Clinical trial NCT02377466
Conditions: Obstetric Labour, Premature
Keywords: Spontaneous Preterm Labor GSK221149 Retosiban
Sponsor: GlaxoSmithKline
Start date: 2016-02-29; Completion date: 2017-07-24
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study's primary objective is to demonstrate the superiority of retosiban to prolong pregnancy and improve neonatal outcomes compared with placebo. It is a Phase III, randomized, double-blind, parallel-group, multicenter study and will be conducted in approximately 900 females, aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact membranes in preterm labor between 24\^0/7 and 33\^6/7 weeks of gestation. Eligible maternal subjects will be randomly assigned in a 1:1 ratio to receive either retosiban IV infusion or placebo IV infusion over 48 hours. If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of betamethasone administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the antecedent treatment was at least 7 days prior to study enrolment. Investigators have discretion to use a standardized regimen of magnesium sulphate, as well as intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection. Prior to randomization, each subject will be stratified by progesterone treatment and gestational age. The progesterone strata will consist of subjects on established progesterone therapy or subjects not on established progesterone therapy at Screening. The study will comprise 6 phases: Screening, Inpatient Randomized Treatment, Post Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal Medical Review. The duration of any subject's (maternal or neonatal) participation in the study will be variable and dependent on gestational ages (GA) at study entry and the date of delivery.

Detailed description:

Arms: arm 1: Retosiban treatment will be administered as a 6 mg IV loading dose over 5 minutes followed by a 6 milligram per hour (mg/hour) continuous infusion over 48 hours. For subjects with an inadequate response after the first hour of treatment, another 6 mg loading dose will be administered and infusion rate will be increased to 12 mg/hour for the remainder of the 48 hour treatment period. The retosiban dosing regimen will require adjustment in subjects treated concomitantly with drugs that are strong Cytochrome 3A4 inhibitors or inducers. arm 2: The placebo control will be a normal saline (0.9% sodium chloride \[NaCl\]) infusion matched for the loading dose and continuous infusion rates, including a dose increase in subjects with an inadequate response after the first hour of treatment.
Interventions: intervention 1: Retosiban IV infusion intervention 2: Placebo IV infusion
Intervention descriptions: intervention 1: Retosiban for IV administration will be supplied as solution for infusion, consisting of a clear colorless solution of retosiban at a concentration of 15 milligram per milliliter (mg/mL). intervention 2: 0.9% NaCl matched for the retosiban loading dose and continuous infusion rates

Protocol documents:
Prot_001.pdf: 
2014N194467_06 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
200719 
1 
 
 
 
 
GTITLE PAGE 
Division: Worldwide Development 
Information Type: Protocol Amendment 
 
Title: 
Randomized, Double-Blind, Multicenter, Phase III Study 
Comparing the Efficacy and Safety of Retosiban Versus Placebo 
for Women in Spontaneous Preterm Labor 
 
 
 
 
 
Compound Number: GSK221149 
 
Development Phase: 
III 
 
Effective Date: 
05-JAN-2017 
 
 
Protocol Amendment Number: 05 
 
Authors (GSK): 
 
 
Authors (PPD): 
PPD 
 
 
 
 
PPD 
 
Author (Parexel): PPD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved. 
Unauthorized copying or use of this information is prohibited. 


2014N194467_06 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
200719 
2 
 
 
 
Revision Chronology 
 
GlaxoSmithKline 
Document Number 
Date 
Version 
2014N194467_00 
2014-NOV-26 
Original 
2014N194467_01 
2015-FEB-17 
Republished 
The protocol was republished to make Section 6.4 (Blinding) consistent with the protocol 
template. 
2014N194467_02 
2015-AUG-13 
Amendment No. 1 
The following changes are reflected in Protocol Amendment No. 1: 
• 
Revise the time-to-delivery co-primary endpoint into a composite endpoint 
consisting of (1) time to delivery or (2) time to treatment failure, whichever occurs 
first 
• 
Revise the description of the study design to indicate that investigators have 
discretion to use a standardized regimen of magnesium sulfate 
• 
Revise the description of the study design to indicate that investigators have 
discretion to use intrapartum antibiotic prophylaxis for perinatal group B 
streptococcal infection 
• 
Revise to standardize the magnesium sulfate regimen in order to avoid wide 
variations in the magnesium sulfate dose given to subjects 
• 
Revise to standardize the betamethasone or dexamethasone regimen in order to 
control for wide variations in the antenatal corticosteroid doses 
• 
Add the secondary endpoints of (1) time to delivery, (2) time to treatment failure, 
and (3) proportion of women receiving any putative tocolytic 
• 
Revise the guidance regarding an adequate treatment response to be based on (1) a 
clinically relevant reduction of contraction frequency and/or intensity or (2) no 
change in the cervical examination 
• 
Provide the volume of maternal blood that will be collected for hematology, 
chemistry, and liver function tests; biomarker analyses; genetic analyses; and 
pharmacokinetic analyses 
• 
Add guidance for monitoring the total volume of oral and intravenous fluid 
administered during preterm labor 
• 
Remove the requirement to collect a placental tissue sample for pathologic 
examination 
• 
Remove the requirement to collect cord blood samples for biomarker and genetic 
testing 
• 
Add that US and Canadian investigational centers will collect a maternal blood 


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sample for cell-free fetal DNA in women who provide informed consent for genetic 
research 
• 
Clarify that any SAEs and AEs of special interest that are unresolved at 28 days post 
EDD should be followed to stabilization or resolution in those infants participating in 
the follow-up study. 
• 
Add the prohibition of calcium-channel blockers, nonsteroidal anti-inflammatory 
drugs, and -agonists either for tocolysis during investigational product 
administration or for maintenance tocolysis in subjects who remained undelivered 
following the Inpatient Treatment Phase 
• 
Revise the statistical methodology to control the Type I error for the planned interim 
analyses 
• 
Incorporate other administrative changes 
2014N194467_03 
2015-SEP-14 
Amendment No. 2 
The following changes are reflected in Protocol Amendment No. 2: 
• 
Revise the guidance for administration of antenatal corticosteroids to read as follows: 
If not previously administered, antenatal corticosteroid treatment should be 
administered as either (1) two 12-mg doses of betamethasone given intramuscularly 
24 hours apart or (2) four 6-mg doses of dexamethasone administered 
intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is 
permitted if the antecedent treatment was at least 7 days prior to study enrollment. 
• 
Clarify in the Time and Events Table (footnote 15) that hematology, chemistry, and 
liver function tests will only be determined through a central laboratory at the 
screening, Day 2, and the face-to-face post-infusion assessment visits. 
• 
Incorporate other administrative changes 
2014N194467_04 
2016-APR-19 
Country-Specific Protocol 
Amendment for Sites in 
Italy(Amendment No. 3) 
The following changes are reflected in the Country-Specific Protocol Amendment for 
Italy: 
• 
Amend inclusion criteria 1 and 2 to specify that subjects must be at least 18 years of 
age to participate in Study 200719. Text was revised throughout to reflect the change 
in the subject age criterion. 
• 
Revise text throughout to indicate that subjects recruited into Study 200719 in Italy 
must not be dosed with the investigational product until the results of their chemical 
parameters have been reviewed by the Investigator and no indicators of altered liver 
function (AST and ALT values and bilirubinemia) are apparent. This check for 
altered liver function must be carried out before the study drug is administered, i.e., 
before initiating randomized treatment. 


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2014N194467_06 
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200719 
 
 
 
2014N194467_05 
2016-JUN-20 
Amendment No.4 
The following changes are reflected in Protocol Amendment No. 4: 
• 
Add the proportion of women experiencing subsequent episodes of preterm labor as 
a supportive other secondary endpoint. 
• 
Clarify the assessments performed at the 1-week face-to-face post-infusion visit and 
at the weekly telephone calls during the Post-Infusion Assessment Phase. 
• 
Clarify the concomitant medications that are considered putative tocolytics and add 
exceptions for putative tocolytic drug use with regard to the definition of treatment 
failure. 
• 
Clarify the methods for documentation of gestational age at Screening. 
• 
Add that manual palpations may be used for determining contraction frequency in 
situations where technical difficulties may prohibit accurate measurement. 
• 
Clarify the criteria for confirming sufficient dilation and effacement at Screening. 
• 
Clarify that withdrawal from the study will mean that no additional visits can occur 
or procedures performed. 
• 
Define inadequate treatment response. 
• 
Add procedures that should be followed for managing dose interruptions. 
• 
Add that subject use of a pessary is allowed if use began before the current episode 
of preterm labor; otherwise, use of a pessary is prohibited. 
• 
Revise the previous requirements for continuous fetal heart rate monitoring to 
electronic fetal monitoring for a minimum of 6 hours from the start of the infusion or 
from the start of a dose increase, provided the heart rate pattern is consistently 
reassuring. 
• 
Clarify that confirmation of uterine contraction eligibility criterion must occur within 
60 minutes before study drug dosing. 
• 
Add respiratory rate to the vital sign measures assessed during the study, and clarify 
the frequency that vital sign and oxygen saturation measurements are assessed 
relative to dosing. 
• 
Clarify that if a subject does not deliver at the investigative center, central laboratory 
assessments for hematology, chemistry, and liver function tests should be performed 
at the investigative center within 1 week (acceptable range: 3 to 14 days) after 
completion of the study drug infusion. 
• 
Revise the visit window for the administration of the Edinburgh Postnatal 
Depression Scale from 2 weeks to 6 weeks. 
• 
Clarify that a maternal blood sample for PK analyses may need to be collected at the 
same time as the cord blood sample if the sample time does not already coincide with 
a PK sampling window. 
• 
Revise the assessment requirement for the first interim analysis from the time when 


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approximately 150 women/pairs complete all assessment to the time when 
approximately 150 subjects have time-to-delivery results available. 
• 
Clarify that the second interim analysis will occur when approximately 
400 women/newborn pairs are followed up to 28 days post EDD. 
• 
Add an appendix that provides guidelines for reporting maternal, fetal, and neonatal 
adverse events (AEs) of special interest. 
• 
Clarify that the intensity categories for AEs and serious AEs can be found in the 
Study Procedures Manual. 
• 
Incorporate the changes detailed in the country-specific amendment for sites in Italy 
(dated 19 Apr 2016). 
• 
Incorporate other administrative changes. 
2014N194467_06 
2017-JAN-05 
Amendment No. 5 
The following changes are reflected in Protocol Amendment No. 5: 
• 
Remove screening urine drug and alcohol tests. 
• 
Remove requirement that investigator confirm uterine contraction rate and cervical 
dilation after randomization and just before study drug administration. 
• 
Add that after randomization and prior to study drug administration investigators will 
re-assess that tocolytic therapy is still indicated, according to their medical 
discretion. 
• 
Clarify that an abdominal ultrasound to assess fetal growth is needed at Screening 
unless the most recent ultrasound is within 3 weeks (21 days) before the date of 
randomization. 
• 
Update the list of maternal disease-related events to clarify the reporting process for 
events of subsequent preterm labor and hospitalization for delivery that are not worse 
than expected. 
• 
Add that the amniotic fluid index should be measured using the 4-quadrant method. 
• 
Incorporate other administrative changes. 


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SPONSOR SIGNATORY 
 
 
 
 
 
 
 
 
Kathleen J Beach, MD, MPH 
Medicine Development Leader, 
Maternal and Neonatal Health Unit 
Alternative Discovery and Development 
Date 


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Medical Monitor/SAE Contact Information: 
 
Role 
Name 
Day Time 
Phone 
Number 
After-Hours 
Phone/Cell/ 
Pager 
Number 
Fax Number 
Site Address 
Primary 
Medical 
Monitor 
PPD 
PPD 
PPD 
PPD 
PPD 
Pharmacovigilance 
MD 
PPD 
PPD 
PPD 
Secondary 
Medical 
Monitor 
PPD 
PPD 
PPD 
PPD 
PPD 
Pharmacovigilance 
MD 
PPD 
PPD 
PPD 
SAE Fax 
Number 
PPD 
PPD 
 
 
Sponsor Legal Registered Address: 
 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application. 
Regulatory Agency Identifying Number(s): 
IND Number: 73287 
EudraCT Number: 2014-003326-41 


8 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol 200719 (NEWBORN-1) 
 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
 
 
 
 
Investigator Name: 
Investigator Address: 
Investigator Phone Number: 
Investigator Signature 
Date 


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TABLE OF CONTENTS 
 
PAGE 
1. 
PROTOCOL SYNOPSIS FOR STUDY 200719 .............................................................. 13 
2. 
INTRODUCTION ................................................................................................................. 17 
2.1. 
Study Rationale ...................................................................................................... 17 
2.2. 
Brief Background .................................................................................................... 18 
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................... 20 
4. 
STUDY DESIGN ................................................................................................................. 24 
4.1. 
Overall Design ........................................................................................................ 24 
4.2. 
Treatment Arms and Duration .............................................................................. 25 
4.3. 
Type and Number of Subjects .............................................................................. 28 
4.4. 
Design Justification ................................................................................................ 29 
4.5. 
Dose Justification ................................................................................................... 29 
4.5.1. 
Retosiban ............................................................................................... 29 
4.5.2. 
Matched Placebo ................................................................................... 30 
4.6. 
Benefit:Risk Assessment ...................................................................................... 31 
4.6.1. 
Risk Assessment ................................................................................... 32 
4.6.2. 
Benefit Assessment .............................................................................. 38 
4.6.3. 
Overall Benefit:Risk Conclusion .......................................................... 38 
5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .................. 39 
5.1. 
Inclusion Criteria ..................................................................................................... 39 
5.2. 
Exclusion Criteria ................................................................................................... 40 
5.3. 
Withdrawal From Study, Discontinuation of IP, and Stopping Criteria .............. 42 
5.3.1. 
Withdrawal From Study ........................................................................ 42 
5.3.1.1. 
Withdrawal From Study Participation After 
Randomization but Prior to Investigational 
Product Administration ...................................................... 42 
5.3.1.2. 
Withdrawal From Study Participation After 
Beginning Randomized Treatment .................................. 43 
5.3.2. 
Discontinuation of Investigational Product ......................................... 44 
5.3.3. 
Liver Chemistry Stopping Criteria........................................................ 44 
5.3.3.1. 
Study Treatment Restart or Rechallenge ........................ 46 
5.3.4. 
QTc Stopping Criteria ........................................................................... 46 
5.4. 
Subject and Study Completion ............................................................................. 47 
6. 
STUDY TREATMENT ........................................................................................................ 47 
6.1. 
Investigational Product and Other Study Treatment .......................................... 47 
6.2. 
Treatment Assignment .......................................................................................... 49 
6.3. 
Subject-Specific Dose Adjustment Criteria ......................................................... 49 
6.3.1. 
Inadequate Response........................................................................... 49 
6.3.2. 
Concurrent Administration of Investigational Product With 
Strong CYP3A4 Inhibitors or Strong CYP3A4 Inducers .................... 50 
6.4. 
Managing Dose Interruptions................................................................................ 50 
6.5. 
Blinding .................................................................................................................... 50 
6.6. 
Packaging and Labeling ........................................................................................ 51 
6.7. 
Preparation/Handling/Storage/Accountability ..................................................... 52 


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6.8. 
Compliance With Study Treatment Administration ............................................ 52 
6.9. 
Treatment of Study Treatment Overdose ............................................................ 52 
6.10. Treatment After the End of the Study .................................................................. 53 
6.11. Prior Medications and Nondrug Therapies ......................................................... 53 
6.12. Concomitant Medications and Nondrug Therapies ............................................ 53 
6.12.1. 
Permitted Medications and Nondrug Therapies ................................ 53 
6.12.1.1. Antenatal Corticosteroids .................................................. 53 
6.12.1.2. Magnesium Sulfate ............................................................ 53 
6.12.1.3. Progesterone ...................................................................... 54 
6.12.1.4. Antibiotics ............................................................................ 54 
6.12.1.5. Strong CYP3A4 Inhibitors ................................................. 54 
6.12.1.6. Strong CYP3A4 Inducers .................................................. 54 
6.12.1.7. Breast Cancer Resistance Protein or 
P-Glycoprotein Inhibitors .................................................. 54 
6.12.2. 
Prohibited Medications and Nondrug Therapies ............................... 54 
6.12.2.1. Tocolytic Drugs .................................................................. 55 
7. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................. 57 
7.1. 
Time and Events Table .......................................................................................... 58 
7.2. 
Screening and Critical Assessments Prior to Investigational Product 
Administration ......................................................................................................... 64 
7.3. 
Efficacy .................................................................................................................... 64 
7.3.1. 
Time to Delivery or Treatment Failure ................................................ 64 
7.3.1.1. 
Time to Delivery ................................................................. 64 
7.3.1.2. 
Time to Treatment Failure................................................. 65 
7.3.2. 
Neonatal Composite and Other Outcomes ........................................... 65 
7.4. 
Safety ....................................................................................................................... 66 
7.4.1. 
AEs and SAEs ....................................................................................... 66 
7.4.1.1. 
Time Period and Frequency for Collecting AE 
and SAE Information ......................................................... 67 
7.4.1.2. 
Method of Detecting AEs and SAEs ................................ 67 
7.4.1.3. 
Follow-up of AEs and SAEs .............................................. 68 
7.4.1.4. 
AEs of Special Interest ...................................................... 68 
7.4.1.5. 
Cardiovascular and Death Events ................................... 68 
7.4.1.6. 
Congenital Anomalies ....................................................... 68 
7.4.1.7. 
Disease-Related Events and/or Disease- 
Related Outcomes Not Qualifying as SAEs .................... 69 
7.4.1.7.1. 
Disease-Related Maternal Events ............. 69 
7.4.1.7.2. 
Disease-Related Neonatal Events 
(Occurring in Infants Born Prior to 
37 Completed Weeks) ................................ 70 
7.4.1.8. 
Regulatory Reporting Requirements for SAEs ............... 71 
7.4.2. 
Physical Examinations .......................................................................... 71 
7.4.3. 
Vital Signs and Oxygen Saturation ..................................................... 72 
7.4.4. 
Electronic Fetal Monitoring ................................................................... 72 
7.4.5. 
Abdominal Ultrasound .......................................................................... 74 
7.4.6. 
Clinical Safety Laboratory Assessments ............................................ 74 
7.4.7. 
Electrocardiogram ................................................................................. 75 
7.4.8. 
Fluid Management ................................................................................ 75 
7.4.9. 
Breastfeeding Status............................................................................. 75 
7.4.10. 
Maternal Depression ............................................................................. 75 
7.5. 
Health Outcomes .................................................................................................... 75 


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7.5.1. 
Health Outcomes – Maternal ............................................................... 76 
7.5.1.1. 
Maternal Health Care Resource Use ............................... 76 
7.5.2. 
Health Outcomes – Neonatal ............................................................... 76 
7.5.2.1. 
Neonatal Hospital Admission ........................................... 76 
7.5.2.2. 
Neonatal Health Care Resource Use .............................. 76 
7.6. 
Pharmacokinetics ................................................................................................... 77 
7.6.1. 
Sampling ................................................................................................. 77 
7.6.2. 
Umbilical Cord Blood ............................................................................ 77 
7.6.3. 
Retosiban Levels in Breast Milk .......................................................... 77 
7.7. 
Cervical Length ....................................................................................................... 78 
7.8. 
Fetal Fibronectin ..................................................................................................... 78 
7.9. 
Biomarkers .............................................................................................................. 78 
7.10. Genetics .................................................................................................................. 78 
8. 
DATA MANAGEMENT ....................................................................................................... 79 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ....................................... 79 
9.1. 
Hypotheses ............................................................................................................. 79 
9.2. 
Sample Size Considerations ................................................................................. 80 
9.2.1. 
Sample Size Assumptions ................................................................... 80 
9.2.2. 
Sample Size Sensitivity ........................................................................ 80 
9.2.3. 
Sample Size Re-Estimation or Adjustment ........................................ 81 
9.3. 
Data Analysis Considerations ............................................................................... 81 
9.3.1. 
Analysis Populations (Maternal) .......................................................... 81 
9.3.1.1. 
Maternal Safety Population .............................................. 81 
9.3.1.2. 
Maternal ITT Population .................................................... 81 
9.3.1.3. 
Maternal Per-Protocol Population .................................... 82 
9.3.2. 
Analysis Population (Neonatal) ........................................................... 82 
9.3.2.1. 
Neonatal Safety Population .............................................. 82 
9.3.2.2. 
Neonatal ITT Population ................................................... 82 
9.3.2.3. 
Neonatal Per-Protocol Population ................................... 82 
9.3.3. 
Treatment Comparisons ....................................................................... 82 
9.3.3.1. 
Primary Comparisons of Interest ..................................... 82 
9.3.3.2. 
Other Comparisons of Interest ......................................... 83 
9.3.3.3. 
Subgroup Analysis ............................................................. 83 
9.3.3.4. 
Exploratory Covariate Analyses ....................................... 83 
9.3.4. 
Interim Analyses .................................................................................... 83 
9.4. 
Key Elements of Analysis Plan ............................................................................. 84 
9.4.1. 
Efficacy Analyses .................................................................................. 84 
9.4.1.1. 
Primary Analyses ............................................................... 84 
9.4.1.2. 
Secondary Analyses .......................................................... 85 
9.4.1.2.1. 
Key Secondary Analyses ............................ 85 
9.4.1.2.2. 
Other Secondary and Exploratory    
Analysis ........................................................ 85 
9.4.2. 
Safety Analyses ..................................................................................... 86 
9.4.2.1. 
Extent of Exposure (Maternal) .......................................... 86 
9.4.2.2. 
Adverse Events .................................................................. 86 
9.4.3. 
Health Outcomes Analyses .................................................................. 87 
9.4.4. 
Pharmacokinetic Analyses ................................................................... 87 
9.4.5. 
Genetic Analyses .................................................................................. 87 
10. STUDY GOVERNANCE CONSIDERATIONS ................................................................ 88 


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10.1. Posting of Information on Publicly Available Clinical Trial Registers ................ 88 
10.2. Regulatory and Ethical Considerations, Including the Informed 
Consent Process .................................................................................................... 88 
10.3. Quality Control (Study Monitoring) ....................................................................... 89 
10.4. Quality Assurance .................................................................................................. 89 
10.5. Study and Site Closure .......................................................................................... 89 
10.6. Records Retention ................................................................................................. 90 
10.7. Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ...................... 90 
10.8. Independent Data Monitoring Committee ........................................................... 91 
11. REFERENCES .................................................................................................................... 92 
12. APPENDICES ...................................................................................................................... 95 
12.1. Appendix 1: Abbreviations and Trademarks ...................................................... 95 
12.2. Appendix 2: Liver Safety Required Actions and Follow-up 
Assessments........................................................................................................... 97 
12.3. Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Following Up, and Reporting of Adverse Events .......................... 101 
12.3.1. 
Definition of Adverse Events .............................................................. 101 
12.3.2. 
Definition of Serious Adverse Events ................................................ 102 
12.3.3. 
Definition of Cardiovascular Events .................................................. 104 
12.3.4. 
Recording of AEs and SAEs .............................................................. 104 
12.3.5. 
Evaluating AEs and SAEs .................................................................. 105 
12.3.6. 
Reporting of SAEs to GSK/PPD ........................................................ 106 
12.4. Appendix 4: Adverse Events of Special Interest .............................................. 107 
12.5. Appendix 5: Safety Reporting Cheat Sheet ..................................................... 109 
12.6. Appendix 6: Genetic Research .......................................................................... 110 
12.7. Appendix 7: Cytochrome P450 3A4 Enzyme Inhibitors and                 
Inducers ................................................................................................................. 113 
12.8. Appendix 8: Country-Specific Requirements ................................................... 116 
12.9. Appendix 9: Protocol Changes .......................................................................... 117 


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1. 
PROTOCOL SYNOPSIS FOR STUDY 200719 
Rationale 
 
Retosiban (GSK221149), a nonpeptide small molecule that behaves as a selective, 
competitive antagonist for oxytocin receptors, has been shown to prolong pregnancy and 
reduce prematurity rates in women between 300/7 and 356/7 weeks’ gestation. Given 
intravenously over 48 hours, retosiban increased days to delivery by a mean of 8.2 days 
relative to placebo and the incidence of birth prior to 37 weeks’ gestation was 18.7% in 
retosiban group compared with 47.2% in the placebo group. No placebo-controlled 
tocolytic studies have demonstrated an effect of this magnitude in spontaneous preterm 
labor. External experts have generally agreed that prolonging the time to delivery by 
1 week in the absence of harm may benefit the newborn, particularly in women who 
experience spontaneous preterm labor at early gestational ages (GAs). 
 
This study (NEWBORN-1) aims to show that retosiban provides additional neonatal 
benefit through its effect to arrest labor and prolong pregnancy sufficiently to allow for 
fetal maturation without significant increased risk to the fetus or neonate. Clinical 
validation of the relationship between prolongation of pregnancy and neonatal benefit 
would establish retosiban as the first drug to add benefit to that of the well-established 
benefits of antenatal corticosteroids for this indication. 
 
Objectives/Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the superiority of retosiban 
to prolong pregnancy and improve 
neonatal outcomes compared with placebo 
• Time to delivery or treatment failure, 
whichever occurs first 
• Proportion of neonates with any 
diagnosis from the neonatal morbidity 
and mortality composite determined up to 
28 days after the estimated date of 
delivery (EDD) of 400/7 weeks 
Secondary 
• 
To describe the maternal, fetal, and 
neonatal safety profile during and after 
intravenous (IV) retosiban treatment 
compared with placebo 
Maternal: 
• 
Incidence of reported adverse events 
(AEs) and serious AEs (SAEs) 
• 
Significant changes in vital signs and 
clinical laboratory tests 
• 
Incidence of clinical and laboratory 
toxicities causing subject to discontinue 
study treatment 
• 
Incidence of women scoring 12 or higher 
on the Edinburgh Postnatal Depression 
Scale 
• 
Maternal AEs of special interest 


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Objectives 
Endpoints 
Fetal: 
• 
Incidence of reported AEs and SAEs 
• 
Fetal acidosis 
• 
Fetal AEs of special interest 
Neonatal: 
• 
Neonatal Apgar scores 
• 
Growth parameters 
• 
Incidence of reported AEs and SAEs 
• 
Neonatal AEs of special interest 
• 
To determine the effect of retosiban 
treatment compared with placebo on health 
care resource use for the maternal and 
neonatal hospitalizations 
• 
Assess maternal and neonatal health care 
resource use associated with preterm labor 
and preterm delivery 
• 
To obtain further data on the 
pharmacokinetics of retosiban in 
pregnant women, including the effect of 
covariates such as age, weight, 
race/ethnicity, and GA on retosiban 
clearance and volume of distribution 
• 
Retosiban clearance and volume of 
distribution and the effect of covariates on 
these parameters 
 
 
Overall Design 
 
• 
NEWBORN-1 is a Phase III, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study 
• 
Eligible subjects will be randomly assigned in a 1:1 ratio to receive either retosiban 
IV infusion over 48 hours or matched placebo IV infusion over 48 hours 
• 
If not previously administered, antenatal corticosteroid treatment should be 
administered as either (1) two 12-mg doses of betamethasone given intramuscularly 
24 hours apart or (2) four 6-mg doses of dexamethasone administered 
intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is 
permitted if the antecedent treatment was at least 7 days prior to study enrollment. 
Investigators have discretion to use a standardized regimen of magnesium sulfate, as 
well as intrapartum antibiotic prophylaxis for perinatal group B streptococcal 
infection. 
• 
Prior to randomization, each subject will be stratified by progesterone treatment at 
Screening (subjects on established progesterone therapy vs subjects not on 
established progesterone therapy) and GA (240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7, 
or 310/7 to 336/7) 


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Treatment Arms and Duration 
 
• 
NEWBORN-1 will comprise 6 phases:  Screening, Inpatient Randomized Treatment, 
Post-Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and 
Neonatal Medical Review. The duration of any subject’s (maternal or neonatal) 
participation in the study will be variable and dependent on GA at study entry and 
the date of delivery 
• 
Retosiban treatment will be administered as a 6-mg IV loading dose over 5 minutes 
followed by a 6-mg/hour continuous infusion for the remainder of the 48-hour 
treatment period. 
• 
The placebo control will be a normal saline (0.9% sodium chloride) infusion 
matched for the retosiban volume, IV loading dose over 5 minutes, and continuous 
infusion rate for the remainder of the 48-hour treatment period 
• 
An adequate response is based on (1) a clinically relevant reduction of contraction 
frequency and/or intensity or (2) no change in the cervical examination. 
• 
Subjects with an inadequate response any time after the first hour of treatment will 
be administered another 6-mg retosiban or matched placebo loading dose and the 
retosiban or matched placebo infusion rate will be increased to 12 mg/hour for the 
remainder of the 48 hour treatment period. 
• 
At each of the 2 planned interim analysis, all available safety and efficacy data will 
be reviewed by the unblinded independent data monitoring committee who may 
make recommendations to terminate the study based on prespecified criteria or at 
any time for an unfavorable benefit:risk profile 
Type and Number of Subjects 
 
The study population is women aged 12 to 45 years with an uncomplicated singleton 
pregnancy in preterm labor with intact membranes between 240/7 and 336/7 weeks’ 
gestation. Approximately 900 women (450 per treatment group) will be randomly 
assigned to ensure that approximately 800 women/newborns have recorded birth data 
(assumes approximately 10% missing data). 
 
Italian Subjects: In Italy, the age restriction for study enrollment is 18 to 45 years. 
 
Analysis 
 
The primary comparison of interest is retosiban versus placebo for the co-primary 
endpoints:  time to delivery or treatment failure, whichever occurs first, and neonatal 
composite outcome. The statistical analysis will test the null hypothesis in the 
Intent-to-Treat Population that there is no difference between retosiban and placebo 
versus the alternative hypothesis that there is a difference between the 2 co-primary 
endpoints. 


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Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 subjects have completed delivery and have time-to-delivery results 
available. The second interim analysis will occur after approximately 
400 women/newborn pairs are followed up to 28 days post EDD. 


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2. 
INTRODUCTION 
Retosiban (GSK221149) is nonpeptide small molecule that behaves as a selective, 
competitive antagonist for oxytocin receptors. Retosiban is being developed as a solution 
for intravenous (IV) infusion for the treatment of spontaneous preterm labor in women 
with an uncomplicated pregnancy and intact membranes. 
 
2.1. 
Study Rationale 
 
The inverse relationship between neonatal mortality and morbidity and gestational age 
(GA) at birth has been the basis for treatments to prolong pregnancy with the goal of 
improving neonatal outcomes by allowing continued maturation of fetal organ systems. 
Inhibition of uterine contractions as a means to reduce prematurity rates has been 
extensively investigated. However, there is no evidence that current tocolytic regimens 
improve neonatal or infant outcomes beyond the effect of antenatal corticosteroids 
[Sanchez-Ramos, 1999; Royal College of Obstetricians and Gynecologists; RCOG 
Green-top Guideline No. 1B, 2011a; American College of Obstetricians and 
Gynecologists; ACOG Practice Bulletin No. 127, 2012; Roos, 2013]. As a result, 
tocolytic therapy is only recommended for short-term delay of delivery in order to 
administer antenatal corticosteroids and in utero transfer to a neonatal specialized care 
unit. 
 
In contrast, results from the OTA10256 Phase II placebo-controlled study found that 
retosiban prolonged pregnancy and reduced prematurity rates in women between 300/7 
and 356/7 weeks’ gestation. Retosiban, given intravenously over 48 hours, increased days 
to delivery by a mean of 8.2 days relative to placebo; this difference was consistent 
across GAs (Figure 1). The incidence of birth prior to 37 weeks’ gestation in the 
retosiban group was 18.7% compared with 47.2% in the placebo group (see the 
investigator’s brochure [IB] Section 5.3.2.2.2 [GlaxoSmithKline Document Number 
CM2006/00201/05]). No placebo-controlled tocolytic studies have demonstrated an 
effect of this magnitude in spontaneous preterm labor. External experts have generally 
agreed that prolonging the time to delivery by 1 week in the absence of harm may benefit 
the newborn, particularly in women who experience spontaneous preterm labor at early 
GAs. 


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Figure 1 
Retosiban Effect on Time to Delivery 
 
 
The emerging safety profile for retosiban also appears favorable. All reported adverse 
events (AEs) (maternal, fetal, and neonatal) were generally similar to placebo or 
consistent with expected events in the population under study. A summary of the 
complete results for Study OTA105256 is included in the IB (Section 5.3.2.1 
[GlaxoSmithKline Document Number CM2006/00201/05]). 
 
This study (NEWBORN-1) aims to show that retosiban provides additional neonatal 
benefit through its effect to arrest labor and prolong pregnancy sufficiently to allow for 
fetal maturation without significant increased risk to the fetus or neonate. Clinical 
validation of the relationship between prolongation of pregnancy and neonatal benefit 
would establish retosiban as the first drug to add benefit to that of the well-established 
benefits of antenatal corticosteroids for this indication. 
 
2.2. 
Brief Background 
 
Spontaneous preterm labor is responsible for more than half of preterm births, with the 
remainder resulting from preterm premature rupture of membranes (PPROM) and clinical 
indications for delivery in at-risk mothers and fetuses [Goldenberg, 1998; Meis, 1998; 
Pennell, 2007]. The pathogenesis of spontaneous preterm labor is not well understood. 
Clinical and experimental studies provide evidence that 4 separate pathways can result in 
premature labor and delivery:  inflammation, maternal-fetal endocrine activation, 
abnormal uterine distension, and decidual hemorrhage [Romero, 1994; Lockwood, 2001]. 


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The use of tocolytics to prevent preterm birth has been based on the assumption that 
clinically apparent contractions signal the initiation of parturition [Simhan, 2007]. 
Stopping contractions would therefore halt labor progression, prolong the pregnancy, and 
reduce neonatal morbidity and mortality. However, when examining the benefits of 
tocolysis, systematic reviews have consistently concluded that current tocolytic treatment 
does not provide direct benefit in terms of neonatal mortality, neonatal morbidity, or 
perinatal outcome beyond that of antenatal corticosteroids [Gyetvai, 1999; 
Sanchez-Ramos, 1999; RCOG Green-top Guideline No. 1B, 2011a; ACOG Practice 
Bulletin No. 127, 2012]. 
 
Despite the lack of direct neonatal benefit, controlled studies have generally shown that 
tocolysis reduces the likelihood of delivery within 48 hours or 7 days following initiation 
of treatment. Based on these findings, practice guidelines advise physicians to consider 
tocolysis in those women for whom a delay in delivery would benefit the newborn via 
administration of antenatal corticosteroids or in utero transfer to a specialized care unit 
[RCOG Green-top Guideline No. 7, 2010; ACOG Practice Bulletin No. 127, 2012]. 
 
