject meets the inclusion criteria. If an 
abdominal ultrasound examination has not been performed at 140 through 203 weeks of 
gestation, one must be arranged prior to randomization. The results of the ultrasound must also 
be reviewed to check for exclusion criteria and, if it is the subject’s first ultrasound, gestational 
age. The ultrasound results will be made available to the subject’s physician. 
At Baseline (Visit 1), potential subjects will undergo the following procedures: 
• If not already done, obtain written informed consent. No study specific procedures will be 
performed without informed consent.  Informed consent may be obtained at a gestational 
age of 10 weeks or greater to facilitate obtaining records from the qualifying delivery.   
• At centers participating in the 17P-FU-004 study, every effort will be made to obtain 
informed consent for the 17P-FU-004 study from all randomized subjects while they are 
pregnant.  If it is not possible to obtain consent during the pregnancy, consent may be 
obtained up to the point that their child reaches one year of age. 
• If not already done, obtain permission to release medical records from previous preterm 
birth. 
• Obtain demographic information including age, ethnicity, and race. 
• Obtain social history including marital status, years of education, alcohol use, tobacco use, 
and illicit drug use. 
• Obtain medical and obstetrics history, including pre-pregnancy weight, history of 
significant illnesses, previous surgical history, sexually transmitted disease history, history 
of douching before and during pregnancy, history of uterine and vaginal infection, history 
of corticosteroid use, outcome of all prior pregnancies, potential risk factors for 
miscarriage.  
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• Collect prior medications information, including all medications taken at any time since the 
start of this pregnancy, defined as 40 weeks before the project EDC, through the current date. 
• Obtain height. 
• Obtain weight. 
• Determine the project gestational age and EDC if an ultrasound has been completed.  
• A brief physical examination including a brief head-to-toe visual inspection must be 
conducted at either Baseline (Visit 1) or Visit 2. 
• Receive the trial injection. 
• Monitor for and record presence or absence of pulmonary oil microemboli (POME) 
symptoms, such as transient coughing or dyspnea, that may occur within the first 10 
minutes after administration of the injection (please refer to Section 8.1 – Adverse Events). 
• Record AE(s) associated with the trial injection. 
• Record information related to risk factors of miscarriage. 
• If one has not been conducted, schedule an ultrasound. 
• Schedule randomization (Visit 2). 
6.2 
Active Treatment Period (Visit 2 to 366 Weeks of Gestation or Delivery) 
During the Active Treatment Period, subjects will report to the site weekly until the subject is 
366 weeks of gestation or delivers, whichever occurs first.  
At Active Treatment Period Visits, subjects will undergo the following procedures: 
• Review medications and record as concomitant medications on the subject’s eCRF. 
• At visit 2, confirm the subject still meets the inclusion and exclusion criteria, randomize 
the subject and record any new AE(s) associated with administration of the trial injection.  
• At visit 2, conduct a brief physical examination including a brief head-to-toe visual 
inspection, if not conducted at Baseline (Visit 1). 
• Obtain weight. 
• Administer intramuscular injection of study drug.   
• Adverse events will be collected at all study visits that occur after the subject’s 
randomization and administration of the initial dose of study medication. 
• Monitor for and record presence or absence of POME symptoms, such as transient 
coughing or dyspnea, that may occur within the first 10 minutes after administration of the 
injection (please refer to Section 8.1 – Adverse Events). 
• Record any pregnancy complications, including complications associated with fetal/early 
infant death, visits for labor and delivery or hospitalization(s) for preterm labor. 
• For subjects in the PK substudy, collect a blood sample for PK analysis as appropriate:  
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1. Before study drug dosing at either Visit 6 or 7 (i.e., Dose 5 or 6). 
2. Before dosing at either Visit 8 or 9 (i.e., Dose 7 or 8).  
3. At a separate, non-dosing visit 1 to 6 days after Visit 9, 10, or 11 (i.e., 1 to 6 days after 
Doses 8, 9, or 10). Subjects will be stratified 2:1 (17P: vehicle) such that an even 
distribution of samples will be drawn on day 1, day 2, day 3, day 4 or day 5/6 post-
dose. This will result in approximately 60 17P and 30 vehicle samples on each day 
interval. 
6.3 
Delivery and Hospitalization 
As soon as possible after discharge from delivery hospitalization, subjects will undergo the 
following procedures: 
• Review concomitant medications if prior to End of Treatment Period Visit. 
• Record any pregnancy complications, including complications associated with fetal/early 
infant death. 
• Record the date of hospital admission and discharge. 
• Record delivery data including the date and time of labor onset, membrane rupture, 
delivery, and delivery route. 
• Record neonatal baseline data. 
• Record AE(s) if prior to End of Treatment Period Visit. 
6.4 
Neonatal Hospitalization 
All live births who are admitted to the NICU (NICU level 2-3 or equivalent, specialty or sub-
specialty care)20, who experienced one of the morbidities in the neonatal index or who died 
will undergo the following procedures: 
• Record neonate’s clinical data including composite index measures (See Section 13.2 for 
definitions). 
• If applicable, record hospital transfer information. 
• If applicable, collect autopsy information on neonatal death. 
6.5 
Neonate Follow-Up 
Neonates born to randomized subjects will be followed through 28 days of life or discharge 
from the NICU whichever is later. Therefore, the status of all neonates (alive or dead), 
regardless of when they are delivered and discharged from the hospital will be obtained at least 
28 days after delivery (this contact may occur at later than 28 days after delivery as long as the 
status of the infant on Day 28 after delivery is determined). If the neonate has been discharged 
from the birth hospitalization, the subject may be contacted by telephone to obtain the 
neonate’s status.  If the infant is still in the NICU or equivalent 28 days after delivery, then 
their status (alive or dead) will be determined upon discharge from the NICU or equivalent.  
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This status may be obtained after the infant is discharged as long as the status of the infant on 
the day of discharge is determined.   
6.6 
End of Treatment Period Visit 
All randomized subjects, regardless of when they deliver, should be contacted for an End of 
Treatment Period Visit to collect concomitant medications and AE information including 
medications to treat AE(s). The contact can be either in person or by telephone and should 
occur 35 ± 7 days after the last dose of study drug.  
At the End of Treatment Period Visit, subjects will undergo the following procedures: 
• Record AE(s).  
• Review concomitant medications and medications used to treat AE(s). 
6.7 
Early Withdrawal Procedures  
If a subject prematurely discontinues study medication she will be asked about her reason for 
discontinuation of study drug. The subject will remain in the study and maternal or fetal deaths, 
delivery and neonatal data will be obtained. If a subject prematurely discontinues study 
medication and is no longer making regular visits to the study site, every attempt will be made 
to obtain the last known date that she was pregnant from clinic records, emergency room 
records, labor and delivery visits, or records from other hospitals. If the subject is permanently 
lost to follow-up a brief explanation will be documented. 
7 STUDY ASSESSMENTS  
7.1 
Demographic Data/Medical and Obstetrical History 
Demographic data and a complete medical/obstetrical history including information related to 
additional risk factors of miscarriage will be collected at Baseline (Visit 1).  
7.2 
Physical Examination  
A brief physical examination including visual inspection of the subject’s anterior and posterior 
torso and extremities will be conducted at either Baseline (Visit 1) or Visit 2.   
7.3 
Height and Weight Measurements 
The subject’s height and pre-pregnancy weight will be recorded at Baseline (Visit 1) only. The 
subject’s weight will be recorded at each study visit from Baseline through the last dose of 
study drug. 
7.4 
Prior and Concomitant Medication 
Prior medications, defined as all medications taken during pregnancy from the start of this 
pregnancy, defined as 40 weeks before the project EDC, until study drug is randomly assigned 
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will be recorded at Baseline and Randomization visits. Concomitant medications will be 
recorded at each study visit after the subject is randomized (Visit 2) through the End of 
Treatment Period Visit. 
7.5 
Ultrasound 
All subjects must have an ultrasound at 140 through 203 weeks of gestation to rule out fetal 
anomalies. If one has not been done as part of standard prenatal care, one must be completed 
prior to randomization. 
7.6 
Pharmacokinetic Testing 
Pharmacokinetic assessments will be made based on a sparse sampling of approximately 
450 subjects (300 active and 150 vehicle) to analyze the dose-plasma concentration-time 
relationship of 17P. Participation in the PK substudy will be stratified by pre-pregnancy BMI, 
into ≤ 28 and > 28 such that approximately 40% and 60% of subjects are expected to be in 
each BMI category, respectively. In addition, for the third blood sample, subjects will be 
stratified 2:1 (17P: vehicle) such that an even distribution of samples will be drawn on day 1, 
day 2, day 3, day 4 or day 5/6 post-dose. This will result in approximately 60 17P and 30 
vehicle samples on each day interval.  
All subjects randomized into the clinical trial may participate in the PK substudy until the 
necessary number of subjects in each treatment group and BMI category complete the PK 
study.  
A total of 3 blood samples will be drawn from each subject in the PK substudy: 
1. Before study drug dosing at either Visit 6 or 7 (i.e., Dose 5 or 6). 
2. Before study drug dosing at either Visit 8 or 9 (i.e., Dose 7 or 8). 
3. At a separate, non-dosing visit 1 to 6 days after Visit 9, 10, or 11 (i.e., 1 to 6 days after 
Doses 8, 9, or 10). Subjects will be stratified 2:1 (17P: vehicle) such that an even 
distribution of samples will be drawn on day 1, day 2, day 3, day 4 or day 5/6 post-dose.  
Samples will be processed and shipped as described in the Study Manual.  
8 REPORTING ADVERSE EVENTS 
8.1 
Definitions 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical event not present prior to exposure to study 
medication or any event already present that worsens in either intensity or frequency following 
exposure to study medication from trial injection at Baseline through End of Treatment Period 
Visit, regardless of its causal relationship to study treatment.  Non-treatment-emergent events 
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(i.e., events occurring prior to study medication exposure) should be recorded as medical 
history. 
A treatment-emergent AE (TEAE) is defined as any event not present prior to exposure to 
study medication or any event already present that worsens in either intensity or frequency 
following exposure to study medication from Randomization through End of Treatment Period 
Visit. 
All AEs that occur after trial injection through the End of Treatment Period Visit must be 
reported in detail on the appropriate eCRF and followed to satisfactory resolution or until the 
investigator deems the event to be not significant for further follow up. The description of the 
AE will include the onset date, date of resolution, severity, seriousness (see Section 8.5), and 
the likelihood of relationship of the AE to study treatment (see Section 8.4). For the purposes 
of this study, preterm birth and associated neonatal morbidities will not be reported as an AE. 
Preterm birth and associated neonatal morbidities are an anticipated outcome of this population 
and will be captured on a specific page in the subject’s eCRF but will not be recorded on the 
AE page. 
Because other drugs which contain a castor oil-based vehicle have been associated with rare 
cases of POME, investigators will be asked to monitor for symptoms of POME, such as 
transient coughing or dyspnea, for 10 minutes after each injection. Although the volume of 
castor oil in these other preparations is larger than is used in the study drug, investigators will 
monitor for the presence or absence of these symptoms and record observations in the eCRF. 
A serious adverse event (SAE) is defined as any event that results in maternal, fetal, neonatal 
death; is immediately life threatening; requires subject inpatient hospitalization (for more than 
24 hours) for reasons other than pregnancy complications and/or preterm delivery; or 
prolongation 
of 
existing 
hospitalization; 
results 
in 
persistent 
or 
significant 
disability/incapacity; or is a congenital anomaly/birth defect. For the purposes of this study, 
hospitalization due to preterm labor/pPROM that does not result in delivery, is expected and 
will be recorded on the subject’s eCRF and not reported as an SAE.  
Hospitalization for labor that results in birth is an expected outcome in this population and will 
be captured in the subject’s eCRF (not reported as an SAE). However, complications requiring 
the mother to remain hospitalized longer than expected will be treated as an SAE.  
For the purposes of this study, preterm births that result in admission to the NICU and/or a 
prolonged stay in the NICU are expected and will be recorded on the subject’s eCRF and not 
reported as an SAE.  
For the purposes of this study, all congenital anomalies detected at the time of birth will be 
recorded in the eCRF and will not be reported as an SAE.  Any congenital anomalies that 
become apparent after birth through 28 days after birth or discharge from the NICU, whichever 
is later, will be reported as SAEs. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
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one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of 
drug dependency or drug abuse. 
8.2 
Eliciting Adverse Event Information  
Adverse events will be assessed from the time the subject receives the trial injection through 
35 ± 7 days after the last dose of study drug.  
At every study visit, subjects will be asked a standard question to elicit any medically related 
changes in their well-being. They will also be asked if they have been hospitalized, had any 
accidents, used any new medication, or changed concomitant medication regimens (both 
prescription and OTC medications). 
All randomized subjects, regardless of when they deliver, should be contacted for an End of 
Treatment Period Visit to obtain AE information including medications to treat AE(s). The 
contact can be either in person or by telephone and should occur 35 ± 7 days after the last dose 
of study drug.  Maternal or fetal deaths will be recorded through delivery. 
If a subject receives the trial injection but is not randomized, adverse events that the 
investigator becomes aware of should be reported up to 42 days after the trial injection. 
8.3 
Adverse Event Reporting  
All AEs reported or observed during the study will be recorded in the AE eCRF. Information 
to be collected includes type of event, date of onset, investigator-specified assessment of 
severity and relationship to study drug, date of resolution of the event, and seriousness. 
Treatments for AEs will be recorded on the concomitant medications eCRF. Adverse events 
resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported. All AEs will be followed 
to adequate resolution. Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 
or higher will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates or worsens significantly 
from baseline at any time during the study, it should be recorded as an AE. 
8.4 
Assessment of Causality  
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of the study medication in causing or contributing to the AE 
will be characterized using the following classification and criteria: 
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Definite: 
a. A reaction that follows a reasonable temporal sequence from administration of the drug, or 
in which the drug level has been established in body fluids or tissues and, 
b. Improves or disappears on stopping or reducing the dosage (dechallenge) and, 
c. Is an unusual event that is known to be associated with the drug or this class of compound, 
and cannot be explained by other therapy or the subject's physical condition, or 
d. Reappears on a repeated exposure (rechallenge). 
Probable: 
a. A reaction that follows a reasonable temporal sequence from administration of the drug 
and, 
b. Improves or disappears by dechallenge and, 
 
