A Phase 3B, Multi-Center, Randomized, Double-Blind Study of Hydroxyprogesterone Caproate (HPC) Injection, 250 mg/mL, Versus Vehicle for the Prevention of Preterm Birth in Women With a Previous Singleton Spontaneous Preterm Delivery
Phase: PHASE3
Conditions: Preterm Birth
Sponsor: AMAG Pharmaceuticals, Inc.

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The info1mation contained in this document, especially unpublished data,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. 
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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-
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