Oxytocin is a potent uterotonic whose role in the initiation and progression of human 
labor, both term and preterm, has been actively investigated for many years. Although 
preterm labor may well be a syndrome with various etiologies, oxytocin action on the 
uterus likely represents a common step in activation of the myometrium. Paracrine rather 
than endocrine mechanisms may mediate this process, in which the effects of oxytocin 
are governed by tissue-specific oxytocin receptor expression, which leads to direct 
contractile effects in myometrium and prostaglandin formation in the decidua. 
Prostaglandins in turn mediate myometrial contractions and cervical ripening [Fuchs, 
1982; Benedetto, 1990]. 
 
Retosiban (GSK221149) is a nonpeptide small molecule that behaves as a selective, 
competitive antagonist for oxytocin receptors and is under development for the treatment 
of spontaneous preterm labor in women with intact membranes. NEWBORN-1 is 
designed to show that retosiban provides neonatal benefit beyond that of antenatal 
corticosteroids through its effect to arrest labor and prolong pregnancy sufficiently to 
allow for fetal maturation without increased risk to the fetus or neonate. 


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3. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the superiority of 
retosiban to prolong pregnancy and 
improve neonatal outcomes compared 
with placebo 
• Time to delivery or treatment failure, 
whichever occurs first. Time to delivery will be 
calculated from the start of study treatment 
administration until delivery. Time to treatment 
failure will be calculated from the start of 
study treatment administration to the 
administration of any putative tocolytic 
medication 
• Proportion of neonates with any diagnosis 
from the neonatal morbidity and mortality 
composite determined up to 28 days after the 
estimated date of delivery (EDD) of 400/7 
weeks: 
• 
Fetal or neonatal death 
• 
Respiratory distress syndrome (RDS) 
o Requiring continuous positive 
airway pressure or mechanical 
ventilation. Diagnosis requires a 
chest radiograph consistent with 
RDS (reticulogranular appearance 
to the lung fields or air 
bronchograms) within the first 24 
hours of life, OR 
o Received surfactant for a clinical 
picture of RDS within the first 
24 hours of life 
• 
Bronchopulmonary dysplasia at 
≥36 weeks postmenstrual age 
(determined by adding chronological 
age to GA at delivery), defined as 
follows: 
o >21% supplemental oxygen 
requirement, OR 
o Use of high-flow nasal cannula at 
≥1 L (21% oxygen) 
• 
Necrotizing enterocolitis or 
isolated perforation 
o Diagnosed by radiographic 
evidence of Stage II or higher 
according to Bell’s staging criteria 
(fixed/unchanging bowel loops, 
pneumatosis intestinalis, portal 
venous gas, pneumoperitoneum), 


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Objectives 
Endpoints 
OR 
o Pneumatosis intestinalis, bowel 
necrosis, or perforation noted at 
surgery 
• 
Sepsis based on positive blood culture 
with clinical features of sepsis 
• 
Meningitis based on positive results for 
cerebrospinal fluid culture performed as 
part of infection workup 
• 
Retinopathy of prematurity 
o Confirmed by an ophthalmologist 
based on international committee 
Stage 4 or 5, OR 
o Requiring surgical treatment with 
laser or other surgical intervention 
including cryotherapy or treatment 
with antivascular endothelial growth 
factor 
• 
Intraventricular hemorrhage (IVH) 
o Grade 3 or 4 (severe IVH), OR 
o Any grade of IVH with 
posthemorrhagic hydrocephalus 
requiring a shunt 
• 
White matter injury, documented on 
cranial ultrasound or magnetic 
resonance imaging, as indicated by the 
following: 
o Multiple cystic lucencies in 
periventricular white matter (may be 
bilateral or unilateral, may vary in 
size, and be diffuse or focal in 
distribution), OR 
o Porencephalic 
cyst 
(not 
including 
subependymal 
or 
choroid plexus cysts), OR 
o Persistent ventriculomegaly, 
moderate to severe 
• 
Cerebellar hemorrhage (unilateral or 
bilateral) 
Supportive Key Secondary 
• Time to delivery 
• Proportion of births prior to 370/7 weeks’ 
gestation 
• Proportion of births at term (370/7 to 416/7 
weeks’ gestation) 
• Length of neonatal hospital stay 


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Objectives 
Endpoints 
Supportive Other Secondary 
• Proportion of births prior to 320/7 weeks’ 
gestation 
• Proportion of births prior to 280/7 weeks’ 
gestation 
• Proportion of births ≤7 days 
• Proportion of births ≤48 hours 
• Proportion of births ≤24 hours 
• Proportion of neonates with any of the 
co-primary composite neonatal morbidity and 
mortality, excluding RDS 
• Proportion of neonates with each individual 
component of the composite neonatal 
morbidity and mortality endpoints 
• Neonatal admission to a specialized care 
unit and length of stay 
• Newborn hospital readmission and length of 
stay 
• Ambulatory surgery 
• Time to treatment failure 
• Proportion of women receiving any putative 
tocolytic 
• Proportion of women experiencing 
subsequent episodes of preterm labor 
Secondary 
• 
To describe the maternal, fetal, and 
neonatal safety profile during and after 
IV retosiban treatment compared with 
placebo 
Maternal: 
• 
Incidence of reported AEs and serious AEs 
(SAEs) 
• 
Significant changes in vital signs and clinical 
laboratory tests 
• 
Incidence of clinical and laboratory toxicities 
causing subject to discontinue study 
treatment 
• 
Incidence of women scoring 12 or higher on 
the Edinburgh Postnatal Depression Scale 
(EPDS) 
• 
Maternal AEs of special interest 
• 
Maternal death 
• 
Chorioamnionitis and its complications 
o Clinical chorioamnionitis, preterm 
premature rupture of membranes, 
endomyometritis, wound infection, 
pelvic abscess, bacteremia, septic 
shock, disseminated intravascular 
coagulation, and adult RDS 


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Objectives 
Endpoints 
• 
Placental abruption 
• 
Postpartum hemorrhage – postpartum 
hemorrhage and/or retained placenta 
• 
Pulmonary edema 
Fetal: 
• 
Incidence of reported AEs and SAEs 
• 
Fetal acidosis 
• 
Fetal AEs of special interest 
• 
Intrauterine fetal demise 
• 
Category II or III fetal heart rate tracing 
(defined according to ACOG Practice 
Bulletin 106 [ACOG Practice Bulletin 
No. 106, 2009]) 
• 
Fetal inflammatory response syndrome 
characterized by cord blood interleukin- 
6 >11 pg/mL, funisitis, or chorionic 
vasculitis 
Neonatal: 
NOTE:  Information collected from the time of birth 
through 28 days post EDD. 
• 
Neonatal Apgar scores (at 1 and 5 minutes 
after birth), 
• 
Growth parameters (weight, length, and head 
circumference) at birth and at discharge 
• 
Incidence of reported AEs and SAEs 
• 
Neonatal AEs of special interest will 
include the following: 
• 
Neonatal death 
• 
Asphyxia 
• 
Infections (early onset neonatal sepsis, 
septic shock, pneumonia, meningitis) 
• 
RDS 
• 
Hypotension 
• 
IVH/periventricular leukomalacia 
• 
Bronchopulmonary dysplasia 
• 
Neonatal acidosis 
• 
Hyperbilirubinemia 
• 
Necrotizing enterocolitis 
• 
Hypoxic ischemic encephalopathy 


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Objectives 
Endpoints 
• 
To determine the effect of retosiban 
treatment compared with placebo on 
health care resource use for the 
maternal and neonatal hospitalizations 
• 
Assess maternal and neonatal health care 
resource use associated with preterm labor 
and preterm delivery. Health care resource 
use of interest include: 
• 
Maternal hospital admission (e.g., 
length of stay by hospital unit and type) 
and resource use (e.g., use of transport 
services and admission to extended 
stay facility) 
• 
Neonatal interventions of interest (e.g., 
parenteral nutrition, surfactants, blood 
products), procedures (e.g., imaging, 
such as ultrasound and computed 
tomography), and surgical procedures 
• 
Neonatal hospital admission (e.g., 
length of stay by hospital unit and type) 
and resource use (e.g., use associated 
with neonatal comorbidities of interest). 
• 
To obtain further data on the 
pharmacokinetics of retosiban in 
pregnant women, including the effect of 
covariates such as age, weight, 
race/ethnicity, and GA on retosiban 
clearance and volume of distribution 
• 
Retosiban clearance and volume of 
distribution and the effect of covariates on 
these parameters 
 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
 
NEWBORN-1 is a Phase III, randomized, double-blind, placebo-controlled, parallel-
group, multicenter study. This study will be conducted in approximately 
900 females, aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact 
membranes in preterm labor between 240/7 and 336/7 weeks of gestation. Eligible subjects 
(for the purposes of this protocol, subject refers to the mother and not the infant unless 
otherwise stated) will be randomly assigned in a 1:1 ratio to receive either retosiban IV 
infusion over 48 hours or matched placebo IV infusion over 48 hours (approximately 
450 subjects in each group). 
 
If not previously administered, antenatal corticosteroid treatment should be administered 
as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or 
(2) four 6-mg doses of dexamethasone administered intramuscularly every 12 hours. A 
single rescue course of antenatal corticosteroids is permitted if the antecedent treatment 
was at least 7 days prior to study enrollment. Investigators have discretion to use a 
standardized regimen of magnesium sulfate, as well as intrapartum antibiotic prophylaxis 
for perinatal group B streptococcal infection (for additional details see Section 6.12). 


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Prior to randomization, each subject will be stratified by progesterone treatment and GA. 
The progesterone strata will consist of subjects on established progesterone therapy or 
subjects not on established progesterone therapy at Screening (see Section 6.12.1.3 for 
details). The GA strata are 240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7, or 310/7 to 336/7. 
All subjects exposed to randomized treatment will be asked to remain in the study 
through delivery and maternal post-delivery assessments and review of the newborn 
records. Withdrawal from the study should only occur if a subject either refuses to 
continue participation or is lost to follow-up (see Section 5.3.1). 
 
4.2. 
Treatment Arms and Duration 
 
NEWBORN-1 will comprise 6 phases:  Screening, Inpatient Randomized Treatment, 
Post-Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal 
Medical Review (Figure 2). The duration of any subject’s (maternal or neonatal) 
participation in the study will be variable and dependent on GA at study entry and the 
date of delivery. 


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Figure 2 
Study Design 
 
 
1 
Stratification (1:1) to retosiban or matched placebo based on established progesterone therapy at Screening 
(subjects on established progesterone therapy versus subjects not on established progesterone therapy) and 
gestational age (240/7 to 256/7; 260/7 to 276/7; 280/7 to 306/7; 310/7 to 336/7). 
2 
If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg 
doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of dexamethasone 
administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the 
antecedent treatment was at least 7 days prior to study enrollment. Investigators have discretion to use a 
standardized regimen of magnesium sulfate, as well as intrapartum antibiotic prophylaxis for perinatal group B 
streptococcal infection. 
3 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion visit for obstetric 
assessments 1 week (acceptable range: 3 to 14 days) after the Inpatient Randomized Treatment Phase. The 
subject will then be contacted every week via telephone to determine and record if she has delivered or if she has 
experienced any subsequent episodes of preterm labor. Retreatment with the investigational product (retosiban or 
placebo) is not allowed. 
 
 
 
Each investigational site will have an obstetrician with expertise in high-risk obstetrics as 
the principal investigator who will be responsible for treatment, care, and review of data 
for the mother during the study and a neonatologist as a subinvestigator who will review 
the newborn hospital records to track and record the neonatal information. 
 
Potential subjects who are thought to meet the eligibility criteria for the study will be 
informed of the requirements of the study and will give their written informed consent to 
participate in the study. 


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The Screening Phase will occur on Day 0, and assessments will primarily focus on 
maternal and fetal safety evaluations prior to dosing. The screening assessments must 
include a formal review of medical and obstetric history and a review of all eligibility 
requirements for the study. 
 
Subjects will be randomly assigned to treatment on Day 1 of the Inpatient Randomized 
Treatment Phase. The treatment phase will be 48 hours. Retosiban treatment will be 
administered as a 6-mg IV loading dose over 5 minutes followed by a 6-mg/hour 
continuous infusion for the remainder of the 48-hour treatment period. The placebo 
control will be a normal saline (0.9% sodium chloride [NaCl]) infusion matched for the 
retosiban volume, IV loading dose over 5 minutes, and continuous infusion rate for the 
remainder of the 48-hour treatment period. The duration of the treatment should not 
exceed 48 hours. 
 
An adequate response is based on (1) a clinically relevant reduction of contraction 
frequency and/or intensity or (2) no change in the cervical examination. Subjects with an 
inadequate response any time after the first hour of treatment will be administered 
another 6-mg retosiban or matched placebo loading dose and the retosiban or matched 
placebo infusion rate will be increased to 12 mg/hour for the remainder of the 48-hour 
treatment period. A subject’s response should be assessed for at least 1 hour following a 
dose increase before a decision is made to discontinue randomized treatment due to lack 
of response. Investigators will be required to indicate in the electronic case report form 
(eCRF) the reason or reasons for a dose increase. 
 
Treatment can be discontinued due to labor progression with imminent delivery, 
intolerance to treatment, and any contraindication to continuation of randomized 
treatment. Subjects who discontinue randomized treatment will be asked to remain in the 
study through the maternal post-delivery assessment and review of the newborn records. 
Withdrawal from the study should only occur if a subject either refuses to continue or is 
lost to follow-up. 
 
Subjects who remain undelivered after 48 hours will be scheduled for a face-to-face post-
infusion visit for obstetric assessments as part of the Post-Infusion Assessment 
Phase. The visit will be scheduled 1 week (acceptable range: 3 to 14 days) following the 
Inpatient Randomized Treatment Phase. The subject will then be contacted every week 
via telephone to determine and record if she has delivered or if she has experienced any 
subsequent episodes of preterm labor. Retreatment with the investigational product (IP; 
retosiban or placebo) is not allowed. 
 
Once delivery is confirmed during the Delivery Phase of the study, the maternal delivery 
and hospitalization record will be reviewed for data collection by the investigator 
obstetrician. If delivery occurs at a different hospital, the investigator obstetrician will 
need to obtain the maternal delivery and hospitalization record for review. For those 
subjects who deliver at the investigative center within 12 hours of IP (retosiban or 
placebo) completion or discontinuation, a cord blood sample will be collected for 
pharmacokinetic (PK) analysis, and, if required, a corresponding maternal blood sample 
will be collected for PK analysis (see Section 7.6.1). Likewise, a breast milk/colostrum 


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sample will be collected for PK analysis in women who deliver at the investigative center 
and produce breast milk within 12 hours after IP completion or discontinuation. 
 
During the Maternal Post-Delivery Assessment Phase, the subject will be contacted by 
telephone within 6 weeks of delivery for a post-delivery assessment, including an 
assessment of AEs (±2 weeks), status of breastfeeding (±2 weeks), and completion of the 
EPDS (-2 weeks/+6 weeks). 
 
During the Neonatal Medical Review Phase, the neonatologist subinvestigator will 
conduct a comprehensive review of the newborn’s medical records from delivery through 
28 days EDD (400/7 weeks’ gestation) for all subjects. 
During the course of the study, the subject or other legal guardian for the infant will also 
be asked to consent to participate in a long-term study to follow infants for safety and 
neurodevelopment outcomes. The consenting process for the infant follow-up study can 
occur at any time during the study that is appropriate and convenient for the subject or 
legal guardian, such as during the Inpatient Randomized Treatment Phase or at the 
post-infusion assessment visit. 
 
Detailed summaries of the assessments for each study phase are provided in the Study 
Procedures Manual (SPM). 
 
Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 subjects have completed delivery and have time-to-delivery results 
available. The second interim analysis will occur after approximately 
400 women/newborn pairs are followed up to 28 days post EDD. At each interim 
analysis, all available safety and efficacy data will be reviewed by the unblinded 
independent data monitoring committee (IDMC) who may make recommendations to 
terminate the study based on prespecified criteria. Additionally, the IDMC may make 
recommendations to terminate the study at any time for an unfavorable benefit:risk 
profile. Subjects will continue to be enrolled while the interim analyses are being 
conducted. 
 
Retosiban will not be available for compassionate use and will only be available as 
randomized treatment in this study. 
 
4.3. 
Type and Number of Subjects 
 
The study population is women aged 12 to 45 years with an uncomplicated singleton 
pregnancy in preterm labor with intact membranes between 240/7 and 336/7 weeks’ 
gestation. Approximately 900 women (450 per treatment group) will be randomly 
assigned to ensure that approximately 800 women/newborns have recorded birth data 
(assumes ~10% missing data). 
 
Italian Subjects: In Italy, the age restriction for study enrollment is 18 to 45 years. 


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4.4. 
Design Justification 
 
As discussed in Section 2, there is no convincing evidence that current tocolytic regimens 
sufficiently prolong pregnancy to provide neonatal benefit beyond that of antenatal 
corticosteroids alone. In contrast, results from a Phase II placebo-controlled study suggest 
that retosiban’s effect to prolong pregnancy may be sufficient to improve neonatal 
outcomes. In women with spontaneous preterm labor between 300/7 to 356/7 weeks’ 
gestation, retosiban administered intravenously over 48 hours increased time to delivery 
by a mean of 8.2 days above and beyond that of placebo; this difference was consistent 
across GAs. Further, there is general agreement that prolonging the average time to 
delivery by 1 week in the absence of significant risk is likely to benefit the newborn, 
particularly in women who present in spontaneous preterm labor at early GAs. Together, 
these findings form the basis of the clinical hypothesis, which states that retosiban 
provides neonatal benefit beyond that of antenatal corticosteroids by prolonging 
pregnancy sufficiently to allow for continuing fetal maturation without causing 
significant risk to the fetus or neonate. To test this hypothesis, the study uses a 
randomized design that compares retosiban with placebo. 
 
Placebo-controlled studies provide scientific rigor through their effect to distinguish an 
effective treatment from an ineffective treatment by controlling for all potential 
influences on the actual or apparent course of the disease or condition other than those 
arising from the pharmacologic action of the test drug. Such influences include the 
natural history of the disease or condition, subject or investigator expectations, use of 
other therapy, and subjective elements of diagnosis or assessment. 
 
The study population represents a particularly vulnerable group for poor infant outcomes, 
for whom effective treatment options are limited. As a result, the protocol allows for the 
use of antenatal corticosteroids, either betamethasone or dexamethasone, magnesium 
sulfate in a standardized regimen, and intrapartum antibiotic prophylaxis for perinatal 
group B streptococcal infection. 
 
To fulfill regulatory requirements to study pediatric subjects, pregnant adolescents aged 
12 to 17 years are allowed to participate in this study, with the exception of sites in Italy, 
where pregnant adolescents are not eligible to enroll in the study (see Section 5.1). 
Adolescent pregnancy is complicated by a higher likelihood of preterm labor and 
subsequent delivery, but there is no evidence that the pathophysiology of spontaneous 
labor and delivery differs between pregnant adolescents and adults or that the clinical 
course differs. Pregnant adolescents are more likely to deliver a low birth weight or 
preterm infant than older females (<40 years), and their babies have a higher risk of dying 
during infancy [Mathews, 2010; Martin, 2012]. Since local laws, customs, and 
institutional practice vary globally, investigator discretion in the enrollment of pediatric 
subjects is permitted. 
 
4.5. 
Dose Justification 
 
4.5.1. 
Retosiban 
 
Retosiban will be administered as a 6-mg IV loading dose over 5 minutes followed by a 6-
mg/hour continuous infusion for 48 hours. An adequate response is based on (1) a 


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clinically relevant reduction of contraction frequency and/or intensity or (2) no change in 
the cervical examination. For subjects with an inadequate response any time after the first 
hour of treatment, investigators should administer another 6-mg loading dose and 
increase the infusion rate to 12 mg/hour for the remainder of the 48-hour treatment period 
(see Section 6.1 and Section 6.3 for IP administration and dose adjustments, 
respectively). 
 
The proposed retosiban dosing regimen has been informed primarily by results from the 
Phase II study (OTA105256) where a wide range of doses was evaluated in women with 
preterm labor. In Parts A and B of this Phase II study, the retosiban regimen was 
designed to yield a target concentration range based on preclinical models of preterm 
labor. Based on interim analysis of Parts A and B, the target mean steady-state 
concentration was refined in Part C to 75 ng/mL. The option to double the dose after 
1 hour allows for between-subject variability in retosiban pharmacokinetics, receptor 
density, and half-maximal inhibitory concentration (IC50) values. Findings from Study 
OTA105256 Part C indicate this dosing strategy was successful, as 60% of subjects 
responded to the 6-mg/hour infusion, whereas 40% of subjects required an increase in the 
infusion rate to 12 mg/hour. These findings also support the initial 6-mg/hour infusion 
rate as the lowest effective dose for the majority of subjects, while recognizing that the 
higher 12-mg/hour infusion rate may be required in subjects failing to respond to the 
initial infusion rate. 
 
Although a “highest–tolerated dose” strategy was not employed in selecting the retosiban 
dosing regimen, the retosiban infusion was well tolerated by pregnant women during the 
Phase II study, OTA105256. Moreover, there was no evidence for maternal, fetal, or 
neonatal toxicity. Pharmacokinetic simulations indicate that the Phase III dosing regimen 
will likely yield steady-state concentrations in the range of 50 to 388 ng/mL at 2 hours 
after starting retosiban treatment and decreasing to 8.9 to 128 ng/mL at 48 hours. These 
exposures are significantly less than those studied in the Phase I program, where 
retosiban doses were well tolerated [GlaxoSmithKline Document Number 
CM2006/00201/05]. 
 
Retosiban is primarily metabolized by the cytochrome P450 3A4 enzyme (CYP3A4). 
Drug-drug interaction studies indicate retosiban exposure is increased approximately 
9-fold during co-administration of the strong CYP3A4 inhibitor ketoconazole, whereas 
concomitant administration of the strong CYP3A4 inducer efavirenz decreased retosiban 
exposure by 30%. As a result, the retosiban dosing regimen requires adjustment in 
subjects treated concomitantly with drugs that are strong CYP3A4 inhibitors or CYP3A4 
inducers in order to achieve therapeutic retosiban concentrations. Refer to Section 6.3.2 
for a description of the adjustments to the retosiban loading dose and infusion rate during 
co-administration with strong CYP3A4 inhibitors or CYP3A4 inducers. 
 
4.5.2. 
Matched Placebo 
 
Normal saline 0.9% NaCl administered intravenously will serve as the placebo control. 
The normal saline infusion will be matched for the retosiban volume, IV loading dose 
over 5 minutes, and continuous infusion rate, including a dose increase in subjects with 


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an inadequate response any time after the first hour of treatment (see Section 6.1 and 
Section 6.3 for IP administration and dose adjustments, respectively). 
 
As discussed in Section 4.4, use of a placebo control serves to distinguish an effective 
treatment from an ineffective treatment by controlling for all potential influences on the 
actual or apparent course of preterm labor other than those arising from the 
pharmacologic effect of retosiban. 
 
4.6. 
Benefit:Risk Assessment 
 
Summaries of findings from both clinical and nonclinical studies conducted with 
GSK221149 can be found in the IB. Table 1 and Table 2 outline the risk assessment and 
mitigation strategy for this protocol: 


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4.6.1. 
Risk Assessment 
 
Table 1 
Potential Risks of Clinical Significance 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Fetal exposure through placental transfer 
Retosiban is a substrate of P-gp and BCRP transporters, 
which are thought to play a role in keeping xenobiotics out of 
the CNS and out of the fetal blood. 
The preclinical data indicate very minimal, if any, maternal 
CNS penetration or placental transfer of retosiban as 
supported by: 
• 
In pregnant monkeys, there was no detectable 
retosiban in the cord blood when mothers were dosed 
up to 100 mg/kg (~7-fold human exposure). However, 
approximately 4% of circulating drug was detected in 
the cord blood when mothers were dosed at 300 mg/kg 
(~24-fold human exposure). 
• 
In reproductive toxicology studies in monkeys, where 
retosiban was given to pregnant monkeys, there were 
no adverse mother or infant behavioral, locomotor 
effects observed that were suggestive of CNS toxicity. 
• 
In rodent neurobehavioral safety studies, there were no 
adverse clinical signs observed at doses up to 
1000 mg/kg. 
Adverse events and serious AEs reported in retosiban clinical 
trials to date have not indicated that retosiban has access to 
the maternal or fetal CNS; however, this has not been 
rigorously investigated. 
The short half-life of retosiban (~2 hours) is expected to 
minimize any significant risk. 
Maternal blood and cord blood samples will be analyzed 
for levels of retosiban in women who deliver at an 
investigative center within 12 hours of the completion or 
discontinuation of the study infusion. 
Infants exposed to retosiban in utero will be followed for a 
minimum of 5 years in a separate follow-up study to 
assess overall safety and neurodevelopmental outcomes. 
Unblinded safety data will be monitored by an IDMC. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Neonatal exposure via breast milk 
There were no effects on offspring growth and development 
in monkey reproductive toxicology studies, where systemic 
exposure to retosiban reached 14-fold the maximum clinical 
exposures. These findings suggest that exposure to 
retosiban during pregnancy had no adverse effect on breast 
milk or feeding. 
While there are no clinical data on the degree of retosiban 
transfer into breast milk, the available data based on 
physiochemical properties suggest retosiban will be excreted 
into breast milk if dosed close to or during the time of milk 
production. Given the rapid clearance of retosiban, the risk 
for neonatal drug exposure via breast milk appears low but 
could occur in the situation where the infant is fed breast 
milk/colostrum produced within 12 hours of the end of the 
infusion. Since lactogenesis is typically delayed 30 to 48 
hours postpartum in mothers going to term (and is further 
delayed in mothers who deliver preterm), it seems unlikely 
that any drug would be in the plasma postpartum to transfer 
into the milk. 
Breast milk/colostrum samples will be collected for 
measurement of retosiban when delivery occurs and 
lactation has started within 12 hours of receiving study 
treatment infusion. 
• 
When breast milk/colostrum is produced prior to 
4 hours of the completion or discontinuation of the 
study treatment, a sample will be collected for 
evaluation, and consumption by the baby is not 
permitted. 
• 
When breast milk/colostrum is produced between 
4 and 12 hours of the completion or discontinuation 
of the study treatment, a sample will be collected for 
evaluation, and the remainder of the breast milk can 
be consumed if the potential benefits to the infant are 
believed to outweigh the potential risks. The subject 
should be advised on the potential risks associated 
with feeding the infant her breast milk/colostrum that 
was expressed within 12 hours of the completion or 
discontinuation of the study treatment. 
• 
When breast milk is produced more than 12 hours 
after the completion or discontinuation of study 
treatment, no samples will be collected for evaluation 
and there will be no restrictions on consumption, 
given that this time frame is beyond 5 half-lives of 
retosiban. 
Safety monitoring for signals indicating adverse effects in 
infants following exposure to retosiban via breastfeeding 
will be performed throughout the study. 
Unblinded safety data will be monitored by an IDMC, 
including infants exposed to retosiban via breastfeeding. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Uterine atony and postpartum hemorrhage due to 
oxytocin receptor antagonism 
Retosiban is a competitive oxytocin antagonist whose effects 
can be reversed by oxytocin agonists. Retosiban has a short 
elimination half-life (approximately 2 hours) and is rapidly 
removed from the body. 
Given the rapid clearance of retosiban, the risk for uterine 
atony appears low and would most likely occur in the 
situation where delivery occurs within 24 hours of treatment. 
The available clinical data for other oxytocin antagonists 
suggest the adverse effects of atony and postpartum 
hemorrhage are limited [Valenzuela, 1995; Thornton, 2009]. 
In monkey reproductive toxicology studies, where retosiban 
systemic exposure reached up to 14-fold of the maximum 
clinical exposures, there were no observations of postpartum 
hemorrhage. However, all monkey infants whose mothers 
received retosiban were born about 4 to 5 days after end of 
dosing. 
During the Phase II Study, OTA105256, 2 cases of 
postpartum hemorrhage were reported in subjects treated 
with retosiban. Both cases had confounding circumstances, 
as follows: 
One event occurred <48 hours from drug discontinuation and 
2 hours after delivery in a subject with a prior history of 
retained placenta in a previous 23-week preterm delivery of 
twins. A history of retained placenta is a known risk factor for 
recurrent retained placenta [Stones, 1993; Endler, 2012]. 
The other event occurred >30 days after discontinuation of 
retosiban. 
The incidence of primary PPH (within 24 hours of delivery) is 
estimated to be between 4% to 6% of mothers who delivered 
[ACOG Practice Bulletin No. 76, 2006]. 
Given the rapid clearance of retosiban, the risk for uterine 
atony appears low and would most likely occur in the 
situation where delivery occurs within 24 hours of 
treatment. 
Investigators will be advised to refer to practice guidelines 
for treatment and/or management of postpartum 
hemorrhage, using agents approved for postpartum 
hemorrhage. These include oxytocin agonists and 
prostaglandin analogs. 
Retained placenta and PPH are AEs of special interest 
requiring the collection/assessment of risk factors for PPH, 
eCRFs for any event of PPH, and clinical parameters 
related to PPH. Evaluations will include outcomes such as 
time from delivery to expulsion of placenta and estimated 
blood loss. 
Unblinded safety data will be monitored by an IDMC. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Adverse maternal, fetal, or neonatal outcomes due to 
prolonging pregnancy in the presence of subclinical 
intrauterine infection 
The study population includes women, particularly those 
presenting in labor prior to 300/7 weeks of gestation, in whom 
intrauterine infection is implicated as a major etiologic factor. 
Infection may be chronic and asymptomatic with the first 
indication being preterm labor or rupture of the membranes. 
The asymptomatic nature of intrauterine infection, including 
lack of fever, abdominal pain, and fetal tachycardia, makes 
the diagnosis challenging. Infection is thought to trigger the 
labor process as a protective means for both the mother and 
baby [Goldenberg, 2002]. 
The protocol will exclude women with a temperature 
>100.4°F (38°C) for more than 1 hour or ≥101°F (38.3°C), 
as well as women with confirmed or suspected 
contraindication for continuation of pregnancy, such as 
chorioamnionitis, premature rupture of membranes, and 
abruption. 
Placental tissue samples will be collected in study 200721 
(ZINN) when delivery occurs at an investigative center to 
examine safety and efficacy outcomes in subjects with 
subclinical intrauterine infection. 
A set of AEs of special interest identified in the literature as 
linked to maternal clinical or subclinical infection has been 
generated and will be used to collect targeted information 
of these AEs. This information will be monitored in stream 
by an IDMC. The unblinded IDMC will review all available 
safety and efficacy data. 
Potential drug-drug interaction with inhibitors of BCRP or 
P-gp 
Retosiban is a substrate of murine BCRP and P-gp in vitro. 
Inhibitors of BCRP and P-gp have the potential to increase 
exposure of retosiban when co-administered. 
BCRP and P-gp is expressed in placental membranes and 
the blood-brain barrier, and there is the potential of increased 
maternal CNS and fetal exposure to retosiban when 
co-administered with inhibitors. 
Clinical experience with exposures 10-fold higher than the 
exposure at the planned therapeutic dose has shown 
retosiban to be safe and well tolerated, with no observed 
untoward effects in adult women of childbearing potential. 
Retosiban will only be given for 48 hours, limiting both 
maternal and fetal exposure. The impact of concomitant 
use of retosiban with inhibitors of BCRP or P-gp will be 
assessed through AE monitoring. 
Analysis of maternal serum and cord blood samples will be 
performed when delivery occurs within 12 hours of study 
treatment infusion with co-administration of a BCRP or 
P-gp inhibitor to assess the effect of P-gp inhibition on 
placental transfer of retosiban. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Potential drug-drug interaction: Increased exposure of 
retosiban when co-administered with inhibitors of 
CYP3A4 
In a clinical study with healthy subjects, co-administration of 
retosiban with ketoconazole (a strong CYP3A4 inhibitor) 
increased the Cmax and AUC of retosiban, 5.2- and 8.7-fold, 
respectively. 
Administration of strong CYP3A4 inhibitors concomitantly 
with IP requires an adjustment to the retosiban dosing 
regimen (see Section 6.3.2 and the IB). Retosiban will only 
be given for 48 hours, limiting both maternal and fetal 
exposure. 
Potential drug-drug interaction: Decreased exposure of 
retosiban when co-administered with inducers of 
CYP3A4 
In healthy, nonpregnant females, co-administration of 
intravenous retosiban with efavirenz (a moderate CYP3A4 
inducer) increased the clearance of retosiban by 42% and 
reduced total exposure by 30% and peak exposure by about 
20%. 
Administration of strong CYP3A4 inducer concomitantly 
with IP requires an adjustment to the retosiban dosing 
regimen (see Section 6.3.2 and the IB). Retosiban will only 
be given for 48 hours, limiting both maternal and fetal 
exposure. 
Potential decreased therapeutic effect of drugs 
metabolized by CYP3A4 when co-administered with 
retosiban 
Evidence of metabolic auto-induction has been observed with 
repeat intravenous dosing of retosiban in women with 
preterm labor, as well as in healthy nonpregnant women 
given repeat oral doses of retosiban over 2 weeks. 
As 48-hour administration of retosiban has the potential to 
increase the rate of metabolism of drugs metabolized by 
CYP3A4, it is recommended that these drugs be monitored 
for a decrease in their therapeutic effect. Details are 
provided in the IB. Retosiban will only be given for 
48 hours, limiting both maternal and fetal exposure. 
AE = adverse event; AUC = area under the plasma concentration time curve; BCRP = breast cancer resistance protein; Cmax = maximum plasma concentration; CNS = central 
nervous system; eCRF = electronic case report form; CYP3A4 = cytochrome P450 3A4 enzyme; IB = investigator’s brochure; IDMC = independent data monitoring committee; 
P-gp = P-glycoprotein; PPH = postpartum hemorrhage. 


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Table 2 
Potential Safety Concerns 
 
Potential Safety Concern 
Summary of Data/Rationale for Concern 
Mitigation Strategy 
Pulmonary edema 
Pulmonary edema is a rare but potentially life-threatening 
complication of pregnancy. In the setting of preterm labor, 
pulmonary edema is thought to involve both increased 
hydrostatic pressure and altered vascular permeability. 
Factors associated with pulmonary edema include 
spontaneous preterm labor, multifetal pregnancy, 
chorioamnionitis, pre-eclampsia, cardiac disease, fluid 
overload, blood transfusion, corticosteroid therapy, and 
tocolytic treatment. Magnesium sulfate is implicated 
especially when additional risk factors are present. 
Randomized studies have not shown an increased risk of 
pulmonary edema or other serious maternal complications 
with antenatal magnesium sulfate [Doyle, 2009; Conde- 
Agudelo, 2009; Bain, 2013]. A retrospective chart review 
showed that contributing factors for pulmonary edema during 
magnesium sulfate treatment included high dose, high 
infusion rate, high net positive fluid balance, concomitant 
tocolysis, and multifetal gestations [Samol, 2005]. 
Women with identified risk factors for pulmonary edema 
are excluded from the clinical study. These include 
multifetal pregnancies, pre-eclampsia, chorioamnionitis, 
and certain pre-existing cardiovascular conditions. 
Combination administration of a tocolytic is not permitted in 
the clinical studies. 
Maintenance tocolysis is not allowed. 
Guidance is provided to investigators regarding monitoring 
fluid intake and output up to the time of starting treatment 
and for the duration of treatment (see Section 7.4.8). 
Pulmonary edema is designated as an AE of special 
interest requiring the collection and/or assessment of 
specific, relevant history and physical examination 
findings, targeted eCRFs to characterize any reported 
events, and a maximum duration of tocolytic treatment with 
magnesium sulfate of 48 hours. 
AE = adverse event; eCRF = electronic case report form. 