c. The reaction cannot be reasonably explained by the known characteristics of the subject's 
clinical state or other modes of therapy administered to the subject, and  
d.  Rechallenge was not attempted. 
Possible: 
a. A reaction that follows a reasonable temporal sequence from administration of the drug 
and, 
b. It is reasonable to suspect drug causation after considering basic illness, concomitant 
illness, and other modes of therapy administered to the subject. 
Unlikely/Remote:  
a. Any reaction not meeting the criteria for definite, probable or possible and, 
b. Current knowledge indicates that a relationship is unlikely. 
Definitely Not: 
a. Any reaction not meeting the criteria for definite, probable or possible and, 
b. That is known to be associated with the subject's clinical condition, or with other 
medication taken by the subject. 
8.5 
Assessment of Severity 
The intensity of the AE will be rated as mild, moderate, or severe using the following criteria: 
Mild events require minimal or no treatment and do not interfere with the subject’s daily 
activities. 
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15 calendar days.  For other unexpected events associated with the use of the study drug, the 
sponsor or its designee will notify FDA, EMA and other relevant regulatory authorities 
according to local regulatory requirements as soon as possible, but no later than 15 days, of the 
initial receipt of information. The investigator is responsible for informing the Institutional 
Review Board (IRB). Copies of SAE correspondence with all investigator, governing 
authorities, ethics committees, and the sponsor must be submitted to the sponsor for filing. 
A subject experiencing 1 or more SAEs will receive treatment and follow-up evaluations by 
the investigator or will be referred to another appropriate physician for treatment and follow-
up. 
All AEs, whether serious or nonserious, should be followed to resolution or until the AE is 
determined by the investigator not to be clinically significant. 
8.7 
Investigating the Cause of Stillbirth/Fetal Death/In-Utero Fetal Loss 
The etiology of a death following a live birth may be different from that of a stillbirth/fetal 
death/in-utero fetal loss. The investigation of the cause of stillbirth/fetal death/in-utero fetal 
loss involves evaluation of some fetal and maternal factors and is based on the 
recommendations from the Stillbirth Collaborative Research Network of the NICHD and the 
2009 American College of Obstetricians and Gynecologists (ACOG) guideline on 
management of stillbirths.21,22 
The fetal components of the investigation include: 
• Autopsy if parental/legal guardian consent is obtained. It should be performed by a 
pathologist, with perinatal autopsy expertise whenever possible.  If consent for autopsy is 
not obtained, every attempt should be made to gather information through options such as 
photographs, X-ray imaging, ultrasonography, magnetic resonance imaging or sampling of 
tissues.   
• Placental evaluation along with the cord and the membrane. 
• Karyotype if parental/legal guardian consent is obtained to collect tissue/specimen. 
• Weight, length and head circumference, and description of any gross abnormalities. 
The investigation of the maternal factors that may provide the cause of the stillbirth will 
involve the performance of the following tests shortly after the delivery:  
• Thyroid stimulating hormone, 
• Indirect Coombs test (If not performed as part of routine clinical care), 
• Serologic test for syphilis, 
• Urine toxicology screen, 
• Screen for fetal-maternal hemorrhage (Kleihauer-Betke or other) and, 
• Parvovirus serology. 
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Relevant family medical history will also be collected to investigate the etiology of the 
stillbirth. 
If there is clinical suspicion, the following maternal tests will be considered: 
• Lupus anticoagulant screen, 
• Anticardiolipin antibodies, 
• Factor V Leiden mutation, 
• Prothrombin G20210A mutation, 
• Screen for protein C, protein S, Antithrombin III deficiency and 
• Uterine imaging study. 
9 STATISTICAL METHODS 
9.1 
Sample Size 
In 3 studies of high-risk pregnant women, the rate of preterm birth < 350 weeks of gestation in 
women receiving vehicle ranged from 26.5% to 30%.15,23,24 The NICHD study also found that 
17.2% of live born infants in women receiving vehicle had the neonatal composite index.  
Using a 2:1 randomization, a total of 1665 live born infants are required to detect a reduction 
of 35% in the rate of the composite index (from 17% to 11%) with a power of 90% (assuming 
a two-sided type I error of 5%).  Assuming 2.5% of pregnancies will result in miscarriage or 
stillbirth, an additional 42 women need to be enrolled for a total of 1707 women (1138 active 
and 569 vehicle).  A total sample size of 1707 subjects provides 98% power to detect a 
reduction of approximately 30% in the rate of preterm birth < 350 weeks of gestation (from 
30% to 21%) using a two-sided type I error of 5%.  The effect size for the neonatal composite 
index as well as preterm birth < 350 weeks gestation was chosen to represent a clinically 
significant reduction.  
Since these outcome measures are co-primary outcomes, the power to detect significant 
differences between the treatment groups for both outcome measures may be reduced.  If the 
outcome measures are independent, the power is 88.2% and if the outcome measures are 
perfectly correlated, the power is 90%.  Data from the NICHD Study indicate these outcome 
measures are highly correlated with 56% of liveborn infants of women who delivered < 350 
weeks gestation with the neonatal composite index compared with 2% of live born infants of 
women who delivered ≥ 350 weeks gestation.  Thus, the power to detect significant differences 
between the treatment groups for both outcome measures is expected to be close to 90%.  
There is also sufficient power to detect clinically significant reductions in the secondary 
outcomes of delivery < 320 and < 370 weeks of gestation as indicated in Table 3 Sample Size 
Calculation. 
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Table 3 
Sample Size Calculation  
 
Secondary Outcome 
Outcome Rate in 
Vehicle Group 
Percent 
Reduction 
Power 
 
 
 
 
Delivery < 320 weeks of gestation 
20% 
33% 
92% 
Delivery < 370 weeks of gestation 
40% 
33% 
>99% 
Assuming a 4% fetal/early infant death rate with a two-sided alpha of 5%, a sample size of 
1707 subjects provides 82.8% power to rule-out a doubling in the risk of fetal/early infant death 
(i.e., the upper bound of the confidence interval for the relative risk of 17P compared to vehicle 
will be ≤2.0). 
A fetal/early infant death rate of 4.0% is based on the results of Study 17P-CT-002 (the NICHD 
17P trial).  
Approximately 450 subjects will participate in the population PK substudy. Subjects in the PK 
population will be stratified based on BMI (≤ 28 and > 28), such that approximately 40% and 
60% of subjects are in each BMI category, respectively. Additionally, for the third blood 
sample draw, subjects will be stratified 2:1 (17P: vehicle) such that an even distribution of 
samples will be drawn on day 1, day 2, day 3, day 4 or day 5/6 post-dose. This sample size, 
while not based on any statistical considerations, will enable generation of a sparse sample that 
will permit adequate nonlinear modeling of the PK/PD effects of 17P.  
9.2 
Populations to be Analyzed 
Six populations are defined in the analyses:  
Intent-to-treat (ITT) Population: ITT Population will consist of all randomized subjects. All 
subjects will be analyzed in the group to which they were randomized regardless of whether 
the subject received study drug. 
Modified ITT (MITT) Population: MITT Population will consist of all subjects in the ITT 
Population with outcome data of delivery date available. 
Per-Protocol (PP) Population: PP Population will consist of all subjects who are compliant 
with the study protocol. Each subject will be classified as compliant or not with the protocol 
based on the following criteria: subject was fully eligible (met all inclusion and had none of 
the exclusion criteria), at least 90% compliant with study drug, and outcome data available. 
Safety Population: The Safety Population will consist of all subjects who received any amount 
of study drug. 
Liveborn Neonate Population: The Liveborn Neonate Population will consist of all babies of 
randomized women (ITT Population) who were liveborn and have morbidity data available. 
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Pharmacokinetic (PK) Population: The PK Population will consist of subjects who received 
study drug and had PK data appropriate for PK analysis. Three blood samples will be drawn 
from each subject participating in the PK Population portion of the study. 
9.3 
Statistical Methodology 
Inferential statistical analyses as specified will be conducted and all comparisons will be 
between the 17P and vehicle groups. An alpha level of 0.05 will be used for the co-primary 
and secondary analyses. Descriptive statistics, including the numbers and percentages for 
categorical variables, and the numbers, means, standard deviations, medians, minimums and 
maximums for continuous variables will be provided. Listings of individual subjects’ data will 
also be provided. A comprehensive Statistical Analysis Plan will be prepared and finalized 
prior to database lock and analysis of the data. 
9.3.1 
Subject Population and Characteristics 
Enrollment, protocol deviations, withdrawals from the study (i.e., discontinuation from study 
drug), and subjects who are lost to follow-up will be summarized by treatment group. 
Demographics (age, race, marital status, and years of education), pre-pregnancy and 
enrollment weight/BMI, diabetic status, use of cigarettes, alcohol and street drugs during 
pregnancy, and obstetrical history (e.g., gestational age of the qualifying delivery, number of 
previous preterm deliveries, previous miscarriage, previous stillbirth, uterine and vaginal 
infection or use of corticosteroids prior to randomization, additional risk factors of miscarriage, 
etc.) will be summarized. Differences between treatment groups will be analyzed using the chi-
square or Fisher’s exact test for dichotomous variables and the Wilcoxon Rank Sum test for 
ordinal and continuous variables. 
9.4 
Efficacy Analysis  
9.4.1 
Primary Efficacy Outcome Measure 
The primary hypothesis for efficacy compares the proportion of subjects with a preterm 
delivery < 350 weeks of gestation between the 17P (∏17P) and vehicle (∏V) treatment groups 
in the ITT Population and the percent of neonates with the neonatal composite index between 
the 17P (P17P) and vehicle (PV) treatment groups in the Liveborn Neonatal Population.  The 
null (HO) and alternative (HA) hypotheses are as follows: 
HO: ∏17P = ∏V    and    P17P = PV            
HA: ∏17P ≠ ∏V     or     P17P ≠ PV 
An alpha level of 0.05 will be used for the primary analysis of both primary outcome measures 
as an adjustment for multiple comparisons is not required for testing the null hypothesis when 
stated as above. 
The percentage of subjects with a preterm birth <350 weeks of gestation will be determined as 
the point estimate of the survival function from a staggered entry Kaplan-Meier analysis 
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(which adjusts for gestational age at randomization) using time from randomization to delivery 
as the analysis variable.  Subjects with missing delivery data will be censored at the last known 
pregnancy.  Significant differences between the 17P and vehicle group in the proportion of 
subjects who deliver prior to 350 weeks gestation will be determined using a Cochran-Mantel-
Haenszel test stratified by gestational age at randomization (160 weeks - 176 weeks gestation 
and 180 weeks – 206 weeks gestation), where the effective sample sizes for each treatment 
group and stratum will be derived from Greenwood’s formula and a staggered entry Kaplan-
Meier analysis using the time from randomization until delivery as the analysis variable.  
Subjects with missing outcome data will be censored on the date last known pregnant. 
The number and percentage of infants in the Liveborn Neonatal Population with the neonatal 
composite index will be presented by gestational age at randomization and overall, for each 
treatment group.  Significant differences between the 17P and vehicle group will be determined 
using the Cochran-Mantel-Haenszel procedure stratified by gestational age at randomization.  
The percentage of subjects who deliver prior to 350 weeks of gestation will also be determined 
for subjects who received study drug (the Safety Population) and for the PP Population using 
the same analytic method as described above for the ITT Population.  
If there are baseline imbalances between the treatment groups with respect to prognostic factors 
such as the number of previous preterm deliveries, an adjusted analysis of the primary outcome 
measures will be conducted using the Cochran-Mantel-Haenszel procedure (for the neonatal 
composite index) and/or a Cox regression model (for preterm delivery <350 weeks gestations). 
An additional analysis of the primary efficacy outcomes will be performed to determine if there 
is a treatment-by-site interaction. A Breslow-Day test for the neonatal composite index and/or 
treatment-by-site interaction terms will be included in a Cox regression model to determine if 
there is consistency of results across the sites. 
9.4.2 
Secondary Outcomes 
Analysis of the secondary outcome of fetal/early infant death will be conducted in the ITT 
Population.  The relative risk of fetal/early infant death for the 17P group relative to the vehicle 
group will be determined using the Cochran-Mantel-Haenszel procedure stratified by 
gestational age at randomization. A two-sided 95% confidence interval (CI) for the relative 
risk will be constructed using the method of Cochran-Mantel-Haenszel adjusted for gestational 
age at randomization. If the upper bound of the CI is less than or equal to 2.0, a doubling in 
the risk of fetal/early infant death can be ruled out.  Treatment-by-gestational age at 
randomization interaction terms will be included in a logistic regression model to determine 
the relationship, if any, between gestational age at randomization and the risk of fetal/early 
infant death in the 17P group compared to the vehicle group.  
Analyses of the secondary maternal outcomes (delivery < 320 and < 370 weeks of gestation) 
will be conducted using the ITT, Safety and PP Populations. The number and percentages of 
subjects with delivery < 320 and < 370 weeks of gestation will be presented by treatment group 
and will be determined using the same analytic method as described above for the primary 
outcome. The number and percentage of subjects with a stillbirth (MITT Population), and 
whose neonates died (liveborn infants of subjects in the MITT Population) will also be 
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presented by treatment group. Differences between treatment groups will be analyzed using 
the Cochran-Mantel-Haenszel test stratified by gestational age at randomization. 
9.4.3 
Additional Analyses 
The numbers and percentages of subjects with a spontaneous preterm birth prior to 370 and 350 
weeks of gestation, and indicated preterm birth prior to 370 weeks of gestation will be 
determined and analyzed from a staggered Kaplan-Meier analysis as indicated above for the 
primary outcome.  The number and percentages of subjects with a miscarriage and the numbers 
and percentages of neonates who had RDS, BPD, IVH, sepsis, NEC, ROP, PDA or seizures 
will be presented by treatment group.  Differences between treatment groups will be analyzed 
using the Cochran-Mantel-Haenszel test stratified by gestational age at randomization. 
Descriptive statistics of gestational age at delivery, birth weight, infant hospital days and days 
of neonatal respiratory therapy will be provided and the Wilcoxon Rank Sum test will be used 
to test for statistically significant differences between the 17P and vehicle groups. 
9.5 
Pharmacokinetic/Pharmacodynamic Analysis 
Pharmacokinetic/pharmacodynamic analysis will be conducted in the PK Population. 
Nonlinear mixed effects modeling will be used to analyze the dose-plasma concentration-time 
data of 17P using a population PK approach and the NONMEM software 
 
.  
As a starting point for the sparse data to be collected in the study, a structural PK model will 
be initially developed. The structural PK model will contain PK parameters such as clearance 
and volume as fixed-effect parameters. The dependence of apparent clearances and volumes 
on BMI will be examined as primary covariate. Based on available literature, it is anticipated 
that a two-compartment model with first order absorption and elimination rates will be 
adequate to describe this data.25-28  In addition, the between-subject (intersubject) variability in 
the parameter estimates and the random residual error in the data will be estimated with an 
appropriate error model. The best base model will be selected based on the standard criteria 
such as minimum objective function value and diagnostic plots. 
The relationship of 17P steady-state exposure with the pharmacodynamic (PD) response 
markers will be defined using an appropriate PK/PD model such as an inhibitory maximum 
observed effect (Emax) model. The selection of a starting base PD model will be based on 
graphical evaluation of the exposure-response data as well as biological meaningfulness. 
The PK Population will be stratified by BMI at the time of randomization. Body mass index 
will be investigated as the primary covariate for its potential influence on the volume of 
distribution and clearance of 17P through its formal inclusion in the NONMEM models. 
Statistical significance will be concluded by suitable reduction in the objective function. 
Other factors including race, and number of previous preterm delivery(ies) may be considered 
as covariates. Findings of a clinical relevant magnitude will be investigated further. 
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While there exists a number of compounds that interact with progesterone, it is not known 
what the effect of these compounds will be on 17P.  Therefore, PK/PD models to evaluate 
effects on concomitant medications that may affect the inhibition or induction of HPC will be 
evaluated and modeled as data permit. 
9.6 
Safety Analysis 
Safety analyses will be conducted in the Safety Population. 
Summaries will be provided for all AEs. The incidence of AEs will be presented by system- 
organ class, higher level term and preferred term according to MedDRA, relationship to study 
treatment, severity and seriousness. AEs leading to premature discontinuation from the study 
drug will be summarized in a table. 
The percentage of subjects with pregnancy complications including gestational diabetes, 
oligohydramnios, significant antepartum bleeding or hemorrhage, preeclampsia, gestational 
hypertension, abruption and chorioamnionitis will be presented and compared between 
treatment groups using the Cochran-Mantel-Haenszel test stratified by gestational age at 
randomization. 
9.6.1 
Interim Analyses 
During the trial, an external and independent DSMB will meet periodically to review safety 
data. The timing of the DSMB reviews and scope of the safety review will be detailed in the 
DSMB Charter. Since the DSMB will not be reviewing efficacy data, no adjustment to the 
alpha level is required. The DSMB Charter will indicate whether the data are reviewed in a 
blinded or unblinded manner. 
10 DATA HANDLING AND QUALITY ASSURANCE 
10.1 Electronic Case Report Forms 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories.  
All eCRF information is to be filled in. If an item is not available or is not applicable, this fact 
should be indicated. Each completed eCRF must be reviewed, signed, and dated by the 
investigator in a timely manner.  
10.2 Monitoring of the Study 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulations with respect to current GCP and current 
standard operating procedures. 
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The monitor will visit the investigator and study facility at periodic intervals, in addition to 
maintaining necessary telephone and letter contact. The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and staff. 
10.3 Inspection of Records 
Investigators and institutions involved in the study will permit trial-related monitoring, audits, 
Internal Review Board/Internal Ethics Committee (IRB/IEC) review, and regulatory 
inspection(s) by providing direct access to all study records. In the event of an audit, the 
investigator agrees to allow the sponsor, representatives of the sponsor and applicable 
regulatory authorities access to all study records. 
The investigator should promptly notify the sponsor of any audits scheduled by any regulatory 
authorities and promptly forward copies of any audit reports received to the sponsor. 
10.4 Study Record Retention 
Essential documents will be retained until at least 2 years have elapsed since the formal 
discontinuation of the clinical trial of 17P. These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with 
the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained. 
11 ADMINISTRATIVE CONSIDERATIONS 
The following administrative items are meant to guide the investigator in the conduct of the 
trial but may be subject to change based on industry and government Standard Operating 
Procedures or Working Practice Documents or Guidelines. Changes will be reported to the 
IRB/IEC, but will not result in protocol amendments. 
11.1 Confidentiality 
All PK specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain subject confidentiality. All records will be kept in a secure storage area 
with limited access. Clinical information will not be released without the written permission 
of the subject (or the subject’s legal guardian), except as necessary for monitoring and auditing 
by the sponsor, its designee, applicable regulatory authorities, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
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11.2 Institutional Review Board /Independent Ethics Committee Approval 
National regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
prior to participation of human subjects in research studies. Prior to the study onset, the 
protocol, informed consent, advertisements to be used for subject recruitment, and any other 
written information regarding this study to be provided to the subject or the subject’s legal 
guardian and must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and 
of the IRB/IEC compliance with ICH Guideline E6 will be maintained by the site and will be 
available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC Chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title and/or protocol number 
and the date approval and/or favorable opinion was granted. 
The investigator is responsible for obtaining continued review of the clinical research at 
intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator must 
supply the sponsor or its designee with written documentation of continued review of the 
clinical research. 
11.3 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the subject, must be reviewed and approved by the sponsor or its designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB/IEC for 
approval prior to subjects being enrolled into an amended protocol. 
11.4 Informed Consent 
A written informed consent in compliance with ICH and Part 50 of Title 21 of the Code of 
Federal Regulations (CFR) shall be obtained from each subject/legal guardian prior to entering 
the study or performing any unusual or nonroutine procedure that involves risk to the subject. 
If permitted by local regulations and approved by the applicable ethics committee/IRB, 
subjects may use a computerized learning tool as part of the informed consent process.  If 
required by local regulations, consent must be obtained from parent(s)/legal guardians to 
collect data on neonates.  An informed consent template may be provided by the sponsor to 
investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent should be reviewed by the sponsor and/or its 
designee, if appropriate prior to IRB/IEC submission. Once reviewed, the consent will be 
submitted by the investigator to his or her IRB/IEC for review and approval prior to the start 
of the study. If a protocol amendment significantly alters the study design, increases potential 
risk to the subject, or otherwise affects statements in the ICF, the ICF must be revised 
accordingly and submitted to regulatory authorities and/or IRB/IECs as required for review 
and approval. The approved ICF must be used to obtain informed consent from new subjects 
prior to randomization and must be used to re-obtain informed consent from subjects currently 
participating in the study if they are affected by the amendment as determined by local 
regulatory requirements.  For purposes of this study, a subject is considered currently 
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participating if they have not yet completed protocol-related procedures associated with 
whichever of the following protocol events occurs latest: 
• End of Treatment Period Visit date (to occur 35 + 7 days after receipt of last dose of 
study drug) 
• 28 days following neonate delivery 
• Discharge of the neonate from the NICU (only applicable if the neonate was admitted 
into the NICU)   
 
At centers participating in the 17P-FU-004 study, every effort will be made to obtain informed 
consent for the 17P-FU-004 study from all randomized subjects while they are pregnant.  If it 
is not possible to obtain consent during the pregnancy, consent may be obtained up to the point 
that their child reaches one year of age.  Agreement to participate in the follow-up study is not 
required to participate in this study.  Every attempt will be made to keep study subjects and 
clinical site staff blinded to treatment assignment.  
 
Women who need translation assistance will be enrolled by a person fluent in their language 
and both verbal and written informed consent obtained in that language; if such are not 
available, they will not be included. 
Before recruitment and enrollment, each prospective subject and/or her legal guardian will be 
given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to participate 
in the study by signing the ICF. 
The investigator shall provide a copy of the signed ICF to the subject and/or legal guardian. 
The original form shall be maintained in the subject’s medical records at the site. 
11.5 Protocol Deviations 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. Protocol deviations will also be 
documented by the clinical monitor throughout the course of monitoring visits. The 
investigator will be notified of deviations in writing by the monitor. The IRB/IEC should be 
notified of significant protocol deviations in a timely manner. 
11.6 Study Reporting Requirements 
By participating in this study the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol. In addition, the investigator agrees to submit 
annual reports to his/her IRB/IEC as appropriate. The investigator also agrees to provide the 
sponsor with an adequate report shortly after completion of the investigator’s participation in 
the study. 
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11.7 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
Part 54 of Title 21 of the CFR. In addition, the investigator must provide to the sponsor a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year following the completion of the study. 
The sponsor is not financially responsible for further testing/treatment of any medical 
condition that may be detected during the baseline process. In addition, in the absence of 
specific arrangements, the sponsor is not financially responsible for further treatment of the 
subject’s disease. 
11.8 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH 
Guidance E6 8.2 and Title 21of the CFR by providing the following essential documents, 
including but not limited to: 
• An original investigator-signed Investigator’s Agreement page of the protocol.  
• An IRB/IEC-approved ICF, samples of site advertisements for recruitment for this study, 
and any other written information regarding this study that is to be provided to the 
subject/legal guardian. 
• IRB/IEC approval. 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572. 
• Curriculum vitae (CV) for the principal investigator and each subinvestigator listed on 
Form FDA 1572. Current licensure must be noted on the CV. They will be signed and dated 
by the principal investigators and subinvestigators at study start-up, indicating that they are 
accurate and current. 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under Part 54 of Title 21 of the CFR. In 
addition, the investigators must provide to the sponsor a commitment to promptly update 
this information if any relevant changes occur during the course of the investigation and 
for 1 year following the completion of the study. 
11.9 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of the ICH 
E6 Guideline on GCP and the principles of the World Medical Association Declaration of 
Helsinki. The investigator will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations. 
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11.10 Publications 
Following completion of the study, the data will be considered for reporting at a scientific 
meeting or for publication in a scientific journal. A publications committee comprised of 
representatives of the sponsor and leading investigators will be established to oversee all 
publications from the study. The publications committee will recommend how the primary 
multi-site manuscript is written and edited, the number and order of authors, the publication to 
which it will be submitted, and other related issues. The publications committee will make 
similar recommendations for any proposed publication involving subjects from multiple 
institutions. 
Publication of the results of the Study results at any individual site shall not be made before 
the first multi-site publication. 
 
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12 INVESTIGATOR’S STATEMENT 
By signing below, I acknowledge the Clinical Research Study presented in this protocol is 
clearly understood and agreed upon. The effort is feasible in terms of resources and testing 
requirements. I agree to conduct the study as outlined in the protocol entitled, “A Phase 3B, 
Multi-center, Randomized, Double-blind Study of Hydroxyprogesterone Caproate Injection, 
250 mg/mL, Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous 
Singleton Spontaneous Preterm Delivery” in accordance with the guidelines and all applicable 
government regulations including Part 54 of Title 21 of the CFR. I have read and understand 
all sections of the protocol, including Section 11, Administrative Considerations. 
 
<Principal Investigator’s Name> 
 
 
 
Date 
 
 
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13 MATERNAL COMPLICATIONS AND NEONATAL OUTCOMES 
13.1 Maternal Pregnancy Complications 
• Gestational Diabetes: Any degree of glucose intolerance with onset or first recognition 
during the current pregnancy.  A fasting plasma glucose level >126 mg/dL (7.0 
mmol/L) or random plasma glucose >200 mg/dL (11.1 mmol/L) meets the threshold 
for the diagnosis of diabetes, if confirmed on a subsequent day, and precludes the need 
for any glucose challenge. 29  
• Oligohydramnios: Using ultrasound, amniotic fluid index (the sum of measurements 
of the deepest cord-free amniotic fluid pocket in each of the abdominal quadrants) less 
than 5 cm or if clinically diagnosed. 
• Significant antepartum bleeding or hemorrhage: Bleeding after the subject was 
randomized, including placenta previa, abruption placenta, or threatened abortion.  
Spotting is not considered significant. 
• Gestational Hypertension: Having 2 blood pressures ≥140/90 mmHg on at least 2 
occasions (4 or more hours apart) and a clinical diagnosis of gestational hypertension 
(without proteinuria or other signs of preeclampsia). 
• Preeclampsia: Within a 24-hour period having blood pressure measurements ≥140/90 
mmHg on at least 2 occasions (4 or more hours apart) and proteinuria of 0.3 g or greater 
in a 24-hour urine specimen or +1 or greater protein on urine dipstick. 
• Eclampsia: Occurrence of generalized convulsion and/or coma in the setting of 
preeclampsia, with no other neurological condition. 
• HELLP Syndrome: Meets all three of the following conditions 
1. Hemolysis: abnormal peripheral smear, increased bilirubin >1.2 mg/dL 
2. Elevated liver enzymes: aspirate aminotransferase (AST) ≥72 IU/L, lactate 
dehydrogenase (LDH) >600 IU/L; and  
3. Thrombocytopenia: platelet count <100,000/mm3 
• Abruption: Diagnosed clinically with placental abruption (retroplacental hematoma).  
Do not include abruption diagnosed by pathologist’s report. 
• Chorioamnionitis: Clinical diagnosis of chorioamnionitis and body temperature of 
≥ 100ºF (37.8ºC) and no other defined infection. Maternal physical symptoms may 
include the following: fever: body temperature of ≥ 100ºF (37.8ºC) and no other 
defined infection, tachycardia (>120 beats per minute), hypotension, diaphoresis, cool 
or clammy skin, uterine tenderness, and foul-smelling or abnormal vaginal discharge. 
The fetus may present with tachycardia (>160 beats per minute). 
Does not include chorioamnionitis diagnosed only by a placental pathology report. 
• Placenta Previa: Implantation of the placenta over or near the internal os of the cervix. 
 
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13.2 Neonatal Outcomes 
• Neonatal Death: Death of a liveborn infant from minutes after birth until 28 days of 
life.  Note: for the purposes of the neonatal morbidity and mortality index only, a death 
prior to discharge from the NICU will also be counted as a neonatal death. 
• Transient Tachypnea (TTN):   Term or late preterm infant presents in the first hours 
after birth with mild cyanosis and respiratory distress (grunting, nasal flare, chest 
retractions and/or tachypnea).  The chest films shows perihilar streaky infiltrate.  Final 
clinical impression excludes pneumonia or RDS Type I. 
• Respiratory Distress Syndrome (RDS):  
Must meet both criteria A and B below: 
A. PaO2 <50 mmHg in room air, central cyanosis in room air, a requirement for 
supplemental oxygen to maintain PaO2 >50 mmHg, or a requirement for supplemental 
oxygen to maintain a pulse oximeter saturation over 85% within the first 24 hours of 
life. 
AND 
B. A chest radiograph consistent with RDS (for example, reticulogranular appearance 
to lung fields with or without low lung volumes and air bronchograms) within the first 
24 hours of life. 
Note:  Include diagnosis of hyaline membrane disease, Type I RDS, hyaline membrane 
disease and respiratory insufficiency of prematurity.  Do not include transient 
tachypnea of the newborn (TTN or Type II RDS). Do not include (brief) 'blow by' 
oxygen administration. 
• Bronchopulmonary Dysplasia (BPD): Chronic lung disease, defined as 
– Respiratory symptoms and 
– Chest radiograph abnormalities and 
– A requirement for supplemental oxygen in an infant born <32 weeks who is 
now 36 weeks post menstrual age (PMA). 
 
• Persistent Pulmonary Hypertension of the Newborn (PPHN):  Diagnosed clinically 
by echocardiogram or catheterization. 
• Duration of Ventilator Support: The total calendar days, including multiple periods 
on the ventilator.   This refers to mechanical ventilation only that is the infant was on a 
ventilator with a rate recorded and does not include CPAP.  This does include the use 
of synchronized mechanical ventilation (SIMV) but does not include simultaneous 
combination of CPAP with mechanical ventilation, sometimes referred to as cycled 
CPAP. Count the number of calendar days on which the infant received treatment at 
some point during the day (e.g., if the infant was started at noon on one day and taken 
off at noon the following day, this would count as two calendar days rather than one 
day). 
• Duration of Oxygen Therapy: The number of calendar days that the infant received 
supplemental oxygen (Fi02 > 0.21) after admission to nursery from Labor and Delivery 
(e.g., if the infant was started at noon on one day and taken off at noon the following 
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day, this would count as two calendar days rather than one). Do not include "blow by" 
oxygen administration. Record "000 if no oxygen was administered outside Labor and 
Delivery. If infant receives oxygen while also on the ventilator include those hours in 
the totals for both duration of ventilator support and duration of oxygen therapy. 
• Patent Ductus Arteriosus (PDA): Clinical evidence of left to right PDA shunt 
documented by continuous murmur, hyperdynamic precordium, bounding pulses, wide 
pulse pressure, congestive heart failure, increased pulmonary vasculature or 
cardiomegaly by CXR, and/or increased oxygen requirement or ECHO evidence of 
PDA with documentation of left to right ductal shunting. 
• Seizures: 3 level categorical variable: No, Suspect, Yes. 
 