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4.6.2. 
Benefit Assessment 
 
Birth prior to 34 weeks’ gestation represents roughly 30% of preterm births in the United 
States, half of which are preceded by spontaneous labor [Martin, 2012; Tucker, 1991; 
Berkowitz, 1998; Meis, 1998; Goldenberg, 2008]. Premature birth in this group carries a 
disproportionately high risk for death, neonatal complications, and long-term disabilities. 
Infants born prior to 32 weeks’ gestation die at a rate 72 times that of term infants; the 
mortality rate for infants born between 32 and 33 weeks’ gestation is 7-fold higher 
[Mathews, 2010]. Surviving infants remain susceptible to both short-term and long-term 
prematurity complications, resulting from injury to immature organ systems [Stoll, 2010; 
Saigal, 2008]. 
 
Unfortunately, neonatal mortality and morbidity remain disproportionately high in the 
study population despite the proven benefit of antenatal corticosteroids. Therefore, if the 
retosiban program confirms the clinical hypothesis, it would provide the first compelling 
and unambiguous evidence that a therapeutic intervention during spontaneous preterm 
labor can prolong pregnancy sufficiently to reduce the risk for prematurity complications 
beyond that of antenatal corticosteroids. 
 
4.6.3. 
Overall Benefit:Risk Conclusion 
 
Based on the Phase II results showing retosiban treatment significantly increased the time 
to delivery and reduced preterm births, this study will test whether retosiban can provide 
neonatal benefit by prolonging pregnancy and allowing for continued maturation of fetal 
organs and systems. 
 
Although experience in pregnant women is limited, the retosiban safety profile is 
favorable, and no clinical or preclinical safety issues have been identified that preclude 
further development. In addition, the protocol institutes a number of measures aimed at 
mitigating potential risks to subjects participating in the study. These include extensive 
maternal, fetal, and neonatal safety assessments and an IDMC to monitor maternal, fetal, 
and neonatal safety in an ongoing manner throughout the study. 
 
Balancing the potential risks of retosiban treatment against the anticipated benefits 
afforded to subjects with preterm labor, the overall benefit:risk assessment of retosiban 
appears reasonable for the mother, fetus, and infant. 
 
For detailed information on the identified risks and risk-benefit assessment of retosiban, 
refer to the IB [GlaxoSmithKline Document Number CM2006/00201/05]. 


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5. 
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA 
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GlaxoSmithKline (GSK) IP or other study treatment that 
may affect subject eligibility is provided in the IB and other pertinent documents 
[GlaxoSmithKline Document Number CM2006/00201/05]. 
 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
 
5.1. 
Inclusion Criteria 
 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
 
1. Signed and dated written informed consent is required prior to a subject’s 
participation in the study and the performance of any protocol-specific procedures. 
At sites where enrollment of adolescents is allowed, adolescents aged 12 to 17 years 
must provide written agreement to participate in the study in accordance with 
applicable regulatory and country or state requirements. Subjects will also be asked 
to sign a release for medical records at the time of consenting to allow access to both 
the maternal and neonatal records including information about delivery and infant 
care as well as information collected prior to the consent having been signed 
NOTE: Prescreening alone does not necessarily require consent as this activity may 
be accomplished in the absence of study-specific procedures or assessments. In many 
cases, standard care and standard medical triage will provide sufficient information 
or evidence as to whether or not the subject is eligible for the study 
2. Females aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact 
membranes in spontaneous preterm labor (NOTE: Since local laws, customs, and 
institutional practice vary globally, investigator discretion in the enrollment of 
pediatric subjects is permitted, except in Italy) 
Italian Subjects: In Italy, the age restriction for study enrollment is 18 to 45 years. 
3. Gestational age between 240/7 and 336/7 weeks as determined by (1) known 
fertilization date, either in vitro fertilization or intrauterine insemination or (2) a best 
estimated due date confirmed or established by the earliest ultrasound performed 
before 240/7 weeks gestation. 
In situations where prenatal ultrasound records are not available at the time the 
subject presents, the investigator may enroll the subject using the GA based on a 
verbal history from the subject with the intent of getting confirmation from the 
medical records or from the subject’s primary care obstetrician as soon as possible. 


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4. Females must be diagnosed with preterm labor according to both of the following 
criteria (a and b): 
a. Regular uterine contractions, confirmed by tocodynamometry, at a rate of 
≥4 contractions of at least 30 seconds’ duration during a 30-minute interval. 
Where tocodynamometry is not technically feasible, assessment by manual 
palpation will be permitted and must be documented. 
AND 
b. At least 1 of the following: 
i. 
Cervical dilation ≥2 cm and ≤4 cm by digital cervical examination OR 
ii. If <2 cm dilation by the required initial digital cervical examination, a 
cervical change (2 examinations must be documented) consistent with 1 of 
the following: 
• 
An absolute increase of at least 25% effacement (e.g., a change in 
effacement from 50% to 75%) by digital examination or a 10-mm 
decrease in cervical length by transvaginal ultrasound 
OR 
• 
A 1-cm increase in cervical dilation by digital cervical examination 
5. Current or past tocolytic treatment as follows: 
a. Subjects in whom tocolytic treatment has not been initiated prior to consent are 
eligible for the study 
b. Transferred or referred subjects for whom parenteral magnesium sulfate 
treatment has been started before Screening are eligible provided they meet all 
eligibility criteria 
c. Subjects receiving a prohibited tocolytic in this study are eligible only if the 
treatment is stopped before randomization and provided they meet all eligibility 
criteria 
d. Subjects with a historical failure of a tocolytic treatment in a previous episode of 
preterm labor during the current pregnancy are eligible provided they meet all 
eligibility criteria 
5.2. 
Exclusion Criteria 
 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
 
1. Fever with a temperature >100.4°F (38°C) for more than 1 hour or ≥101°F (38.3°C) 
in the 24 hours prior to the start of study treatment 
2. Women with maternal-fetal conditions that potentially necessitate the need for 
delivery, such as pre-eclampsia or fetal compromise 


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3. A fetus with any diagnosis, condition, treatment, or other factor that in the opinion of 
the investigator has the potential to affect or confound assessments of efficacy or 
safety (e.g., nonreassuring fetal status, intrauterine growth restriction, major 
congenital anomaly) 
4. Preterm premature rupture of membranes 
5. Women with any confirmed or suspected contraindication to prolongation of 
pregnancy, such as placental abruption, chorioamnionitis, or placenta previa 
6. Evidence of polyhydramnios (amniotic fluid index [AFI] >25 cm) or 
oligohydramnios (AFI <5 cm) 
7. Women with co-morbid medical or obstetric conditions that in the opinion of the 
investigator have the potential to complicate the pregnancy course and outcomes, 
such as uncontrolled hypertension or uncontrolled diabetes (if known, history of 
glycosylated hemoglobin >8% at any time during pregnancy), known or suspected 
maternal Zika infection during gestation (see SPM for details), or compromise the 
safety of the subject, such as underlying cardiovascular disorder (specifically 
ischemic cardiac disease, congenital heart disease, pulmonary hypertension, valvular 
heart disease, arrhythmias, and cardiomyopathy) 
8. Women with a history of substance abuse during the pregnancy or dependency that 
may have the potential to complicate the pregnancy outcome 
9. Women with any diagnosis, condition, treatment, or other factor that, in the opinion 
of the investigator, has the potential to affect or confound assessments of efficacy or 
safety 
10. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment) 
NOTES: 
• 
Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric 
varices, or persistent jaundice, or cirrhosis 
• 
Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen (or 
positive hepatitis C antibody test result at Screening or within 3 months prior to 
first dose of study treatment) are acceptable if subject otherwise meets entry 
criteria 
11. History of sensitivity to any of the IPs or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or PPD medical monitor, 
contraindicates the subject’s participation 


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5.3. 
Withdrawal From Study, Discontinuation of IP, and Stopping 
Criteria 
 
The section describes and distinguishes the following: 
 
• 
Withdrawal of the subject from the study after randomization but before 
administration of IP (Section 5.3.1.1) and after administration of IP (Section 5.3.1.2) 
• 
Discontinuation of the IP (Section 5.3.2), wherein subjects who receive but then 
discontinue from IP will not be considered withdrawn from the study and should 
remain in the study and continue to be followed for efficacy and safety. 
• 
Specific stopping criteria before and during dosing, including liver function test 
criteria (Section 5.3.3) and QTc findings (Section 5.3.4). 
5.3.1. 
Withdrawal From Study 
 
5.3.1.1. 
Withdrawal From Study Participation After Randomization but Prior to 
Investigational Product Administration 
 
Any subject with a nonreassuring fetal heart rate pattern, a re-assessment that determines 
tocolytic therapy is no longer indicated (according to investigator’s medical discretion), 
abnormal levels of alanine aminotransferase (ALT) or bilirubin (if results are available), 
or a clinically significant abnormal finding on an electrocardiogram (ECG) cannot be 
dosed and will be withdrawn from the study. The reasons for not dosing a subject will be 
recorded in the eCRF and source documents. Subjects who are withdrawn prior to 
receiving randomized IP will not be followed. 
 
A nonreassuring fetal heart rate is defined as either unresolved Category 3 tracings 
(including either [1] the absence of baseline fetal heart rate variability and any of the 
following: recurrent late decelerations, recurrent variable decelerations, or bradycardia; 
or [2] sinusoidal pattern) or at the investigator’s discretion. 
 
Sites Not in Italy: If local laboratory results are available before the start of dosing and 
reveal that ALT is ≥2 × the upper limit of normal (ULN) or total bilirubin is >1.5 × ULN 
(>35% direct bilirubin), the subject should not be dosed and should be withdrawn from 
the study. An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and 
direct bilirubin is <35%. 
 
With the exception of sites in Italy, dosing may be started before local liver function test 
results are available. If the local laboratory results reveal liver abnormalities as defined in 
Section 5.3.3 and Appendix 2, study drug treatment must be discontinued. 
 
Sites in Italy: For sites located in Italy, dosing must not start before local laboratory liver 
function test results are obtained and reviewed by the investigator. If local laboratory 
liver function test results reveal that ALT is ≥2 × ULN or total bilirubin is >1.5 × ULN 
(>35% direct bilirubin), the subject must not be dosed and should be withdrawn from the 
study. An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and 
direct bilirubin is <35%. 


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5.3.1.2. 
Withdrawal From Study Participation After Beginning Randomized 
Treatment 
 
All subjects who are randomly assigned to and begin treatment (i.e., randomized 
treatment) should be encouraged to complete all phases of the study, including those who 
discontinue randomized treatment. However, a subject may voluntarily withdraw from 
study participation at any time or be withdrawn at any time at the discretion of the 
investigator for any maternal obstetrical or medical complications after consultation with 
the PPD medical monitor. If a subject withdraws from the study, no additional visits can 
occur or procedures performed, and the subject may request destruction of any samples 
taken; the investigator must document this request in the site study records. 
 
Subjects who are withdrawn from study participation after starting randomized treatment 
will not be replaced. Reasons for study withdrawal will be recorded in the eCRF and the 
subject’s source document. A subject may be withdrawn from the study for the following 
reasons: 
 
• 
Lost to follow-up 
• 
Subject voluntarily withdrew consent 
• 
Investigator decision to withdraw the subject from participation; investigators must 
consult the PPD medical monitor before withdrawing a subject from participation in 
the study 
• 
Termination of the study by GSK 
Subjects who are withdrawn after starting the Inpatient Randomized Treatment Phase but 
before the Post-Infusion Assessment Phase will be asked to return and complete the 
assessments specified for the 1-week face-to-face post-infusion assessment visit before 
withdrawing from the study (Table 5). 
 
Withdrawal from this study after beginning randomized treatment does not preclude 
involvement in the separate infant follow-up study. 
 
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit: 
 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible 
• 
The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study 
• 
In cases where the subject is deemed “lost to follow-up,” the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record 


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• 
Should the subject continue to be unreachable, only then will she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up.” For all 
other subjects withdrawing from the study, an alternative reason for discontinuation 
should be recorded in the eCRF 
5.3.2. 
Discontinuation of Investigational Product 
 
Subjects who receive but who discontinue from IP will not be considered withdrawn 
from the study and should remain in the study and continue to be followed for efficacy 
and safety. Once delivered, newborns will also continue to be followed for safety and 
outcomes through the 28 days post EDD. 
 
A subject may voluntarily discontinue from the IP at any time. The investigator may also, 
at his or her discretion, discontinue the IP at any time for any medical reason or maternal 
or fetal complications. Subjects who discontinue randomized treatment will be managed 
by the investigator according to standard care. 
 
Subjects who discontinue the IP will not be replaced. Reasons for discontinuation from IP 
will be recorded in the eCRF and the subject’s source documents 
 
A subject will also be discontinued from IP under the following circumstances: 
 
1. Labor progression or delivery (vaginal or caesarean section) occurs during the 
Inpatient Randomized Treatment Phase 
2. Intolerance of assigned treatment occurs during the Inpatient Randomized Treatment 
Phase 
3. An obstetric indication for delivery (e.g., nonreassuring fetal status) 
4. Contraindication for continuing randomized treatment including, but not limited to, 
infection (i.e., chorioamnionitis) or placental insufficiency as evidenced by, for 
example, abruptio placentae, intrauterine growth restriction, nonreassuring fetal 
status or death, severe pre-eclampsia/eclampsia, maternal bleeding with 
hemodynamic instability, or other conditions at the discretion of the investigator 
5. Abnormal liver function test result (see Section 5.3.3) 
6. An abnormal corrected QT interval (see Section 5.3.4) 
Subjects discontinuing the IP for any of the above reasons can and should continue to 
receive antenatal corticosteroids (either betamethasone or dexamethasone) for fetal 
maturation if not yet completed and still clinically indicated. 
 
Subjects discontinuing the IP who have not yet delivered will continue in the study 
through delivery, the maternal post-delivery assessment, and newborn record review. 
These subjects will be included in the Intent-to-Treat (ITT) and Safety Populations. 
Additionally, all infants should be consented for the separate infant follow-up study. 
 
5.3.3. 
Liver Chemistry Stopping Criteria 
 
Blood samples will be collected for central laboratory evaluation at Screening (prior to 
treatment), during Day 2 of the randomized treatment phase, and at the 1-week 


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face-to-face post-infusion assessment visit for additional liver function testing to ensure 
subject safety and to evaluate liver event etiology (in alignment with the US Food and 
Drug Administration premarketing clinical liver safety guidance); 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM174090.pdf. 
 
Sites Not in Italy: At Screening, before IP administration, ALT and bilirubin test results 
from a local laboratory should be obtained, although dosing may be started prior to the 
availability of these results. However, if the local laboratory results are available before 
the start of dosing and meet the following criteria, the subject should not be dosed and 
should be withdrawn from the study: 
 
• 
ALT ≥2 × ULN OR total bilirubin >1.5 × ULN (>35% direct bilirubin). An isolated 
bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is 
<35%. 
Phase III-IV liver chemistry stopping criteria are presented in Figure 3 and Appendix 2. 
 
The local and central laboratory liver function test results should be reviewed for the 
abnormalities shown in Figure 3. If the laboratory results are not available at the start of 
dosing and subsequent local OR central laboratory results are abnormal, dosing may be 
continued at the discretion of the investigator, as long as they do not exceed the liver 
chemistry stopping criteria shown in Figure 3 and detailed in Appendix 2. 
 
Sites in Italy: At Screening, before IP administration, ALT and bilirubin test results from 
a local laboratory must be obtained and reviewed by the investigator. If the local 
laboratory liver function test results meet the following criteria, the subject must not be 
dosed and should be withdrawn from the study: 
 
• 
ALT ≥2 × ULN OR total bilirubin >1.5 × ULN (>35% direct bilirubin). An isolated 
bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is 
<35%. 
Phase III-IV liver chemistry stopping criteria are presented in Figure 3 and Appendix 2. 
 
The local and central laboratory liver function test results should be reviewed for the 
abnormalities shown in Figure 3. If after the start of dosing, the central laboratory results 
are abnormal, dosing may be continued at the discretion of the investigator, as long as 
they do not exceed the liver chemistry stopping criteria shown in Figure 3 and detailed in 
Appendix 2. 
 
NOTE for All Sites: The central laboratory report will include results for ALT, aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin, and direct bilirubin. 


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Figure 3 
Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
 
 
 
No 
Plus 
Bilirubin 
Continue Study Treatment 
 
 
Plus 
 
 
 
 
ALT≥3×ULN but 
 
 
ALT≥3×ULN 
Yes 
≥2×ULN (>35%  No 
direct) 
or plus 
INR>1.5, if 
measured* 
Possible 
Hy’s Law 
Symptoms of 
No 
liver injury 
or 
hypersensitivity 
ALT 
No 
≥8×ULN 
<8×ULN and 
stopping criteria 
not met, see 
required 
monitoring in 
Appendix 2 
Yes 
Yes 
Yes 
Discontinue Study Treatment 
 
 
➢ Must refer to Liver Safety Required Actions and Follow-up Assessments section in Appendix 2 
➢ Report as an SAE if possible Hy’s Law case: ALT≥3×ULN and Bilirubin ≥2×ULN (>35% direct) 
or INR >1.5, if measured 
*INR measurement is not required; if measured, the threshold value stated will not apply 
to subjects receiving anticoagulants 
 
ALT = alanine aminotransferase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal. 
 
 
 
The complete Liver Safety Required Actions and Follow-up Assessments section can be 
found in Appendix 2. 
 
5.3.3.1. 
Study Treatment Restart or Rechallenge 
 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed. 
 
5.3.4. 
QTc Stopping Criteria 
 
Should the subject require an ECG during the infusion and the results meet the following 
defined corrected QT interval (QTc) criteria, the IP will be discontinued: 
 
• 
An abnormal QTc using the Fridericia formula (QTcF) detected during standard care 
of the subject based on the following criteria: 
• 
QTcF >500 msec or uncorrected QT >600 msec 
• 
Change from baseline QTcF value of >60 msec 


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For subjects with underlying bundle branch block, treatment should be discontinued in 
the following circumstances: 
• 
QTcF >500 msec in a subject with a baseline QTcF value of <450 msec 
• 
QTcF ≥530 msec in a subject with a baseline QTcF value between 450 and 
480 msec 
• 
The QTc should be based on single electrocardiogram 
5.4. 
Subject and Study Completion 
 
A completed subject is defined as one who has completed all phases of the study 
including the post-delivery assessment visit. Subjects who receive but who discontinue 
from IP will not be considered withdrawn from the study and should remain in the study 
and continue to be followed for efficacy and safety (see Section 5.3.2). 
 
The end of the study is defined as the neonatal record review at 28 days post EDD for the 
last subject randomly assigned to and treated with IP. 
 
6. 
STUDY TREATMENT 
6.1. 
Investigational Product and Other Study Treatment 
 
The term “study treatment” is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. 
 
Retosiban for IV administration will be supplied as solution for infusion, consisting of a 
clear colorless solution of retosiban at a concentration of 15 mg/mL in 56% vol/vol 
ethanol/acetate buffer concentrate. The solution is sterilized by filtration and aseptically 
filled into glass vials. The vials are sealed with rubber stoppers and aluminum seals with 
a plastic flip-off lid. Each single-use 5-mL vial contains 75 mg retosiban as solution for 
infusion (see Table 3). 
 
The retosiban infusion will be prepared by an unblinded pharmacist or other qualified 
professional, using two 5 mL retosiban vials admixed in a 500 mL 0.9% NaCl infusion 
bag to obtain a concentration of 0.3 mg/mL (150 mg retosiban in 500 mL 0.9% NaCl). 
The infusion admixture is a clear, colorless solution. 
 
An unblinded pharmacist or other qualified individual will prepare the placebo infusion 
using 0.9% NaCl 500 mL matched for the retosiban loading dose and continuous infusion 
rates, including a dose increase in subjects with an inadequate response any time after the 
first hour of treatment. 
 
Table 3 summarizes the study treatments. 


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Table 3 
Retosiban Investigational Product and Other Study Treatment 
 
Product Name 
Study Treatment 
Retosiban (GSK221149) 
Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
Drug product 
description 
Clear, colorless solution for infusion in a 5-mL 
vial containing 75 mg of retosiban 
A placebo-matched glass vial is not provided. 
Unit dose 
strengths/ 
Dosage levels 
Retosiban 15 mg/mL 
The total dose given over 48 hours should not 
exceed 300 mg at the 6-mg/hour infusion rate 
and 582 mg at the 12-mg/hour infusion rate. 
0.9% NaCl matched for the retosiban loading 
dose and continuous infusion rates 
Route of 
administration 
IV 
IV 
Dosing 
instructions: 
The retosiban 6-mg loading dose is 
administered at an infusion rate of 240 mL/hour 
for 5 minutes. After 5 minutes, the infusion rate 
is reduced to 20 mL/hour to deliver retosiban at 
a rate of 6 mg/hour for the remainder of the 
48-hour treatment period. 
For subjects with an inadequate response any 
time after the first hour of treatment, 
investigators should administer another 6-mg 
loading dose by increasing the infusion rate to 
240 mL/hour for 5 minutes, after which the 
infusion rate is set to 40 mL/hour in order to 
deliver retosiban at a rate of 12 mg/hour. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inhibitor, the retosiban 
3-mg loading dose is administered at an 
infusion rate of 120 mL/hour for 5 minutes. 
After 5 minutes, the infusion rate is reduced to 
6.7 mL/hour to deliver retosiban at a rate of 
2 mg/hour. For subjects with an inadequate 
response any time after the first hour, an 
additional 1-mg loading dose is administered 
by increasing the infusion rate to 40 mL/hour 
over 5 minutes after which the infusion rate is 
set to 10 mL/hour to deliver retosiban at 
3 mg/hour for the remainder of the 48-hour 
treatment period. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inducer, the retosiban 
8.5-mg loading dose is administered at an 
infusion rate of 340 mL/hour for 5 minutes. 
After 5 minutes, the infusion rate is reduced to 
28 mL/hour to deliver retosiban at a rate of 
8.5 mg/hour. For subjects with an inadequate 
response any time after the first hour, an 
additional 3.5-mg loading dose is administered 
by increasing the infusion rate to 140 mL/hour 
for 5 minutes. After 5 minutes, the infusion rate 
is reduced to 40 mL/hour to deliver retosiban at 
a rate of 12 mg/hour. 
See the Study Pharmacy Manual for detailed 
instructions. 
Intravenous administration of the 0.9% NaCl 
solution will be matched to the loading dose 
rate of 240 mL/hour for 5 minutes, after which 
the infusion rate is set to 20 mL/hour. 
For subjects with an inadequate response any 
time after the first hour of treatment, 
investigators should administer another loading 
dose by increasing the infusion rate to 
240 mL/hour for 5 minutes, after which the 
infusion rate is set to 40 mL/hour. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inhibitor, the loading 
dose is administered at an infusion rate of 
120 mL/hour for 5 minutes. After 5 minutes, the 
infusion rate is reduced to 6.7 mL/hour. For 
patients with an inadequate response any time 
after the first hour, an additional loading dose is 
administered by increasing the infusion rate to 
40 mL/hour over 5 minutes, after which the 
infusion rate is set to 10 mL/hour. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inducer, the loading 
dose is administered over 5 minutes at an 
infusion rate of 340 mL/hour for 5 minutes. 
After 5 minutes, the infusion rate is reduced to 
28 mL/hour. For patients with an inadequate 
response any time after the first hour, an 
additional loading dose is administered by 
increasing the infusion rate to 140 mL/hour for 
5 minutes. After 5 minutes, the infusion rate is 
reduced to 40 mL/hour. 
See Study Pharmacy Manual for detailed 
instructions. 


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Product Name 
Study Treatment 
Retosiban (GSK221149) 
Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
Manufacturer/ 
Source of 
procurement 
GSK 
Not applicable – to be sourced locally 
CYP3A4 = cytochrome P450 3A4 enzyme; IV = intravenous; GSK = GlaxoSmithKline; NaCl = sodium chloride; 
PTM = placebo to match. 
 
 
6.2. 
Treatment Assignment 
 
Subjects will be stratified by progesterone treatment and GA. The progesterone strata will 
consist of subjects on established progesterone therapy or subjects not on established 
progesterone therapy at Screening. The GA strata are 240/7 to 256/7, 260/7 to 276/7, 280/7 to 
306/7, or 310/7 to 336/7. Subjects within each stratum will be randomly assigned in 1:1 ratio 
to receive either retosiban or placebo using an interactive voice response system 
(IVRS)/interactive web response system (IWRS) in accordance with the randomization 
schedule generated by PPD, prior to the start of the study, using validated internal 
software. 
 
The retosiban and matching placebo regimen are described in Table 3. The IP will be 
administered by study personnel during each dosing session. Retreatment with the IP 
(retosiban or placebo) is not allowed. Temporary interruptions of the IP are permitted, 
and the reasons must be recorded in the eCRF (e.g., problems with IV line). 
 
The time of dosing (i.e., start of the infusion) will be designated as time 0. All subsequent 
time points will be in relation to this time point. Information regarding IV administration, 
dosing adjustments, and admixture preparation can also be found in the SPM and Study 
Pharmacy Manual. 
 
6.3. 
Subject-Specific Dose Adjustment Criteria 
 
6.3.1. 
Inadequate Response 
 
An adequate response is based on (1) a clinically relevant reduction of contraction 
frequency and/or intensity or (2) no change in the cervical examination. An inadequate 
response is defined as a clinically significant change in the cervical examination or no 
significant reduction in contraction frequency and/or intensity. For subjects with an 
inadequate response any time after the first hour of treatment with retosiban or matching 
placebo, investigators should administer another 6-mg loading dose by increasing the 
infusion rate to 240 mL/hour for 5 minutes, after which the infusion rate is set to 
40 mL/hour in order to deliver retosiban at a rate of 12 mg/hour. Investigators will be 
required to indicate in the eCRF the reason or reasons for a dose increase. A subject’s 
response should be assessed for at least 1 hour following a dose increase before a 
decision is made to discontinue randomized treatment due to an inadequate response. 
 
See Section 5.3.2 for details regarding discontinuation of the IP. 


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6.3.2. 
Concurrent Administration of Investigational Product With 
Strong CYP3A4 Inhibitors or Strong CYP3A4 Inducers 
 
Retosiban undergoes oxidative metabolism, primarily mediated by CYP3A4 (see 
Section 4.5.1). As a result, concomitant administration of drugs that are strong CYP3A4 
inhibitors may result in increased exposure to retosiban. When given orally, retosiban 
exposure was increased 8.7-fold, as measured by area under the plasma 
concentration-time curve (AUC), in the presence of ketoconazole, a strong CYP3A4 
inhibitor. 
 
To achieve exposures similar to those achieved with the retosiban 6-mg/hour dosing 
regimen, retosiban should be administered as a 3-mg loading dose over 5 minutes 
followed by a 2-mg/hour continuous infusion in subjects who are being treated 
concomitantly with a strong CYP3A4 inhibitor (see Section 6.12.1.5). See Table 3 for 
additional dosing instructions. 
 
For subjects chronically taking a drug known to be a strong CYP3A4 inducer, the initial 
dose of retosiban should be an 8.5-mg loading dose over 5 minutes followed by an 
8.5-mg/hour continuous infusion for the remainder of the 48-hour treatment period (see 
Section 6.12.1.6). See Table 3 for additional dosing instructions. 
 
See the Study Pharmacy Manual for detailed instructions. A list of strong, moderate, and 
weak CYP3A4 inhibitors and inducers is provided in Appendix 7. 
 
6.4. 
Managing Dose Interruptions 
 
Temporary interruptions of the IP are permitted. The following procedures should be 
followed in the event of a dose interruption: 
 
• 
If the interruption is <60 minutes, restart the IP infusion. 
• 
If the interruption is from 60 to 90 minutes, inclusive, administer a loading dose at a 
rate equal to one-half of the prior loading dose rate. For example, if the loading dose 
rate prior to the interruption was 240 mL/hour over 5 minutes, administer the loading 
dose at 120 mL/hour over 5 minutes, and then resume the infusion. 
• 
If the interruption is >90 minutes, administer a loading dose at a rate equal to the 
prior loading dose rate. For example, if the prior loading dose was administered at 
240 mL/hour over 5 minutes, administer the loading dose at 240 mL/hour over 
5 minutes, and then resume the infusion. 
Any changes in the dose rate, corresponding start and stop times, and the reason for an 
interruption must be recorded in the eCRF. 
 
6.5. 
Blinding 
 
The pharmacist or other qualified individual responsible for IP accountability, storage, 
and preparation will be unblinded, as will the PPD clinical research associate responsible 
for IP accountability. These personnel will maintain the integrity of the study blind. All 
other subjects and study personnel (i.e., investigators, GSK, PPD) will be blinded for the 


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duration of this study. Subjects (or parents/legal guardians of the neonate) will remain 
blinded throughout the duration of the separate long-term infant follow-up study. 
 
The IDMC will review unblinded data periodically in addition to 2 formal interim 
analyses in accordance with the IDMC charter. Unblinded data will be provided by an 
independent statistical data analysis center. 
 
This will be a double-blind study and the following will apply: 
 
• 
The investigator or treating physician may unblind a subject’s treatment assignment 
in the case of an emergency OR in the event of a serious medical condition when 
knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 
• 
Investigators have direct access to the subject’s individual study treatment (refer to 
the PPD IVRS/IWRS Site User Guide for details). 
• 
It is preferred (but not required) that the investigator first contact the PPD medical 
monitor to discuss options before unblinding the subject’s treatment assignment. 
• 
If PPD personnel are not contacted before the unblinding, the investigator must 
notify PPD as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study (refer to the SPM for details). 
• 
The date and reason for the unblinding must be fully documented in the eCRF. 
• 
A subject may continue in the study if that subject’s treatment assignment is 
unblinded (refer to the SPM). 
• 
GSK’s Global Clinical Safety and Pharmacovigilance staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
6.6. 
Packaging and Labeling 
 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 


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6.7. 
Preparation/Handling/Storage/Accountability 
 
A description of the methods and materials required for preparation of the retosiban 
solution and the matching placebo are detailed in the Study Pharmacy Manual. 
 
The following considerations must be made with regard to IP preparation, handling, 
storage, and accountability in this study: 
 
• 
Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff 
• 
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation and final disposition records) 
• 
Further guidance and information for final disposition of unused study treatment are 
provided in the Study Pharmacy Manual 
• 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, medical monitor, and/or 
GSK study contact 
• 
A material safety data sheet or equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, 
where this is required by local laws, or will be made available upon request from 
GSK 
6.8. 
Compliance With Study Treatment Administration 
 
This study will be conducted under the direct supervision of the investigator obstetrician 
or his/her designees; IP will be administered under the supervision of study personnel and 
compliance will be monitored. 
 
The exact start and stop times of the infusion should be recorded in the eCRF. 
 
6.9. 
Treatment of Study Treatment Overdose 
 
Any signs or symptoms of retosiban overdosage will be treated symptomatically. No 
specific antidote is known. 
 
In the event of an overdose, the principal investigator should take the following actions: 
 
1. Contact the medical monitor immediately 
2. Closely monitor the subject for AEs or SAEs and laboratory abnormalities 


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3. Obtain a plasma sample for PK analysis within 12 hours from the time of the 
overdose if requested by the medical monitor (determined on a case-by-case basis) 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the subject. 
 
6.10. 
Treatment After the End of the Study 
 
The investigator is responsible for ensuring that consideration has been given to the 
poststudy care of the subject’s medical condition whether or not GSK is providing 
specific poststudy treatment. 
 
6.11. 
Prior Medications and Nondrug Therapies 
 
Prior medications will be reviewed and the investigator will attempt to obtain a complete 
history of any medications taken during the pregnancy (including the trimester of 
exposure, if possible) and during any previous episodes of preterm labor (e.g., 
magnesium sulfate or antenatal corticosteroid treatment). 
 
6.12. 
Concomitant Medications and Nondrug Therapies 
 
All concomitant medications taken by the mother during the study will be recorded in the 
eCRF; the indication for the concomitant medication must be specified. Prespecified 
concomitant medications of interest will be assessed. Concomitant medications taken 
during time of delivery and hospitalization will be obtained through a review of the 
hospital records. 
 
6.12.1. 
Permitted Medications and Nondrug Therapies 
 
6.12.1.1. 
Antenatal Corticosteroids 
 
If not previously administered, antenatal corticosteroid treatment should be administered 
as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or 
(2) four 6-mg doses of dexamethasone administered intramuscularly every 12 hours. A 
single rescue course of antenatal corticosteroids is permitted if the antecedent treatment 
was at least 7 days prior to study enrollment. 
 
6.12.1.2. 
Magnesium Sulfate 
 
Investigators have the option to use magnesium sulfate. Magnesium sulfate should be 
given intravenously using a 4- to 6-g loading dose and 1- to 2-g/hour infusion rate. The 
total duration of magnesium sulfate administration should not exceed 48 hours. Doses 
exceeding this range will be considered a putative tocolytic and will be classified as a 
treatment failure. 


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6.12.1.3. 
Progesterone 
 
Progesterone in any form and hydroxyprogesterone caproate may be continued for 
subjects already on established progesterone therapy for prevention of preterm birth but 
should not be initiated in subjects after they have been enrolled in the study. Established 
progesterone therapy refers to any formulation of progesterone supplementation intended 
for risk reduction of preterm birth. 
 
6.12.1.4. 
Antibiotics 
 
Intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection will be 
permitted. 
 
6.12.1.5. 
Strong CYP3A4 Inhibitors 
 
Drugs that are strong CYP3A4 inhibitors are permitted. Administration of strong 
CYP3A4 inhibitors concomitantly with IP requires an adjustment to the retosiban dosing 
regimen (see Section 6.3.2). A list of strong, moderate, and weak CYP3A4 inhibitors is 
provided in Appendix 7. 
 
6.12.1.6. 
Strong CYP3A4 Inducers 
 
Drugs that are strong CYP3A4 inducers are permitted. Administration of strong CYP3A4 
inducers concomitantly with IP requires an adjustment to the retosiban dosing regimen 
(see Section 6.3.2). A list of strong, moderate, and weak CYP3A4 inducers is provided in 
Appendix 7. 
 