Suspect – when attending physician records questionable seizures 
Yes – when the attending physician believes that seizures definitely occurred.  
A positive EEG may be available to confirm the diagnosis. 
• Intraventricular Hemorrhage (IVH): Bleeding from blood vessels in the 
periventricular germinal matrix of the brain. The hemorrhage may be confined to the 
matrix or may extend to the ventricles and the parenchyma of the brain.  
The degree of IVH is graded as None, Grade I, Grade II, Grade III and Grade IV (5 
level categorical variable). 
Grade I – Isolated subependymal hemorrhage 
Grade II – IVH without ventricular dilation 
Grade III – IVH with ventricular dilation 
Grade IV – IVH with parenchymal extension 
Note: The grade of the hemorrhage will be determined by the most severe cranial 
imaging finding prior to discharge and will be recorded according to the system of 
Papile et al.30 Do not use the grade indicated on the autopsy report. Diagnosis should 
be made either by Ultrasound, CT or MRI. 
 
• Periventricular Leukomalacia (PVL): Defined by the following31: 
 Grade I involves periventricular flares persisting for more than 7 days 
 Grade II indicates small periventricular cysts 
 Grade III is defined as extensive periventricular cysts 
 Grade IV is multicystic leukomalacia in the periventricular and subcortical  
region 
• Retinopathy of Prematurity (ROP) Stage: Defined by the worst stage documented 
on any exam in the eye with the most advanced stage. 
• Proven Sepsis: If an infant has at least one of the following signs/symptoms or in the 
judgment of the investigator has other symptoms that are indicative of sepsis, the 
physician should order appropriate cultures to document sepsis.  
 
 
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Sign/Symptom 
Blood 
Culture 
Urine 
Culture 
CSF 
Culture 
Fever (>38oC core) 
X 
X 
X 
Hypothermia 
(<37oC 
core) 
X 
X 
X 
Apnea 
X 
X 
X 
Bradycardia 
X 
X 
X 
Dysuria 
 
X 
 
Lethargy 
 
X 
 
Vomiting 
 
X 
 
Stiff neck 
 
 
X 
Meningeal signs 
 
 
X 
Cranial nerve signs 
 
 
X 
Irritability 
 
 
X 
 
The infant must have a positive blood, urine or CSF culture to be recorded as proven 
sepsis. 
 
In the case of a positive blood culture the infant must either have two cultures within a 
3 calendar day period showing the same organism or the investigator must document 
that, in his/her judgment: 
• Other causes of infection have been ruled out 
• A single positive blood culture is not due to a skin contaminant 
In the case of a positive urine culture, the culture must also meet the following criterion: 
• The culture has ≥105 microorganisms per cc of urine and no more than two 
species of microorganisms. 
If the infant does not have a positive blood, CSF or urine culture for the purposes of 
study documentation a diagnosis of proven sepsis cannot be made, even if the 
investigator makes a clinical diagnosis of sepsis and treats the subject with antibiotics.   
 
• Confirmed Pneumonia: Pneumonia diagnosed clinically within 72 hours of birth and 
confirmed by either an x-ray demonstrating consolidation with air bronchograms, or a 
positive blood culture performed at the time of clinical diagnosis. 
• Necrotizing Enterocolitis (NEC): Presence of one or more of the following clinical 
signs: bilious gastric aspirate or emesis, abdominal distension, occult or gross blood in 
stool (no fissure) AND one or more of the following radiographic findings present: 
pneumatosis intestinalis (cystic or linear), hepato-biliary gas, pneumoperitoneum. 
• Neonatal Hypoglycemia: Newborns with a plasma glucose concentration less than 40 
mg/dL (2.2 mmol/L) during the first 24 hours of life and less than 50 mg/dL (2.8 
mmol/L) after 24 hours of age.32 
 
 
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14 LIST OF DRUGS METABOLIZED BY CYP1A2, CYP2A6, AND CYP2B6 
Possible P450 Drug Interactions33-35  
  
CYP1A2 
CYP2A6 
CYP2B6 
Amitriptyline 
Caffeine 
Clomipramine 
Clozapine 
Cyclobenzaprine 
Estradiol 
Fluvoxamine 
Haloperidol 
Mexiletine 
Naproxen 
Olanzapine 
Ondansetron 
Phenacetin 
Acetaminophen 
Propranolol 
Riluzole 
Ropivacaine 
Tacrine 
Theophylline 
Tizanidine 
Verapamil 
(R)-Warfarin 
Zileuton 
Zolmitriptan 
Acetaminophen 
Coumarin 
Fadrozole 
Halothane 
Nicotine 
Valproic acid 
 
Bupropion 
Cyclophosphamide 
Efavirenz 
Ifosphamide 
Methadone 
Sorafenib 
 
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15 REFERENCES 
 
1. 
ACOG practice bulletin no. 127: Management of preterm labor. Obstet Gynecol. Jun 
2012;119(6):1308-1317. 
2. 
Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2006. National vital 
statistics reports : from the Centers for Disease Control and Prevention, National 
Center for Health Statistics, National Vital Statistics System. 2009;57(7):1-104. 
3. 
Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S. Births: 
final data for 2004. National vital statistics reports : from the Centers for Disease 
Control and Prevention, National Center for Health Statistics, National Vital 
Statistics System. Sep 29 2006;55(1):1-101. 
4. 
Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, wilson EC, Mathews TJ. Births: 
final data for 2010. National vital statistics reports : from the Centers for Disease 
Control and Prevention, National Center for Health Statistics, National Vital 
Statistics System. 2012;61(1):1. 
5. 
Iams JD, Goldenberg RL, Mercer BM, et al. The Preterm Prediction Study: 
recurrence risk of spontaneous preterm birth. National Institute of Child Health and 
Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol. 
May 1998;178(5):1035-1040. 
6. 
Mercer BM, Goldenberg RL, Moawad AH, et al. The preterm prediction study: effect 
of gestational age and cause of preterm birth on subsequent obstetric outcome. 
National Institute of Child Health and Human Development Maternal-Fetal Medicine 
Units Network. Am J Obstet Gynecol. Nov 1999;181(5 Pt 1):1216-1221. 
7. 
Creasy RK. Preterm birth prevention: where are we? Am J Obstet Gynecol. Apr 
1993;168(4):1223-1230. 
8. 
Keirse MJ, Grant A, King J. Preterm Labour. In: Chalmers L, Enkin M, Keirse MJ, 
eds. Effective Care in Pregnancy and Childbirth. New York: Oxford University 
Press; 1989:694-745. 
9. 
Keirse MJ. Progestogen administration in pregnancy may prevent preterm delivery. 
Br J Obstet Gynaecol. Feb 1990;97(2):149-154. 
10. 
Meis PJ, Aleman A. Progesterone treatment to prevent preterm birth. Drugs. 
2004;64(21):2463-2474. 
11. 
Levine L. Habitual Abortion. A Controlled Study Of Progestational Therapy. Western 
journal of surgery, obstetrics, and gynecology. Jan-Feb 1964;72:30-36. 
12. 
Papiernik-Berkhauser E. Double blind study of an agent to prevent pre-term delivery 
among women at increased risk. . Edition Schering. 1970;Serie IV(fiche 3):65-68. 
13. 
Johnson JW, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17alpha-
hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med. 
Oct 2 1975;293(14):675-680. 
14. 
Yemini M, Borenstein R, Dreazen E, et al. Prevention of premature labor by 17 
alpha-hydroxyprogesterone caproate. American Journal of Obstetrics and 
Gynecology. Mar 1 1985;151(5):574-577. 
15. 
Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 
alpha-hydroxyprogesterone caproate. N Engl J Med. Jun 12 2003;348(24):2379-2385. 
16. 
ACOG Committee Opinion. Use of progesterone to reduce preterm birth. Obstet 
Gynecol. Nov 2003;102(5 Pt 1):1115-1116. 
Version: 6.0, Version Date: 06 April 2016 
 
Protocol Number: 17P-ES-003 
 
56 
CONFIDENTIAL 


 
17. 
ACOG Committee Opinion number 419 October 2008 (replaces no. 291, November 
2003). Use of progesterone to reduce preterm birth. Obstet Gynecol. Oct 
2008;112(4):963-965. 
18. 
Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 
Oct 2012;120(4):964-973. 
19. 
Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: 
standards obtained from measurements in 7 dimensions of infants born between 25 
and 44 weeks of gestation. The Journal of pediatrics. Jun 1969;74(6):901-910. 
20. 
Stark AR. Levels of neonatal care. Pediatrics. Nov 2004;114(5):1341-1347. 
21. 
Silver RM, Varner MW, Reddy U, et al. Work-up of stillbirth: a review of the 
evidence. Am J Obstet Gynecol. May 2007;196(5):433-444. 
22. 
ACOG Practice Bulletin No. 102: management of stillbirth. Obstet Gynecol. Mar 
2009;113(3):748-761. 
23. 
O'Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of 
recurrent preterm birth: primary results from a randomized, double-blind, placebo-
controlled trial. Ultrasound in Obstetrics and Gynecology. 2007;30(5):687-696. 
24. 
Gonzalez-Quintero VH, Smarkusky L, Carter J, Istwan N, Rhea DJ. 17 Alpha-
hydroxyprogesterone Caproate: Perinatal Mortality and Pregnancy Outcomes. Obstet 
Gynecol. 2007;109(4 Supplement):1S-2S. 
25. 
Caritis SN, Sharma S, Venkataramanan R, et al. Pharmacology and placental 
transport of 17-hydroxyprogesterone caproate in singleton gestation. Am J Obstet 
Gynecol. Aug 16 2012. 
26. 
Onsrud M, Paus E, Haug E, Kjorstad K. Intramuscular administration of 
hydroxyprogesterone caproate in patients with endometrial carcinoma. 
Pharmacokinetics and effects on adrenal function. Acta Obstet Gynecol Scand. 
1985;64(6):519-523. 
27. 
Davis ME, Plotz EJ, Lupu CI, Ejarque PM. The metabolism of progesterone and its 
related compounds in human pregnancy. Fertil Steril. Jan-Feb 1960;11:18-48. 
28. 
Zhang S, Mada SR, Mattison D, Caritis S, Venkataramanan R. Development and 
validation of a high-performance liquid chromatography-mass spectrometric assay for 
the determination of 17alpha-hydroxyprogesterone caproate (17-OHPC) in human 
plasma. J Chromatogr B Analyt Technol Biomed Life Sci. Sep 1 2007;856(1-2):141-
147. 
29. 
Gestational diabetes mellitus. Diabetes Care. Jan 2004;27 Suppl 1:S88-90. 
30. 
Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of 
subependymal and intraventricular hemorrhage: a study of infants with birth weights 
less than 1,500 gm. The Journal of pediatrics. Apr 1978;92(4):529-534. 
31. 
de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial 
ultrasound. Behavioural brain research. Jul 31 1992;49(1):1-6. 
32. 
Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of 
neonatal hypoglycemia: suggested operational thresholds. Pediatrics. May 
2000;105(5):1141-1145. 
33. 
Flockhart D. Drug Interactions: Cytochrome P450 Drug Interaction Table. Version 
5.0 released on January 12, 2009.  Indiana University School of Medicine 
2009; http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed January 21, 2010. 
Version: 6.0, Version Date: 06 April 2016 
 
Protocol Number: 17P-ES-003 
 
57 
CONFIDENTIAL 


 
34. 
Nakajima M, Kuroiwa Y, Yokoi T. Interindividual differences in nicotine metabolism 
and genetic polymorphisms of human CYP2A6. Drug metabolism reviews. Nov 
2002;34(4):865-877. 
35. 
Le Gal A, Dreano Y, Lucas D, Berthou F. Diversity of selective environmental 
substrates for human cytochrome P450 2A6: alkoxyethers, nicotine, coumarin, N-
nitrosodiethylamine, and N-nitrosobenzylmethylamine. Toxicol Lett. Sep 15 
2003;144(1):77-91. 
 
 
Version: 6.0, Version Date: 06 April 2016 
 
Protocol Number: 17P-ES-003 
 
58 
CONFIDENTIAL 





SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A PHASE 3B, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND STUDY OF 
HYDROXYPROGESTERONE CAPROATE INJECTION, 250 MG/ML, VERSUS 
VEHICLE FOR THE PREVENTION OF PRETERM BIRTH IN WOMEN WITH A 
PREVIOUS SINGLETON SPONTANEOUS PRETERM DELIVERY 
PROTOCOL NUMBER: 17P-ES-003 
29 JANUARY 2019
NCT01004029










TABLE OF CONTENTS 
1 
INTRODUCTION ....................................................................................................................... 7 
2 
STUDY DESIGN ......................................................................................................................... 7 
3 
STUDY OBJECTIVES ............................................................................................................... 7 
3.1 
Primary Objective ..................................................................................................... 7 
3.2 
Secondary Objectives ............................................................................................... 8 
4 
GESTATIONAL AGE DETERMINATION ............................................................................ 8 
5 
DEFINITIONS OF OUTCOME MEASURES ......................................................................... 9 
5.1 
Efficacy Outcomes .................................................................................................... 9 
5.1.1 Primary Efficacy Outcomes ...................................................................................... 9 
5.1.2 Secondary Neonatal Efficacy Outcomes .................................................................. 11 
5.1.3 Secondary Maternal Efficacy Outcomes .................................................................. 11 
5.1.4 Additional Neonatal Efficacy Outcomes .................................................................. 11 
5.1.5 Additional Maternal Efficacy Outcomes .................................................................. 12 
5.2 
Safety Outcomes .....................................................................................................12 
5.2.1 Primary Safety Outcome ......................................................................................... 12 
5.2.2 Secondary Safety Outcomes ................................................................................... 13 
6 
STATISTICAL METHODS ..................................................................................................... 14 
6.1 
Sample Size ............................................................................................................14 
6.2 
Randomization and Blinding ....................................................................................15 
6.3 
Interim Analysis .......................................................................................................15 
6.4 
Analysis Populations ................................................................................................15 
6.5 
Comments on Statistical Analysis ............................................................................16 
6.6 
Handling of Missing Data .........................................................................................16 
7 
STATISTICAL ANALYSES .................................................................................................... 19 
7.1 
Subject Population and Baseline Characteristics .....................................................19 
7.2 
Efficacy Analyses.....................................................................................................21 
7.2.1 Primary Efficacy Analyses ..................................................................................... 21 
7.2.1.1 
Additional Analyses of Primary Efficacy Outcome Measures ....................... 22 
7.2.2 Secondary Neonatal Efficacy Analyses .................................................................. 23 
7.2.3 Secondary Maternal Efficacy Analyses .................................................................. 23 
7.2.4 Additional Neonatal Efficacy Analyses .................................................................. 23 
7.2.5 Additional Maternal Efficacy Analyses .................................................................. 24 
7.3 
Safety Analyses .......................................................................................................25 
7.3.1 Primary Safety Analysis ..........................................................................................  25 
7.3.1.1 
Additional Analyses of Primary Safety Outcome Measure ............................ 25 
7.3.2 Secondary Safety Analyses ..................................................................................... 26 


7.3.2.1 
Miscarriages and Stillbirths ............................................................................ 26 
7.3.2.2 
Adverse Events and Maternal Complications ................................................. 26 
7.4 
Other Analyses ........................................................................................................27 
7.4.1 Study Drug Administration ..................................................................................... 27 
7.4.2 Prior and Concomitant Medications ....................................................................... 28 
7.4.3 Post-randomization Cervical Length by Gestational Age ...................................... 28 
7.4.4 Gestational Diabetes ............................................................................................... 28 
7.4.5 Maternal Delivery Data........................................................................................... 28 
7.4.6 Gestational Age at Delivery and Neonatal Outcome .............................................. 29 
8 
CHANGES FROM ANALYSES AS DESCRIBED IN THE PROTOCOL ......................... 30 
9 
APPENDIX A – SCHEDULE OF EVENTS ........................................................................... 31 
10 
REFERENCES .......................................................................................................................... 33 


AMAG Pharma USA, Inc.. 
Protocol No.:  17P-ES-003 
Statistical Analysis Plan V 2.0 
1 Introduction 
This Statistical Analysis Plan (SAP) provides the framework for the analysis and 
summarization of the clinical data from the study, “A Phase 3B, Multi-center, Randomized, 
Double-Blind Study of Hydroxyprogesterone Caproate Injection, 250 mg/ml, versus Vehicle 
for the Prevention of Preterm Birth in Women with a Previous Singleton Spontaneous 
Preterm Delivery” (protocol 17P-ES-003). Pharmacokinetic (PK) and pharmacodynamic 
(PD) analyses will not be presented in this SAP.  Any changes made to the SAP after it has 
been signed-off but prior to database lock will be detailed in a Statement of Change 
document.  Any changes made to the analyses after database lock will be described in the 
clinical study report (CSR).  
2 Study Design 
This study is a multi-center, randomized, double-blind, vehicle-controlled clinical trial in 
women with a singleton pregnancy, aged 18 years or older, with a history of a previous 
singleton spontaneous preterm delivery.  A total of 1707 subjects will be randomized in a 
2:1 ratio to receive either 17P or vehicle, respectively.  Subjects who provide informed 
consent and are 150 to 203 weeks gestational age are eligible for screening.  Potentially eligible 
subjects undergo the procedures as outlined in Appendix A at baseline (Visit 1) including 
receipt of a trial injection of vehicle.  Approximately 7 days later and at 160 to 206 weeks 
gestational age, subjects who met all inclusion and have no exclusion criteria are randomized 
to study treatment. Subjects receive weekly injections of study drug from randomization (160 
through 206 weeks of gestation) until 366 weeks of gestation or delivery, whichever occurs 
first.  Randomized subjects will be followed for efficacy outcomes through the date of 
delivery and for adverse events up to the End of Treatment Period Visit defined as up to 35 ± 
7 days after the last dose of study drug.  If the End of Treatment Period Visit is prior to the 
date of delivery, maternal and fetal deaths will be reported until delivery.  Neonates of 
randomized subjects will be followed until day 28 or the date of discharge from the NICU or 
equivalent, whichever occurs later.  Discharge from the NICU is defined as discharge to any 
of the following: home, a non-medical facility, a chronic-care facility, or a step-down unit.  
The schedule of assessments is provided in Appendix A. 
3 Study Objectives 
3.1 
Primary Objective 
The two co-primary objectives of this study are to: 
•
Determine if treatment with 17P reduces the rate of preterm birth < 350 weeks of
gestation in women with a singleton pregnancy, aged 18 years or older, with a previous
singleton spontaneous preterm delivery.


• Determine if 17P reduces the rate of neonatal mortality or morbidity. Neonatal mortality 
or morbidity is measured by a composite index comprised of: 
o Neonatal death. 
o Grade 3 or 4 intraventricular hemorrhage (IVH). 
o Respiratory distress syndrome (RDS). 
o Bronchopulmonary dysplasia (BPD). 
o Necrotizing enterocolitis (NEC). 
o Proven sepsis. 
3.2 
Secondary Objectives 
The secondary objectives of this study are to: 
• Exclude a doubling of the risk of fetal/early infant death, defined as spontaneous 
abortion/miscarriage (delivery from 160 through 196 weeks of gestation) or neonatal 
death (from minutes after birth until 28 days of life) occurring in liveborns born at less 
than 24 weeks of gestation or stillbirth (antepartum or intrapartum death from 20 weeks 
of gestation through term), in the 17P group compared to the vehicle group. 
• Determine if 17P reduces the rate of preterm birth < 320 weeks of gestation. 
• Determine if 17P reduces the rate of preterm birth < 370 weeks of gestation. 
• Determine if 17P reduces the rate of stillbirth defined as all stillbirths/fetal deaths/in-
utero fetal losses occurring from 20 weeks of gestation until term. 
• Determine if 17P reduces the rate of neonatal death (from minutes after birth until 28 
days of life) occurring in liveborns born at 24 weeks of gestation or greater. 
• Evaluate the PK/PD of 17P in a subset of pregnant women (analysis not described in this 
SAP) 
 
 
4 Gestational Age Determination 
Gestational age is determined from the combination of a reliable menstrual history and 
measurements obtained at the subject’s first ultrasound.  It is determined at screening and is 
used to determine whether or not a subject is eligible for the study and as a randomization 
stratification factor using the categories 160
 weeks – 176 weeks of gestation and 180 weeks – 
206 weeks of gestation.  For some subjects, after randomization, it was determined that 
gestational age was calculated incorrectly at screening, and the subject was assigned to the 
incorrect randomization stratum.  Gestational age is then corrected; however, the subject’s 
randomization stratum cannot be changed.  To distinguish these two different gestational 
ages, the following terminology is used: 
• Randomization gestational age stratum: refers to the gestational age stratum 
determined at screening and used for  randomization. It had the categories 160
 weeks 


– 176 weeks of gestation and 180 weeks – 206 weeks of gestation. It does not vary 
over time and is not used for any purpose other than randomization.  
• Project gestational age: refers to the correct gestational age calculated from the 
subject’s menstrual history and measurements obtained at the subject’s first 
ultrasound.  In particular, project gestational age at the time of randomization will be 
used as an explanatory variable in statistical models (either as a continuous variable 
or as a categorical variable) or as a stratification variable in analyses (as a categorical 
variable, e.g., in Cochran-Mantel-Haenszel analyses), and project gestational age at 
the time of delivery will be used to define the primary and secondary efficacy 
outcomes (i.e., preterm birth prior to 350, 320, and 370 weeks of gestation). The terms 
“gestational age” and “weeks of gestation” will be used to refer to project gestational 
age. 
 
 
5 Definitions of Outcome Measures 
5.1 
Efficacy Outcomes 
5.1.1 Primary Efficacy Outcomes 
There are two co-primary outcomes: 
• Preterm birth prior to 350 weeks of gestation (as determined by project gestational age at 
time of delivery).  All deliveries occurring from randomization up through 346 weeks of 
gestation, including miscarriages occurring from 160 through 196 weeks of gestation and 
elective abortions, will be included.  
• Composite neonatal morbidity and mortality index, defined as a liveborn neonate with 
any of the following occurring at any time during the birth hospitalization up through 
discharge from the NICU (except as specified below): 
o Neonatal death occurring in a liveborn at any time through discharge from the 
NICU. 
o Grade 3 or 4 IVH: Bleeding from blood vessels in the periventricular matrix 
germinal matrix of the brain.  Determined by cranial ultrasound, CT scan or 
MRI performed as part of routine clinical care. Grade III is defined as IVH 
with ventricular dilation and Grade 4 is defined as IVH with parenchymal 
extension. 
o RDS: A) PaO2 <50 mmHg in room air, central cyanosis in room air, a 
requirement for supplemental oxygen to maintain PaO2 >50 mmHg, or a 
requirement for supplemental oxygen to maintain a pulse oximeter saturation 
over 85% within the first 24 hours of life, AND B) A chest radiograph 
consistent with RDS within the first 24 hours of life. 
  


o BPD: defined as having  
 Respiratory symptoms and 
 Chest radiograph abnormalities and 
 A requirement for supplemental oxygen in an infant born at <32 weeks 
who is now 36 weeks post menstrual age (PMA). 
o NEC: defined by the presence of one or more of the following clinical signs: 
bilious gastric aspirate or emesis, abdominal distension, occult or gross blood 
in stool (no fissure) AND one or more of the following radiographic findings 
present: pneumatosis intestinalis (cystic or linear), hepato-biliary gas, 
pneumoperitoneum. 
o Proven sepsis: If an infant has at least one of the following signs/symptoms or 
in the judgment of the investigator has other symptoms that are indicative of 
sepsis, the physician is to order appropriate cultures to document sepsis. 
Sign/Symptom 
Blood 
Culture 
Urine 
Culture 
CSF 
Culture 
Fever (>38oC core) 
X 
X 
X 
Hypothermia (<37oC core) 
X 
X 
X 
Apnea 
X 
X 
X 
Bradycardia 
X 
X 
X 
Dysuria 
 
X 
 
Lethargy 
 
X 
 
Vomiting 
 
X 
 
Stiff neck 
 
 
X 
Meningeal signs 
 
 
X 
Cranial nerve signs 
 
 
X 
Irritability 
 
 
X 
 
The infant must have a positive blood, urine or CSF culture to be recorded as 
proven sepsis.  In a case of a positive blood culture, the infant must have 
either two cultures within a 3 calendar-day period showing the same organism 
or the investigator must document that in his/her judgment: 
• Other causes of infection have been ruled out 
• A single positive blood culture is not due to a skin contaminant 
In the case of a positive urine culture, the culture must also show ≥105 
microorganisms per cc of urine and no more than two species of 
microorganisms. 
If the infant does not have a positive blood, CSF or urine culture for the 
purposes of study documentation, a diagnosis of proven sepsis cannot be 


made, even if the investigator makes a clinical diagnosis of sepsis and treats 
the subject with antibiotics. 
5.1.2 Secondary Neonatal Efficacy Outcomes 
Secondary neonatal outcomes that will be measured include: 
• Neonatal death (from minutes after birth until 28 days of life) occurring in liveborns born 
at 24 weeks of gestation or greater. 
5.1.3 Secondary Maternal Efficacy Outcomes 
Secondary maternal efficacy outcomes that will be measured include: 
• Preterm birth prior to 320 weeks of gestation (as determined by project gestational age at 
time of delivery). All deliveries occurring from randomization up through 316 weeks of 
gestation, including miscarriages occurring from 160 through 196 weeks of gestation and 
elective abortions, will be included. 
• Preterm birth prior to 370 weeks of gestation (as determined by project gestational age at 
time of delivery). All deliveries occurring from randomization up through 366 weeks of 
gestation, including miscarriages occurring from 160 through 196 weeks of gestation and 
elective abortions, will be included. 
5.1.4 Additional Neonatal Efficacy Outcomes  
Additional neonatal efficacy outcomes that will be measured include: 
• The following individual components of the neonatal morbidity and mortality index: 
o IVH 
o RDS 
o BPD 
o NEC 
o Proven sepsis 
• Birth weight 
• Seizures 
• Retinopathy of prematurity (ROP) 
• Patent ductus arteriosus (PDA) 
• Infant hospital days, defined as the number of days from birth to hospital discharge. 


• Number of days of neonatal respiratory therapy, defined as the number of days on 
ventilator support and/or oxygen therapy. 
• Transient tachypnea 
• Persistent pulmonary hypertension 
5.1.5 Additional Maternal Efficacy Outcomes  
Additional maternal efficacy outcomes that will be measured include: 
• Spontaneous preterm birth prior to 370 weeks of gestation and prior to 350 weeks of 
gestation. Spontaneous delivery is defined as following preterm premature rupture of 
membranes (pPROM) or spontaneous labor from 200 weeks up through 366 weeks of 
gestation (for prior to 370 weeks) and 200 weeks up through 346 weeks of gestation (for 
prior to 350 weeks) or miscarriage from 160 weeks through 196 weeks of gestation. 
• Indicated preterm birth prior to 370 weeks of gestation for either fetal or maternal 
indications. Elective abortions will also be defined as indicated preterm births. 
• Gestational age at delivery.  Gestational age at delivery is calculated from the Project 
Estimated Date of Confinement (Project EDC) captured on the CRF and the date of 
delivery as follows:  
280 – (Project EDC – Date of Delivery) and is presented in weeks, days 
• Spontaneous abortion/miscarriage defined as delivery from 160 through 196 weeks of 
gestation. 
5.2 
Safety Outcomes 
5.2.1 Primary Safety Outcome 
The primary safety outcome is fetal/ early infant death.  
Fetal/early infant death will be defined as: 
• Spontaneous abortion/miscarriage (delivery from 160 up through 196 weeks of 
gestation) or; 
• stillbirth (antepartum or intrapartum death) from 20 weeks of gestation through term, 
or; 
• neonatal death (from minutes after birth until 28 days of life) occurring in liveborns 
born at less than 24 weeks of gestation. 


5.2.2 Secondary Safety Outcomes 
The secondary safety outcome is stillbirth defined as all stillbirths/fetal deaths/in-utero fetal 
losses occurring from 20 weeks of gestation until term. 
 
Safety will also be assessed by analysis of the occurrence of treatment emergent adverse 
events (TEAEs) and maternal pregnancy complications.  A TEAE is defined as an adverse 
event (AE) that starts or worsens at or during the time of the first blinded study medication 
injection (active drug or vehicle) through the End of Treatment Period Visit. Adverse events 
will also be provided for the time period starting from the trial injection and ending on the 
day of, but prior to, administration of the first study medication injection.   
Maternal pregnancy complications include the following: 
• Gestational diabetes: Any degree of glucose intolerance with onset or first recognition 
during pregnancy. A fasting plasma glucose level > 126 mg/dL (7.0 mmol/L) or random 
plasma glucose > 200 mg/dL (11.1 mmol/L) meets the threshold for the diagnosis of 
diabetes, if confirmed on a subsequent day, and precludes the need for any glucose 
challenge.1 
• Oligohydramnios: Using ultrasound, amniotic fluid index (the sum of measurements of 
the deepest cord-free amniotic fluid pocket in each of the abdominal quadrants) less than 
5 cm or if clinically diagnosed. 
• Significant antepartum bleeding or hemorrhage: Bleeding after the subject was 
randomized, including placenta previa, abruption placenta, or threatened abortion. 
Spotting is not considered significant. 
• Preeclampsia: Within a 24-hour period having blood pressure measurements ≥ 140/90 
mmHg on at least 2 occasions (4 or more hours apart) and proteinuria of 0.3 g or greater 
in a 24-hour urine specimen or +1 or greater protein on urine dipstick. 
• Eclampsia: Occurrence of generalized convulsion and/or coma in the setting of 
preeclampsia, with no other neurological condition.   
• HELLP syndrome: Meets all three of the following conditions: 
Hemolysis: abnormal peripheral smear, increased bilirubin > 1.2 mg/dL 
Elevated liver enzymes: aspartate aminotransferase (AST) ≥72 IU/L, lactate 
dehydrogenase (LDH) > 600 IU/L; and 
Thrombocytopenia: platelet count < 100,000/mm3. 
• Gestational hypertension: Having 2 blood pressure measurements ≥ 140/90 mmHg on at 
least 2 occasions (4 or more hours apart) and a clinical diagnosis of gestational 
hypertension (without proteinuria or other signs of preeclampsia). 
• Abruption: Clinical diagnosis of placental abruption (retroplacental hematoma). Does not 
include abruption diagnosed by pathologist’s report. 