6.12.1.7. 
Breast Cancer Resistance Protein or P-Glycoprotein Inhibitors 
 
Drugs that are inhibitors of breast cancer resistance protein (BCRP) and P-glycoprotein 
(P-gp) are permitted during the study. A list of strong, moderate, and weak BCRP and P-
gp inhibitors is provided in the SPM. 
 
6.12.2. 
Prohibited Medications and Nondrug Therapies 
 
Except for IP administered during this study, no additional investigational drugs or 
investigational devices are permitted for the mother from the time of study entry through 
completion of the follow-up visit (i.e., the maternal post-delivery assessment) or 30 days 
after administration of the last dose of IP, whichever is longer. 
 
The use of a pessary may be continued for subjects who were using a pessary prior to the 
current episode of preterm labor; however, initiating use of a pessary during the study is 
prohibited. 


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6.12.2.1. 
Tocolytic Drugs 
 
The concomitant medications listed below will be considered putative tocolytics when 
administered for active preterm labor or for the prevention of preterm labor. Apart from 
the exceptions listed in Table 4, use of any of the following putative tocolytics at any 
time prior to delivery will be considered a treatment failure: 
 
• 
Calcium-channel blockers:  nifedipine 
• 
-agonists: ritodrine, terbutaline, and salbutamol 
• 
NSAIDs: celecoxib, ibuprofen, indomethacin, ketorolac, naproxen 
Likewise, subjects administered any of the calcium-channel blockers, NSAIDs, or 
-agonist medications listed above for maintenance tocolysis (prevention of recurrent 
preterm labor) who remained undelivered following the Inpatient Treatment Phase will 
be considered a treatment failure. Subjects administered doses of magnesium sulfate that 
exceed the dose specified in Section 6.12.1.2 (i.e., any dose that exceeds a 4- to 6-g IV 
loading dose and then a 1- to 2-g/hour infusion rate, with total duration of magnesium 
sulfate administration up to 48 hours) will also be considered a treatment failure. 
 
Table 4 
Guidelines for Exceptions to Putative Tocolytic Drug Use 
 
Drug Class 
Example Drugs 
Exceptions for Use 
Calcium-channel blockers 
nifedipine 
• Administration for chronic or pregnancy-induced 
hypertension will not be considered a treatment 
failure if the indication is provided when 
documenting concomitant medications. 
• Administration for new onset of hypertension 
would not be considered a treatment failure. The 
new onset must be recorded on the AE/SAE 
page of the eCRF. 
• A dose increase due to exacerbation of 
hypertension will be not considered a treatment 
failure. Exacerbation must be recorded on the 
AE/SAE page of the eCRF. 
-agonists 
ritodrine, salbutamol, and 
terbutaline 
• Administration for chronic or new onset 
respiratory indications is permitted. Acute 
short-term courses for respiratory conditions will 
not be considered a treatment failure if the 
indication is provided when documenting 
concomitant medications. 
• New onset of a respiratory condition would not 
be considered a treatment failure. The new 
onset must be recorded on the AE/SAE page of 
the eCRF. 
• A dose increase due to exacerbation of a 
respiratory condition will be not considered a 
treatment failure. Exacerbation to be recorded 
on the AE/SAE page of the eCRF. 


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Drug Class 
Example Drugs 
Exceptions for Use 
NSAIDs1 
celecoxib, ibuprofen, 
indomethacin, ketorolac, and 
naproxen 
• Administration for chronic medical conditions, 
such as rheumatoid arthritis, will not be 
considered a treatment failure if the indication is 
provided when documenting concomitant 
medications. 
• Single doses of NSAIDs not taken for treatment 
of preterm labor (e.g., taken for headache, 
dysmenorrhea, or fever) will not be considered a 
putative tocolytic. 
NSAID = nonsteroidal anti-inflammatory drug. 
1. 
Subjects should be discouraged from using NSAIDs without first discussing with the investigator. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table (Table 5). 
 
As maternal subjects will be enrolled as part of an emergency situation, prestudy 
screening information that is collected by the study site may need to come from records 
that are obtained before the subject has signed the informed consent. Such information 
will only include items that are collected as part of standard care (e.g., symptoms of 
preterm labor, vital signs, cervical examination, medical and obstetrics history, and 
estimated GA). However, the subject will be required to provide informed consent for use 
of any information collected prior to consenting and before any additional study-specific 
procedures are performed. 
 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
 
The following points must be noted: 
 
• 
The timing and number of planned study assessments, including safety, PK, 
genetic, and biomarker assessments, may be altered during the course of the 
study based on newly available data (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring. 
• 
The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File, which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 
• 
The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will 
be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the informed consent form. 


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7.1. 
Time and Events Table 
 
Table 5 
Time and Events Table 
 
Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Clinical and Other Assessments 
Written informed consent 
and medical releases for 
treatment3 
X 
Discuss and request 
consent for participation in 
the infant follow-up study4 
X
X 
X 
Inclusion/exclusion criteria 
confirmation 
X 
Baseline characteristics 
and demographic data 
X 
Medical history (including 
obstetrics history)5 
X 
Physical examination 
(including height and 
weight) 
X 
Cervical examination6 
X 
X 
X 
X 
Estimated fetal weight and 
head circumference via 
ultrasound7 
X 
Determine AFI via 
ultrasound8 
X 
Uterine contractions9 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Schedule post-infusion 
assessment visit 
X 
Investigational Products10 
Retosiban or placebo 
X 
X 
Efficacy Assessments 
Date and time of delivery11 
X 
Mode of delivery11 
X 
Indication for delivery11 
X 
Neonatal composite 
outcomes 
X 
Neonatal hospital stay 
X 
Maternal Safety Assessments 
Concomitant medications 
X
X 
X 
ECG 12-lead12 
X 
Vital sign measurements 
(BP, pulse rate, 
temperature, respiratory 
rate, and oxygen 
saturation)13 
X 
X 
X 
X 
AEs, SAEs, and DREs : 
maternal 
X
X 
X 
Monitor fluid intake and 
output 
X 
X 
X 
Breastfeeding status 
X 
Edinburgh Postnatal 
Depression 
Scale14(maternal) 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Local laboratory 
assessments (LFTs only)15 
X 
Central laboratory 
assessments (including 
hematology, chemistry, 
and LFTs)16 
X 
X 
X16 
Physical examination 
(brief) 
X 
Status of postpartum 
bleeding 
X 
Fetal Safety Assessments 
Electronic fetal monitoring 
X17 
X18 
X18 
X19 
X20 
AEs, SAEs, and DREs: 
fetal 
X
X 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: 
neonatal 
X
X 
Neonatal Apgar Scores 
(1 and 5 minutes)11 
X 
Neonatal growth 
parameters11 
X 
Neonatal umbilical cord 
blood gases11 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Health Outcome Assessments 
Maternal and neonatal 
health care resource use21 
X 
X 
Pharmacokinetic Assessments 
Maternal PK blood 
sample22 
X21 
X 
Cord blood sample23 
X 
Breast milk/colostrum 
sample24 
X 
Genetic and Biomarker Assessments 
Genetic blood sample for 
maternal DNA25 
X 
Biomarker maternal blood 
sample26 
X 
Genetic blood sample for 
cell-free fetal DNA27 
X 
Other Assessments 
Fetal fibronectin 
(optional)28 
X 
Cervical length via 
transvaginal ultrasound 
(optional)29 
X 
AE = adverse event; AFI = amniotic fluid index; ALT = alanine aminotransferase; BP = blood pressure; DRE = disease-related event; ECG = electrocardiogram; eCRF = electronic case 
report form; EDD = estimated date of delivery; IP = investigational product; LFT = liver function test; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of 
normal. 
1. 
Subjects who remain undelivered after 48 hours will return for a face-to-face post-infusion visit for obstetric assessments 1 week (acceptable range: 3 to 14 days) following the 
Inpatient Randomized Treatment Phase. The subject will then be contacted every week via telephone to determine and record if she has delivered or experienced any subsequent 


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episodes of preterm labor. Note: If the subject is scheduled to visit the clinic for reasons not required by this protocol and/or she happens to be present at the time the telephone 
assessment is due, this assessment may be completed face-to-face. 
2. 
During the Maternal Post Delivery Assessment Phase, subjects will be contacted by telephone within 6 weeks of delivery for a post-delivery assessment, including an assessment 
of AEs (±2 weeks), status of breastfeeding (±2 weeks), and completion of the EPDS (-2 weeks/+6 weeks). 
3. 
Prestudy screening information that is collected by the study site may need to come from records that are obtained before the subject has signed the informed consent. The  
subject will be required to provide written informed consent before any study-specific procedures are performed, and the consent will request permission for use of any information 
collected prior to its having been signed. 
4. 
During the study, the subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant to participate in a separate long-term 
infant follow-up study for safety and neurodevelopment. Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude involvement in the 
infant follow-up study. 
5. 
Medical history will be collected at Screening. If a condition with a start date predating Day 0 (Screening) is subsequently discovered, the condition should be recorded in the 
Medical History eCRF. For obstetrics history, the investigator will make every effort to obtain this information either via computer records, directly from the subject’s primary care 
obstetrician, or via telephone. However, in cases in which these records are not readily available (e.g., off hours, holiday), the investigator can use gestational age based on the 
verbal history from the subject with the intent of getting confirmation from the medical records or from the subject’s primary care obstetrician as soon as possible. 
6. 
A cervical examination (including dilation, effacement, and station) will occur at Screening, and an additional cervical examination may be performed before dosing based on 
investigator discretion. Additional cervical examinations (Day 1, Day 2, and/or at the 1-week face-to-face post-infusion assessment visit) are not required but may be performed 
based on investigator discretion. If inclusion criteria are based on cervical change (see Section 5.1), 2 examinations must be documented (either 2 digital cervical examinations or 
2 cervical length examinations). 
7. 
An ultrasound for estimation of fetal weight and head circumference is needed at Screening unless the date of the most recent ultrasound that includes fetal weight and head 
circumference is within 3 weeks (21 days) of the date of randomization. 
8. 
The abdominal ultrasound for determination of the AFI will be performed at Screening for all subjects. The AFI should be measured using the 4-quadrant method. 
9. 
Uterine tocography or manual palpation (if necessary) will be performed at Screening. Manual palpations will be permitted if there are technical challenges with measuring 
contraction frequency. 
10. If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or 
(2) four 6-mg doses of dexamethasone administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the antecedent treatment 
was at least 7 days prior to study enrollment. Investigators have discretion to use a standardized regimen of magnesium sulfate, as well as intrapartum antibiotic prophylaxis for 
perinatal group B streptococcal infection. 
11. Information regarding delivery will be obtained through a review of the hospital and medical records. Growth parameters include neonatal weight, length, and head circumference. 
12. A 12-lead ECG will be performed prior to dosing. If the results are interpreted by the investigator to have clinically significant abnormalities, the subject cannot be dosed. 
13. Blood pressure, pulse rate, respiratory rate, and temperature will be assessed at Screening, as part of maternal safety monitoring during the Inpatient Randomized Treatment 
Phase, and at the post-infusion assessment visit. During the Inpatient Randomized Treatment Phase, vital signs and oxygen saturation will be assessed and recorded within the 
following windows relative to the start of the infusion: 15 to 30 minutes, 4 to 8 hours, 20 to 24 hours, at the end of the infusion, at the time of any dose changes, and as warranted 
by a medical condition. Oxygen saturation less than 92% should be recorded as an AE or SAE, as appropriate. 
14. Maternal subjects will complete the Edinburgh Postnatal Depression Scale, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (-2 weeks/+6 weeks) after 
delivery. 


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15. The LFTs should be ordered from the local laboratory before dosing with the IP. If the local laboratory results are available before the start of dosing, confirm that ALT is not 
≥2 × ULN OR total bilirubin is not >1.5 × ULN (>35% direct bilirubin). An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%. With the 
exception of sites in Italy, screening LFT laboratory results do not need to be available for the subject to be randomly assigned to treatment or for the start of dosing with IP; 
however, see Section 5.3.3 if ALT or bilirubin is abnormal. Sites in Italy: Subjects must not be dosed before local laboratory LFT results are obtained and reviewed by the 
investigator, see Section 5.3.1.1 and Section 5.3.3 for details. 
16. Hematology, chemistry, and LFTs will be determined through a central laboratory at the screening, Day 2, and the 1-week face-to-face post infusion assessment visits. The LFT 
values from the central laboratory should be reviewed for abnormalities (see Section 5.3.3). For subjects who deliver within 24 hours after completion or discontinuation of IP and 
for subjects who deliver at the investigative center after discharge but before the 1-week face-to-face post-infusion assessment visit, central laboratory assessments for 
hematology, chemistry, and LFTs should be performed. For subjects that do not deliver at the investigative center, central laboratory assessments for hematology, chemistry, and 
LFTs should be performed at the investigative center within 1 week (acceptable range: 3 to 14 days) after completion of the study drug infusion. 
17. Prior to dosing, if the fetal heart rate pattern is nonreassuring, the subject cannot be dosed. 
18. Electronic fetal monitoring is required for a minimum of 6 hours from the start of the infusion or from the start of a dose increase. As long as the fetal heart rate pattern is 
consistently reassuring throughout the required 6-hour duration of monitoring and the contraction frequency is 2 in a 30-minute window within the last hour of monitoring, 
continuous monitoring may be discontinued and nonstress tests initiated at a minimum of every 8 hours and as needed. Electronic fetal monitoring, including the fetal heart rate 
and fetal heart rate category, will be recorded in the eCRF with maternal vital signs. Any fetal heart rate assessment of Category II or III will be reported as an AE of special 
interest on a specified eCRF (details in Section 7.4.4). 
19. If the subject has not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate will be recorded at the 1-week face-to-face post-infusion assessment visit. 
Any fetal heart rate assessment of Category II or III will be reported as an AE of special interest on a specified eCRF (details in Section 7.4.4). 
20. During the Delivery Phase, fetal heart rate just prior to delivery will be collected, if available, from review of delivery records. Any fetal heart rate assessment of Category II or III 
will be reported as an AE of special interest on a specified eCRF (details in Section 7.4.4). 
21. Maternal and neonatal health care resource use may include, but is not limited to, neonatal complications requiring intensive or specialized care, neonatal hospital readmission, 
and neonatal ambulatory surgery. 
22. PK samples will be taken at each of the following sampling windows (relative to the start of the infusion on Day 1): 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 to 
54 hours. In addition, a PK sample should be taken at the onset of any maternal or fetal SAE that occurs within 12 hours after completion or discontinuation of IP. 
23. In subjects who deliver at an investigative center within 12 hours following completion or discontinuation of the IP, a single cord blood sample will be collected for PK analysis. 
Additionally, a maternal blood sample should be collected at the same time as the cord blood sample if the sample time does not already coincide with a PK sampling window (see 
Section 7.6.1). 
24. A breast milk/colostrum sample is only to be collected in women who deliver and produce breast milk within 12 hours after completion or discontinuation of the IP. 
25. All participating investigational centers will collect a blood sample for maternal DNA in women who provide informed consent for genetic research. 
26. All participating investigational centers will collect a maternal blood sample for biomarker research. 
27. Only US and Canadian investigational centers will collect a maternal blood sample for cell-free fetal DNA in women who provide informed consent for genetic research. 
28. Fetal fibronectin results will be collected only at those institutions that perform fetal fibronectin testing as routine practice. Fetal fibronectin will not be used to determine study 
eligibility. 
29. Cervical length determined by transvaginal ultrasound will be collected only at those institutions that measure cervical length as routine practice. Cervical length will not be used to 
determine study eligibility. 


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7.2. 
Screening and Critical Assessments Prior to Investigational 
Product Administration 
 
The following assessments are required before dosing (i.e., before initiating randomized 
treatment): 
 
• 
Electronic fetal monitoring to confirm that the fetal heart rate pattern remains 
reassuring 
• 
Re-assess that tocolytic therapy is still indicated, according to the investigator’s 
medical discretion. 
• 
Liver function tests from a local laboratory to confirm that ALT is not ≥2 × ULN OR 
total bilirubin is not >1.5 × ULN (>35% direct bilirubin), if available. An isolated 
bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is 
<35% (see Section 5.3.3).With the exception of sites in Italy, dosing may be started 
prior to the availability of these results. 
Sites in Italy: Dosing must not be started prior to the availability of liver function 
tests results from a local laboratory (see Section 5.3.3). 
• 
Electrocardiogram that is interpreted by the investigator to not have any significant 
abnormalities that may place the subject at risk for a cardiopulmonary complication 
during the study 
If the fetal heart rate pattern is nonreassuring, tocolytic therapy is no longer indicated, 
levels of ALT or bilirubin are abnormal (if results are available), or the ECG has been 
interpreted to have clinically significant abnormalities, the subject cannot be dosed and 
will be withdrawn from the study (see Section 5.3.1). 
 
7.3. 
Efficacy 
 
7.3.1. 
Time to Delivery or Treatment Failure 
 
The first of the two co-primary efficacy endpoints is a composite for the time elapsed 
between the beginning of treatment and delivery or treatment failure, whichever occurs 
first. 
 
7.3.1.1. 
Time to Delivery 
 
The time to delivery will be assessed from the start of study treatment administration 
(time 0) in the Inpatient Randomized Treatment Phase until delivery. For this efficacy 
assessment, medical records for the delivery and hospitalization for mother and newborn 
will be reviewed in order to record the following information: 
 
• 
Date and time of delivery 
• 
Mode of delivery 
• 
Indication for delivery 


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Operational procedures will be instituted to optimize data collection and reporting 
consistency in those situations where the subject’s delivery is performed by her referring 
primary care obstetrician. Details of these procedures are provided in the SPM. 
 
7.3.1.2. 
Time to Treatment Failure 
 
Treatment failure will be defined as the administration of any putative tocolytic 
medication for active preterm labor or as prevention of preterm labor, such as calcium-
channel blockers, NSAIDs, or -agonists, apart from the exceptions listed in 
Table 4, and magnesium sulfate doses that exceed a 4- to 6-g IV loading dose and 1- to 
2-g/hour infusion rate and total duration of magnesium sulfate administration greater than 
48 hours (see Section 6.12.1.2). The time to treatment failure will be assessed from the 
start of study treatment administration (time 0) in the Inpatient Randomized Treatment 
Phase until a putative tocolytic is administered. 
 
Treatment failure will be considered to have occurred in the following situations: 
 
• 
Administration of a putative tocolytic following IP discontinuation during the 
Inpatient Randomized Treatment Phase. 
• 
Administration of a putative tocolytic in an undelivered subject for the management 
of recurrent preterm labor. 
• 
Maintenance tocolysis is prohibited (Section 6.12.2.1); any subject treated with a 
tocolytic as maintenance treatment during the Post-infusion Assessment Phase will 
be considered a treatment failure. 
For this efficacy assessment, the following information will be collected: 
 
• 
Date and time of administration of any putative tocolytics 
• 
Name and dose of the putative tocolytics 
• 
Reason for administration of putative tocolytics 
Operational procedures will be instituted to optimize data collection and reporting 
consistency in those situations when the subject is administered an alternative putative 
tocolytic by her referring primary care obstetrician. Details of these procedures are 
provided in the SPM. 
 
7.3.2. 
Neonatal Composite and Other Outcomes 
 
The proportion of neonates with any diagnosis from the neonatal morbidity and mortality 
composite will be determined from time of delivery up to 28 days after the EDD of 
400/7 weeks. For infants who are still hospitalized 28 days post EDD, no further data will 
be collected as part of this study. Data after 28 days post EDD may be captured as part of 
a separate infant follow-up study. 


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For this efficacy assessment, newborn medical records will be reviewed in order to record 
the following information: 
 
• 
Variables relevant to the composite (see complete list in Section 3, Primary 
Endpoints) 
• 
Hospital length of stay 
• 
Neonatal admission to a specialized care unit and length of stay 
• 
Newborn hospital readmission and length of stay 
• 
Ambulatory surgery 
7.4. 
Safety 
 
Planned time points for all safety assessments (maternal, fetal, and neonatal) are listed in 
the Time and Events Table (Table 5). Additional time points for safety tests may be 
added during the course of the study based on newly available data to ensure appropriate 
safety monitoring. 
 
During the Delivery Phase, the following safety information regarding the delivery and 
hospitalization for mother and newborn will be obtained through a review of the hospital 
records: 
 
Maternal 
 
• 
AEs and SAEs (Section 7.4.1) 
• 
AEs of special interest (Section 7.4.1.4 and Appendix 4) 
• 
Disease-related events (DREs) (Section 7.4.1.7.1) 
Neonatal 
 
• 
Apgar scores at 1 and 5 minutes 
• 
Length, weight, and head circumference 
• 
Umbilical cord blood gases (when available) 
• 
AEs and SAEs (Section 7.4.1) 
• 
AEs of special interest (Section 7.4.1.4 and Appendix 4) 
• 
DREs (Section 7.4.1.7.2) 
7.4.1. 
AEs and SAEs 
 
The definitions of an AE or SAE can be found in Appendix 3. 
 
The investigator and their designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE. Maternal, fetal, and neonatal 
AEs will be reported separately. 


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7.4.1.1. 
Time Period and Frequency for Collecting AE and SAE Information 
 
• 
AEs and SAEs will be collected from the start of study treatment until the follow-up 
contact (see Section 7.4.1.3) at the time points specified in Table 5. 
• 
Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF. Additionally, if a condition with a start date 
predating Day 0 (Screening) is subsequently discovered, the condition should be 
recorded in the Medical History eCRF. 
• 
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 
• 
All SAEs will be recorded and reported to GSK/PPD within 24 hours, as indicated in 
Appendix 3. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK/PPD. 
NOTE: The method of recording, evaluating, and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK/PPD are provided 
in Appendix 3 
 
7.4.1.2. 
Method of Detecting AEs and SAEs 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include: 
 
• 
“How are you feeling?” 
• 
“Have you had any (other) medical problems since your last visit/contact?” 
• 
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 


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7.4.1.3. 
Follow-up of AEs and SAEs 
 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and nonserious AEs of special interest (as 
defined in Section 7.4.1.4) will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the subject is lost to follow-up (as defined 
in Section 5.3.1.2). For newborns participating in the infant follow-up study, unresolved 
SAEs and AEs of special interest will be followed to stabilization or resolution in the 
long-term follow-up study. Further information on follow-up procedures is given in 
Appendix 3. 
 
7.4.1.4. 
AEs of Special Interest 
 
Certain AEs are of special interest for evaluating and characterizing the outcomes of 
women, fetuses, and/or neonates participating in this study. These AEs will be recorded 
on the events of special interest eCRFs pages in addition to the AE/SAE eCRF to capture 
additional details for the safety analyses. 
 
Maternal, fetal, and neonatal AEs of special interest are listed in Section 3 and in 
Appendix 4. Guidelines for reporting these events are provided in Appendix 5. 
 
7.4.1.5. 
Cardiovascular and Death Events 
 
For any cardiovascular events detailed in Appendix 3 (Section 12.3.3) and all deaths, 
whether or not they are considered SAEs, specific cardiovascular and death sections of 
the eCRF will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and noncardiovascular death. 
 
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
Screening. The cardiovascular eCRFs are presented as queries in response to reporting of 
certain cardiovascular Medical Dictionary for Regulatory Activities (MedDRA) terms. 
The cardiovascular information should be recorded in the specific cardiovascular section 
of the eCRF within 1 week of receipt of a cardiovascular event data query prompting its 
completion. 
 
The death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 
 
7.4.1.6. 
Congenital Anomalies 
 
The proportion of infants with congenital anomalies diagnosed between the date of birth 
and 28 days post EDD will be assessed. NOTE: A congenital anomaly is a condition 
present at birth that results from malformation, deformation, or disruption in 1 or more 
parts of the body; a chromosomal abnormality; or a known clinical syndrome. Major 
congenital anomalies have a serious adverse effect on health, development, and 
functional ability or may require surgical or medical management. Minor anomalies are 
physical findings that vary from norms in the general population but do not cause 
increased morbidity. 


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When a congenital anomaly is reported, it will be reviewed by an expert in teratology 
who serves as the birth defect evaluator for this study. The birth defect evaluator’s 
responsibilities will include the review, evaluation, and classification of all reports of 
birth defects. Additionally, he/she will provide an opinion regarding the possible 
etiologies for the development of the observed anomalies. The birth defect evaluator will 
reference medically confirmed reports in making the evaluation and issue targeted 
queries to the infant’s heath care provider when necessary. If medical data are deemed 
insufficient to complete the evaluation, the birth defect evaluator may request additional 
medical evaluation of the infant. 
 
For the purpose of this study, the US Centers for Disease Control and Prevention (CDC) 
Metropolitan Atlanta Congenital Defects Program (MACDP) criteria and the European 
Surveillance of Congenital Anomalies (EUROCAT) criteria will be used by the birth 
defect evaluator to code and classify congenital anomalies [EUROCAT, 2005; 
CDC, 2007]. 
 
Infants enrolled in the separate long-term infant follow-up study will be assessed for 
congenital anomalies diagnosed after 28 days post EDD. 
 
7.4.1.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
 
The DREs listed in Section 7.4.1.7.1 and Section 7.4.1.7.2 will be monitored by an 
internal GSK safety review team (reviewing blinded data). 
 
7.4.1.7.1. 
Disease-Related Maternal Events 
 
The following DREs are common maternal events during pregnancy, labor, and delivery: 
 
• 
Signs and symptoms of labor discomfort (e.g., cramping, backache, muscle aches, 
nausea) 
• 
Subsequent episodes of preterm labor (even if hospitalization is required) unless 1 of 
the conditions listed at the end of Section 7.4.1.7.2 applies 
• 
Hospitalization for delivery, unless prolonged or 1 of the conditions listed at the end 
of Section 7.4.1.7.2 applies 


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7.4.1.7.2. 
Disease-Related Neonatal Events (Occurring in Infants Born Prior to 
37 Completed Weeks) 
 
The following DREs are common neonatal events related to prematurity and can be 
serious or life threatening: 
 
• 
Lungs and respiratory system 
• 
Apnea (severe) 
• 
Respiratory failure due to fatigue, hypoxia, or air leak from alveolar injury 
• 
Cardiovascular 
• 
Patent ductus arteriosus 
• 
Bradycardia 
• 
Neurological 
• 
Ventriculomegaly 
• 
Cerebellar hemorrhage 
• 
Hydrocephalus other than congenital 
• 
Gastrointestinal 
• 
Gastroesophageal reflux 
• 
Aspiration pneumonia 
• 
Hematologic 
• 
Anemia 
• 
Vision 
• 
Retinopathy of prematurity (all stages) 
• 
Auditory 
• 
Hearing disorder 
• 
Other 
• 
Temperature instability 
• 
Hypoglycemia 
Because these events (Section 7.4.1.7.1 and Section 7.4.1.7.2) are typically associated 
with preterm labor and prematurity, they will not be reported according to the standard 
process for expedited reporting of SAEs to GSK/PPD (even though the event may meet 
the definition of a SAE). These events will be recorded on the DRE page in the eCRFs, 
and additional data will be recorded for any DREs related to study endpoints (see 
Section 3). These DREs will be monitored by the internal GSK safety review team. 


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However, if one or all of the following conditions apply, then the event should be 
reported as an AE/SAE as indicated in Appendix 3 (Section 12.3.4): 
 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, 
• 
The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the IP, or 
• 
An event defined as a disease-related neonatal event occurs in an infant born 
≥37 completed weeks 
7.4.1.8. 
Regulatory Reporting Requirements for SAEs 
 
Prompt notification by the investigator to GSK/PPD of SAEs and nonserious AEs related 
to study treatment is essential so that legal obligations and ethical responsibilities towards 
the safety of subjects and the safety of a product under clinical investigation are met. 
 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK/PPD 
will comply with country specific-regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK/PPD will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
 
7.4.2. 
Physical Examinations 
 
An admission physical examination will include at a minimum maternal height, weight, 
and assessment of heart, lungs, abdomen, and cervical examination including dilation, 
effacement, and station. 
 
A brief physical examination, assessing heart, lungs, and abdomen, at a minimum, and, if 
undelivered, a cervical examination at the discretion of the investigator will be performed 
at the 1-week face-to-face post-infusion assessment visit, following conclusion of the 
treatment phase. 
 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 


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7.4.3. 
Vital Signs and Oxygen Saturation 
 
Blood pressure, pulse rate, respiratory rate, and temperature will be measured at the 
following time points during the study:  Screening, Inpatient Randomized Treatment 
Phase, and at the 1-week face-to-face post-infusion assessment visit. During the Inpatient 
Randomized Treatment Phase, vital signs and oxygen saturation will be assessed and 
recorded within the following windows relative to the start of the infusion: 15 to 30 
minutes, 4 to 8 hours, 20 to 24 hours, at the end of the infusion, at the time of any dose 
changes, and as warranted by a medical condition. Subjects may be either in a 
semirecumbent or seated position. Clinically relevant abnormal findings, including 
oxygen saturation less than 92%, should be recorded as an AE or SAE, as appropriate. 
 
7.4.4. 
Electronic Fetal Monitoring 
 
Electronic fetal monitoring is required for a minimum of 6 hours from the start of the 
infusion or from the start of a dose increase if the following are confirmed during 
monitoring: 
 
• 
The fetal heart rate pattern is consistently reassuring throughout the required 
minimum 6-hour duration of monitoring 
• 
The contraction frequency is 2 in a 30-minute window within the last hour of 
monitoring. 
A reassuring nonstress test (defined as meeting Category I criterion), accounting for GA 
expectations, is required at a minimum of every 8 hours and as needed. An additional 
6 hours of electronic fetal monitoring will be required for dose interruptions that are 
sufficiently long as to require an additional infusion of the IP. 
 
Electronic fetal monitoring, including the fetal heart rate and fetal heart rate category, 
should be recorded in the eCRF at approximately the same time that maternal vital sign 
measurements are collected (Section 7.4.3). The electronic fetal heart rate tracing (paper 
or electronic) must be archived and retained in site records. Fetal heart rate will be 
recorded at the 1-week face-to-face post-infusion assessment visit if the subject remains 
undelivered. During the Delivery Phase, fetal heart rate just prior to delivery will be 
summarized, if available, from review of delivery records. Any fetal heart rate 
assessment of Category II or III according to the following criteria and based on ACOG 
guidelines [ACOG Practice Bulletin No. 106, 2009] will be reported as an AE of special 
interest on a specified eCRF in addition to the corresponding AE or SAE eCRF: 


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Category I fetal heart rate tracings include all of the following: 
 
• 
Baseline rate: 110 to 160 beats per minute 
• 
Baseline fetal heart rate variability:  moderate 
• 
Late or variable decelerations:  absent 
• 
Early decelerations: present or absent 
• 
Accelerations: present or absent 
Category II fetal heart rate tracings include all fetal heart rate tracings not categorized as 
Category I or III. Category II tracings may represent an appreciable fraction of those 
encountered in clinical care. Examples of Category II fetal heart rate tracings include any 
of the following: 
 
• 
Baseline rate 
• 
Bradycardia not accompanied by absent baseline variability 
• 
Tachycardia 
• 
Baseline fetal heart rate variability 
• 
Minimal baseline variability 
• 
Absent baseline variability with no recurrent decelerations 
• 
Marked baseline variability 
• 
Accelerations 
• 
Absence of induced accelerations after fetal stimulation 
• 
Periodic or episodic decelerations 
• 
Recurrent variable decelerations accompanied by minimal or moderate baseline 
variability 
• 
Prolonged deceleration more than 2 minutes but less than 10 minutes 
• 
Recurrent late decelerations with moderate baseline variability 
• 
Variable decelerations with other characteristics such as slow return to baseline, 
overshoots, or “shoulders” 
Category III fetal heart rate tracings include either of the following: 
 
• 
Absent baseline fetal heart rate variability and any of the following: 
• 
Recurrent late decelerations 
• 
Recurrent variable decelerations 
• 
Bradycardia 
• 
Sinusoidal pattern 


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7.4.5. 
Abdominal Ultrasound 
 
An abdominal ultrasound for determination of the AFI will be performed at Screening for 
confirmation that subject does not have evidence of polyhydramnios or oligohydramnios 
(per exclusion criterion 6, Section 5.2). The AFI should be measured using the 4-quadrant 
method (see SPM for details). An abdominal ultrasound to assess fetal growth will be 
done at Screening (unless records are available documenting an ultrasound-derived 
estimated fetal weight and head circumference within 3 weeks of Screening, with the 
results and date of assessment recorded in the eCRF). 
 
7.4.6. 
Clinical Safety Laboratory Assessments 
 
The following laboratory tests will be performed locally: 
 
• 
Liver function tests, including ALT and bilirubin, performed at Screening (see 
Section 5.3.3) 
If additional nonprotocol-specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), the results must be recorded in the eCRF. Refer to the SPM for appropriate 
processing and handling of samples to avoid duplicate and/or additional blood 
collections. 
 
With the exception of the above, all protocol-required laboratory assessments must be 
performed by the central laboratory. For subjects that do not deliver at the investigative 
center, central laboratory assessments for hematology, chemistry, and LFTs should be 
performed at the investigative center within 1 week (acceptable range: 3 to 14 days) after 
completion of the study drug infusion. 
 
Laboratory assessments must be conducted in accordance with the Central Laboratory 
Manual and protocol Time and Events Table. Laboratory requisition forms must be 
completed and samples must be clearly labeled with the subject number, protocol 
number, site/center number, and visit date. Details for the preparation and shipment of 
samples will be provided by the central laboratory. Reference ranges for all safety 
parameters will be provided to the site by the central laboratory. 
 
The volume of blood required for hematology, chemistry, and liver function tests, as 
specified in the Time and Events Table (Table 5), is approximately 20 mL. 


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7.4.7. 
Electrocardiogram 
 
A single 12-lead ECG will be obtained prior to dosing (after the subject has been in a 
supine position for 10 to 15 minutes). If the investigator determines there is a clinically 
significant ECG abnormality, the subject will not be dosed and will be withdrawn from 
the study (Section 5.3.1.1). Performance of a follow-up ECG after an abnormal finding 
will be at the discretion of the investigator. 
 
7.4.8. 
Fluid Management 
 
Care should be taken to assess for fluid overload by monitoring the total fluid intake and 
output from the Screening Phase through Inpatient Randomized Treatment Phase and 
assessing for signs and symptoms of fluid overload. Details regarding this assessment are 
provided in the SPM. 
 
7.4.9. 
Breastfeeding Status 
 
At the maternal post-delivery assessment, the subjects will be asked questions regarding 
their breastfeeding status, as appropriate. 
 
Details regarding this assessment are provided in the SPM. 
 