• Chorioamnionitis: Clinical diagnosis of chorioamnionitis and body temperature of ≥ 100° 
F (37.8° C) and no other defined infection.  Does not include chorioamnionitis diagnosed 
only by a placental pathology report.  
6 Statistical Methods 
6.1 
Sample Size 
In 3 studies of high-risk pregnant women, the rate of preterm birth < 350 weeks of gestation 
in women receiving vehicle ranged from 26.5% to 30%.2,3,4 The NICHD study also found 
that 17.2% of live born infants in women receiving vehicle had the neonatal composite index.  
Using a 2:1 randomization of subjects to 17P and vehicle, respectively, a total of 1665 
liveborn infants are required to detect a reduction of 35% in the rate of the composite index 
(from 17% to 11%) with a power of 90% (assuming a two-sided type I error of 5%).  
Assuming 2.5% of pregnancies will result in miscarriage or stillbirth, an additional 42 
women need to be enrolled, for a total of 1707 women (1138 active and 569 placebo).  A 
total sample size of 1707 subjects provides 98% power to detect a reduction of approximately 
30% in the rate of preterm birth <350 weeks of gestation (from 30% to 21%) using a two-
sided type I error of 5%. The effect size for the neonatal composite index as well as preterm 
birth <350 weeks gestation was chosen to represent a clinically significant reduction. 
Since these outcome measures are co-primary outcomes, the power to detect statistically 
significant differences between the treatment groups for both outcome measures may be 
reduced. If the outcome measures are independent, the power is 88.2% and if the outcome 
measures are correlated as highly as possible, the power is 90%.  Data from the NICHD 
Study indicate these outcome measures are highly correlated with 56% of liveborn infants of 
women who delivered <350 weeks of gestation with the neonatal composite index compared 
with 2% of liveborn infants of women who delivered ≥350 weeks of gestation.  Thus, the 
power to detect differences between the treatment groups for both outcome measures is 
expected to be close to 90%. 
 
There is also sufficient power to detect clinically significant reductions in the secondary 
outcomes of delivery <320 weeks of gestation and < 370 weeks of gestation as indicated in 
Table 1 Sample Size Calculation. 
 
Table 1: Sample Size Calculation 
Secondary Outcome 
Outcome Rate in 
Vehicle Group 
Percentage 
Reduction 
Power 
Delivery < 320 weeks of 
gestation 
20% 
33% 
92% 
Delivery < 370 weeks of 
gestation 
40% 
33% 
>99% 


Assuming a 4% fetal/early infant death rate in both treatment arms with a two-sided alpha of 
5%, a sample size of 1707 subjects provides 82.8% power to rule-out a doubling in the risk 
of fetal/early infant death (i.e., the upper bound of the confidence interval for the relative risk 
of 17P compared to vehicle will be <2.0). 
A fetal/early infant death rate of 4.0% is based on the results of Study 17P-CT-002 (the 
NICHD 17P trial).  
6.2 
Randomization and Blinding 
Subjects will be randomly assigned in a 2:1 ratio to 17P or vehicle treatment (two 17P 
subjects to each vehicle subject) using a blocked randomization sequence stratified by study 
site and randomization gestational age stratum (160 weeks - 176 weeks gestation and 180 
weeks – 206 weeks gestation).  Randomization is stratified by study site to ensure balance 
between the 2 treatment groups with respect to anticipated differences in the clinic 
population and possible site-to-site differences in subject management.  The rationale for 2:1 
randomization is that because the study involves weekly injections, subjects may be more 
willing to participate if they know that they have a 2 to 1 chance of receiving active 
medication.  Randomization will be performed through the use of an interactive voice 
response system (IVRS). 
This will be a double-blind study.  The subjects, clinical site staff, and sponsor will not be 
aware of the treatment assignment.  A Data and Safety Monitoring Board (DSMB) will 
review unblinded summary safety data. 
6.3 
Interim Analysis 
During the trial, an external and independent DSMB will meet periodically to review safety 
data.  Because the DSMB will not be reviewing efficacy data to determine whether the study 
should be stopped for efficacy, no adjustment to the alpha level is required.  The timing of 
the DSMB reviews and the scope of the safety review are detailed in the DSMB Charter.  
Unblinded data are reviewed by the DSMB. 
6.4 
Analysis Populations 
Five analysis populations are defined:  
All Enrolled Population: The All Enrolled Population will consist of all subjects who receive 
a trial injection.  
Intent-to-Treat (ITT) Population: The ITT Population will consist of all randomized subjects.  
All subjects will be analyzed in the treatment group to which they were randomized 
regardless of whether the subject received the correct blinded study medication (active or 
vehicle). 
Per-Protocol (PP) Population: The PP Population will consist of all subjects who are 
compliant with the study protocol.  Each subject will be classified as compliant or not 


compliant with the protocol based on the following compliance criteria: subject did not have 
a major protocol deviation potentially affecting efficacy or the evaluation of efficacy as 
determined by the Sponsor in a blinded review, received the correct blinded study medication 
for the majority of the duration of study drug receipt, at least 90% compliant with study 
medication (based on receipt of study medication through 366 weeks of gestation or delivery, 
whichever occurs first), and had outcome data available. 
Safety Population: The Safety Population will consist of all subjects who received at least 
one dose of blinded study medication.  Subjects who received the wrong blinded study 
medication will be analyzed in the treatment group based on the medication received.   
Liveborn Neonatal Population: The Liveborn Neonatal Population will consist of all babies 
of randomized women (ITT Population) who were liveborn and have morbidity data 
available. 
6.5 
Comments on Statistical Analysis 
• Inferential statistical analyses as specified will be conducted and all comparisons will be 
between the 17P and vehicle treatments.  
• An alpha level of 0.05 will be used for the primary and secondary efficacy analyses.  
Additional efficacy analyses are provided as supportive analyses to the primary and 
secondary efficacy analyses and no conclusion of statistical significance will be made. 
Thus, no adjustment to the alpha level is required for the additional efficacy analyses.  
Unless specified otherwise, all p-values will be presented to three significant digits. 
• Unless specified otherwise, data will be pooled across study sites for all statistical 
analyses. 
• Descriptive statistics, including the numbers and percentages for categorical variables, 
and the number of subjects, mean, standard deviation, median, minimum, and maximum 
for continuous variables will be provided.  
• Listings of individual subject's clinical data will be provided.  
• Study day will be calculated as the date of the AE/medication/assessment minus the date 
of the first dose of blinded study medication (active or vehicle), plus one.  
• Version 9.4 (or higher) of SAS statistical software package will be used to provide all 
summaries, listings, and statistical analyses. 
6.6 
Handling of Missing Data 
• All missing and partial dates for events occurring after randomization or for medications 
received after randomization will be queried for a value.  If no value can be obtained, 
substitutions will be made as follows: 


− For start dates, missing months and days will be defined by “01”, as long as this 
occurs on or after the first dose of blinded study medication.  If the algorithm 
produces a date prior to the first dose of blinded study medication, the date of the 
first dose of blinded study medication will be used for the partial date.  For stop 
dates, missing months will be defined as “12” and days will be defined by the last 
day of the respective month. If the date is associated with a maternal event and the 
algorithm produces a date after delivery, the date of delivery will be used for the 
partial date.  If the date is associated with a neonatal event and the algorithm 
produces a date after 28 days of life or discharge from the NICU, whichever is 
later, the date associated with 28 days of life or discharge from the NICU will be 
used for the partial date.  These substitutions will be used in calculations; 
however, the actual value recorded on the CRF will be used for all listings. 
• Missing data for the severity and causality assessment for adverse events and maternal 
complications will be queried for a value. If severity remains missing, the adverse 
event/maternal complication will be considered severe. If causality remains missing, the 
adverse event/maternal complication will be considered definitely related to study drug. 
• The primary efficacy analysis of delivery <350 weeks gestation will utilize the ITT 
Population. Missing primary outcome data will be imputed with multiple imputation 
methods as follows:   
If the data initially have a monotone missing data pattern, the missing data will be 
imputed using SAS® PROC MI with the MONOTONE REG option for continuous 
variables and the MONOTONE LOGISTIC option for categorical variables.  One 
hundred imputed datasets will be created. 
If the data do not initially have a monotone missing data pattern, a two-step imputation 
procedure will be performed. First, enough missing data will be imputed for the 
independent variables using the MCMC option of SAS® PROC MI to produce a 
monotone missing data pattern.  One hundred imputed datasets will be created in this first 
step.  Next, the missing data in the 100 resulting datasets will be imputed using SAS® 
PROC MI with the MONOTONE REG option for continuous variables and the 
MONOTONE LOGISTIC option for categorical variables.  A single imputation for each 
of the 100 datasets from the first step will be done in the second step resulting in a total 
of 100 datasets with complete data. 
The model for the MONOTONE REG/LOGISTIC option(s) will include terms for 
treatment, project gestational age at randomization, the interaction of treatment and 
project gestational age at randomization, the number of previous preterm deliveries, and 
gestational age at qualifying delivery included as predictive variables.  Project gestational 
age at randomization will be treated as a categorical variable with categories of week, i.e., 
160 - 166, 170 - 176, 180 - 186, 190 - 196, and 200 - 206.  Subjects with a project gestational 
age at randomization < 160 and subjects with a project gestational age at randomization > 
206 will be included in the 160 - 166 and 200 - 206 categories, respectively.  If a subject is 
known to still be pregnant on or after 350 weeks gestation, she will be considered not to 


have delivered prior to 35 weeks even if her delivery date is unknown. The logistic 
regression analysis used to assess whether there is an interaction between treatment and 
project gestational age at the time of randomization and the logistic regression analysis 
including prognostic factors for which there is an imbalance at baseline between the 
treatment groups will be based on these same imputed datasets.  
• The primary efficacy analysis of neonatal composite index will utilize the Liveborn 
Neonatal Population.  By definition, neonates in this population must have morbidity data 
available.  If any component of the neonatal composite index is missing and the non-
missing component data do not definitively indicate the presence or absence of the index, 
a multiple imputation analysis will be used to impute the missing composite index value 
as follows: 
If the data initially have a monotone missing data pattern, the missing data will be 
imputed using SAS® PROC MI with the MONOTONE REG option for continuous 
variables and the MONOTONE LOGISTIC option for categorical variables.  One 
hundred imputed datasets will be created. 
If the data do not initially have a monotone missing data pattern, a two-step imputation 
procedure will be performed. First, enough missing data will be imputed for the 
independent variables using the MCMC option of SAS® PROC MI to produce a 
monotone missing data pattern.  One hundred imputed datasets will be created in this first 
step.  Next, the missing data in the 100 resulting datasets will be imputed using SAS® 
PROC MI with the MONOTONE REG option for continuous variables and the 
MONOTONE LOGISTIC option for categorical variables.  A single imputation for each 
of the 100 datasets from the first step will be done in the second step resulting in a total 
of 100 datasets with complete data. 
The model for the MONOTONE REG/LOGISTIC option(s) will include terms for 
treatment, project gestational age at randomization, the interaction of treatment and 
project gestational age at randomization, the number of previous preterm deliveries, and 
gestational age at qualifying delivery included as predictive variables. Project gestational 
age at randomization will be treated as a categorical variable with categories of week, i.e., 
160 - 166, 170 - 176, 180 - 186, 190 - 196, and 200 - 206.  Subjects with a project gestational 
age at randomization < 160 and subjects with a project gestational age at randomization > 
206 will be included in the 160 - 166 and 200 - 206 categories, respectively. The logistic 
regression analysis used to assess whether there is an interaction between treatment and 
project gestational age at the time of randomization and the logistic regression analysis 
including prognostic factors for which there is an imbalance at baseline between the 
treatment groups will be based on these same imputed datasets. Sensitivity analyses will 
be conducted whereby neonates with missing data are assumed not to have the neonatal 
composite index and with these neonates excluded from the analysis.  
• For the secondary efficacy analyses of delivery prior to 370 weeks of gestation and 
delivery prior to 320 weeks of gestation, and additional analyses of spontaneous preterm 
birth prior to 370 weeks of gestation, spontaneous preterm birth prior to 350 weeks of 


gestation, and indicated preterm birth prior to 370 weeks of gestation, missing data will be 
imputed using the same methodology as for the primary efficacy outcome analysis. 
• The safety analysis of fetal/early infant death will be conducted in the ITT Population.  
Multiple imputation methods assuming a monotone missing data pattern will be used to 
impute the missing data for fetal/early infant death.  One hundred imputed datasets will 
be created using a logistic regression model with treatment, project gestational age at 
randomization, the interaction of treatment and project gestational age at randomization, 
and the number of previous preterm deliveries included as predictive variables.  Project 
gestational age at randomization will be treated as a categorical variable with categories 
of week, i.e., 160 - 166, 170 - 176, 180 - 186, 190 - 196, and 200 - 206.   Subjects with a 
project gestational age at randomization < 160 and subjects with a project gestational age 
at randomization > 206 will be included in the 160 - 166 and 200 - 206 categories, 
respectively. Sensitivity analyses will be conducted whereby subjects with missing data 
are assumed not to have a fetal/early infant death and with these subjects deleted from the 
analysis. The analyses will also be conducted in the Safety Population.   
• Missing values for other individual data points will remain as missing. For these data 
points, missing values will not be imputed and only observed values will be used in data 
analyses and presentations.  
• Where individual data points are missing, categorical data will be summarized based on 
reduced denominators (i.e., only subjects with available data will be included in the 
denominators). 
7 Statistical Analyses 
7.1 
Subject Population and Baseline Characteristics 
The total number of subjects who received the trial injection (enrolled subjects) and who 
were randomized will be summarized by geographic region, country, and site, by treatment 
group and overall.  A summary of the reasons for not randomizing subjects who received the 
trial injection will also be provided for all enrolled subjects.  The demographic characteristics 
(age, ethnicity, and race) of all enrolled subjects will be presented separately for subjects who 
were randomized and subjects who were not randomized.  The number of randomized 
subjects included in each of the analysis populations (All Enrolled, ITT, PP, Safety, and 
Liveborn Neonatal), and the primary reason for exclusion from the PP population will be 
summarized by treatment group.   
The total number of subjects in the ITT Population with a protocol deviation will be 
summarized by geographic region, site, and treatment group.  A distribution of the type of 
protocol deviation (e.g., inclusion criteria, exclusion criteria, study drug, etc.) will be 
summarized by treatment group.  Protocol deviations will also be provided in a listing. The 
number and percentage of randomized subjects who withdrew from the study and the 
primary reason for withdrawal will be presented by treatment group.  A subject is considered 
withdrawn from the study if the subject delivery data are not obtained.  The number and 


percentage of randomized subjects who discontinued study medication prior to 370 weeks of 
gestation or delivery (whichever came first) and the primary reason for discontinuation will 
be presented by treatment group.  Statistically significant differences between treatment 
groups in the percentages of subjects who withdrew from the study and who discontinued 
study medication prior to 370 weeks of gestation or delivery will be determined using 
Fisher’s exact test. 
Demographics (age, ethnicity, race, pre-pregnancy weight, and pre-pregnancy BMI) will be 
summarized by treatment group for the ITT Population, as will the subject's social history 
(marital status, years of education, and use of cigarettes, alcohol and street drugs during 
pregnancy).  Subject’s obstetrical characteristics, project gestational age at randomization (as 
a continuous variable and also categorized as <160 weeks, 160 – 176 weeks, 180 – 206 weeks 
and >206 weeks), randomization gestational age stratum (categorized as 160 – 176 weeks and 
180 – 206 weeks), and cervical length by ultrasound (for those patients with data available) 
and history of douching will be summarized by treatment group.  Project gestational age at 
randomization is calculated from the Project Estimated Date of Confinement (Project EDC) 
captured on the CRF and the date of randomization as follows:  
(280 – (Project EDC – Date of Randomization))/7. 
A table will provide data on previous pregnancy history including descriptive statistics of the 
number of previous preterm deliveries, number of previous spontaneous preterm deliveries, 
miscarriages, and stillbirths, as well as the percentage of patients with 1 and >1 previous 
preterm deliveries, none, 1 and >1 miscarriages, and none, 1 and >1 stillbirths.  The 
percentage of subjects with a prior spontaneous preterm delivery (following PTL or pPROM) 
and a prior indicated (for maternal or fetal indications) preterm delivery will be provided.  
The gestational age of the qualifying delivery and the percentage of subjects with a 
qualifying delivery at <37 weeks, <35 weeks, <32 weeks, and <28 weeks will be provided.  
Descriptive statistics of the gestational age at the earliest (i.e., earliest gestational age) prior 
spontaneous preterm delivery will also be provided. 
The chi-square test or Fisher’s exact test will be used for dichotomous variables and the 
Wilcoxon Rank Sum test for ordinal and continuous variables to test for differences between 
treatment groups. 
Obstetrical complications occurring prior to randomization and during the current pregnancy, 
relevant and significant obstetrical or gynecological surgical procedures occurring prior to 
randomization, and other relevant and significant medical history will be summarized in the 
ITT Population by MedDRA system organ class and higher level or preferred term, as 
appropriate. A summary of abnormal findings from the physical examination at Visit 2 will 
be provided by body site and treatment group. 