7.4.10. 
Maternal Depression 
 
The effect of preterm birth on maternal health status will be assessed using the EPDS. 
The EPDS is a 10-item self-reported assessment of depression, validated for 
administration during both the antenatal and the post-natal periods. Items are rated on a 
4-point variable Likert scale, ranging from 0 to 3. A score of 12+ indicates an increased 
probability of depression and investigators or designated investigative center personnel 
will be notified immediately. Certain items in the scale also assess anxiety and will be 
used to assess level of anxiety. Maternal subjects will complete the EPDS at the maternal 
follow-up assessment 6 weeks (-2 weeks/+6 weeks) post-delivery (Table 5). 
 
Additional details regarding the questionnaire administration, recording of health 
outcomes data, and collection and storage of the information are provided in the SPM. 
 
7.5. 
Health Outcomes 
 
• 
Assess maternal and neonatal health care resource use associated with preterm labor 
and preterm delivery. Health care resource use of interest includes: 
• 
Maternal and neonatal hospital admission (e.g., length of stay, hospital unit and 
type) and resource use (e.g., use of transport services, admission to extended 
stay facility) 
• 
Neonatal interventions of interest (e.g., parenteral nutrition, surfactants, blood 
products), procedures (e.g., imaging, such as ultrasound, computed 
tomography), and surgical procedures. 


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7.5.1. 
Health Outcomes – Maternal 
 
7.5.1.1. 
Maternal Health Care Resource Use 
 
Details on maternal health care resource use (both for hospitalizations related to preterm 
labor not resulting in a delivery and hospitalizations related to preterm labor/normal labor 
resulting in a delivery) associated with an episode of preterm labor, preterm delivery, and 
normal term delivery will be collected from review of medical records and recorded in 
the eCRF. The following information will be collected in the eCRF: 
 
• 
Hospital admissions for preterm labor and normal term labor:  number of hospital 
admissions related to preterm labor/preterm delivery, length of hospital stay (in days, 
hours) associated with hospital admission for preterm labor and normal term 
labor/term delivery, and associated hospital unit and type 
• 
Health care resource use associated with preterm labor and normal term delivery: 
whether the mother was transported to the hospital and by what means 
(ground/aircraft), whether the mother was discharged to an extended stay facility for 
bed rest and days spent at extended stay facility prior to delivery, whether the mother 
was discharged home on uterine activity monitoring and days monitored, and 
delivery method (vaginal or caesarean section). 
7.5.2. 
Health Outcomes – Neonatal 
 
7.5.2.1. 
Neonatal Hospital Admission 
 
For the delivery visit hospitalization, the length of the hospital stay (days) and associated 
hospital unit (neonatal intensive care unit, nursery level, or level of care 1 to 4) will be 
collected from review of medical records and recorded. In addition, whether the baby was 
transported to a different hospital or extended stay facility and length of stay (days) and 
number of hospital readmissions in the month following discharge from the delivery visit 
hospitalization will also be captured. 
 
7.5.2.2. 
Neonatal Health Care Resource Use 
 
Details of neonatal health care resource use associated with neonatal comorbidities of 
interest will be collected from review of medical records and recorded in the eCRF. 
 
In addition to capturing health care resource use associated with neonatal morbidities, the 
following resource use, which may or may not be associated with neonatal comorbidities 
of interest, should be captured: 
 
• 
Use of parenteral nutrition, including number of days of use 
• 
Use of surfactant and number of doses administered 
• 
Imaging (ultrasound, computed tomography, magnetic resonance imaging, 
radionuclide) 
• 
Other surgical procedures 


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7.6. 
Pharmacokinetics 
 
The PK analysis will determine retosiban clearance and volume of distribution and the 
effect of covariates on these parameters. Plasma analysis will be performed under the 
control of GSK PTS-Drug Metabolism and Pharmacokinetics (DMPK)/Scinovo. 
Concentrations of retosiban will be determined in plasma samples using the currently 
approved bioanalytical methodology. Raw data will be archived at the bioanalytical site. 
 
7.6.1. 
Sampling 
 
Maternal blood samples for the quantification of retosiban in plasma will be taken at the 
following sampling windows (relative to the start of the infusion on Day 1):  2 to 4 hours, 
10 to 14 hours, 22 to 26 hours, and 48 to 54 hours, the last point being after the end of the 
infusion. Samples may be taken at any time within these windows, but the exact time of 
the sample should be recorded in the eCRF. The volume of blood required for PK 
sampling, as specified in the Time and Events Table (Table 5), is approximately 8 mL. 
 
Additionally, a maternal blood sample should be collected at the same time as the cord 
blood sample (see Section 7.6.2) if the sample time does not already coincide with one of 
the PK sampling windows listed above. 
 
A blood sample also should be taken at the onset of any maternal or fetal SAE that occurs 
within 12 hours after completion or discontinuation of IP. 
 
7.6.2. 
Umbilical Cord Blood 
 
For those subjects who deliver at the investigative center within 12 hours following 
completion or discontinuation of IP, a single 3 mL cord blood sample will be collected 
for a PK analysis of fetal drug exposure. The date and time the sample was collected 
should be noted in the eCRF. If the investigator deems that umbilical cord blood is 
needed to provide care for the infant (e.g., neonatal transfusion or laboratory testing), 
collection for clinical use will be prioritized over PK sampling for the study. 
 
7.6.3. 
Retosiban Levels in Breast Milk 
 
If breast milk/colostrum is expressed within 12 hours of receiving study treatment, a 
small sample (0.25 mL) will be collected and analyzed to determine if retosiban is 
present in the sample. The date and time of the sample should be noted in the eCRF. 
 
• 
Breast milk/colostrum produced prior to 4 hours of the completion or discontinuation 
of the study treatment will not be permitted to be consumed but will be collected for 
evaluation. 


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• 
A sample of breast milk/colostrum produced between 4 and 12 hours of the 
completion or discontinuation of the study treatment will be collected for evaluation, 
and the remainder can be consumed if the potential benefits to the infant are believed 
to outweigh the potential risks. The subject should be advised on the potential risks 
associated with feeding the infant her breast milk/colostrum that was expressed 
within 12 hours of the completion or discontinuation of the study treatment. 
• 
Breast milk produced more than 12 hours after the completion or discontinuation of 
the study treatment will not be tested and there will be no restrictions on 
consumption given that the time frame is beyond 5 half-lives of retosiban. 
7.7. 
Cervical Length 
 
As routine practice, some institutions may measure cervical length by transvaginal 
ultrasound as an indicator of risk of delivery within hours to days. For these institutions 
already routinely performing this measurement, the cervical length data should be 
recorded in the eCRF. The data will not be used to determine eligibility but should be 
recorded for use in an exploratory analysis of cervical length as a marker of preterm labor 
and response to treatment. Additional details are provided in the SPM. 
 
7.8. 
Fetal Fibronectin 
 
Institutions that routinely perform fetal fibronectin (fFN) testing should record the result 
in the eCRF. Results will not be used to determine subject eligibility but will be used in 
an exploratory analysis of fFN as a marker of preterm labor and response to treatment. 
Details for sample collection and processing are in the SPM. 
 
7.9. 
Biomarkers 
 
A biomarker is a molecule associated specifically with a disease or condition such that it 
allows for the diagnosis, risk identification, or optimization of treatment. A 3.5-mL 
maternal blood sample for biomarker research will be collected at Screening. The 
samples will be stored and may be analyzed for future exploratory research. 
 
7.10. 
Genetics 
 
Pharmacogenetics is the study of how drug response varies in individuals due to genetic 
differences. Genetic differences also may contribute to preterm labor risk and 
progression. Two blood samples will be collected at Screening in subjects who provide 
informed consent for genetic research: a 6-mL sample for maternal DNA (at all 
participating investigational centers) and a 8.5-mL sample for cell-free fetal DNA (at US 
and Canadian investigational centers only). 
 
Information regarding genetic research is included in Appendix 6. 


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8. 
DATA MANAGEMENT 
• 
For this study subject data will be entered into GSK/PPD-defined eCRFs, transmitted 
electronically to GSK/PPD or designee and combined with data provided from other 
sources in a validated data system. 
• 
Management of clinical data will be performed in accordance with applicable 
GSK/PPD standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data. 
• 
AEs, medical history, and surgical procedures will be coded using the current 
version of MedDRA, and concomitant medications terms will be coded using an 
internal validated medication dictionary, GSKDrug. 
• 
eCRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy. Subject initials will 
not be collected or transmitted to GSK according to GSK policy. 
9. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
9.1. 
Hypotheses 
 
The co-primary endpoints assess prolongation of pregnancy using time to delivery or 
treatment failure, whichever comes first, and neonatal outcomes using a morbidity and 
mortality composite. The following are the null (H0) and alternative (H1) hypotheses for 
the co-primary endpoints in this study: 
 
Time to delivery or treatment failure: 
 
• 
H0:  prolongation of pregnancy as measured by time to delivery or treatment failure 
of women is equal between retosiban versus placebo 
• 
H1:  prolongation of pregnancy as measured by time to delivery or treatment failure 
of women is unequal between retosiban versus placebo 
Neonatal composite outcome: 
 
• 
H0:  Incidence of neonatal composite outcome is equal between retosiban versus 
placebo 
• 
H1:  Incidence of neonatal composite outcome is unequal between retosiban versus 
placebo 
The hypotheses will be tested using a sequential testing procedure to control the overall 
type I error rate at the 5% level. Additionally, an O’Brian-Fleming alpha spending 
function will be employed to control the type I error for the planned interim analyses. The 
O’Brien-Fleming boundaries to be used at the second interim analysis and final analysis 
will be based on the actual information fraction, which will be the ratio of the actual 
sample size at the second interim analysis and the re-estimated final sample size (see 
Section 9.2.3). For example, if the actual sample size at the second interim analysis is 
400 women/newborn pairs and the re-estimated sample size remains at 


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800 women/newborn pairs, the hypotheses would be tested at the 0.52% and 4.8% levels, 
respectively. Thus, at the second interim analysis, the hypothesis for time to delivery or 
treatment failure would be tested first at the 0.52% level, and the hypothesis for neonatal 
outcome would then be tested at the 0.52% level only if the null hypothesis for the time 
to delivery or treatment failure is rejected. Similarly, at the final analysis, the hypothesis 
for time to delivery or treatment failure would be tested first at the 4.8% level, and the 
hypothesis for neonatal outcome would then be tested at the 4.8% level only if the null 
hypothesis for the time to delivery or treatment failure is rejected. No further adjustments 
to the type I error rate are planned for the co-primary endpoints. Details of the 
methodologies to control the type I error will be included in the IDMC charter and study 
reporting and analysis plans (RAPs). 
 
9.2. 
Sample Size Considerations 
 
9.2.1. 
Sample Size Assumptions 
 
A total of 900 women (450 women in each group) will be recruited into the study and 
randomly assigned to ensure that 800 (400 women/newborns in each group) have 
recorded birth data, which provides 86% statistical power to detect a relative risk of 68% 
between retosiban and placebo in neonatal outcomes in the proposed adaptive design with 
futility stopping, success stopping, and sample size re-estimation. Calculations assume a 
placebo incidence rate of 34%. 
 
Additionally, the sample size of 800 women (400 women/newborn pairs per group) 
provides at least 90% statistical power to detect a difference of 5.5 days in the co-primary 
endpoint, time to delivery or treatment failure, and the key secondary endpoint, time to 
delivery, between retosiban and placebo. 
 
The sample size calculations are based on a 2-sided testing procedure with a type I error 
rate of 4.8% (e.g., O’Brien-Fleming boundary based on planned information fraction) and 
an approximate 10% dropout rate. Calculations are based on simulations and assume that 
the percentage of women enrolled into each of the GA strata 240/7 to 256/7, 260/7 to 276/7, 
280/7 to 306/7, and 310/7 to 336/7 will be 7%, 13%, 27%, and 53% (1:2:4:8 ratio), 
respectively, and approximately 55% of women in the placebo arm will deliver within the 
3 weeks of randomization. The details of model assumption and simulation are on file 
with GSK. 
 
9.2.2. 
Sample Size Sensitivity 
 
It is expected that the placebo incidence rate of the co-primary endpoint of neonatal 
morbidity and mortality composite will be dependent on the percentage of women 
enrolled into each of the GA strata, the percentage of women that deliver within 3 weeks 
of randomization, and the frequency of neonatal composite. Subsequently, the power of 
the study to detect a relative risk of 68% between retosiban and placebo in neonatal 
outcomes is expected to be sensitive to the assumptions used to determine the study 
sample size. 
 
Further work has been done by GSK (details on file with GSK) to evaluate the sensitivity 
of the power of the study to detect a relative risk reduction in neonatal outcomes if the 


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assumptions do not hold. In those analyses, the power of the study was most sensitive to 
assumptions regarding the percentage of women that delivered within 3 weeks of 
randomization and the frequency of neonatal composite. If these are modestly lower than 
expected, such that the placebo response rate is 28%, then the power of the study will be 
approximately 76% to detect a relative risk of 68% between retosiban and placebo in 
neonatal outcomes. If these are significantly lower, such that the placebo response rate is 
22%, the power of the study could be as low as 60%. 
 
In order to mitigate the uncertainty around these assumptions, the proposed adaptive 
design allows for the sample size of the study to be increased following the second 
interim analysis (see Section 9.3.4). 
 
9.2.3. 
Sample Size Re-Estimation or Adjustment 
 
The sample size may be adjusted at the second interim analysis. The sample size 
re-estimation will be conducted in a manner to maintain the study blind and will be 
carried out prior to the formal statistical interim analysis described in Section 9.3.4 The 
re-estimation sample size will be based only on the blinded observed overall pooled rate 
of neonatal composite and will be conducted by the blinded team. The sample size may 
be increased by a minimum of 50 women/newborn pairs up to a maximum sample size of 
1200 women/newborn pairs. The re-estimated sample size in conjunction with the actual 
sample size for the second interim analysis will be used to determine the 
O’Brien-Fleming boundaries to be used in the interim and final analyses. 
 
The details of the sample size re-estimation methods and determination of the 
corresponding O’Brien-Fleming boundaries will be provided in the RAP. 
 
9.3. 
Data Analysis Considerations 
 
9.3.1. 
Analysis Populations (Maternal) 
 
9.3.1.1. 
Maternal Safety Population 
 
The Maternal Safety Population is defined as all subjects randomly assigned to treatment 
that have been exposed to study treatment. Randomly assigned subjects will only be 
excluded if there is clear evidence the subject did not receive IP. Subjects will be 
analyzed according to their actual treatment in case this differs from their randomized 
treatment. This will be the primary population for assessing maternal and fetal safety. 
 
9.3.1.2. 
Maternal ITT Population 
 
The Maternal ITT Population, also known as the full analysis set, comprises all randomly 
assigned subjects who have been exposed to study treatment. Subjects who are randomly 
assigned but fail to receive any study treatment (as described in Section 5.3.1.1) will be 
excluded from the ITT Population. This is the primary analysis data set and will be used 
for evaluation of all maternal and fetal efficacy endpoints. 


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9.3.1.3. 
Maternal Per-Protocol Population 
 
This Maternal Per-Protocol Population is defined as all subjects in the Maternal ITT 
Population excluding those who are major protocol violators. Subjects will be analyzed 
according to their actual treatment in case this differs from their randomly assigned 
treatment. This will include exclusions for use of prohibited concomitant medications and 
treatment failure to meet inclusion criteria specified by the protocol. 
 
9.3.2. 
Analysis Population (Neonatal) 
 
9.3.2.1. 
Neonatal Safety Population 
 
The Neonatal Safety Population is defined as neonates whose mothers received 
randomized treatment. The neonates will be analyzed according to the actual treatment 
the mother received in case this differs from randomized treatment. This will be the 
primary population for assessing neonatal safety. 
 
9.3.2.2. 
Neonatal ITT Population 
 
The Neonatal ITT Population, also known as the full analysis set, comprises all neonates 
of mothers who were randomly assigned subjects exposed to study treatment. This 
population is the primary analysis data set and will be used for evaluation of all neonatal 
efficacy endpoints. 
 
9.3.2.3. 
Neonatal Per-Protocol Population 
 
The Neonatal Per-Protocol Population is defined as all subjects in the Neonatal ITT 
Population excluding those with major protocol violations. 
 
9.3.3. 
Treatment Comparisons 
 
9.3.3.1. 
Primary Comparisons of Interest 
 
The primary comparison of interest is retosiban versus placebo for the co-primary 
endpoints:  time to delivery or treatment failure and neonatal composite endpoint. The 
comparison will be based on the ITT Population, and a sequential testing procedure will 
be used to control the overall type I error rate at 5% level with time to delivery or 
treatment failure being tested first. 


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9.3.3.2. 
Other Comparisons of Interest 
 
The comparison of retosiban versus placebo will also be performed for key secondary 
endpoints: time to delivery, proportion of preterm births (<370/7 weeks’ gestation), 
proportion of births ≥370/7 weeks’ gestation, and neonatal length of hospital stay. Other 
comparisons of exploratory endpoints between retosiban and placebo will be discussed in 
the RAP. 
 
9.3.3.3. 
Subgroup Analysis 
 
Additionally, comparisons of retosiban versus placebo for co-primary and key secondary 
endpoints may also be performed for the following subgroups: 
 
• 
GA strata 240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7, or 310/7 to 336/7 
• 
Established progesterone use (yes or no) 
• 
Magnesium sulfate use 
• 
Putative tocolytic use following IP discontinuation 
Other potential subgroup comparisons will be described in the RAP. 
 
9.3.3.4. 
Exploratory Covariate Analyses 
 
Other exploratory covariate analyses will be performed to examine the relationship 
between the treatment response and potential covariates including baseline fFN value, 
subclinical intrauterine infection, and other concomitant medications. Details of analysis 
will be included in final RAP. 
 
9.3.4. 
Interim Analyses 
 
Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 subjects have completed delivery and have time-to-delivery results 
available. The primary objective of the first interim analysis is to determine if the study 
should be terminated for lack of efficacy (futility) based on prespecified criteria. The 
decision will be based primarily on the analysis of the key secondary endpoint of time to 
delivery; however, all available safety and efficacy data will be reviewed. 
 
Time to delivery will be analyzed similarly to analyses described in Section 9.4.1.1. An 
estimate of the difference in time to delivery between the retosiban and placebo groups 
will be computed. Additionally, the conditional power of rejecting the null hypothesis at 
the end of the study based on the observed difference will be computed. 
 
The second interim analysis will occur after approximately 400 women/newborn pairs are 
followed up to 28 days post EDD. The primary objectives of the second interim analysis 
are to determine if the study should be terminated for either lack of efficacy (futility) or 
for greater than expected efficacy (success). The decision to terminate for futility will be 
based on prespecified criteria, the key secondary endpoint of time to delivery, and the 
co-primary endpoint of neonatal composite. The decision to stop for success will be 
based on the sequential testing of the null hypotheses for co-primary endpoints (time to 


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delivery or treatment failure and then neonatal composite) at the determined 
O’Brian-Fleming boundary (the adjusted alpha level based on an O’Brian-Fleming alpha 
spending function and the actual sample size at the second interim analysis and 
re-estimated sample size at the end of the study, see Section 9.2.3). Decisions will be 
based on prespecified criteria, although all available safety and efficacy data will be 
reviewed. 
 
Time to delivery or treatment failure and the neonatal composite will be analyzed as 
described in Section 9.4.1.1. Point estimate and associated p-value for both the difference 
in time to delivery or treatment failure and the odds ratio of a neonatal composite 
occurring between retosiban and placebo will be computed. Additionally, the conditional 
power of rejecting the null hypothesis at the end of the study based on the observed odds 
ratio of the neonatal composite will be computed. 
 
9.4. 
Key Elements of Analysis Plan 
 
9.4.1. 
Efficacy Analyses 
 
9.4.1.1. 
Primary Analyses 
 
The primary objective of the statistical analysis will be to test the null hypothesis in the 
ITT Population that there is no difference between retosiban and placebo versus the 
alternative hypothesis that there is a difference between the 2 co-primary endpoints. The 
hypotheses tests will be assessed and confidence intervals constructed using the adjusted 
alpha level determined by the O’Brien-Fleming boundaries. 
 
The primary analysis of time to delivery or treatment failure will utilize a finite mixture 
model [McLachlan, 2000] with 2 components, 1 for those women delivering imminently 
and the other for the women delivering at term. The exact weight of each component will 
be determined by the observations from these component and model concomitant 
variables, including treatment, established progesterone use, and GA at randomization. 
Within each component, the expected time to delivery or treatment failure will be 
modeled as a function of treatment as fixed effect and GA at randomization and 
established progesterone use (yes or no) as covariates. The model parameters will be 
estimated using expectation maximization algorithm. Point estimates, associated 
100(1-α)% confidence intervals (CIs), and p-values for the overall average difference in 
time to delivery or treatment failure between retosiban and placebo will then be derived 
using a weighted average of model parameter estimates and variance from each 
subpopulation of the mixture model. 
 
For the neonatal composite outcome endpoint, a logistic regression model will be used 
for comparing retosiban with placebo, with progesterone use (yes or no) and GA at 
randomization as covariates. The model will use a logit link function to estimate the log 
odds of percentage of preterm birth. The model will include terms for treatment group, 
established progesterone use, and GA at randomization. The number and percentage of 
subjects in each treatment group, the odds ratio of response rates (retosiban versus 
placebo), 100(1–α)% CIs for the odds ratio of response rates, and p-value will be 
presented. The relative risk response rates will be computed from the odds ratio. 


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9.4.1.2. 
Secondary Analyses 
 
9.4.1.2.1. 
Key Secondary Analyses 
 
The key secondary analysis for this study includes time to delivery, the proportion of 
births prior to 370/7 weeks’ gestation, proportion of births at term (370/7 to 416/7 weeks’ 
gestation), and length of neonatal hospital stay. To preserve the overall type I error rate, 
the key secondary analysis will be performed if and only if the null hypothesis of the 
primary endpoint is rejected. In addition, a stepwise Holm’s test will be used to adjust for 
multiplicity of the key secondary endpoints such that the type I error rate will be 
maintained at 5%. The endpoint of time to delivery will be analyzed as described in 
Section 9.4.1.1. 
 
The endpoints of proportion of births prior to 370/7 weeks’ gestation and proportion of 
births at term (370/7 to 416/7 weeks’ gestation) will be analyzed analogous to the 
co-primary neonatal composite outcome endpoint. 
 
Length of hospital stay will be log-transformed prior to analysis. Log-transformed length 
of hospital stay will be analyzed using an analysis of covariance adjusting for the 
covariate of established progesterone use (yes or no) and GA at randomization. Other 
covariates may be added at discretion of the study statistician. The model-adjusted length 
of stay will be presented for each treatment group. In addition, the treatment difference 
between retosiban and placebo and associated CIs and p-values will be presented. 
 
The Wilcoxon rank sum test will also be performed for length of hospital stay if the 
assumption of normality is violated after log transformation. 
 
Additionally, interactions between GA at randomization and treatment and established 
progesterone use and treatment will also be investigated. 
 
9.4.1.2.2. 
Other Secondary and Exploratory Analysis 
 
Binary secondary analysis endpoints will be analyzed in a similar fashion to the neonatal 
composite analysis. Binary exploratory endpoints will be analyzed in a similar fashion to 
the key secondary endpoints. The details of analysis will be provided in the RAP. 


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9.4.2. 
Safety Analyses 
 
No formal hypothesis statistical test will be performed for the safety data. All safety 
analyses will be performed using the Safety Population, unless otherwise specified. The 
objective of the safety analysis is to describe the maternal, fetal, and neonatal safety 
profile during/after IV retosiban treatment as compared with placebo treatment. As such, 
maternal, fetal, and neonatal safety data will be summarized by treatment group. 
 
All summary statistics of continuous variables will include the following: number of 
subjects, mean, median, standard deviation, minimum, and maximum. For binary 
outcomes, all summary tables will include the number and percentage of subjects with the 
response/event. All summary tables will include N for each group (i.e., the total number 
of subjects randomly assigned to each group within the appropriate population). 
 
To further describe the maternal, fetal, and neonatal safety profile of retosiban, a GA of 
pregnancy at randomization subgroup may be explored. 
 
For this subgroup, maternal, fetal, and neonate safety data will be summarized by 
treatment and subgroup, as described above. Other potential subgroup comparisons will 
be described in the RAP. 
 
9.4.2.1. 
Extent of Exposure (Maternal) 
 
The total volume administered during the infusion and the total study drug administered 
will be listed and summarized. If applicable, the number of infusion interruptions and the 
time taken for each infusion will be summarized. The frequency and percentage of 
women who discontinued study treatment and who had a dose increase will be presented. 
Full details of the extent of exposure will be provided in the RAP. 
 
9.4.2.2. 
Adverse Events 
 
Adverse events will be coded using the MedDRA dictionary and grouped by body 
system. Adverse events will be summarized by treatment group. Within each group, AEs 
will be summarized by frequency and proportion of total subjects, by event type, and by 
category of body system. Separate summaries will be given for all AEs, drug-related 
AEs, SAEs, and AEs leading to discontinuation. Where appropriate, the AEs will be 
summarized by maternal, fetal, and neonatal events separately. 
 
The proportion of subjects reporting at least 1 AE, 1 IP-related AE, 1 SAE, and 1 AE 
leading to discontinuation will also be calculated for each group. 
 
Adverse events of special interest (see Section 7.4.1.4 and Appendix 4) and DREs (see 
Section 7.4.1.7) will be similarly summarized. 
 
Full details of all safety analyses including AEs, SAE, AEs of special interest, DREs, 
clinical laboratory evaluations, and vital sign measurements will be provided in the RAP. 


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9.4.3. 
Health Outcomes Analyses 
 
Analysis of neonatal length of stay, one of the key secondary endpoints, is described in 
Section 9.4.1.2.1. All other health outcomes will be analyzed using the ITT Population, 
unless otherwise specified. The objective of the analysis is to compare the health 
outcomes profile in mother/infant receiving IV retosiban treatment as compared with 
placebo treatment. The details of this analysis will be included in the final RAP. 
 
In addition, all healthy outcomes will be summarized by treatment group. The summary 
statistics of continuous variables will include the following: number of subjects, mean, 
median, standard deviation, minimum, and maximum. For binary outcomes, all summary 
tables will include the number and percentage of subjects with the response/event. All 
summary tables will include N for each group (i.e., the total number of subjects randomly 
assigned to each group within the appropriate population). 
 
To further describe the health outcomes of retosiban, the following subgroups may be 
explored: 
 
• 
GA of pregnancy at randomization 
• 
Established progesterone use 
• 
Magnesium sulfate use 
• 
Putative tocolytic use following IP discontinuation 
• 
Region/sites 
9.4.4. 
Pharmacokinetic Analyses 
 
The PK data will be analyzed using a nonlinear mixed-effects approach. The details of 
the analysis will be provided in a separate RAP. 
 
9.4.5. 
Genetic Analyses 
 
Any genetic analyses may be reported concurrently with the clinical study report or 
described in a separate genetic research analysis plan and may be reported separately 
from the main clinical study report. See Appendix 6 for details about the genetic research 
analysis plan. 


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10. 
STUDY GOVERNANCE CONSIDERATIONS 
10.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins. 
 
10.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
 
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements. 
 
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy. 
 
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki. This includes, but is not limited to, the following: 
 
• 
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments, as applicable 
• 
Obtaining signed informed consent 
• 
Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol deviations 
to IRB/IEC) 
GSK/PPD will provide full details of the above procedures, either verbally, in writing, or 
both. 
• 
Signed informed consent must be obtained for each subject prior to participation in 
the study 
• 
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research. 
• 
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission. 
• 
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated. 


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10.3. 
Quality Control (Study Monitoring) 
 
• 
In accordance with applicable regulations, including GCP and GSK/PPD procedures, 
PPD monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK/PPD requirements. 
• 
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will 
serve as the source document. 
GSK will monitor the study and site activity to verify that the 
 
• 
Data are authentic, accurate, and complete 
• 
Safety and rights of subjects are being protected 
• 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements 
The investigator and the head of the medical institution (where applicable) agree to allow 
the monitor direct access to all relevant documents. 
 
10.4. 
Quality Assurance 
 
• 
To ensure compliance with GCP and all applicable regulatory requirements, 
GSK/PPD may conduct a quality assurance assessment and/or audit of the site 
records, and the regulatory agencies may conduct a regulatory inspection at any time 
during or after completion of the study. 
• 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues, and to implement any corrective 
and/or preventative actions to address any findings/issues identified. 
10.5. 
Study and Site Closure 
 
• 
Upon completion or premature discontinuation of the study, the PPD monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations, including GCP and GSK/PPD standard 
operating procedures. 
• 
GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
noncompliance. For multicenter studies, this can occur at one or more or at all sites. 
• 
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the investigator 
or the head of the medical institution, where applicable, of the impending action. 


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• 
If the study is suspended or prematurely discontinued for safety reasons, GSK/PPD 
will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institution(s) conducting the study. GSK/PPD will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. 
• 
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation. 
10.6. 
Records Retention 
 
• 
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere) in a safe and secure location. 
• 
The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK/PPD audit or regulatory inspection), and must be available for 
review in conjunction with assessment of the facility, supporting systems, and 
relevant site staff. 
• 
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken. 
• 
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
regenerating a hard copy, if required. Furthermore, the investigator must ensure there 
is an acceptable back-up of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
• 
GSK/PPD will inform the investigator of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK/PPD 
standards/procedures, and/or institutional requirements. 
• 
The investigator must notify GSK/PPD of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site. 
10.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually 
agreeable location. 


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GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK policy. 
 
10.8. 
Independent Data Monitoring Committee 
 
This study will be conducted under the auspices of an IDMC. The membership and 
activities are outlined in the IDMC charter. This committee will review the accumulating 
data as the study progresses, as well as data across the retosiban program. 


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11. 
REFERENCES 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Practice Bulletin No. 76. Postpartum hemorrhage. Obstet Gynecol. 
2006;108(4):1039-47. 
 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Practice Bulletin No. 106. Intrapartum fetal heart rate monitoring: nomenclature, 
interpretation, and general management principles. Obstet Gynecol. 
2009;114(1):192-202. 
 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Practice Bulletin No. 127. Management of preterm labor. Obstet Gynecol. 
2012;119(6):1308-17. 
 
Bain ES, Middleton PF, Crowther CA. Maternal adverse effects of different antenatal 
magnesium sulphate regimens for improving maternal and infant outcomes:  a systematic 
review. BMC Pregnancy Childbirth. 2013;13:195. 
 
Benedetto MT, DeCicco F, Rossiello F, Nicosia AL, Lupi G, Dell’Acqua S. Oxytocin 
receptor in human fetal membranes at term and during labor. J Steroid Biochem. 
1990;35:205-8. 
 
Berkowitz GS, Blackmore-Prince C, Lapinski RH, Savitz DA. Risk factors for preterm 
birth subtypes. Epidemiology. 1998;9(3):279-85. 
 
Centers for Disease Control and Prevention (CDC). Metropolitan Atlanta Congenital 
Defects Program (MACDP) birth defects and genetic diseases branch 6-digit code for 
reportable congenital anomalies. August 2007. Available from: 
http://www.cdc.gov/ncbddd/birthdefects/documents/macdpcode0807.pdf. (Accessed 
05 Nov 2014). 
 
Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of 
cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and 
metaanalysis. Am J Obstet Gynecol. 2009;200(6):595-609. 
 
Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for 
women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst 
Rev. 2009;(1):CD004661. 
 
Endler M, Grünewal C, Saltvedt S. Epidemiology of retained placenta: oxytocin as an 
independent risk factor. Obstet Gynecol. 2012;119(4):801-9. 
 
European Surveillance of Congenital Anomalies (EUROCAT). Guide 1.3:  Instructions 
for registration of congenital anomalies. Belfast: EUROCAT Central Registry, 
University of Ulster, 2005. Available from: http://www.eurocat- 
network.eu/content/EUROCAT-Guide-1.3.pdf. (Accessed 05 Nov 2014). 


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Fuchs AR, Fuchs F, Husslein P, Soloff MS, Fernstrom MJ. Oxytocin receptors and 
human parturition: a dual role for oxytocin in the initiation of labor. Science. 
1982;215(4538):1396–8. 
 
GlaxoSmithKline Document Number CM2006/00201/05. Investigator's brochure 
GSK716755. 29-Jun-2016. 
 
Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm 
birth. Lancet. 2008;371(9606):75-84. 
 
Goldenberg RL, Iams JD, Mercer BM, et al. The preterm prediction study: the value of 
new vs standard risk factors in predicting early and all spontaneous preterm births. 
NICHD MFMU Network. Am J Public Health. 1998;88(22):233-8. 
 
Goldenberg RL. The management of preterm labor. Obstet Gynecol. 
2002;100(5 Pt 1):1020-37. 
 
Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Tocolytics for preterm labor:  a 
systematic review. Obstet Gynecol. 1999;94(5 Pt 2):869-77. 
 
Lockwood CJ, Kuczynski E. Risk stratification and pathological mechanisms in preterm 
delivery. Paediatr Perinat Epidemiol. 2001;15 Suppl 2:78-89. 
 
Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Wilson EC, Mathews TJ. Births: 
final data for 2010. Natl Vital Stat Rep. 2012;61(1):1-72. 
 
Mathews TJ, MacDorman MF. Infant mortality statistics from the 2006 period linked 
birth/infant death data set. Natl Vital Stat Rep. 2010;58(17):1-31. 
 
McLachlan G, Peel D. Finite mixture models. New York (NY):  John Wiley & Sons, Inc; 
2000. 
 
Meis PJ, Goldenberg RL, Mercer BM, et al. The preterm prediction study:  risk factors 
for indicated preterm births. Maternal-Fetal Medicine Units Network of the National 
Institute of Child Health and Human Development. Am J Obstet Gynecol. 
1998;178(3):562-7. 
 
Pennell CE, Jacobsson B, Williams SM, et al. Genetic epidemiologic studies of preterm 
birth: guidelines for research. Am J Obstet Gynecol. 2007;196(2):107-18. 
 
Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor 
syndrome. Ann N Y Acad Sci. 1994;734:414-29. 
 
Roos C, Spaanderman ME, Schuit E, et al; APOSTELL-II Study Group. Effect of 
maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: 
a randomized controlled trial. JAMA. 2013;309(1):41-7. 
 
Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline No. 7. 
Antenatal corticosteroids to reduce neonatal morbidity. Royal College of Obstetricians 
and Gynaecologists. October 2010. Available from: 


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https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-7.pdf (Accessed 
05 Nov 2014). 
 
Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline 
No. 1B. Tocolytic for women in preterm labour. February 2011a. Available from: 
https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg1b/ (Accessed 
05 Nov 2014). 
 
Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from 
infancy to adulthood. Lancet. 2008;371(9608):261-9. 
 