7.2 
Efficacy Analyses 
7.2.1 Primary Efficacy Analyses 
The primary hypothesis for efficacy compares the percentage of subjects with a preterm 
delivery < 350 weeks of gestation between the 17P and vehicle treatment groups in the ITT 
Population and the percentage of neonates with the neonatal composite index between the 
17P and vehicle treatment groups in the Liveborn Neonatal Population.  The null hypothesis 
(HO) is that 1) there is no difference between the 17P (∏17P) and vehicle (∏V) treatments in 
the percentage of subjects with a preterm delivery < 350 weeks of gestation in the ITT 
population; and 2) there is no difference between the 17P (P17P) and vehicle (PV) treatments 
in the percentage of neonates with the neonatal composite index in the Liveborn Neonatal 
Population, while the alternative hypothesis (HA) is that there is a difference between the 
treatments for at least one of the endpoints.  The null and alternative hypotheses are as 
follows: 
HO1: ∏17P = ∏V  
HA1: ∏17P ≠ ∏V , and 
HO2: P17P = PV 
HA2: P17P ≠ PV 
An alpha level of 0.05 will be used for the primary analysis of both primary outcomes, as an 
adjustment for multiple comparisons is not required for testing the null hypotheses when 
stated as above. 
Statistically significant differences between the 17P and vehicle treatments in the percentage 
of subjects who deliver prior to 350 weeks gestation will be determined using a Cochran-
Mantel-Haenszel (CMH) test stratified by project gestational age at randomization (160 
weeks - 176 weeks gestation and 180 weeks – 206 weeks gestation). Subjects with missing 
delivery data will have delivery <350 weeks and ≥ 350 weeks of gestation imputed with 
multiple imputation methods as described in Section 6.6. The combined CMH statistic from 
the imputed datasets will be determined using the Wilson-Hilferty transformation. 
For each treatment group, the number and percentage of subjects with a preterm delivery at 
< 350 weeks of gestation will be presented for each project gestational age at randomization 
stratum and overall.  Kaplan-Meier curves of the time from randomization to delivery will 
also be provided for each project gestational age at randomization stratum and overall for 
each treatment group. 
The number and percentage of neonates in the Liveborn Neonatal Population with the 
neonatal composite index will be presented by project gestational age at randomization 
stratum and overall for each treatment group.  Statistically significant differences between 
the 17P and vehicle treatments will be determined using the Cochran-Mantel-Haenszel test 
stratified by project gestational age at randomization. Subjects with missing neonatal 


composite index data will have their data imputed with multiple imputation methods as 
described in Section 6.6 and the combined CMH statistic from the imputed datasets will be 
determined using the Wilson-Hilferty transformation. 
7.2.1.1 Additional Analyses of Primary Efficacy Outcome Measures  
An analysis will be conducted in the ITT population where the neonatal composite index is 
defined with all deaths including miscarriages, abortions and stillbirths included as death in 
the composite index. The number and percentage of neonates with the neonatal composite 
index will be presented by project gestational age at randomization stratum and overall for 
each treatment group.  Additional sensitivity analyses will be conducted whereby neonates 
with missing data are assumed not to have an event in the neonatal composite index and 
neonates with missing data are excluded from the analysis. For each sensitivity analysis, 
statistically significant differences between the 17P and vehicle treatments will be 
determined using the Cochran-Mantel-Haenszel test stratified by project gestational age at 
randomization. 
A logistic regression model of preterm delivery < 350 weeks of gestation with terms for 
treatment, project gestational age at randomization stratum, and treatment-by-project 
gestational age at randomization stratum interaction will be used to assess whether there is an 
interaction between treatment and project gestational age at the time of randomization. A 
similar analysis will be performed for the neonatal composite index. For these analyses, 
subjects with missing delivery data or neonatal composite index data will have their data 
imputed with multiple imputation methods as described in Section 6.6. 
For each treatment group, the number and percentage of subjects with a delivery at <350 
weeks by gestational age at the qualifying delivery (200 –<28 weeks, 280 – <32 weeks, 320 – 
<35 weeks, and 350 – <37 weeks), by gestational age of the earliest prior preterm birth (200 –
<28 weeks, 280 – <32 weeks, 320 – <35 weeks, and 350 – <37 weeks), by number of previous 
preterm deliveries (1, 2 and ≥3 prior preterm deliveries), by country, and by region (US and 
non-US) will be presented.  For each treatment group, the number and percentage of neonates 
with the composite index by gestational age at the qualifying delivery, by gestational age at 
the earliest prior preterm birth, by the number of previous preterm deliveries, by country, and 
by geographic region will also be presented. The qualifying delivery is the previous singleton 
spontaneous preterm delivery that meets inclusion criterion number 4.  If more than one 
previous preterm delivery meets inclusion criterion number 4, the qualifying delivery is the 
most recent preterm delivery. 
If there are baseline imbalances between the treatment groups with respect to the prognostic 
factors (gestational age at qualifying delivery and number of previous preterm deliveries), an 
adjusted analysis of preterm delivery <350 weeks of gestation will be conducted using a 
logistic regression model. The logistic regression model will include terms for project 
gestational age at randomization, the prognostic factor(s), and treatment group.  The p-value 
for treatment from the logistic regression model will be provided.  Similarly, for the neonatal 
composite index, a logistic regression analysis will be conducted including terms for project 
gestational age at randomization, the prognostic factor(s), and treatment group.  The p-value 


for treatment from the logistic regression model will be provided. For these analyses, 
subjects with missing delivery data or neonatal composite index data will have their data 
imputed with multiple imputation methods as described in Section 6.6. 
The percentage of subjects with a preterm birth <350 weeks of gestation will also be analyzed 
for the PP Population using the same analytic method as described for the primary efficacy 
analysis in the ITT Population. The percentage of neonates with the neonatal composite 
index will also be analyzed for the PP Population using the same analytic method as 
described for the primary efficacy analysis in the Liveborn Neonatal Population. 
Exploratory subgroup analyses may also be conducted.  These analyses will be performed for 
black and nonblack subjects and also for subjects with a cervical length by ultrasound <25 
mm at baseline and those for whom the cervical length is ≥25 mm.  The same analytic 
method as described for the primary efficacy analysis will be utilized.  
7.2.2 Secondary Neonatal Efficacy Analyses 
The number and percentage of neonatal deaths (from minutes after birth until 28 days of life) 
for neonates in the Liveborn Neonatal Population born at 24 weeks gestational age or greater 
will be presented by project gestational age at randomization stratum (160 weeks - 176 weeks 
gestation and 180 weeks – 206 weeks gestation) and overall, for each treatment group.  
Statistically significant differences between the 17P and vehicle treatments will be 
determined using the Cochran-Mantel-Haenszel test stratified by project gestational age at 
randomization.  
7.2.3 Secondary Maternal Efficacy Analyses 
Analyses of the secondary maternal outcomes (delivery prior to 370 weeks and prior to 320 
weeks of gestation) will be conducted using the ITT and PP Populations.  The proportions of 
subjects with a preterm birth <370 weeks and <320 weeks of gestation will be presented for 
each project gestational age at randomization stratum (160 weeks - 176 weeks gestation and 
180 weeks – 206 weeks gestation)and overall, by treatment group. Statistically significant 
differences between treatments will be determined using the Cochran-Mantel-Haenszel test 
stratified by project gestational age at randomization.  Subjects with missing delivery data 
will have preterm birth <370 weeks and <320 weeks of gestation imputed with multiple 
imputation.   
The number and percentage of deliveries <370 weeks of gestation and <320 weeks of 
gestation will be presented by country.   
7.2.4 Additional Neonatal Efficacy Analyses 
A summary of neonatal morbidity data will be provided for the Liveborn Neonatal 
Population.  The number and percentage of neonates with IVH (any IVH and grade III/IV 
IVH), RDS, BPD, NEC, proven sepsis, confirmed pneumonia, seizures, ROP (any ROP and 
grade 3/4/5 ROP), PDA, transient tachypnea, cystic periventricular leukomalacia, other 


intercranial hemorrhage, persistent pulmonary hypertension and neonatal hypoglycemia will 
be provided by treatment group. Liveborn neonates not admitted to the NICU will be defined 
as not having any of the above listed morbidities.  Statistically significant differences 
between the 17P and vehicle treatments will be determined using the Cochran-Mantel-
Haenszel test stratified by project gestational age at randomization stratum. A distribution of 
the final status of the neonate (i.e., NICU outcome) will also be presented. The number and 
percentage of neonates on ventilator support or receiving supplemental oxygen will be 
provided for each treatment group, as will descriptive statistics of the number of days of 
respiratory therapy.  Continuous variables will be tested using the Van Elteren test stratified 
by project gestational age at randomization stratum. 
Descriptive statistics (mean, standard deviation, median, minimum and maximum) will be 
calculated by treatment group for birth weight, length, head circumference, APGAR scores 
(1, 5 and 10 minutes), the number of total infant hospital days (only for infants who did not 
die) and the number of NICU days.  The number of total infant hospital days is defined as the 
time (in days) from birth to discharge to home, a chronic care facility, or a non-medical 
facility.  For those infants who die, the number of NICU days will be set to the longest 
number of days.  Since the analysis is nonparametric, this codes the deaths as the worst 
possible outcome. Continuous variables (other than the number of NICU days) will be tested 
using the Van Elteren test stratified by project gestational age at randomization stratum.  The 
number of NICU days is defined as the time in days from admission to the NICU to 
discharge.  If a neonate is admitted more than once to the NICU, the number of NICU days 
for each NICU stay will be calculated separately; the neonate’s number of NICU days will 
then be calculated as the sum of NICU days from all NICU stays.  Neonates not admitted to 
the NICU will be assigned a value of 0 days, and neonates who died will be censored at the 
date of death.  A Kaplan-Meier analysis will be conducted, and statistically significant 
differences between treatments will be determined using a stratified (for project gestational 
age at randomization stratum) log-rank test.  The numbers and percentages of neonates 
admitted to the NICU and with a major congenital malformation will be provided.  
7.2.5 Additional Maternal Efficacy Analyses 
Analyses of the secondary maternal outcomes of spontaneous preterm birth prior to 370 
weeks of gestation, spontaneous preterm birth prior to 350 weeks of gestation, and indicated 
preterm birth prior to 370 weeks of gestation will be conducted in the ITT and PP 
Populations.  The proportion of subjects within each preterm birth category will be presented 
for each project gestational age at randomization stratum and overall.  Missing data will be 
imputed as detailed for the primary efficacy outcome.  Statistically significant differences 
between treatments will be determined using the Cochran-Mantel-Haenszel test stratified by 
project gestational age at randomization stratum. 
Descriptive statistics of gestational age at delivery will be provided by treatment group in the 
ITT and PP Populations, and the Van Elteren test stratified by project gestational age at 
randomization stratum will be used to test for statistically significant differences between 
treatments.   


7.3 
Safety Analyses 
7.3.1 Primary Safety Analysis 
Analysis of the safety outcome of fetal/early infant death will be conducted in the ITT  
Population.  For each project gestational age at randomization stratum and overall, the 
percentage of subjects with a fetal/early infant death will be provided. The relative risk of 
fetal/early infant death for the 17P treatment relative to the vehicle treatment will be 
determined using the Cochran-Mantel-Haenszel procedure stratified by project gestational 
age at randomization stratum.  A two-sided 95% confidence interval (CI) for the relative risk 
will be constructed using the Cochran-Mantel-Haenszel method adjusted for project 
gestational age at randomization stratum.  If the upper bound of the 95% CI is less than 2.0, a 
doubling in the risk of fetal/early infant death can be ruled out.   
7.3.1.1 Additional Analyses of Primary Safety Outcome Measure 
A logistic regression model including terms for treatment, project gestational age at 
randomization stratum, and treatment-by-project gestational age at randomization stratum 
interaction will be used to assess whether there is an interaction between treatment and 
project gestational age at randomization.  
The association of project gestational age at randomization as a continuous variable and 
fetal/early infant death will also be explored in a logistic regression model with terms for 
treatment, project gestational age at randomization (continuous), and treatment-by-project 
gestational age at randomization (continuous) interaction.  In addition, the effect of project 
gestational age at randomization as a continuous variable on fetal/early infant death will be 
modeled as an additive rather than multiplicative effect by fitting a generalized linear model 
with terms for treatment, project gestational age at randomization as a continuous variable, 
and the interaction of treatment and project gestational age at randomization as a continuous 
variable.  
Two sensitivity analyses will be completed.  In the first sensitivity analysis, subjects with 
missing data will be assumed not to have a fetal/early infant death.  The second sensitivity 
analysis will utilize only subjects with available data, i.e., subjects with missing data will not 
be considered.  For both analyses, the percentage of subjects with a fetal/early infant death 
will be provided for each project gestational age at randomization stratum and overall, by 
treatment group. The relative risk of fetal/early infant death for the 17P treatment relative to 
the vehicle treatment will be determined using the Cochran-Mantel-Haenszel procedure 
stratified by project gestational age at randomization.   
 
The analysis of fetal/early infant death as described above for the primary safety analysis will 
also be conducted in the Safety Population. 