Samol JM, Lambers DS. Magnesium sulfate tocolysis and pulmonary edema:  the drug or 
the vehicle? Am J Obstet Gynecol. 2005;192(5):1430-2. 
 
Sanchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of maintenance therapy 
after acute tocolysis:  a meta-analysis. Am J Obstet Gynecol. 1999;181(2):484-90. 
 
Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med. 2007;357(5):477-
87. 
 
Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child 
Health and Human Development Neonatal Research Network. Neonatal outcomes of 
extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 
2010;126(3);443-56. 
 
Stones RW, Paterson CM, Saunders NJ. Risk factors for major obstetric haemorrhage. 
Eur J Obstet Gynecol Reprod Biol. 1993;48(1):15-8. 
 
Thornton S, Goodwin TM, Greisen G, Hedegaard M, Arce JC. The effect of barusiban, a 
selective oxytocin antagonist, in threatened preterm labor at late gestational age: a 
randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 
2009;200(6):627e1-627e10. 
 
Tucker JM, Goldenberg RL, Davis RO, Copper RL, Winkler CL, Hauth JC. Etiologies of 
preterm birth in an indigent population:  is prevention a logical expectation? Obstet 
Gynecol. 1991;77(3):343-7. 
 
Valenzuela GJ, Craig J, Bernhardt MD, Holland ML. Placental passage of the oxytocin 
antagonist atosiban. Am J Obstet Gynecol.l 1995;172(4 Pt 1):1304-6. 


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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
 
Abbreviations 
 
ACOG 
American College of Obstetricians and Gynecologists 
AE 
adverse event 
AFI 
amniotic fluid index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BCRP 
breast cancer resistance protein 
CDC 
Centers for Disease Control and Prevention 
CI 
confidence interval 
cm 
centimeter 
CYP3A4 
cytochrome P450 3A4 enzyme 
DMPK 
Drug Metabolism and Pharmacokinetics 
DRE 
disease-related event 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDD 
estimated date of delivery 
EPDS 
Edinburgh Postnatal Depression Scale 
EUROCAT 
European Surveillance of Congenital Anomalies 
fFN 
fetal fibronectin 
GA 
gestational age 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
IB 
investigator’s brochure 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IV 
intravenous 
IVH 
intraventricular hemorrhage 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
kg 
kilogram 
L 
liter 
MACDP 
Metropolitan Atlanta Congenital Defects Program 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
msec 
millisecond 


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NaCl 
sodium chloride 
ng 
nanogram 
NSAID 
nonsteroidal anti-inflammatory drug 
pg 
picogram 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PPROM 
preterm premature rupture of membranes 
QTc 
corrected QT interval 
QTcF 
corrected QT interval using the Fridericia formula 
RAP 
reporting and analysis plan 
RCOG 
Royal College of Obstetricians and Gynecologists 
RDS 
respiratory distress syndrome 
SAE 
serious adverse event 
SPM 
Study Procedures Manual 
ULN 
upper limit of normal 
 
 
Definitions 
 
Chronological age 
Defined as the time elapsed after birth; it is usually 
described in days, months, and years 
Estimated date of delivery 
Defined as 400/7 weeks’ gestation for all subjects 
Gestational age 
Determined by (1) known fertilization date, either in vitro 
fertilization or intrauterine insemination or (2) a best 
estimated due date confirmed or established by the earliest 
ultrasound performed before 240/7 weeks gestation. 
Postmenstrual age 
Determined by adding chronological age to gestational age 
at delivery 
 
 
Trademark Information 
 
Trademarks of the GlaxoSmithKline 
group of companies 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
MedDRA 


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12.2. 
Appendix 2: Liver Safety Required Actions and Follow-up 
Assessments 
 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
ALT-Absolute 
ALT 8 × ULN 
ALT-Increase 
ALT ≥5 × ULN but <8 × ULN persists for ≥2 weeks 
ALT ≥3 × ULN but <5 × ULN persists for ≥4 weeks 
Bilirubin1,2 
ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) 
INR2 
ALT ≥3 × ULN and INR >1.5, if INR measured 
Cannot 
Monitor 
ALT ≥5 × ULN but <8 × ULN and cannot be monitored weekly for ≥2 weeks 
ALT ≥3 × ULN but <5 × ULN and cannot be monitored weekly for ≥4 weeks 
Symptomatic3 
ALT 3 × ULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions and Follow-up Assessments Following ANY Liver Stopping Event 
Actions 
Follow-up Assessments 
• Immediately discontinue study treatment 
• Report the event to GSK/PPD within 
24 hours 
• Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow-up assessments 
• Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below) 
• Do not restart/rechallenge subject with 
study treatment but continue subject in the 
study for any protocol-specified follow-up 
assessments 
• Viral hepatitis serology4 
• Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5 
• A blood sample for pharmacokinetic 
analysis will be obtained within 12 hours of 
last dose (completion or discontinuation)6 
• Serum creatine phosphokinase and 
lactate dehydrogenase 
• Fractionated bilirubin, if total bilirubin 
2 × ULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on 
the concomitant medications report form 


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MONITORING: 
For bilirubin or INR criteria: 
• Repeat liver chemistries (include ALT, AST, 
ALP, bilirubin) and perform liver event follow-
up assessments within 24 hours 
• Monitor subjects twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
For all other criteria: 
 
• Repeat liver chemistries (include ALT, AST, 
ALP, bilirubin) and perform liver event 
follow-up assessments within 24 to 72 hours 
• Monitor subjects weekly until liver chemistries 
resolve, stabilize, or return to within baseline 
including acetaminophen, herbal 
remedies, other over-the-counter 
medications. 
• Record alcohol use on the liver event 
alcohol intake case report form 
For bilirubin or INR criteria: 
• Antinuclear antibody, antismooth muscle 
antibody, type 1 antiliver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). 
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) 
and/or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
IgM = immunoglobulin M; INR = international normalized ratio; eCRF = electronic case report form; GSK = 
GlaxoSmithKline; HPLC = high-performance liquid chromatography; PK = pharmacokinetic; SAE = serious 
adverse event; ULN = upper limit of normal. 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT ≥3 × ULN and bilirubin ≥2 × ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2. 
All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 x ULN and INR >1.5, if INR 
measured, which may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants. 
3. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash, or 
eosinophilia). 
4. 
Includes: hepatitis A immunoglobulin M (IgM) antibody; hepatitis B surface antigen, and hepatitis B core antibody 
(IgM); hepatitis complementary RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing); hepatitis E IgM antibody. 
5. 
If hepatitis delta antibody assay cannot be performed, it can be replaced with a polymerase chain reaction of 
hepatitis D RNA virus (where needed) [Le Gal, 2005]. 
6. 
The PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample collection and the date/time of the last dose of study 
treatment prior to blood sample collection on the eCRF. If the date or time of the last dose is unclear, provide the 
subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the Study Reference Manual. 


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Liver Chemistry Increased Monitoring Criteria With Continued Therapy 
 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT 5 × ULN and <8 × ULN and 
bilirubin <2 × ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT 3 × ULN and <5 × ULN and 
bilirubin <2 × ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks. 
• Notify the PPD medical monitor within 24 hours 
of learning of the abnormality to discuss subject 
safety. 
• Subject can continue study treatment 
• Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize, or return to 
within Baseline 
• If at any time subject meets the liver 
chemistry stopping criteria, proceed as 
described above 
• If ALT decreases from ALT 5 × ULN and 
<8 × ULN to ≥3 × ULN but <5 × ULN, continue to 
monitor liver chemistries weekly. 
• If, after 4 weeks of monitoring, ALT <3 × ULN and 
bilirubin <2 × ULN, monitor subjects twice 
monthly until liver chemistries normalize or return 
to within baseline
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GSK = GlaxoSmithKline; ULN = upper limit of 
normal. 


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References 
 
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos. 2009;37(8):1779-84. 
 
Le Gal F, Gordien E, Affolabi D, et al. Quantification of hepatitis delta virus RNA in 
serum by consensus real-time PCR indicates different patterns of virological response to 
interferon therapy in chronically infected patients. J Clin Microbiol. 2005;43(5):2363-9. 


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12.3. 
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Following Up, and Reporting of Adverse Events 
 
12.3.1. 
Definition of Adverse Events 
 
Adverse Event Definition: 
 
• 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. 
 
 
 
Events meeting AE definition include: 
 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., electrocardiograms, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/serious AE (SAE) unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This should be reported regardless of sequelae.) 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfill the definition 
of an AE or SAE. 


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Events NOT meeting definition of an AE include: 
 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
 
 
12.3.2. 
Definition of Serious Adverse Events 
 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b.   Is life threatening 
NOTE: 
The term “life threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE: 
• 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from Baseline is not considered an AE. 


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d. Results in disability/incapacity 
NOTE: 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle), which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. 
• 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
g. Is associated with liver injury and impaired liver function defined as: 
• 
Alanine aminotransferase (ALT) 3 × upper limit of normal (ULN) and total 
bilirubin* 2 × ULN (>35% direct) 
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3 × ULN 
and total bilirubin 2 × ULN, then the event is still to be reported as an SAE. 


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12.3.3. 
Definition of Cardiovascular Events 
 
Cardiovascular event definition: 
 
Investigators will be required to fill out the specific cardiovascular event page of the 
electronic case report form (eCRF) for the following AEs and SAEs: 
 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
 
 
12.3.4. 
Recording of AEs and SAEs 
 
AEs and SAE Recording: 
 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. 
• 
The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GlaxoSmithKline (GSK)/PPD AE/SAE 
eCRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK/PPD. In this instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission to GSK/PPD. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 


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12.3.5. 
Evaluating AEs and SAEs 
 
Assessment of intensity: 
 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to an intensity category. Refer to the SPM for details 
on assessing intensity of maternal and fetal AEs and SAEs. 
 
• 
Note: An event is defined as “serious” when it meets at least one of the predefined 
outcomes as described in the definition of an SAE. 
 
 
 
Assessment of causality: 
 
• 
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE. 
• 
A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated. 
• 
The investigator will also consult the investigator brochure and/or product 
information, for marketed products, in the determination of his/her assessment. 
• 
For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK/PPD. However, it is very 
important that the investigator always make an assessment of causality for 
every event prior to the initial transmission of the SAE data to GSK/PPD. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 


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Follow-up of AEs and SAEs: 
 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK/PPD 
to elucidate as fully as possible the nature and/or causality of the AE or SAE. 
• 
The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK/PPD with a copy of any postmortem 
findings, including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE or AE of special interest data to 
GSK/PPD within the designated reporting time frames. 
 
 
 
12.3.6. 
Reporting of SAEs to GSK/PPD 
 
SAE reporting to GSK/PPD via electronic data collection tool 
 
• 
Primary mechanism for reporting SAEs to GSK/PPD will be the electronic data 
collection tool 
• 
If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE hotline fax number, as provided 
on medical monitor/sponsor information page of the protocol. 
• 
Site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator will be required to confirm review of the SAE causality by ticking 
the “reviewed” box at the bottom of the eCRF page within 72 hours of submission of 
the SAE. 
• 
After the study is completed at a given site, the electronic data collection will be 
taken off-line to prevent the entry of new data or changes to existing data 
• 
If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or by telephone 
using the SAE hotline telephone number, as provided on medical monitor/sponsor 
information page of the protocol. 
• 
Contacts for SAE receipt can be found at the beginning of this protocol on the 
sponsor/medical monitor contact information page. 


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12.4. 
Appendix 4: Adverse Events of Special Interest 
 
The safety endpoints in this study include the following maternal, fetal, and neonatal 
adverse events (AEs) of special interest: 
 
Maternal AEs of special interest 
 
• 
Maternal death 
• 
Chorioamnionitis and its complications 
• 
Clinical chorioamnionitis, preterm premature rupture of membranes, 
endomyometritis, wound infection, pelvic abscess, bacteremia, septic shock, 
disseminated intravascular coagulation, and adult respiratory distress syndrome 
(RDS) 
• 
Placental abruption 
• 
Postpartum hemorrhage – postpartum hemorrhage and/or retained placenta 
• 
Pulmonary edema 
 
 
Fetal AEs of special interest: 
 
• 
Intrauterine fetal demise 
• 
Category II or III fetal heart rate tracing (defined according to American College of 
Obstetricians and Gynecologists [ACOG] Practice Bulletin 106 [ACOG Practice 
Bulletin No. 106, 2009]) 
• 
Fetal inflammatory response syndrome characterized by cord blood interleukin-6 
>11 pg/mL, funisitis, or chorionic vasculitis 
 
 
Neonatal AEs of special interest: 
 
NOTE: Information collected from the time of birth through 28 days post EDD. 
 
Neonatal AEs of special interest are defined by their relationship to maternal 
chorioamnionitis and will include the following: 
 
• 
Neonatal death 
• 
Asphyxia 
• 
Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis) 
• 
RDS 
• 
Hypotension 
• 
Intraventricular hemorrhage/periventricular leukomalacia with cysts or porencephaly 
• 
Bronchopulmonary dysplasia 


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• 
Neonatal acidosis 
• 
Hyperbilirubinemia 
• 
Necrotizing enterocolitis (any modified Bell’s staging criteria) 
• 
Hypoxic ischemic encephalopathy 


 
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12.5. 
Appendix 5: Safety Reporting Cheat Sheet 
 
 
NEWBORN 1 SAFETY REPORTING CHEAT SHEET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; ARDS = adult respiratory distress syndrome, BDP = bronchopulmonary dysplasia; DIC = Disseminated Intravascular Coagulation; DRE = disease-related event; 
GERD = gastroesophageal reflux disease, IP = investigational product; IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; PDA = patent ductus arteriosus; 
RDS = respiratory distress syndrome; SAE = serious adverse event. 
 
 
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12.6. 
Appendix 6: Genetic Research 
 
Genetic Research Objectives and Analyses 
 
The objectives of the genetic research are to investigate the relationship between genetic 
variants and 
 
• 
Response to medicine, including retosiban or any concomitant medicines; 
• 
Preterm labor susceptibility, severity, and progression and related conditions 
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will use data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives. 
 
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a reporting and analysis plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report or in a 
separate genetics RAP and report, as appropriate. 
 
Study Population 
 
Any subject who is enrolled in the study can participate in genetic research. 
 
Study Assessments and Procedures 
 
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response. 
 
• 
Two blood samples will be taken for DNA extraction: one for maternal DNA (at all 
participating investigational centers) and one for cell-free fetal DNA (at US and 
Canadian investigational centers only). These samples will be collected at the 
screening visit, after the subject has provided informed consent for genetic research. 
Instructions for collection and shipping of the genetic sample(s) are described in the 
laboratory manual. The DNA from the sample(s) may undergo quality control 
analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample(s), then the sample(s) may be destroyed. The genetic samples 
are collected on a single occasion unless a duplicate sample is required due to an 
inability to use the original sample(s). 
The genetic sample(s) is labeled (or “coded”) with the same study-specific number used 
to label other samples and data in the study. This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 


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The need to conduct genetic analysis may be identified after a study (or a set of studies) 
of retosiban has been completed and the clinical study data are reviewed. In some cases, 
the samples may not be studied, e.g., no questions are raised about how people respond to 
retosiban or other treatment. 
 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner. GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product. 
 
Subjects can request their sample(s) be destroyed at any time. 
 
Informed Consent 
 
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being collected. 
 
Subject Withdrawal From Study 
 
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample(s), if already 
collected: 
 
• 
Continue to participate in the genetic research in which case the genetic DNA 
sample(s) is retained 
• 
Discontinue participation in the genetic research and destroy the genetic DNA 
sample(s) 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the time frame specified by GSK and maintain the documentation in 
the site study records. 
 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
• 
If a subject withdraws consent for genetic research and genotype data have not been 
analyzed, it will not be analyzed or used for future research. 
• 
Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 


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Subjects Who Do Not Receive Study Treatment 
 
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process. In this instance a sample destruction form will not be available to 
include in the site files. 
 
Provision of Study Results and Confidentiality of Subject’s Genetic Data 
 
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined. Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care. 


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12.7. 
Appendix 7: Cytochrome P450 3A4 Enzyme Inhibitors and 
Inducers 
 
Medications that are considered cytochrome P450 3A4 enzyme (CYP3A4) inducers and 
inhibitors are permitted; however, concomitant administration of strong CYP3A4 
inducers or strong inhibitors with the investigational product requires an adjustment to 
the retosiban dosing regimen (see Protocol Section 6.3.2). 
 
Following is a list of CYP3A4 inhibitors and inducers, each classified as strong, 
moderate, or weak on the basis of changes in the AUCi/AUC (area of the curve of 
substrate in the presence of an inhibitor/area under the curve of substrate in a control 
condition). This is not an exhaustive list; the summary of product characteristics and/or 
the package insert for each concomitant medication should be reviewed to determine if 
the product is a strong CYP3A4 inducer or inhibitor. 
 
Strong1 
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
Inhibitors 
Amprenavir 
Aprepitant 
Amlodipine 
Atazanavir 
Cimetidine 
Atomoxetine 
Clarithromycin 
Darunavir 
Atorvastatin 
Conivaptan 
Diltiazem 
Azithromycin 
Fosamprenavir 
Erythromycin 
Bicalutamide 
Grapefruit juice4 
Fluconazole 
Chlorzoxazone 
Indinavir 
Imatinib 
Cilostazol 
Itraconazole 
Nifedipine 
Cyclosporine 
Ketoconazole 
Tofisopam 
Darifenacin 
Nefazodone 
Verapamil 
Dasatinib 
Nelfinavir 
Ezetimibe 
Ritonavir 
Fentanyl 
Saquinavir 
Fluvoxamine 
Telithromycin 
Gemfibrozil 
Troleandomycin 
Isoniazid 


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Strong1 
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
Voriconazole 
Lacidipine 
Omeprazole 
Posaconazole 
Propiverine 
Propofol 
Quinidine 
Ranitidine 
Ranolazine 
Roxithromycin 
Tabimorelin 
Inducers 
Strong1 
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
Carbamazepine 
Bosentan 
Aprepitant 
Efavirenz 
Etravirine 
Amprenavir 
Phenytoin 
Nafcillin 
Avasimibe 
Rifampin 
Nevirapine 
Dexamethasone 
St. Johns Wort 
Phenobarbital 
Glycyrrhizin 
Modafinil 
Oxcarbazepine 


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Strong1 
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
Pioglitazone 
Prednisone 
Rifabutin 
Rufinamide 
1. 
Strong inhibitor: >5 AUCi/AUC (area of the curve of substrate in the presence of an inhibitor/area under the curve 
of substrate in a control condition); strong inducer: <0.2 AUCi/AUC. Co-administration of study drug with a strong 
inhibitor or strong inducer requires an adjustment to the study drug dosing regimen. 
2. 
Moderate inhibitor: 2 to 5 AUCi/AUC; moderate inducer: 0.2 to 0.5 AUCi/AUC. 
3. 
Weak inhibitor: <2 AUCi/AUC; weak inducer: 0.5 to 0.8 AUCi/AUC. 
4. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation- 
dependent. However, no dose adjustment is needed for retosiban, as grapefruit juice is not expected to cause an 
interaction given that retosiban is administered intravenously. 


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12.8. 
Appendix 8: Country-Specific Requirements 
 
At US and Canadian investigational centers only: 
 
One maternal blood sample will be taken for DNA extraction to provide cell-free fetal 
DNA. This sample will be collected at the screening visit, after the subject has provided 
informed consent for genetic research (see Section 7.10 and Appendix 5). 


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12.9. 
Appendix 9: Protocol Changes 
Protocol Amendment Number 01 
Protocol Amendment Number 01 is applicable to all clinical study centers participating in 
this study. Protocol changes specified in Amendment Number 01 are summarized as 
follows: 
 
• 
Revised the time-to-delivery co-primary endpoint into a composite endpoint 
consisting of (1) time to delivery or (2) time to treatment failure, whichever occurs 
first. The inclusion of time to treatment failure in the co-primary endpoint resulted 
from advice from the US Food and Drug Administration (FDA), where it was 
considered equally important to evaluate treatment effect in the context of the 
investigator’s decision to use tocolytic treatment for the subject’s clinical 
management. Treatment failure will be defined as the administration of any putative 
tocolytic medication, such as calcium-channel blockers, nonsteroidal 
anti-inflammatory drugs (NSAIDs), or -agonists during the course of the study and 
will be considered to have occurred in the following situations: 
• 
Administration of a tocolytic following investigational product (IP) 
discontinuation during the Inpatient Randomized Treatment Phase 
• 
Administration of a tocolytic in an undelivered subject for the management of 
recurrent preterm labor 
• 
Use of maintenance tocolysis is prohibited (Section 6.11.2.1); however, any 
subject treated with a tocolytic as maintenance treatment during the 
Post-infusion Assessment Phase will be considered a treatment failure. 
• 
Revised the description of the study design to remove any implication or impression 
that magnesium sulfate was a required treatment. The protocol now indicates that 
investigators have discretion to use a standardized regimen of magnesium sulfate. 
Likewise, the protocol emphasizes that investigators have discretion to use 
intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection. 
Given the allowance for these discretionary treatments, the study design no longer is 
considered consistent with the International Conference on Harmonisation guidance 
E10 (Choice of Control Group) description of an add-on design. As a result, 
references to an add-on design have been removed from the protocol and the study 
design is described as a Phase III, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study. 
• 
Revised the protocol to stipulate that magnesium sulfate should be administered as a 
standardized regimen if the investigator elects to use magnesium sulfate for the 
subject’s clinical management. The protocol previously allowed the investigator to 
determine the magnesium sulfate regimen. Recognizing that a number of different 
dosing regimens exist for the use of magnesium sulfate in obstetrics, the magnesium 
sulfate regimen has been standardized in order to avoid wide variations in the 
magnesium sulfate dose given to subjects. The intravenous magnesium sulfate 
regimen consists of a 4 to 6 g loading dose and 1 to 2 g/hour infusion rate not to 
exceed 48 hours. 


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• 
Revised the protocol to stipulate that antenatal corticosteroid treatment should be 
administered as either two 12-mg doses of betamethasone given intramuscularly 
24 hours apart or four 6-mg doses of dexamethasone every 12 hours administered 
intramuscularly, if treatment has not been given within 7 days of study enrollment. 
Similar to magnesium sulfate, the change is based on the need to standardize the 
betamethasone or dexamethasone regimen in order to control for wide variations in 
the antenatal corticosteroid doses. 
• 
Added the secondary endpoints of (1) time to delivery, (2) time to treatment failure, 
and (3) proportion of women receiving any putative tocolytic. These endpoints allow 
for an assessment of treatment effect on the individual components of the composite 
co-primary endpoint, time to delivery or treatment failure. 
• 
Revised the guidance regarding an adequate treatment response to be more consistent 
with obstetric practice. An adequate treatment response was previously based on a 
clinically relevant reduction in the frequency of contractions without an increase in 
cervical dilation. Investigators have noted that the clinical assessment of response is 
not necessarily limited to contraction frequency and cervical dilation. As a result, the 
protocol now indicates the investigator can assess treatment response on the basis of 
contraction frequency and/or intensity or cervical examination, including dilation, 
effacement, and station. An adequate response is now based on (1) a clinically 
relevant reduction of contraction frequency and/or intensity or (2) no change in the 
cervical examination. 
• 
Added the volume of maternal blood that will be collected for (1) hematology, 
chemistry, and liver function tests; (2) biomarker analyses, (3) genetic analyses, and 
(4) pharmacokinetic analyses, as well as the amount of umbilical cord blood that will 
be collected for pharmacokinetic analysis in subjects who deliver within 12 hours of 
IP exposure. 
• 
Added guidance to investigators to carefully monitor the total volume of oral and 
intravenous fluid administered during preterm labor management to avoid excessive 
fluid intake and risks for maternal and/or neonatal dilution hyponatremia or 
pulmonary edema. 
• 
Removed the requirement to collect a placental tissue sample for pathologic 
examination when delivery occurred at an investigational center. Limiting the 
collection of placental pathology samples to investigational centers has the potential 
to confound the analysis through selection bias. 
• 
Removed the requirement to collect cord blood samples for biomarker and genetic 
testing when delivery occurred at an investigational center. Limiting collection of 
cord blood samples to investigational centers has the potential to confound the 
analysis through selection bias. 
• 
Added the requirement for US and Canadian investigational centers to collect a 
maternal blood sample for cell-free fetal DNA in women who provide informed 
consent for genetic research. The maternal blood sample will be collected during the 
Screening Phase, therefore removing concern about selection bias associated with 
cord blood samples collected at delivery. 


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• 
Clarified that any SAEs and AEs of special interest that are unresolved at 28 days 
post EDD should be followed to stabilization or resolution in those infants 
participating in the follow-up study. 
• 
Revised the protocol to prohibit the use of calcium-channel blockers, nonsteroidal 
anti-inflammatory drugs, and β-agonists for tocolysis during IP administration or for 
maintenance tocolysis in subjects who remained undelivered following the Inpatient 
Treatment Phase. Because the use of any putative tocolytic medication defines a 
subject as a treatment failure under the revised co-primary endpoint, it is critical for 
investigators to avoid concomitant use of tocolysis during IP administration or the 
use of maintenance tocolysis. 
• 
Changed the methodology to be used to control the Type I error for the planned 
interim analyses, such that the O’Brien-Fleming boundaries to be used at the second 
interim analysis and final analysis will be based on the actual information fraction 
(i.e. the ratio of the actual sample size at the second interim analysis and the 
re-estimated final sample size).  he change resulted from feedback from the 
European Medicines Agency (EMA) Committee for Medicinal Products for Human 
Use (CHMP) Scientific Advice and subsequent review of the Paediatric Investigation 
Plan (PIP) modification by the Paediatric Committee (PDCO). 
• 
Modified the statistical adjustment for the interim analyses such that the O’Brien- 
Fleming boundary to be used at the 2nd interim will be based on the actual 
information fraction (i.e. using the re-estimated final sample size) rather than on a 
fixed information fraction. 
• 
Modified the hypotheses, sample size, interim analyses and primary analyses section 
to reflect the change in the co-primary endpoint of time to delivery or treatment 
failure.  The key secondary analyses section was also modified to reflect the 
inclusion of time to delivery as a key secondary endpoint. 
• 
Added magnesium sulfate use and tocolytic use following IP discontinuation as 
subgroups for comparison of retosiban versus placebo for the co-primary and key 
secondary endpoints. The addition of these subgroups is based on protocol changes 
in which the use of magnesium sulfate is discretionary and the use of a tocolytic 
subsequent to IP discontinuation defines a treatment failure. 
• 
Incorporated other administrative changes. The rationale for these changes is to 
ensure a clear and complete protocol for use at the investigational centers. 
 
 
 
Specific Changes in the Text 
Title page: 
Randomized, Double-blind, Multicenter, Phase III Study Comparing the Efficacy and 
Safety of Retosiban Versus Placebo as Add-on Therapy for Women in Spontaneous 
Preterm Labor 
Authors (GSK): PPD 


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Authors (PPD): PPD 
Author (Parexel): PPD 
 
Synopsis, Rationale: 
 
This study (NEWBORN-1) aims to show that retosiban provides additional neonatal 
benefit through its effect to arrest labor and prolong pregnancy sufficiently to allow for 
fetal maturation without significant increased risk to the fetus or neonate. Clinical 
validation of the relationship between prolongation of pregnancy and neonatal benefit 
would establish retosiban as the first drug to add benefit to that of the well-established 
benefits of antenatal corticosteroids for this indication. 
 
Synopsis, Objectives/Endpoints: 
 
Objectives 
Endpoints 
Primary 
• To demonstrate the superiority of retosiban 
to prolong pregnancy and improve neonatal 
outcomes compared with placebo 
• Time to delivery or treatment failure, 
whichever occurs first 
• Proportion of neonates with any 
diagnosis from the neonatal morbidity 
and mortality composite determined up to 
28 days after the estimated date of 
delivery of 
 
 
Synopsis, Overall Design: 
 
• NEWBORN-1 is a Phase III, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study 
• Eligible subjects will be randomly assigned in a 1:1 ratio to receive either retosiban 
IV infusion over 48 hours or matched placebo IV infusion over 48 hours 
•The study will use an add-on design, in which subjects are randomly assigned to 
treatment with retosiban or placebo in addition to the following treatments, 
administered in accordance with institutional guidelines:  (1) antenatal corticosteroid 
treatment; (2) magnesium sulfate for fetal neuroprotection; AND/OR (3) magnesium 
sulfate for tocolysis (details provided in the protocol) 
• Antenatal corticosteroid treatment should be administered as either (1) two 
12-mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 
6-mg doses of dexamethasone administered intramuscularly every 12 hours, if 
treatment has not been given within 7 days of study enrollment. Investigators 
have discretion to use a standardized regimen of magnesium sulfate, as well as 
intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection. 
• Prior to randomization, each subject will be stratified by progesterone treatment at 
Screening (subjects on established progesterone therapy vs subjects not on 


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established progesterone therapy) and GA (240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7, 
or 310/7 to 336/7) 
 
 
Synopsis, Treatment Arms and Duration 
• NEWBORN-1 will comprise 6 phases:  Screening, Inpatient Randomized Treatment, 
Post-Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and 
Neonatal Medical Review. The duration of any subject’s (maternal or neonatal) 
participation in the study will be variable and dependent on GA at study entry and the 
date of delivery 
• Retosiban treatment will be administered as a 6-mg IV loading dose over 5 minutes 
followed by a 6-mg/hour continuous infusion over 48 hours for the remainder of the 
48-hour treatment period. An adequate treatment response is defined as a clinically 
relevant reduction in the frequency of contractions without an increase in cervical 
dilation 
• The placebo control will be a normal saline (0.9% sodium chloride) infusion matched 
for the retosiban volume, for the IV loading dose over 5 minutes, and continuous 
infusion rates, including a dose increase in subjects with an inadequate response after 
the first hour of treatment for the rate for the remainder of the 48-hour treatment 
period. 
• An adequate response is based on (1) a clinically relevant reduction of 
contraction frequency and/or intensity or (2) no change in the cervical 
examination. 
• Subjects with an inadequate response any time after the first hour of treatment will be 
administered another 6-mg retosiban or matched placebo loading dose and the  
retosiban or matched placebo infusion rate will be increased to 12 mg/hour for the 
remainder of the 48-hour treatment period. 
• At each of the 2 planned interim analysis, all available safety and efficacy data will be 
reviewed by the unblinded independent data monitoring committee who may make 
recommendations to terminate the study based on prespecified criteria or at any 
time for an unfavorable benefit:risk profile 
 
 
 
Synopsis, Analysis 
 
The primary comparison of interest is retosiban versus placebo for the co-primary 
endpoints:  time to delivery or treatment failure, whichever occurs first, and neonatal 
composite outcome endpoint. The statistical analysis will test the null hypothesis in the 
Intent-to-Treat Population that there is no difference between retosiban and placebo 
versus the alternative hypothesis that there is a difference between the 2 co-primary 
endpoints. 


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Section 2, Introduction 
 
In contrast, results from the OTA10256 Phase II placebo-controlled study found that 
retosiban prolonged pregnancy and reduced prematurity rates in women between 300/7 
and 356/7 weeks’ gestation. Retosiban, given intravenously over 48 hours, increased days 
to delivery by a mean of 8.2 days relative to placebo; this difference was consistent 
across GAs (Figure 1). The incidence of birth prior to 37 weeks’ gestation in the 
retosiban group was 18.7% compared with 47.2% in the placebo group (see the 
investigator’s brochure [IB] Section 5.3.2.2.2 [GlaxoSmithKline Document Number 
CM2006/00201/03]). No placebo controlled tocolytic studies have demonstrated an 
effect of this magnitude in spontaneous preterm labor. External experts have generally 
agreed that prolonging the time to delivery by 1 week in the absence of harm may benefit 
the newborn, particularly in women who experience spontaneous preterm labor at early 
GAs. 
 
The emerging safety profile for retosiban also appears favorable. All reported adverse 
events (AEs) (maternal, fetal, and neonatal) were generally similar to placebo or 
consistent with expected events in the population under study. A summary of the 
complete results for Study OTA105256 is included in the IB (Section 5.3.2.1  
[GlaxoSmithKline Document Number CM2006/00201/03]). 
 
This study (NEWBORN-1) aims to show that retosiban provides additional neonatal 
benefit through its effect to arrest labor and prolong pregnancy sufficiently to allow for 
fetal maturation without significant increased risk to the fetus or neonate. Clinical 
validation of the relationship between prolongation of pregnancy and neonatal benefit 
would establish retosiban as the first drug to add benefit to that of the well-established 
benefits of antenatal corticosteroids for this indication. 
 
Section 2.2., Brief Background 
 
Oxytocin is a potent uterotonic whose role in the initiation and progression of human 
labor, both term and preterm, has been actively investigated for many years. Although 
preterm labor may well be a syndrome with various etiologies, oxytocin action on the 
uterus likely represents a common step in activation of the myometrium. Paracrine rather 
than endocrine mechanisms are thought to may mediate this process, in which the effects 
of oxytocin are governed by tissue-specific oxytocin receptor expression, which leads to 
direct contractile effects in myometrium and prostaglandin formation in the decidua. 
Prostaglandins in turn mediate myometrial contractions and cervical ripening [Fuchs, 
1982; Benedetto, 1990]. 


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Section 3., Objectives and Endpoints 
 
 
 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the superiority of retosiban 
to prolong pregnancy and improve 
neonatal outcomes compared with placebo 
• Time to delivery or treatment failure, 
whichever occurs first. Time to delivery 
will be calculated from the start of study 
treatment administration until delivery. Time 
to treatment failure will be calculated 
from the start of study treatment 
administration to the administration of 
any putative tocolytic medication 
• Proportion of neonates with any diagnosis 
from the neonatal morbidity and mortality 
composite determined up to 28 days after 
the estimated date of delivery (EDD) of 400/7 
weeks: 
• 
Fetal or neonatal death 
• 
Respiratory distress syndrome (RDS) 
o Requiring continuous positive 
airway pressure or mechanical 
ventilation. Diagnosis requires a 
chest radiograph consistent with 
RDS (reticulogranular 
appearance to the lung fields or 
air bronchograms) within the first 
24 hours of life, OR 
o Received surfactant for a clinical 
picture of RDS within the first 
24 hours of life 
• 
Bronchopulmonary dysplasia at 
≥36 weeks postmenstrual age 
(determined by adding chronological 
age to GA at delivery), defined as 
follows: 
o >21% supplemental oxygen 
requirement, OR 
o Use of high-flow nasal cannula at 
≥1 L (21% oxygen) 
• 
Necrotizing enterocolitis or isolated 
perforation 
o Diagnosed by radiographic 
evidence of Stage II or higher 
according to Bell’s staging criteria 
(fixed/unchanging bowel loops, 
pneumatosis intestinalis, portal 
venous gas, pneumoperitoneum), 


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Objectives 
Endpoints 
OR 
o Pneumatosis intestinalis, bowel 
necrosis, or perforation noted at 
surgery 
• 
Sepsis based on positive blood 
culture with clinical features of sepsis 
• 
Meningitis based on positive results 
for cerebrospinal fluid culture 
performed as part of infection workup 
• 
Retinopathy of prematurity 
o Confirmed by an ophthalmologist 
based on international committee 
Stage 4 or 5, OR 
o Requiring surgical treatment with 
laser or other surgical intervention 
including cryotherapy or 
treatment with antivascular 
endothelial growth factor 
• 
Intraventricular hemorrhage (IVH) 
o Grade 3 or 4 (severe IVH), OR 
o Any grade of IVH with 
posthemorrhagic hydrocephalus 
requiring a shunt 
• 
White matter injury, documented on 
cranial ultrasound or magnetic 
resonance imaging, as indicated by 
the following: 
o Multiple cystic lucencies in 
periventricular white matter (may 
be bilateral or unilateral, may vary 
in size, and be diffuse or focal in 
distribution), OR 
o Porencephalic 
cyst 
(not 
including 
subependymal 
or 
choroid plexus cysts), OR 
o Persistent ventriculomegaly, 
moderate to severe 
• 
Cerebellar hemorrhage (unilateral or 
bilateral) 
Supportive Key Secondary 
• Time to delivery 
• Proportion of births prior to 370/7 weeks’ 
gestation 
• Proportion of births at term (370/7 to 416/7 
weeks’ gestation) 
• Length of neonatal hospital stay 


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Objectives 
Endpoints 
Supportive Other Secondary 
• Proportion of births prior to 320/7 weeks’ 
gestation 
• Proportion of births prior to 280/7 weeks’ 
gestation 
• Proportion of births ≤7 days 
• Proportion of births ≤48 hours 
• Proportion of births ≤24 hours 
• Proportion of neonates with any of the 
co-primary composite neonatal morbidity 
and mortality, excluding RDS 
• Proportion of neonates with each individual 
component of the composite neonatal 
morbidity and mortality endpoints 
• Neonatal admission to a specialized 
care unit and length of stay 
• Newborn hospital readmission and length of 
stay 
• Ambulatory surgery 
• Time to treatment failure 
• Proportion of women receiving any 
putative tocolytic 
Secondary 
• 
To describe the maternal, fetal, and 
neonatal safety profile during and after IV 
retosiban treatment compared with placebo 
Maternal: 
• 
Incidence of reported AEs and serious AEs 
(SAEs) 
• 
Significant changes in vital signs and 
clinical laboratory tests 
• 
Incidence of clinical and laboratory 
toxicities causing subject to discontinue 
study treatment 
• 
Incidence of women scoring 12 or higher 
on the Edinburgh Postnatal Depression 
Scale (EPDS) 
• 
Maternal AEs of special interest 
• 
Maternal death 
• 
Chorioamnionitis and its complications 
o Clinical chorioamnionitis, preterm 
premature rupture of membranes, 
endomyometritis, wound 
infection, pelvic abscess, 
bacteremia, septic shock, 
disseminated intravascular 
coagulation, and adult RDS 
• 
Placental abruption 


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Objectives 
Endpoints 
• 
Postpartum hemorrhage – postpartum 
hemorrhage and/or retained placenta 
• 
Pulmonary edema 
Fetal: 
• 
Incidence of reported AEs and SAEs 
• 
Fetal acidosis 
• 
Fetal AEs of special interest 
• 
Intrauterine fetal demise 
• 
Category II or III fetal heart rate 
tracing (defined according to ACOG 
Practice Bulletin 106 [ACOG Practice 
Bulletin No. 106, 2009]) 
• 
Fetal inflammatory response 
syndrome characterized by cord blood 
interleukin-6 >11 pg/mL, funisitis, or 
chorionic vasculitis 
Neonatal: 
NOTE:  Information collected from the time of 
birth through 28 days post EDD. 
• 
Neonatal Apgar scores (at 1 and 5 minutes 
after birth), 
• 
Growth parameters (weight, length, and 
head circumference) at birth and at 
discharge 
• 
Incidence of reported AEs and SAEs 
• 
Neonatal AEs of special interest will 
include the following: 
• 
Neonatal death 
• 
Asphyxia 
• 
Infections (early onset neonatal 
sepsis, septic shock, pneumonia, 
meningitis) 
• 
RDS 
• 
Hypotension 
• 
IVH/periventricular leukomalacia 
• 
Bronchopulmonary dysplasia 
• 
Neonatal acidosis 
• 
Hyperbilirubinemia 
• 
Necrotizing enterocolitis 
• 
Hypoxic ischemic encephalopathy 
• 
To determine the effect of retosiban 
treatment compared with placebo on health 
care resource use for the maternal and 
neonatal hospitalizations 
• 
Assess maternal and neonatal health care 
resource use associated with preterm labor 
and preterm delivery. Health care resource 
use of interest include: 
• 
Maternal hospital admission (e.g., 


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Objectives 
Endpoints 
length of stay by hospital unit and 
type) and resource use (e.g., use of 
transport services and admission to 
extended stay facility) 
• 
Neonatal interventions of interest 
(e.g., parenteral nutrition, surfactants, 
blood products), procedures (e.g., 
imaging, such as ultrasound and 
computed tomography), and surgical 
procedures 
• 
Neonatal hospital admission (e.g., 
length of stay by hospital unit and 
type) and resource use (e.g., use 
associated with neonatal 
comorbidities of interest). 
• 
To obtain further data on the 
pharmacokinetics of retosiban in 
pregnant women, including the effect of 
covariates such as age, weight, 
race/ethnicity, and GA on retosiban 
clearance and volume of distribution 
• 
Retosiban clearance and volume of 
distribution and the effect of covariates on 
these parameters 
 
 
Section 4.1., Overall Design 
 
NEWBORN-1 is a Phase III, randomized, double-blind, parallel-group, 
placebo-controlled, multicenter study. This study will be conducted in approximately 
900 females, aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact 
membranes in preterm labor between 240/7 and 336/7 weeks of gestation. Eligible subjects 
(for the purposes of this protocol, subject refers to the mother and not the infant unless 
otherwise stated) will be randomly assigned in a 1:1 ratio to receive either retosiban IV 
infusion over 48 hours or matched placebo IV infusion over 48 hours (approximately 
450 subjects in each group). 
 
The study will use an add-on design, in which subjects are randomly assigned to 
treatment with retosiban or placebo in addition to the following treatments: 
 
 Antenatal corticosteroid treatment: Investigators should administer either 
betamethasone or dexamethasone for fetal maturation in accordance with 
institutional guidelines, 
 Magnesium sulfate for fetal neuroprotection:  Investigators who believe magnesium 
sulfate is an important component of care to improve neonatal outcome have the 
option to use magnesium sulfate for fetal neuroprotection in accordance with 
institutional guidelines, 
AND/OR 


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•Magnesium sulfate for tocolysis:  Investigators can administer magnesium sulfate for up 
to 48 hours as an adjunctive treatment to support antenatal corticosteroid therapy. 
Magnesium sulfate tocolysis can be discontinued once antenatal corticosteroid 
treatment is complete or labor subsides, following established guidelines [Mercer, 
2009; ACOG Committee Opinion No. 573, 2013] 
Antibiotic treatment for group B streptococcal (GBS) infections is also allowed per 
institutional guidelines. 
 
Antenatal corticosteroid treatment should be administered as either (1) two 12-mg 
doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses 
of dexamethasone administered intramuscularly every 12 hours, if treatment has 
not been given within 7 days of study enrollment. Investigators have discretion to 
use a standardized regimen of magnesium sulfate, as well as intrapartum antibiotic 
prophylaxis for perinatal group B streptococcal infection (for additional details see 
Section 6.11). 
 
Prior to randomization, each subject will be stratified by progesterone treatment and GA. 
The progesterone strata will consist of subjects on established progesterone therapy or 
subjects not on established progesterone therapy at Screening (see Section 6.11.1.3 for 
details) The GA strata are 240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7, or 310/7 to 336/7. 
All subjects exposed to randomized treatment will be asked to remain in the study 
through delivery and maternal post-delivery assessments and review of the newborn 
records. Withdrawal from the study should only occur if a subject either refuses to 
continue participation or is lost to follow-up (see Section 5.3.1). 


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Section 4.2., Treatment Arms and Duration 
Figure 2, Study Design 
 
1. 
Stratification (1:1) to retosiban or matched placebo based on established progesterone therapy at Screening 
(subjects on established progesterone therapy versus subjects not on established progesterone therapy) and 
gestational age (240/7 to 256/7; 260/7 to 276/7; 280/7 to 306/7; 310/7 to 336/7). 
2 
Randomized treatment will be added to existing treatment with antenatal corticosteroids and magnesium sulfate 
for fetal neuroprotection and/or tocolysis. Antenatal corticosteroid treatment should be administered as  
either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses 
of dexamethasone administered intramuscularly every 12 hours, if treatment has not been given within 7 
days of study enrollment. Investigators have discretion to use a standardized regimen of magnesium 
sulfate, as well as intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection. 
3 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion visit for obstetric 
assessments 1 week (acceptable range: 3 to 14 days) after the Inpatient Randomized Treatment Phase. The 
subject will then be contacted every week via telephone to determine and record if she has delivered or if she has 
experienced any subsequent episodes of preterm labor. Retreatment with the investigational product (retosiban or 
placebo) is not allowed. 
 
 
 
. . . 
 
Subjects will be randomly assigned to treatment on Day 1 of the Inpatient Randomized 
Treatment Phase. The treatment phase will be 48 hours. Subjects who do not experience 
labor progression and remain undelivered after 48 hours will be scheduled for a face to 
face post-infusion visit for obstetric assessments as part of the Post Infusion Assessment 
Phase. Detailed summaries of the assessments for each study phase are provided in the 
Study Procedures Manual (SPM). Retosiban treatment will be administered as a 6 mg 
IV loading dose over 5 minutes followed by a 6 mg/hour continuous infusion for the 
remainder of the 48-hour treatment period. The placebo control will be a normal 


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saline (0.9% sodium chloride [NaCl]) infusion matched for the retosiban volume, IV 
loading dose over 5 minutes, and continuous infusion rate for the remainder of the 
48-hour treatment period. The duration of the treatment should not exceed 48 
hours. 
 
Retosiban treatment will be administered as a 6 mg IV loading dose over 5 minutes 
followed by a 6 mg/hour continuous infusion over 48 hours. An adequate treatment 
response is defined as a clinically relevant reduction in the frequency of contractions 
without an increase in cervical dilation based on (1) a clinically relevant reduction of 
contraction frequency and/or intensity or (2) no change in the cervical examination. 
For sSubjects with an inadequate response any time after the first hour of treatment will 
be administered another 6-mg retosiban or matched placebo loading dose and the  
retosiban or matched placebo infusion rate will increased to 12 mg/hour for the 
remainder of the 48-hour treatment period. A subject’s response should be assessed for at 
least 1 hour following a dose increase before a decision is made to discontinue 
randomized treatment due to lack of response. The duration of the treatment should not 
exceed 48 hours and the total dose should not exceed 582 mg. 
 
The placebo control will be a normal saline (0.9% sodium chloride [NaCl]) infusion 
matched for the loading dose and continuous infusion rates, including a dose increase in 
subjects with an inadequate response after the first hour of treatment. 
 
Investigators will be required to indicate in the electronic case report form (eCRF) the 
reason or reasons for a dose increase. 
 
Treatment can be discontinued due to labor progression with imminent delivery, 
intolerance to treatment, and any contraindication to continuation of randomized 
treatment. Subjects who discontinue randomized treatment will be asked to remain in the 
study through the maternal post-delivery assessment and review of the newborn records. 
Withdrawal from the study should only occur if a subject either refuses to continue or is 
lost to follow-up. 
 
Subjects who do not experience labor progression and remain undelivered after 48 hours 
will be scheduled for a face-to-face post-infusion visit for obstetric assessments as part of 
the Post Infusion Assessment Phase. The visit will be scheduled 1 week (acceptable 
range: 3 to 14 days) following the Inpatient Randomized Treatment Phase. The subject 
will then be contacted every week via telephone to determine and record if she has 
delivered or if she has experienced any subsequent episodes of preterm labor. 
Retreatment with the investigational product (IP; retosiban or placebo) is not allowed. 
 
For those subjects who deliver at the investigative center, a placental tissue sample will 
be obtained at the time of delivery for both local and central laboratory pathological 
examination. Additionally, for subjects who deliver at the investigative center, a single 
cord blood sample will be collected and divided for potential genetic research and 
biomarker assays. In the event that delivery occurs within 12 hours of IP (retosiban or 
placebo) completion or discontinuation, the single cord blood sample will also be divided 
for pharmacokinetic (PK) analysis. Likewise, a breast milk/colostrum sample will be 
collected for PK analysis in women who deliver and produce breast milk within 12 hours 
after completion or discontinuation of the IP. Once delivery is confirmed during the 


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Delivery Phase of the study, the maternal delivery and hospitalization record will be 
reviewed for data collection by the investigator obstetrician. If delivery occurs at a 
different hospital, the investigator obstetrician will need to obtain the maternal 
delivery and hospitalization record for review. For those subjects who deliver at the 
investigative center within 12 hours of IP (retosiban or placebo) completion or 
discontinuation, a cord blood sample will be collected for pharmacokinetic (PK) 
analysis. Likewise, a breast milk/colostrum sample will be collected for PK analysis 
in women who deliver at the investigative center and produce breast milk within 12 
hours after IP completion or discontinuation. 
 
. . . 
 
Detailed summaries of the assessments for each study phase are provided in the 
Study Procedures Manual (SPM). 
 
Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 women/newborn pairs complete all assessments. The second interim 
analysis will occur after approximately 400 women/newborn pairs complete all 
assessments. At each interim analysis, all available safety and efficacy data will be 
reviewed by the unblinded independent data monitoring committee (IDMC) who may 
make recommendations to terminate the study based on prespecified criteria. At the 
second interim analysis, the IDMC may also make recommendations to increase the 
sample size of the study based on prespecified criteria. Additionally, the IDMC may 
make recommendations to terminate the study at any time for an unfavorable 
benefit:risk profile. Subjects will continue to be enrolled while the interim analyses are 
being conducted. 
 
Section 4.4., Design Justification 
 
As discussed in Section 2, there is no convincing evidence that current tocolytic regimens 
sufficiently prolong pregnancy to provide neonatal benefit beyond that of antenatal 
corticosteroids alone. In contrast, results from a Phase II placebo-controlled study suggest 
that retosiban’s effect to prolong pregnancy may be sufficient to improve neonatal 
outcomes. In women with spontaneous preterm labor between 300/7 to 356/7 weeks’ 
gestation, retosiban administered intravenously over 48 hours increased time to delivery 
by a mean of 8.2 days above and beyond that of placebo; this difference was consistent 
across GAs. Further, there is general agreement that prolonging the average time to 
delivery by 1 week in the absence of significant risk is likely to benefit the newborn, 
particularly in women who present in spontaneous preterm labor at early GAs. Together, 
these findings form the basis of the clinical hypothesis, which states that retosiban 
provides neonatal benefit beyond that of antenatal corticosteroids by prolonging 
pregnancy sufficiently to allow for continuing fetal maturation without causing 
significant risk to the fetus or neonate. To test this hypothesis, the study uses a 
randomized design that compares retosiban with placebo when both are added to 
antenatal corticosteroid treatment for fetal maturation and magnesium sulfate treatment 
for fetal neuroprotection or tocolysis. 
 
The study population represents a particularly vulnerable group for poor infant outcomes, 
for whom effective treatment options are limited. As a result, the protocol allows 


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investigators discretion for the use of betamethasone or dexamethasone in accordance 
with institutional guidelines. Antenatal corticosteroids have been proven to reduce the 
risks for neonatal mortality and morbidity and are recommended in women between 24 
weeks and 34 weeks’ gestation at risk for spontaneous preterm birth [ACOG Practice 
Bulletin No. 127, 2012; RCOG Green top Guideline No. 7, 2010). Investigators have the 
option of using magnesium sulfate for tocolysis according to institutional guidelines in 
order to administer antenatal corticosteroids. Although there is no evidence that 
magnesium sulfate tocolysis improves neonatal outcomes [Mercer, 2009], short-term use 
of magnesium sulfate to prolong pregnancy for administration of antenatal corticosteroids 
in pregnant women between 24 and 34 weeks of gestation at risk of preterm delivery is 
appropriate [ACOG Committee Opinion No. 573, 2013]. Investigators will also have 
discretion to use magnesium sulfate for fetal neuroprotection according to institutional 
guidelines. Fetal neuroprotection is becoming a component of obstetric care based on the 
available evidence indicating magnesium sulfate given prior to anticipated early preterm 
birth reduces the risk of cerebral palsy [ACOG Committee Opinion 455, 2010; Antenatal 
Magnesium Sulphate for Neuroprotection Guideline Development Panel, 2010; RCOG 
Scientific Impact Paper No. 29, 2011b; Society of Obstetricians and Gynaecologists of 
Canada; SOGC Clinical Practice Guideline 258, 2011]. The potential benefit of these 
therapies to a high risk obstetric population forms the basis for permitting their use under 
the add-on design. 
 
Placebo-controlled studies provide scientific rigor through their effect to distinguish 
an effective treatment from an ineffective treatment by controlling for all potential 
influences on the actual or apparent course of the disease or condition other than 
those arising from the pharmacologic action of the test drug. Such influences 
include the natural history of the disease or condition, subject or investigator 
expectations, use of other therapy, and subjective elements of diagnosis or 
assessment. 
 
The study population represents a particularly vulnerable group for poor infant 
outcomes, for whom effective treatment options are limited. As a result, the protocol 
allows for the use of antenatal corticosteroids, either betamethasone or 
dexamethasone, magnesium sulfate in a standardized regimen, and intrapartum 
antibiotic prophylaxis for perinatal group B streptococcal infection. 
 
To fulfill regulatory requirements to study pediatric subjects, pregnant adolescents aged 
12 to 17 years are allowed to participate in this study. Adolescent pregnancy is 
complicated by a higher likelihood of preterm labor and subsequent delivery, but there is 
no evidence that the pathophysiology of spontaneous labor and delivery differs between 
pregnant adolescents and adults or that the clinical course differs. Pregnant adolescents 
are more likely to deliver a low birth weight or preterm infant than older females (<40 
years), and their babies have a higher risk of dying during infancy [Mathews, 2010; 
Martin, 2012]. Since local laws, customs, and institutional practice vary globally, 
investigator discretion in the enrollment of pediatric subjects is permitted. 
 
The add-on design with placebo control represents a reasonable and scientifically valid 
study design, which gives the investigator discretion to provide antenatal corticosteroids 
for fetal maturation and magnesium sulfate treatment for fetal neuroprotection and/or 


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tocolysis in a vulnerable, at risk population while testing the superiority of retosiban to 
provide neonatal benefit beyond that of antenatal corticosteroids. 
 
The add-on design with placebo control is also consistent with International Conference 
on Harmonisation (ICH) Guidance E10, Choice of Control Group, which notes that such 
a design has the advantage of providing evidence of improved clinical outcomes, 
particularly when alternative treatments are not fully effective. This guidance is relevant 
because current tocolytic drugs fail to provide neonatal benefit beyond that of antenatal 
corticosteroids and prematurity complications remain disproportionately high in this 
target population despite antenatal corticosteroids. Further, the add-on design has been 
used in a variety of therapeutic studies. Recent US Food and Drug Administration drug 
approvals in which registration studies used an add on design with a placebo control 
include simeprevir for chronic hepatitis C infection (November 2013), canagliflozin for 
type 2 diabetes mellitus (March 2013), lacosamide for partial-onset seizures (October 
2008), tolvaptan for clinically significant hypervolemic and euvolemic hyponatremia, 
including patients with heart failure and Syndrome of Inappropriate Antidiuretic 
Hormone (May 2009), and belimumab for systemic lupus erythematosus (March 2011). 
 
Section 4.5.1., Retosiban and Matched Placebo 
 
Retosiban will be administered as a 6 mg IV loading dose over 5 minutes followed by a 6 
mg/hour continuous infusion for 48 hours. An adequate treatment response is defined as a 
clinically relevant reduction in the frequency of contractions without an increase in 
cervical dilation based on (1) a clinically relevant reduction of contraction frequency 
and/or intensity or (2) no change in the cervical examination. For subjects with an 
inadequate response any time after the first hour of treatment, investigators should 
administer another 6 mg loading dose and increase the infusion rate to 12 mg/hour for the 
remainder of the 48 hour treatment period (see Section 6.1 for additional dosing details  
and Section 6.3 for IP administration and dose adjustments, respectively). 
 
The proposed retosiban dosing regimen has been informed by animal studies defining 
retosiban concentrations for inhibition of myometrial contractions, evaluations of 
exposure, safety, and tolerability over primarily by results from the Phase II study 
(OTA105256) where a wide range of doses was evaluated in healthy subjects and 
forced titration studies in pregnant women with preterm labor. In Parts A and B of this 
Phase II study, Tthe retosiban regimen is was designed to yield a target concentration 
range based on preclinical models of preterm labor. Based on interim analysis of 
Parts A and B, the target mean steady-state concentration was refined in Part C to of 
75 ng/mL. The option to double the dose after 1 hour allows for between-subject 
variability in retosiban pharmacokinetics, receptor density, and half maximal inhibitory 
concentration (IC50) values. Findings from Study OTA105256 Part C indicate this 
dosing strategy was successful, as 60% of subjects responded to the 6 mg/hour infusion, 
whereas 40% of subjects required an increase in the infusion rate to 12 mg/hour. These 
findings also support the initial 6 mg/hour infusion rate as the lowest effective dose for 
the majority of subjects, while recognizing that the higher 12-mg/hour infusion rate may 
be required in subjects failing to respond to the initial infusion rate. 


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4.5.2.   Matched Placebo 
 
For the placebo control, Normal saline 0.9% NaCl will be administered intravenously  
will serve as the placebo control. The normal saline infusion will be matched for the  
retosiban volume, IV loading dose over 5 minutes, and continuous infusion rates, 
including a dose increase in subjects with an inadequate response any time after the first 
hour of treatment (see Section 6.1 for additional dosing details and Section 6.3 for IP 
administration and dose adjustments, respectively). 
 
As discussed in Section 4.4, use of a placebo control serves to distinguish an effective 
treatment from an ineffective treatment by controlling for all potential influences on 
the actual or apparent course of preterm labor other than those arising from the 
pharmacologic effect of retosiban. 
 
4.5.2.Antenatal Corticosteroids 
 
Antenatal corticosteroid treatment reduces severe neonatal complications and death when 
administered to women between 24 and 34 weeks’ gestation at risk for spontaneous 
preterm birth [Di Renzo, 2006; RCOG Green top Guideline No. 7, 2010; ACOG 
Committee Opinion 475, 2011]. Investigators should administer either betamethasone or 
dexamethasone for fetal maturation in accordance with institutional guidelines. 
 
4.5.3.Magnesium Sulfate 
 
Practice guidelines for the use of magnesium sulfate for fetal neuroprotection have been 
developed by the ACOG Committee on Obstetric Practice and Society for Maternal Fetal 
Medicine [ACOG Committee Opinion 455, 2010], the Antenatal Magnesium Sulphate for 
Neuroprotection Guideline Development Panel [Antenatal Magnesium Sulphate for 
Neuroprotection Guideline Development Panel, 2010], and SOGC [SOGC Clinical 
Practice Guideline 258, 2011]. As these practice guidelines vary according to 
interpretation and generalizability of the available evidence for the effect of magnesium 
sulfate given prior to anticipated early preterm birth to reduce the risk of cerebral palsy, 
investigators electing to administer magnesium sulfate for fetal neuroprotection should 
consider using 1 of the 3 regimens detailed in published guidelines [ACOG Committee 
Opinion 455, 2010; Antenatal Magnesium Sulphate for Neuroprotection Guideline 
Development Panel, 2010; SOGC Clinical Practice Guideline 258, 2011]. 
 
Magnesium sulfate may also be given as tocolysis for up to 48 hours as an adjunctive 
treatment to support antenatal corticosteroid therapy. Magnesium sulfate tocolysis can be 
discontinued once antenatal corticosteroid treatment is complete or labor subsides, 
following established guidelines [Mercer, 2009; ACOG Committee Opinion No. 573, 
2013]. 


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Section 4.6.1., Risk Assessment 
135 
 
 
 
 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Fetal exposure through placental transfer 
Preclinical data indicate very minimal, if any, maternal CNS 
penetration or placental transfer of retosiban as supported 
by the following: 
In pregnant monkeys there was no detectable retosiban in 
the cord blood when mothers were dosed up to 100 mg/kg 
(approximately 7 times the human exposure). However, 
approximately 4% of circulating drug was detected in the 
cord blood when mothers were dosed at 300 mg/kg 
(approximately 24-fold the human exposure). 
Retosiban is a substrate of P-gp and breast cancer 
resistant protein transporters, which are thought to play a 
role in keeping xenobiotics out of the CNS and out of the 
fetal blood, thereby limiting fetal exposure to retosiban. 
In reproductive toxicology studies in pregnant monkeys, 
there were no adverse mother and infant behavioral or 
locomotor effects observed that were suggestive of CNS 
toxicity. 
In rodent neurobehavioral safety studies, there were no 
adverse clinical signs observed at doses up to 1000 mg/kg. 
Analysis of maternal blood and cord blood samples will be 
performed to test for levels of retosiban in women who 
deliver at an investigative center within 12 hours of the 
completion or discontinuation of study treatment infusion in 
this study. 
Surveillance for signals indicating adverse fetal or neonatal 
effects with in utero exposure to retosiban will be 
performed throughout this study. 
Infants exposed to retosiban in utero will be followed for a 
minimum of 24 months up to 5 years in a separate 
follow-up study to assess long-term safety and 
neurodevelopmental outcomes. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
. . . 
•
Adverse maternal, fetal, or neonatal outcomes due to 
prolonging pregnancy in the presence of subclinical 
intrauterine infection 
The study population includes women, particularly those 
presenting in labor prior to 300/7 weeks of gestation, in 
whom intrauterine infection is implicated as a major 
etiologic factor. Infection may be chronic and 
asymptomatic with the first indication being preterm labor 
or rupture of the membranes. The asymptomatic nature of 
intrauterine infection, including lack of fever, abdominal 
pain, and fetal tachycardia, makes the diagnosis 
challenging. Infection is thought to trigger the labor process 
as a protective means for both the mother and baby 
[Goldenberg, 2002]. 
The protocol will exclude women with a temperature 
>100.4°F (38°C) for more than 1 hour or ≥101°F (38.3°C), 
as well as women with confirmed or suspected 
contraindication for continuation of pregnancy, such as 
chorioamnionitis, premature rupture of membranes, and 
abruption. 
Placental tissue samples will be collected when delivery 
occurs at an investigative center to examine safety and 
efficacy outcomes in subjects with subclinical intrauterine 
infection based on histopathologic examination. 
A set of AEs of special interest identified in the literature as 
linked to maternal clinical or subclinical infection has been 
generated and will be used to collect targeted information 
of these AEs. This information, as well as the results from 
the histopathology of the placenta data, will be monitored 
in stream by an IDMC. The unblinded IDMC will review all 
available safety and efficacy data. 
Potential drug-drug interaction with inhibitors of BCRP or P-
gp 
Retosiban is a substrate of murine BCRP and P-gp in vitro. 
Inhibitors of BCRP and P-gp have the potential to increase 
exposure of retosiban when co-administered. 
BCRP and P-gp is expressed in placental membranes and 
the blood-brain barrier, and there is the potential of 
increased maternal CNS and fetal exposure to retosiban 
when co-administered with inhibitors. 
Clinical experience with exposures 10-fold higher than the 
exposure at the planned therapeutic dose has shown 
retosiban to be safe and well tolerated, with no observed 
untoward effects in adult women of childbearing potential. 
Retosiban will only be given for 48 hours, limiting both 
maternal and fetal exposure. The impact of concomitant 
use of retosiban with inhibitors of BCRP or P-gp will be 
assessed through AE monitoring. 
Analysis of maternal serum and cord blood samples will be 
performed when delivery occurs within 12 hours of study 
treatment infusion with co-administration of a BCRP or 
P-gp inhibitor to assess the effect of P-gp inhibition on 
placental transfer of retosiban. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Pulmonary edema 
Pulmonary edema is a rare but potentially life-threatening 
complication of pregnancy. In the setting of preterm labor, 
pulmonary edema is thought to involve both increased 
hydrostatic pressure and altered vascular permeability. 
Factors associated with pulmonary edema include 
spontaneous preterm labor, multifetal pregnancy, 
chorioamnionitis, pre-eclampsia, cardiac disease, fluid 
overload, blood transfusion, corticosteroid therapy, and 
tocolytic treatment. Magnesium sulfate is implicated 
especially when additional risk factors are present. 
Randomized studies have not shown an increased risk of 
pulmonary edema or other serious maternal complications 
with antenatal magnesium sulfate [Doyle, 2009; Conde- 
Agudelo, 2009; Bain, 2013]. A retrospective chart review 
showed that contributing factors for pulmonary edema 
during magnesium sulfate treatment included high dose, 
high infusion rate, high net positive fluid balance, 
concomitant tocolysis, and multifetal gestations [Samol, 
2005]. 
Women with identified risk factors for pulmonary edema 
are excluded from the clinical study. These include 
multifetal pregnancies, pre-eclampsia, chorioamnionitis, 
and certain pre-existing cardiovascular conditions. 
Guidance is provided to investigators regarding 
appropriate duration, therapy, and Magnesium sulfate 
will be administered in a standardized regimen per the 
investigator’s discretion (see Section 6.11.1.2). 
Additional information regarding monitoring of 
magnesium sulfate for neuroprotection and/or tocolysis 
(detailed in the therapy is provided in SPM). 
Guidance is provided to investigators regarding fluid 
balance up to the time of starting treatment and for the 
duration of treatment (see Section 7.4.8). 
Pulmonary edema is designated as an AE of special 
interest requiring the collection and/or assessment of 
specific, relevant history and physical examination 
findings, targeted eCRFs to characterize any reported 
events, and a maximum duration of tocolytic treatment with 
magnesium sulfate of 48 hours. 
AE = adverse event; BCRP = breast cancer resistance protein; CNS = central nervous system; eCRF = electronic case report form; IDMC = independent data monitoring committee; 
P-gp = P-glycoprotein; PPH = postpartum hemorrhage; SPM = Study Procedures Manual. 


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Section 4.6.2, Benefit Assessment 
 
Birth prior to 34 weeks’ gestation represents roughly 30% of preterm births in the United 
States, half of which are preceded by spontaneous labor [Martin, 2012; Tucker, 1991; 
Berkowitz, 1998; Meis, 1998; Goldenberg, 2008]. Premature birth in this group carries a 
disproportionately high risk for death, neonatal complications, and long-term disabilities. 
Infants born prior to 32 weeks’ gestation die at a rate 72 times that of term infants; the 
mortality rate for infants born between 32 and 33 weeks’ gestation is 7-fold higher 
[Mathews, 2010]. Surviving infants remain susceptible to both short-term and long-term 
prematurity complications, resulting from injury to immature organ systems [Stoll, 2010; 
Saigal, 2008]. 
 
The benefit of antenatal corticosteroids for fetal maturation and magnesium sulfate for 
fetal neuroprotection and short term prolongation of pregnancy is available to all subjects 
in accordance with institutional guidelines. 
 
Section 4.6.3., Overall Benefit:Risk Conclusion 
 
Despite the proven benefit of antenatal corticosteroids, neonatal mortality and morbidity 
remain disproportionately high in neonates born prematurely to women who experience 
spontaneous preterm labor. Based on Tthe Phase II program found that results showing 
retosiban treatment significantly increased the time to delivery and reduced preterm 
births, this study will test whether These findings suggest the potential for retosiban to  
can provide additional benefit by prolonging pregnancy and allowing for continued 
maturation of fetal organs and systems. 
 
Taking into account the Although experience in pregnant women is limited, the 
retosiban safety profile is favorable, and no clinical or preclinical safety issues have 
been identified that preclude further development. In addition, the protocol 
institutes a number of incorporated to minimize risk to measures aimed at mitigating 
potential risks to subjects participating in this study including antenatal corticosteroid 
treatment for fetal maturation and magnesium sulfate for fetal neuroprotection and/or 
tocolysis, the. These include extensive maternal, fetal, and neonatal safety 
assessments and an IDMC to monitor maternal, fetal, and neonatal safety in an 
ongoing manner throughout the study. 
 
Balancing the potential risks identified in association with of retosiban treatment 
against are justified by the anticipated benefits that may be afforded to subjects with 
preterm labor, Tthe overall benefit:risk assessment of retosiban appears favorable  
reasonable for the mother, fetus, and infant. Although, experience in pregnant women is 
limited, no clinical or preclinical safety issues have been identified that preclude further 
development. 
 
For detailed information on the identified risks and risk-benefit assessment of retosiban, 
refer to the IB and IB supplement 1 [GlaxoSmithKline Document Number 
CM2006/00201/03; GlaxoSmithKline Document Number 2015N228508_00]. 


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Section 5., Selection of Study Population and Withdrawal Criteria 
 
 
 
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GlaxoSmithKline (GSK) IP or other study treatment that 
may affect subject eligibility is provided in the IB, IB Supplement 1, and other pertinent 
documents [GlaxoSmithKline Document Number CM2006/00201/03; 
GlaxoSmithKline Document Number 2015N228508_00]. 
 
Section 5.1., Inclusion Criteria 
 
5. Current or past tocolytic treatment as follows: 
a. Subjects in whom tocolytic treatment has not been initiated prior to consent are 
eligible for the study 
b. Transferred or referred subjects for whom parenteral magnesium sulfate treatment 
has been started before Screening are eligible provided they meet all eligibility 
criteria 
c. Subjects receiving another a prohibited tocolytic not permitted in this study are 
eligible only if the treatment is stopped before randomization and provided they 
meet all eligibility criteria 
d. Subjects with a historical failure of a tocolytic treatment in a previous episode of 
preterm labor during the current pregnancy are eligible provided they meet all 
eligibility criteria 
e. 
Section 6.1., Investigational Product and Other Study Treatment 
 
The retosiban infusion will be prepared by an unblinded pharmacist or other 
qualified professional, using two 5 mL retosiban vials admixed in a 500 mL 0.9% 
NaCl infusion bag to obtain a concentration of 0.3 mg/mL (150 mg retosiban in 500 
mL 0.9% NaCl). The infusion admixture is a clear, colorless solution. 
 
An unblinded pharmacist or other qualified individual will prepare the placebo of 
infusion using 0.9% NaCl 500 mL matched for the retosiban loading dose and 
continuous infusion rates, including a dose increase in subjects with an inadequate 
response any time after the first hour of treatment. 
 