7.3.2 Secondary Safety Analyses 
Secondary safety analyses will be conducted in the Safety Population unless otherwise 
indicated.  Subjects who received a complete course of the wrong study medication will be 
analyzed in the treatment group based on the medication received. 
7.3.2.1 Miscarriages and Stillbirths 
The numbers and percentages of subjects with a stillbirth and with a miscarriage will be 
presented by treatment group and by project gestational age at randomization. The Cochran-
Mantel-Haenszel test stratified by project gestational age at randomization stratum will be 
used to test for statistically significant differences between treatments.   
7.3.2.2 Adverse Events and Maternal Complications 
An AE is defined as an untoward medical event not present prior to exposure to study 
medication or any event already present that worsens in either intensity or frequency 
following exposure to study medication from trial injection at Baseline through the End of 
Treatment Period Visit, regardless of its causal relationship to study treatment.  A treatment-
emergent AE (TEAE) is defined as any event not present prior to exposure to study 
medication or any event already present that worsens in either intensity or frequency 
following exposure to study medication through the End of Treatment Period Visit. 
Adverse events will be coded using Version 21.1 of MedDRA. A summary table by 
treatment group will provide the number of AEs and the number and percentage of subjects 
with an AE from the trial injection to the date of randomization for the All Enrolled 
Population.  The table will also provide the number of TEAEs and the number and 
percentage of subjects with a TEAE from randomization through the follow-up visit, the 
number of maternal complications and the number and percentage of subjects with a 
maternal complication, the number and percentage of subjects with a TEAE/maternal 
complication that led to study drug discontinuation, and the number and percentage of 
subjects with a serious TEAE/maternal complication for the Safety Population. 
The number and percentage of subjects in each treatment group in the Safety Population 
reporting a TEAE from the date of randomization (inclusive) through the End of Treatment 
Period Visit will be tabulated by MedDRA system organ class and preferred term; by 
geographic region (US and non-US), system organ class and preferred term; by country, 
system organ class and preferred term; by system organ class, preferred term, and severity 
(mild, moderate, and severe); and by system organ class, preferred term, and relationship 
(unrelated or related) to study medication.  Unrelated TEAEs are defined as definitely not or 
probably not related to study medication.  Related TEAEs are defined as definitely, probably, 
or possibly related to study medication.  For all analyses of AEs, if the same AE (based on 
preferred term) is reported more than once for the same subject, the AE will be counted only 
once for that preferred term and at the highest severity and strongest relationship to study 
drug. All TEAEs leading to discontinuation of study medication will be summarized by 
system organ class and preferred term. All serious TEAEs will be summarized by system 


organ class and preferred term. Treatment emergent injection site reactions will also be 
presented by MedDRA higher level and preferred term. 
Maternal pregnancy complications will be coded using Version 14.1 of MedDRA.  The 
number and percentage of subjects in the Safety Population in each treatment group reporting 
a pregnancy complication will be tabulated by MedDRA system organ class and preferred 
term; by geographic region (US and non-US), system organ class and preferred term; by 
country, system organ class and preferred term; by system organ class, preferred term, and 
severity (mild, moderate, and severe); and by system organ class, preferred term, and 
relationship (unrelated or related) to study medication.  Unrelated pregnancy complications 
are defined as definitely not or probably not related to study medication.  Related pregnancy 
complications are defined as definitely, probably, or possibly related to study medication.  
All maternal pregnancy complications leading to discontinuation of study medication will be 
summarized by system organ class and preferred term. All serious maternal complications 
will be summarized by system organ class and preferred term. 
TEAEs and maternal pregnancy complications will be combined and the tables noted above 
for TEAEs will be provided.  In addition, a table will provide all TEAEs and maternal 
complications, summarized by preferred term, occurring in at least 2% of subjects (based on 
preferred term) in either treatment group.   
A listing of all TEAEs/maternal complications leading to discontinuation of study medication 
will be provided and will include subject ID, treatment group, date and Study Day of onset 
for the TEAE/maternal complication, system organ class, preferred term, verbatim term, 
severity, relationship to study medication, action taken, and seriousness.  A listing of all 
serious TEAEs/maternal complications will also be provided and will include subject ID, 
treatment group, date and Study Day of onset of the serious TEAE, system organ class, 
preferred term, verbatim term, severity, relationship to study medication, and action taken. 
7.4 
Other Analyses 
7.4.1 Study Drug Administration 
Dosing information will be summarized by the number of injections received and compliance 
with the expected dosing regimen.  Compliance is defined as the number of injections 
received divided by the number of expected injections multiplied by 100.  Injections are 
expected to occur at least every 7 (-2/+3) days from randomization until delivery or through 
366 weeks of gestation, whichever occurs first.  Full compliance is defined as at least 90% 
compliance.  An additional definition of compliance will be defined as the number of 
injections received divided by the number of expected injections based on a 7 day injection 
schedule.  The percentages of subjects with <80%, 80%-120%, and >120% compliance will 
be presented.  Statistically significant differences between treatments in the number of 
injections and in compliance will be determined using the Wilcoxon Rank Sum test and in 
the percentage of subjects who are fully compliant using the chi-square test. 


7.4.2 Prior and Concomitant Medications 
The World Health Organization (WHO) drug dictionary (Version March 2009) will be used 
to classify all medications.  Prior and concomitant medications, other than tocolytics, will be 
summarized by ATC Class 2 and preferred term, separately by treatment group for the ITT 
population.  Subjects receiving the same medication more than once will be counted only 
once for a particular medication class and medication. A prior medication is defined as any 
medication taken during the current pregnancy (i.e., from 40 weeks before the project EDC 
up to the date of randomization). A concomitant medication is defined as any medication, 
excluding tocolytic medications, taken on or after the date of randomization through the End 
of Treatment Period Visit.  Concomitant tocolytic medications will be summarized by ATC 
Class 2 and preferred term, separately by treatment group for the ITT population.  Subjects 
receiving the same medication more than once will be counted only once for a particular 
medication class and medication. 
7.4.3 Post-randomization Cervical Length by Gestational Age 
Descriptive statistics of post-randomization cervical length (mm) will be provided by 
gestational age at the time of the cervical ultrasound (≤ 206 weeks, 210 - 276 weeks, and ≥280 
weeks) and treatment group for all subjects in the ITT Population.  Cervical length will also 
be defined categorically (<25 mm vs. ≥25 mm), and the number and percentage of subjects in 
each category will be presented. Only cervical length measurements obtained from 
ultrasounds after the date of randomization will be included in these analyses.  The Wilcoxon 
Rank Sum test will be used to test for statistically significant differences between the 17P and 
vehicle treatments for continuous variables, and the chi-square test or Fisher’s exact test will 
be used for dichotomous variables. 
7.4.4 Gestational Diabetes 
The number and percentage of subjects in the ITT Population who were diagnosed with 
gestational diabetes will be summarized by treatment group, along with the primary basis of 
the diagnosis.  The number and percentage of subjects in the ITT Population who were 
screened, but not diagnosed, with gestational diabetes will also be summarized by treatment 
group. The chi-square test or Fisher’s exact test will be used to determine statistically 
significant differences between the treatments with respect to the proportion of subjects 
diagnosed with gestational diabetes and the proportion of subjects screened, but not 
diagnosed, with gestational diabetes. 
7.4.5 Maternal Delivery Data  
Maternal delivery data will be summarized by treatment group.  This includes maternal 
length of stay in the hospital, the percentage of subjects with at least one episode of preterm 
labor, type of labor (spontaneous, induced, spontaneous-augmented, no labor), indication for 
induced or augmented labor, delivery route (normal vaginal, assisted vaginal, cesarean 
section), and indication for cesarean section. 


7.4.6 Gestational Age at Delivery and Neonatal Outcome 
A logistic regression model of the neonatal composite index with covariate terms for 
treatment and gestational age at delivery as a continuous variable will be conducted. The 
odds ratio and 95% CI for the odds ratio for each covariate will be presented. 
 
 


8 Changes from Analyses as Described in the Protocol 
Six analysis populations are defined in the protocol.  The Modified ITT population is not 
used for analyses and PK analyses are not described in this SAP. Thus, both the Modified 
ITT and PK populations are not discussed in this SAP.   
 
Statistically significant differences between treatments for preterm delivery at <350 weeks, 
<320 weeks, and <370 weeks will be determined using a Cochran-Mantel-Haenszel test 
stratified by project gestational age at randomization (160 weeks - 176 weeks gestation and 
180 weeks – 206 weeks gestation).  Multiple imputation will be used to address missing data. 
The staggered entry Kaplan-Meier method will not be used because of issues with this 
approach. One issue is that subjects do not all have the same survival curve, as is assumed by 
this approach. Subjects entering the study at 16 weeks and those entering at 176 weeks, for 
example, do not have the same survival curve, because the former are treated from 16 to 18 
weeks and the latter are not. 
 
The protocol states that the percentages of subjects who deliver prior to 350 weeks gestation 
(primary outcome) and who deliver prior to 320 and prior to 370 weeks gestation (secondary 
outcomes) will be analyzed for the Safety Population, but these analyses will not be done.  
 
The protocol states that, if there are baseline imbalances between the treatment groups with 
respect to prognostic factors such as the number of previous preterm deliveries, an adjusted 
analysis of the primary outcome measures will be conducted using the Cochran-Mantel-
Haenszel procedure (for the neonatal composite index) and/or a Cox regression model (for 
preterm delivery <350 weeks gestation). Instead, logistic regression analyses will be 
performed for both endpoints. The protocol also states that an additional analysis of the 
primary efficacy outcomes will be performed to determine if there is a treatment-by-site 
interaction, but this will not be done. 
 
 
 


9 Appendix A – Schedule of Events  
Table 1 
Schedule of Events 
Procedures 
Baselinea  
Treatment Periodb 
Delivery and 
Hospitalization 
Neonate 
Follow-Upc 
End of 
Treatment 
Period 
Visitd 
Visit 1 
Visits 2 to 366 
Weeks of Gestation 
or Delivery 
Informed consente 
X 
 
 
 
 
Medical records releasef 
X 
 
 
 
 
Medical/obstetrical history 
X 
 
 
 
 
Demographic information/social 
history 
X 
 
 
 
 
Ultrasound (140 through 203) 
Xg 
 
 
 
 
Document previous preterm 
delivery 
X 
 
 
 
 
Brief physical examinationh 
Xh 
Xh 
 
 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
 
 
 
Prior medicationsi 
X 
X 
 
 
 
Concomitant medicationsj 
 
X 
X 
 
X 
Determine project gestational 
age and estimated date of 
confinement 
X 
 
 
 
 
Schedule randomization visit 
X 
 
 
 
 
Trial injection 
X 
 
 
 
 
Randomizationk 
 
X 
 
 
 
Collect blood sample for 
pharmacokinetic analysis 
 
Xl 
 
 
 
Study drug administration 
 
Xm 
 
 
 
Record adverse events (AEs)d 
Xn 
X 
X 
 
X 
Record presence or absence of 
POME symptoms 
X 
X 
 
 
 
Record pregnancy complications 
 
X 
X 
 
 
Record additional risk factors of 
miscarriage 
X 
 
X 
 
 
Maternal delivery information 
 
 
X 
 
 
Neonatal informationc 
 
 
X 
X 
 
a Visit will occur wherever possible within 7 days before randomization. 
b Subject will report to the clinical site weekly for study drug administration until 366 weeks of gestation or delivery, 
whichever occurs first. 
c Neonates born to randomized subjects will be followed through 28 days of life or discharge from the NICU whichever is 
later. Therefore, the status of all neonates (alive or dead), regardless of when they are delivered and discharged from the 
hospital will be obtained at least 28 days after delivery (this contact may occur at later than 28 days after delivery as long as 
the status of the infant on Day 28 after delivery is determined). If the neonate has been discharged from the birth 
hospitalization, the subject may be contacted by telephone to obtain the neonate’s status.  If the infant is still in the NICU or 
equivalent 28 days after delivery, then their status (alive or dead) will be determined upon discharge from the NICU or 
equivalent.  This status may be obtained after the infant is discharged as long as the status of the infant on the day of 
discharge is determined 


d All randomized subjects, regardless of when they deliver, should be contacted for an End of Treatment Period Visit to obtain 
AE information including medications to treat AE(s). The contact can be either in person or by telephone and should occur 
35 ± 7 days after the last dose of study drug. 
e To be completed before performing any baseline procedures.  Informed consent may be obtained at a gestational age of 10 
weeks or greater to facilitate obtaining records from the qualifying delivery.  At centers participating in the 17P-FU-004 
study, every effort will be made to obtain informed consent for the 17P-FU-004 study from all randomized subjects while 
they are pregnant.  If it is not possible to obtain consent during the pregnancy, consent may be obtained up to the point that 
their child reaches one year of age. 
f Must be signed by subject in order to obtain medical records of previous deliveries.   
g If a 140 to 203 weeks of gestation ultrasound to rule out fetal anomalies has not been performed as part of standard prenatal 
care; one must be performed prior to randomization. 
h Conduct a brief physical examination including a brief head-to-toe visual inspection at either Baseline (Visit 1) or Visit 2 
only. 
i Prior medications include all medications taken since the start of this pregnancy, defined as 40 weeks before the project EDC 
and before the study drug is randomly assigned.  Prior medications collection ends at Visit 2. 
j Concomitant medications must be recorded in the case report form through the End of Treatment Period Visit. 
k Between 160 and 206 weeks of gestation. 
l Three blood samples will be drawn from the PK population at the following times: (1) Before study drug dosing at either 
Visit 6 or 7 (i.e., dose 5 or 6). (2) Before dosing at either Visit 8 or 9 (i.e., Dose 7 or 8). (3) At a separate, non-dosing visit 1 
to 6 days after Visit 9, 10, or 11 (i.e., 1 to 6 days after Doses 8, 9, or 10). Subjects will be stratified 2:1 (17P: vehicle) such 
that an even distribution of samples will be drawn on day 1, day 2, day 3, day 4 or day 5/6 post-dose.  
m Subjects will receive one injection for each week they are pregnant from randomization through 366 weeks gestation or 
delivery, whichever occurs first.  As much as possible injections should be given on the same day each week.   However, if a 
schedule change is required, in general injections should be at least 5 days apart and no more than 10 days apart. 
n AEs are recorded from administration of the trial injection through the End of Treatment Period Visit including medications 
to treat the AE. Preterm birth is an anticipated outcome and is not considered an AE.  Maternal or fetal deaths will be 
recorded through delivery.  
 
 
 
 


10 References 
1  
American Diabetes Association. Gestational diabetes mellitus. Diabetes Care. 
2004;27(1): S88-90. 
2  
Gonzalea-Quintero VH. 17 Alpha-hydroxyprogesterone Caproate Perinatal Mortality 
and Pregnancy Outcomes. Obstet Gynecol. 2007;109 (4) Supplement: 1S-2S. 
3  
O’Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of 
recurrent preterm birth: primary results form a randomized, double-blind, placebo-controlled 
trial. Ultrasound Obstet Gynecol. 2007;30:687-696. 
4  
Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 
17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-2385. 
 
5   
Ratitich B, Lipkovich I, O'Kelly M. Combining analysis results from multiply 
imputed categorical data. Proceedings PharmaSUG 2019, Paper SP03.