Table 1 summarizes the study treatments. 


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Table 1 
Retosiban Investigational Product and Other Study Treatment 
 
Product Name 
Study Treatment 
Retosiban (GSK221149) 
Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
Drug product 
description 
Clear, colorless solution for infusion in a 5-mL 
vial containing 75 mg of retosiban 
A placebo-matched glass vial is not provided. 
Unit dose 
strengths/ 
Dosage levels 
Retosiban 15 mg/mL 
The total dose given over 48 hours should not 
exceed 300 mg at the 6-mg/hour infusion rate 
and 582 mg at the 12-mg/hour infusion rate. 
0.9% NaCl matched for the retosiban loading 
dose and continuous infusion rates 
Route of 
administration 
IV 
IV 
Dosing 
instructions: 
The retosiban 6-mg loading dose is 
administered at an infusion rate of 240 mL/hour 
for 5 minutes. After 5 minutes, the infusion rate 
is reduced to 20 mL/hour to deliver retosiban at 
a rate of 6 mg/hour for the remainder of the 
48-hour treatment period. 
An adequate treatment response is defined as 
a clinically relevant reduction in the frequency 
of contractions without an increase in cervical 
dilation. 
For subjects with an inadequate response any 
time after the first hour of treatment, 
investigators should administer another 6-mg 
loading dose by increasing the infusion rate to 
240 mL/hour for 5 minutes, after which the 
infusion rate is set to 40 mL/hour in order to 
deliver retosiban at a rate of 12 mg/hour. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inhibitor, the retosiban 
3-mg loading dose is administered at an 
infusion rate of 120 mL/hour for 5 minutes. 
After 5 minutes, the infusion rate is reduced to 
6.7 mL/hour to deliver retosiban at a rate of 
2 mg/hour. For subjects with an inadequate 
response any time after the first hour, an 
additional 1-mg loading dose is administered 
by increasing the infusion rate to 40 mL/hour 
over 5 minutes after which the infusion rate is 
set to 10 mL/hour to deliver retosiban at 
3 mg/hour for the remainder of the 48-hour 
treatment period. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inducer, the retosiban 
8.5-mg loading dose is administered at an 
infusion rate of 340 mL/hour for 5 minutes. 
After 5 minutes, the infusion rate is reduced to 
28 mL/hour to deliver retosiban at a rate of 
8.5 mg/hour. For subjects with an inadequate 
response any time after the first hour, an 
additional 3.5-mg loading dose is administered 
by increasing the infusion rate to 140 mL/hour 
for 5 minutes. After 5 minutes, the infusion rate 
is reduced to 40 mL/hour to deliver retosiban at 
Intravenous administration of the 0.9% NaCl 
solution will be matched to the loading dose 
rate of 240 mL/hour for 5 minutes, after which 
the infusion rate is set to 20 mL/hour. 
An adequate treatment response is defined as 
a clinically relevant reduction in the frequency 
of contractions without an increase in cervical 
dilation. 
For subjects with an inadequate response any 
time after the first hour of treatment, 
investigators should administer another loading 
dose by increasing the infusion rate to 240 
mL/hour for 5 minutes, after which the infusion 
rate is set to 40 mL/hour. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inhibitor, the loading 
dose is administered at an infusion rate of 
120 mL/hour for 5 minutes. After 5 minutes, the 
infusion rate is reduced to 6.7 mL/hour. For 
patients with an inadequate response any time 
after the first hour, an additional loading dose is 
administered by increasing the infusion rate to 
40 mL/hour over 5 minutes, after which the 
infusion rate is set to 10 mL/hour. 
For subjects receiving concomitant treatment 
with a strong CYP3A4 inducer, the loading 
dose is administered over 5 minutes at an 
infusion rate of 340 mL/hour for 5 minutes. 
After 5 minutes, the infusion rate is reduced to 
28 mL/hour. For patients with an inadequate 
response any time after the first hour, an 
additional loading dose is administered by 
increasing the infusion rate to 140 mL/hour for 
5 minutes. After 5 minutes, the infusion rate is 
reduced to 40 mL/hour. 
See Study Pharmacy Manual for detailed 
instructions. 


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Product Name 
Study Treatment 
Retosiban (GSK221149) 
Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
a rate of 12 mg/hour. 
See the Study Pharmacy Manual for detailed 
instructions. 
Manufacturer/ 
Source of 
procurement 
GSK 
Not applicable – to be sourced locally 
CYP3A4 = cytochrome P450 3A4 enzyme; IV = intravenous; GSK = GlaxoSmithKline; NaCl = sodium chloride; 
PTM = placebo to match. 
 
 
Section 6.3.1., Inadequate Response 
 
An adequate treatment response is defined as a based on (1) clinically relevant reduction 
of contraction frequency and/or intensity or without an increase in (2) no change in 
the cervical dilation examination. For subjects with an inadequate response any time 
after the first hour of treatment with retosiban or matching placebo, investigators should 
administer another 6 mg loading dose by increasing the infusion rate to 240 mL/hour for 
5 minutes, after which the infusion rate is set to 40 mL/hour in order to deliver retosiban 
at a rate of 12 mg/hour. Investigators will be required to indicate in the eCRF the reason 
or reasons for a dose increase. A subject’s response should be assessed for at least 1 hour 
following a dose increase before a decision is made to discontinue randomized treatment 
due to lack of an inadequate response. 
 
Section 6.4., Blinding 
 
The IDMC will review unblinded data periodically as part of in addition to 2 formal 
interim analyses and in accordance with the IDMC charter. Unblinded data will be 
provided by an independent statistical data analysis committee. 
 
This will be a double-blind study and the following will apply: 
 
Section 6.6., Preparation/Handling/Storage/Accountability 
 
The following are the preparation instructions for the retosiban solution for infusion: 
 
• 
Withdraw 10 mL solution from a 500 mL 0.9% NaCl infusion bag and discard the 
solution 
• 
Replace discarded solution with 10 mL retosiban 15 mg/mL concentrate solution for 
infusion from two 5 mL vials to obtain a concentration of 0.3 mg/mL (150 mg 
retosiban in 500 mL 0.9% NaCl). The reconstituted product is a clear, colorless 
solution without particles 
• 
Label the IV bag with the following information: subject number, date, protocol 
number, dosing session number, investigator’s name, dosing session number, and 
the statement, “use as directed per pharmacy manual” (as described in the for 
details see the Study Pharmacy Manual). 


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Once the vial of retosiban solution has been opened, the dilution must be performed 
immediately. The diluted solution for IV administration should be used within 24 hours 
after preparation in order to minimize the risk for microbial growth. The volume for 
the infusion bag must be 500 mL to avoid proportional calculations. 
 
The unblinded pharmacist or other qualified individual will prepare the placebo 
admixture, which will consist of a 500-mL 0.9% NaCl infusion bag, labeled with the  
following information: subject number, date, protocol number, infusion rate, and dosing 
session number, investigator’s name, and the statement, “use as directed per 
pharmacy manual.” The volume of the 0.9% NaCl infusion bag should 500 mL to 
match the 0.9% NaCl infusion bag volume used for the retosiban admixture (for details 
see the Study Pharmacy Manual). 
 
A description of the methods and materials required for preparation of the retosiban 
solution and the matching placebo are detailed in the Study Pharmacy Manual, which will 
be accompanied by a Quality Agreement. 
 
The following considerations must be made with regard to IP preparation, handling, 
storage, and accountability in this study: 
 
• 
Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff 
• 
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation and final disposition records) 
• 
Further guidance and information for final disposition of unused study treatment are 
provided in the SPM Study Pharmacy Manual 
• 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, medical monitor, and/or 
GSK study contact 
• 
A material safety data sheet or equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, 
where this is required by local laws, or will be made available upon request from 
GSK 
Section 6.10., Prior Medications and Nondrug Therapies 
 
Prior medications will be reviewed and the investigator will attempt to obtain a complete 
history of any medications taken during the pregnancy (including the trimester of 
exposure, if possible) and during any previous episodes of preterm labor (e.g., 
magnesium sulfate for neuroprotection or antenatal corticosteroid treatment). 


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Section 6.11.1.1., Antenatal Corticosteroids 
 
Antenatal corticosteroid for fetal maturation treatment should be administered in 
accordance institutional guidelines (see Section 4.5.2) as either (1) two 12-mg doses of 
betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of 
dexamethasone every 12 hours administered intramuscularly, if treatment has not 
been given within 7 days of study. 
 
Section 6.11.1.2., Magnesium Sulfate 
 
Magnesium sulfate for fetal neuroprotection and/or tocolysis is permitted (see Section 
4.5.3). Investigators have the option to use magnesium sulfate. Magnesium sulfate 
should be given intravenously using a 4- to 6-g loading dose and 1- to 2-g/hour 
infusion rate. The total duration of magnesium sulfate administration should not 
exceed 48 hours. 
 
Section 6.11.1.4., Antibiotics 
 
Antibiotic treatment for GBS is allowed per institutional guidelines. Intrapartum 
antibiotic prophylaxis for perinatal group B streptococcal infection will be 
permitted. 
 
Section 6.11.2., Prohibited Medications and Nondrug Therapies 
 
Except for IP administered during this study, no additional investigational drugs or 
investigational devices are permitted for the mother from the time of study entry through 
completion of the follow-up visit (i.e., the maternal post-delivery assessment) or 30 days 
after administration of the last dose of IP, whichever is longer. Concomitant use of other  
tocolytics except for magnesium sulfate is prohibited (see Section 5.1, inclusion criterion  
5, for permitted current or past tocolytic treatment at time of Screening). 
 
Section 6.11.2.1., Tocolytic Drugs 
 
Concomitant use of calcium-channel blockers, nonsteroidal anti-inflammatory 
drugs (NSAIDs), or -agonists for tocolysis during IP administration is prohibited. 
Likewise, the use of calcium-channel blockers, NSAIDs, or -agonists for 
maintenance tocolysis in subjects who remained undelivered following the Inpatient 
Treatment Phase is prohibited. 


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Time and Events Table 
144 
 
 
 
 
 
Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion 
Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical Review 
Phase 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
Information 
collected via 
medical records 
review 
6 weeks 
(±2 weeks) 
after delivery 
Delivery to 
28 days post 
EDD 
Clinical and Other Assessments 
Written informed consent and medical releases for 
treatment2 
X 
Discuss and request consent for participation in 
the infant follow-up study3 
X
X 
Inclusion/exclusion criteria confirmation 
X 
Baseline characteristics and demographic data 
X 
Medical history (including obstetrics history)4 
X 
Urine dDrug screen and alcohol breath analyzer 
screening5 
X 
Physical examination (including height and 
weight) 
X 
Cervical dilation based on digital examination6 
X 
X 
X 
X 
Estimated fetal weight via ultrasound 
X 
Determine AFI via ultrasound7 
X 
Uterine contractions8 
X 
Schedule post-infusion assessment visit 
X 
Investigational Products9 
Retosiban or placebo 
X 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion 
Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical Review 
Phase 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
Information 
collected via 
medical records 
review 
6 weeks 
(±2 weeks) 
after delivery 
Delivery to 
28 days post 
EDD 
Efficacy Assessments 
Date and time of delivery10 
X 
Mode of delivery10 
X 
Indication for delivery10 
X 
Neonatal composite outcomes 
X 
Neonatal hospital stay 
X 
Maternal Safety Assessments 
Concomitant medications 
X
X 
ECG 12-lead11 
X 
Vital sign measurements (BP, pulse rate, 
temperature, and oxygen saturation)12 
X 
X 
X 
X 
AEs, SAEs, and DREs : maternal 
X
X 
Monitor fluid balance 
X 
X 
X 
Breastfeeding status 
X 
Edinburgh Postnatal Depression Scale13 
(maternal) 
X 
Local laboratory assessments (LFTs only)14 
X 
Central laboratory assessments (including 
hematology, chemistry, and LFTs)15 
X 
X 
X15 
Physical examination (brief) 
X 
Status of postpartum bleeding 
X 
Fetal Safety Assessments 
Fetal heart rate monitoring16 
X 
X
X 
X 
AEs, SAEs, and DREs: fetal 
X 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion 
Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical Review 
Phase 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
Information 
collected via 
medical records 
review 
6 weeks 
(±2 weeks) 
after delivery 
Delivery to 
28 days post 
EDD 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: neonatal 
X 
X 
Neonatal Apgar Scores (1 and 5 minutes)10 
X 
Neonatal growth parameters10 
X 
Neonatal umbilical cord blood gases10 
X 
Health Outcome Assessments 
Maternal and neonatal health care resource use17 
X 
X 
Pharmacokinetic Assessments 
Maternal PK blood sample18 
X18 
X 
Cord blood sample19 
X 
Breast milk/colostrum sample20 
X 
Histopathology 
Placental tissue sample21 
X 
Genetic and Biomarker Assessments 
Genetic blood sample for maternal blood sample 
DNA2221 
X 
Biomarker for inflammation (maternal) blood 
sample21 
X 
Cord blood sample for gGenetic and biomarker 
assays blood sample for cell-free fetal DNA23 
X 
Other Assessments 
Fetal fibronectin (optional)24 
X 
Cervical length via transvaginal ultrasound 
(optional)25 
X 
Confirm no other study participation for infant26 
X 


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AE = adverse event; AFI = amniotic fluid index; ALT = alanine aminotransferase; BP = blood pressure; DRE = disease-related event; ECG = electrocardiogram; eCRF = electronic case 
report form; EDD = estimated date of delivery; IP = investigational product; LFT = liver function test; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of 
normal. 
1. 
Subjects who remain undelivered after 48 hours will return for a face-to-face post-infusion visit for obstetric assessments 1 week (acceptable range: 3 to 14 days) following the 
Inpatient Randomized Treatment Phase. The subject will then be contacted every week via telephone to determine and record if she has delivered or experienced any subsequent 
episodes of preterm labor. Note: If the subject is scheduled to visit the clinic for reasons not required by this protocol and/or she happens to be present at the time the telephone 
assessment is due, this assessment may be completed face-to-face. 
2. 
Prestudy screening information that is collected by the study site may need to come from records that are obtained before the subject has signed the informed consent. The  
subject will be required to provide written informed consent before any study-specific procedures are performed, and the consent will request permission for use of any information 
collected prior to its having been signed. 
3. 
During the study, the subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant to participate in a separate long-term 
infant follow-up study for safety and neurodevelopment. Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude involvement in the 
infant follow-up study. 
4. 
Medical history will be collected at Screening. If a condition with a start date predating Day 0 (Screening) is subsequently discovered, the condition should be recorded in the 
Medical History eCRF. For obstetrics history, the investigator will make every effort to obtain this information either via computer records, directly from the subject’s primary care 
obstetrician, or via telephone. However, in cases in which these records are not readily available (e.g., off hours, holiday), it is within the investigator’s discretion to use gestational 
age based on the verbal history from the subject with the intent of getting confirmation from the medical records as soon as possible. 
5. 
The urine drug screen will be performed using a point-of-care, qualitative testing device. A point-of-care breath analyzer for alcohol will be used in some countries in addition to the 
urine drug screen. 
6. 
A cervical examination (including dilation, effacement, and station) will occur at Screening, and an additional cervical examination may be performed before dosing based on 
investigator discretion. If a predosing cervical examination reveals dilation >4 cm, the subject cannot be dosed. Additional cervical examinations (Day 1, Day 2, and/or at the face- 
to-face post-infusion assessment visit) will be performed based on investigator discretion. 
7. 
The abdominal ultrasound for determination of the AFI will be performed at Screening for all subjects. 
8. 
Uterine tocography will be performed prior to dosing to confirm the uterine contraction frequency. If the examination reveals a rate that is <4 contractions over a 30-minute interval, 
the subject cannot be dosed. 
9. 
Antenatal corticosteroid treatment should be administered in accordance with institutional guidelines using either betamethasone or dexamethasone, if treatment has not 
been given within 7 days of study enrollment. Investigators have discretion to use a standardized regimen of magnesium sulfate, as well as intrapartum antibiotic 
prophylaxis for perinatal group B streptococcal infection. Magnesium sulfate can be administered for fetal neuroprotection in accordance with institutional guidelines. 
Magnesium sulfate can also be administered as an adjunctive treatment to support antenatal corticosteroid therapy for up to 48 hours. 
10. Information regarding delivery will be obtained through a review of the hospital and medical records. Growth parameters include neonatal weight, length, and head circumference. 
11. A 12-lead ECG will be performed prior to dosing. If the results are interpreted by the investigator to have clinically significant abnormalities, the subject cannot be dosed. 
12. Blood pressure, pulse rate, and temperature will be assessed at Screening, once every 4 to 8 hours as part of maternal safety monitoring during the Inpatient Randomized 
Treatment Phase, and at the post-infusion assessment visit. Oxygen saturation will be assessed by pulse oximetry at Screening and once every 4 to 8 hours during the Inpatient 
Randomized Treatment Phase; oxygen saturation less than 92% should be recorded as an AE or SAE, as appropriate. 
13. Maternal subjects will complete the Edinburgh Postnatal Depression Scale, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (±2 weeks) after delivery. 


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14. The LFTs should be ordered from the local laboratory to confirm that ALT is not ≥2 × ULN OR total bilirubin is not >1.5 × ULN (>35% direct bilirubin) before dosing with the IP. An 
isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%. Screening LFT laboratory results do not need to be available for the subject to be 
randomly assigned to treatment; however, see Section 5.3.3 if ALT or bilirubin is abnormal. 
15. Hematology, chemistry, and LFTs will be determined through a central laboratory. The LFT values from the central laboratory should be reviewed for abnormalities (see 
Section 5.3.3). For subjects who deliver within 24 hours after completion or discontinuation of IP and for subjects who deliver at the investigative center after discharge but before 
the face-to-face post-infusion assessment visit, central laboratory assessments for hematology, chemistry, and LFTs should be performed. 
16. Prior to dosing, if the fetal heart rate is nonreassuring, the subject cannot be dosed. Fetal heart rate monitoring will be continuous throughout the Inpatient Randomized Treatment 
Phase. The fetal heart rate will be recorded in the eCRF once every 4 to 8 hours in conjunction with maternal vital signs. If the subject has not delivered at the end of the Inpatient 
Randomized Treatment Phase, fetal heart rate will be recorded at the face-to-face post-infusion assessment visit. Any fetal heart rate assessment of Category II or III will be 
reported as an AE of special interest on a specified eCRF (details in Section 7.4.4). 
17. Maternal and neonatal health care resource use may include, but is not limited to, neonatal complications requiring intensive or specialized care, neonatal hospital readmission, 
and neonatal ambulatory surgery. 
18. PK samples will be taken at each of the following sampling windows (relative to the start of the infusion on Day 1): 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 to 
54 hours. In addition, a PK sample should be taken at the onset of any maternal or fetal SAE that occurs within 12 hours after completion or discontinuation of IP. 
19. In subjects who deliver at an investigative center within 12 hours following completion or discontinuation of the IP, the single a cord blood sample will be divided collected for PK 
analysis; this is in addition to using the cord blood sample for biomarker and genetic analyses (if additional consent for genetic testing is provided). 
20. A breast milk/colostrum sample is only to be collected in women who deliver and produce breast milk within 12 hours after completion or discontinuation of the IP. 
21. A placental tissue sample will be collected at delivery in subjects who deliver at an investigative center for both a local and central laboratory pathological examination. All 
participating investigational centers will collect a blood sample for maternal DNA in women who provide informed consent for genetic research. 
22. A blood sample for genetic research will only be collected from subjects who provide informed consent. All participating investigational centers will collect a maternal blood 
sample for biomarker research. 
23. A single cord blood sample will be collected in subjects who deliver at an investigative center, and the sample will be divided for analyses of biomarkers, genetics (if additional 
consent for genetic testing is provided), and pharmacokinetics (if delivery is at an investigative center and within 12 hours after completion or discontinuation of the IP). Only US 
and Canadian investigational centers will collect a maternal blood sample for cell-free fetal DNA in women who provide informed consent for genetic research. 
24. Fetal fibronectin results will be collected only at those institutions that perform fetal fibronectin testing as routine practice. Fetal fibronectin will not be used to determine study 
eligibility. 
25. Cervical length determined by transvaginal ultrasound will be collected only at those institutions that measure cervical length as routine practice. Cervical length will not be used to 
determine study eligibility. 
26. Obtain confirmation from the subject or the legal guardian for the infant that the infant is not participating in any other study. 


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Section 7.3.1., Time to Delivery or Treatment Failure 
 
The first of the two co-primary efficacy endpoints is a composite for the time 
elapsed between the beginning of treatment and delivery or treatment failure, 
whichever occurs first. 
 
Section 7.3.1.1., Time to Delivery 
 
The time to delivery will be assessed from the start of study treatment administration 
(time 0) in the Inpatient Randomized Treatment Phase until delivery. Subjects who have 
not delivered by the end of treatment will return for a face-to-face post infusion visit for 
obstetric assessments 1 week (acceptable range: 3 to 14 days) following the Inpatient 
Randomized Treatment Phase. The subject will then be contacted every week via 
telephone to determine and record if she has delivered. For this efficacy assessment, 
medical records for the delivery and hospitalization for mother and newborn will be 
reviewed in order to record the following information: 
 
Section 7.3.1.2., Time to Treatment Failure 
 
Treatment failure will be defined as the administration of any putative tocolytic 
medication, such as calcium-channel blockers, NSAIDs, or D-agonists. The time to 
treatment failure will be assessed from the start of study treatment administration 
(time 0) in the Inpatient Randomized Treatment Phase until a putative tocolytic is 
administered. 
 
Treatment failure will be considered to have occurred in the following situations: 
 
• 
Administration of a tocolytic following IP discontinuation during the Inpatient 
Randomized Treatment Phase. 
• 
Administration of a tocolytic in an undelivered subject for the management of 
recurrent preterm labor. 
• 
Maintenance tocolysis is prohibited (Section 6.11.2.1); however, any subject 
treated with a tocolytic as maintenance treatment during the Post-infusion 
Assessment Phase will be considered a treatment failure. 
For this efficacy assessment, the following information will be collected: 
 
• 
Date and time of administration of any putative tocolytics 
• 
Name and dose of the putative tocolytics 
• 
Reason for administration of putative tocolytics 
Operational procedures will be instituted to optimize data collection and reporting 
consistency in those situations when the subject is administered an alternative 
tocolytic by her referring primary care obstetrician. Details of these procedures are 
provided in the SPM. 


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Section 7.4.1.3., Follow-up of AEs and SAEs 
 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and nonserious AEs of special interest (as 
defined in Section 7.4.1.4) will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the subject is lost to follow-up (as defined 
in Section 5.3.1.2). For newborns participating in the infant follow-up study, 
unresolved SAEs and AEs of special interest will be followed to stabilization or 
resolution in the long term follow-up study. Further information on follow-up 
procedures is given in Appendix 3. 
 
Section 7.4.1.7.2., Disease-Related Neonatal Events (Occurring in Infants Born Prior 
to 37 Completed Weeks) 
 
• 
Gastrointestinal 
• 
Gastroesophageal reflux 
• 
Aspiration pneumonia 
• 
Hematologic 
• 
Anemia (severe) 
• 
Vision 
• 
Retinopathy of prematurity (all stages) 
However, if one or all of the following conditions apply, then the event should be 
reported as an AE/SAE as indicated in Appendix 3 (Section 12.3.4): 
 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, 
• 
The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the IP, or 
• 
An event defined as a disease-related neonatal event is reported occurs in an 
infant born ≥37 completed weeks 
Section 7.4.4., Fetal Heart Rate Monitoring 
 
Fetal heart rate will be monitored continuously from Screening until completion of the 
48-hour Inpatient Randomized Treatment Phase. Subjects will be allowed breaks of up to 
1 hour if fetal heart rate monitoring up to that point has been reassuring. Fetal heart rate 
should be recorded in the eCRF once every 4 to 8 hours at approximately the same time 
that maternal vital sign measurements are collected (Section 7.4.3). Fetal heart rate also 
will be recorded at the face-to-face post infusion assessment visit if the subject remains 
undelivered. During the Delivery Phase, fetal heart rate monitoring information will be 
collected from review of medical records. Any fetal heart rate assessment of Category II 
or III according to the following criteria and based on ACOG guidelines [ACOG Practice 
Bulletin No. 106, 2009] will be reported as an AE of special interest on a specified eCRF 
in addition to the corresponding AE or SAE eCRF: 


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Section 7.4.6., Clinical Safety Laboratory Assessments 
 
With the exception of the above, all protocol-required laboratory assessments must be 
performed by the central laboratory. Laboratory assessments must be conducted in 
accordance with the Central Laboratory Manual and protocol Time and Events Table. 
Laboratory requisition forms must be completed and samples must be clearly labeled 
with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples will be provided by the central laboratory. 
Reference ranges for all safety parameters will be provided to the site by the central 
laboratory. 
 
The volume of blood required for hematology, chemistry, and liver function tests, as 
specified in the Time and Events Table (Table 2), is approximately 20 mL. 
 
Section 7.4.8., Fluid Management 
 
Care should be taken to assess for fluid overload by monitoring the total fluid 
balance from the Screening Phase through Inpatient Randomized Treatment Phase 
and assessing for signs and symptoms of fluid overload. Details regarding this 
assessment are provided in the SPM. 
 
Section 7.6.1., Sampling 
 
Maternal blood samples for the quantification of retosiban in plasma will be taken at the 
following sampling windows (relative to the start of the infusion on Day 1): 2 to 4 hours, 
10 to 14 hours, 22 to 26 hours, and 48 to 54 hours, the last point being after the end of the 
infusion. Samples may be taken at any time within these windows, but the exact time of 
the sample should be recorded in the eCRF. The volume of blood required for PK 
sampling, as specified in the Time and Events Table (Table 2), is approximately 
8 mL. 
 
In addition, a blood sample should be taken at the onset of any maternal or fetal SAE that 
occurs within 12 hours after completion or discontinuation of IP. 
 
Section 7.6.2., Umbilical Cord Blood 
 
For those subjects who deliver at the investigative center within 12 hours following 
completion or discontinuation of IP, the a single 3 mL cord blood sample will be 
collected and divided for potential biomarker assays (Section 7.10) and genetic research 
(Section 7.11) should also be divided for a PK analysis of fetal drug exposure. The date 
and time the sample was collected should be noted in the eCRF. If the investigator deems 
that umbilical cord blood is needed to provide care for the infant (e.g., neonatal 
transfusion or laboratory testing), collection for clinical use will be prioritized over PK 
sampling for the study. 
 
7.7. 
Histopathology 
 
A placental tissue sample will be collected for pathologic examination when delivery 
occurs at an investigational center. Guidelines have been developed to ensure a consistent 


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evaluation of the placenta, membranes, and umbilical cord across the multiple centers 
participating in this study. Each investigator should review these guidelines and 
procedures, which are provided in the SPM. Gross examination of the intact placenta, 
umbilical cord, and membranes should be performed by the hospital pathology 
department with gross findings reported in a standardized manner. In addition, the 
hospital pathology department will need to prepare tissue sections for histologic 
examination of placenta, membranes, and umbilical cord by a central pathology 
laboratory. 
 
Section 7.9., Biomarkers 
 
Biomarkers may be determined from a maternal blood sample collected at Screening and 
from the single cord blood sample collected during the Delivery Phase (only for those 
subjects who deliver at the investigative center). A Bbiomarkers is a molecule 
associated specifically with a disease or condition such that it allows for the 
diagnosis, risk identification, or optimization of treatment. A 3.5-mL maternal blood 
sample for biomarker research will be collected at Screening. The samples will be 
stored and may be analyzed for future exploratory research. 
 
Section 7.10., Genetics 
 
Pharmacogenetics is the study of how drug response varies in individuals due to 
genetic differences. Genetic differences also may contribute to preterm labor risk 
and progression. Two At Screening (Day 0), a maternal blood samples will be collected  
at Screening in from subjects who sign the optional provide informed consent for 
genetic research: a 6-mL sample for maternal DNA (at all participating 
investigational centers) and a 8.5-mL sample for cell-free fetal DNA (at US and 
Canadian investigational centers only). In addition, for those subjects who deliver at  
the investigative center, the single cord blood sample will be divided and used for genetic 
research. 
 
Information regarding genetic research is included in Appendix 5. 
 
Section 9.1., Hypotheses 
 
The co-primary endpoints are neonatal composite outcome and the assess prolongation of 
pregnancy as measured by using time to delivery (days) or treatment failure, 
whichever comes first, and neonatal outcomes using a morbidity and mortality 
composite. The following are the null (H0) and alternative (H1) hypotheses for the  
co-primary endpoints in this study: 
 
Time to delivery or treatment failure: 
 
• 
H0:  prolongation of pregnancy as measured by time to delivery or treatment failure 
of women is equal between retosiban versus placebo 
• 
H1:  prolongation of pregnancy as measured by time to delivery or treatment failure 
of women is unequal between retosiban versus placebo 
Neonatal composite outcome: 


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• 
H0:  Incidence of neonatal composite outcome is equal between retosiban versus 
placebo 
• 
H1:  Incidence of neonatal composite outcome is unequal between retosiban versus 
placebo 
The hypotheses will be tested using a sequential testing procedure to control the overall 
type I error rate at the 5% level. Additionally, an O’Brian-Fleming alpha spending 
function will be employed to control the type I error for the planned interim analyses. For 
the planned sample size of The O’Brien-Fleming boundaries to be used at the second 
interim analysis and final analysis will be based on the actual information fraction, 
which will be the ratio of the actual sample size at the second interim analysis and 
the re-estimated final sample size (see Section 9.2.3). For example, if the actual 
sample size at the second interim analysis is 400 women/newborn pairs and the 
re-estimated sample size remains at 800 women/newborn pairs at the end of the study, 
the hypotheses will would be tested at the 0.52% and 4.8% levels, respectively. Thus, at 
the second interim analysis, the hypothesis for time to delivery or treatment failure will  
would be tested first at the 0.52% level, and the hypothesis for neonatal outcome will 
would then be tested at the 0.52% level only if the null hypothesis for the time to delivery  
or treatment failure is rejected. Similarly, at the final analysis, the hypothesis for time 
to delivery or treatment failure will would be tested first at the 4.8% level, and the 
hypothesis for neonatal outcome will would then be tested at the 4.8% level only if the 
null hypothesis for the time to delivery or treatment failure is rejected. No further 
adjustments to the type I error rate are planned for the co-primary endpoints. Details of 
the methodologies to control the type I error will be included in the IDMC and study 
reporting and analysis plans (RAPs). 
 
Section 9.2.1, Sample Size Assumptions 
 
A total of 900 women (450 women in each group) will be recruited into the study and 
randomly assigned to ensure that 800 (400 women/newborns in each group) have 
recorded birth data, which provides 86% statistical power to detect a relative risk of 68% 
between retosiban and placebo in neonatal outcomes in the proposed adaptive design with 
futility stopping, success stopping, and sample size re-estimation. Calculations assume a 
placebo incidence rate of 34%. 
 
Additionally, the sample size of 900 800 women (approximately 450 
400 women/newborn pairs per group) provides at least 90% statistical power to detect a 
difference of 95.5 days in the co-primary endpoint, time to delivery or treatment 
failure, and the key secondary endpoint, time to delivery, between retosiban and 
placebo. 
 
The sample size calculations are based on a 2-sided testing procedure with a type I error 
rate of 4.8% (e.g., O’Brien-Fleming boundary based on planned information 
fraction) and an approximate 10% dropout rate. Calculations are based on simulations 
and assume that the percentage of women enrolled into each of the GA strata 240/7 to 
256/7, 260/7 to 276/7, 280/7 to 306/7, and 310/7 to 336/7 will be 7%, 13%, 27%, and 53% 
(1:2:4:8 ratio), respectively, and approximately 55% of women in the placebo arm will 


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deliver within the 3 weeks of randomization. The details of model assumption and 
simulation are on file with GSK. 
 
Section 9.2.3., Sample Size Re-Estimation or Adjustment 
 
The sample size may be adjusted at the second interim analysis. The sample size re 
estimation will be conducted in a manner to maintain the study blind and will be carried 
out prior to the formal statistical interim analysis described in Section 9.3.4. The 
re-estimation sample size will be based only on the blinded observed overall pooled rate 
of neonatal composite and will be conducted by the blinded team. The sample size may 
be increased by a minimum of 50 women/newborn pairs up to a maximum sample size of 
1200 women/newborn pairs. The re-estimated sample size in conjunction with the 
actual sample size for the second interim analysis will be used to determine the 
O’Brien Fleming boundaries to be used in the interim and final analyses. 
 
The details of the sample size re-estimation methods and determination of the 
corresponding O’Brien-Fleming boundaries will be provided in the RAP. 
 
Section 9.3.1.3., Maternal Per-Protocol Population 
 
This Maternal Per-Protocol Population is defined as all subjects in the Maternal ITT 
Population excluding those who are major protocol violators. Subjects will be analyzed 
according to their actual treatment in case this differs from their randomly assigned 
treatment. This will include exclusions for use of prohibited concomitant medications and  
treatment failure to meet inclusion criteria specified by the protocol. 
 
Section 9.3.2.3., Neonatal Per-Protocol Population 
 
The Neonatal Per-Protocol Population is defined as all subjects in the Neonatal ITT 
Population excluding those without major protocol violations. 
 
Section 9.3.3.1., Primary Comparisons of Interest 
 
The primary comparison of interest is retosiban versus placebo for the co-primary 
endpoints:  time to delivery or treatment failure and neonatal composite endpoint. The 
comparison will be based on the ITT Population, and a sequential testing procedure will 
be used to control the overall type I error rate at 5% level with time to delivery or 
treatment failure being tested first. 
 
Section 9.3.3.2., Other Comparisons of Interest 
 
The comparison of retosiban versus placebo will also be performed for key secondary 
endpoints: time to delivery, proportion of preterm births (<370/7 weeks’ gestation), 
proportion of births ≥370/7 weeks’ gestation, and neonatal length of hospital stay. Other 
comparisons of exploratory endpoints between retosiban and placebo will be discussed in 
the RAP. 
 
Section 9.3.3.3., Subgroup Analysis 


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Additionally, comparisons of retosiban versus placebo for co-primary and key secondary 
endpoints may also be performed for the following subgroups: 
 
• 
GA strata 240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7, or 310/7 to 336/7 
• 
Established progesterone use (yes or no) 
• 
Magnesium sulfate use 
• 
Tocolytic use following IP discontinuation 
Other potential subgroup comparisons will be described in the RAP. 
 
Section 9.3.4., Interim Analyses 
 
Two interim analyses are planned, at which time the co-primary endpoints will be 
statistically analyzed. The first interim analysis will occur after approximately 150 
women/newborn pairs complete all assessments. The primary objective of the first 
interim analysis is to determine if the study should be terminated for lack of efficacy 
(futility) based on prespecified criteria. The decision will be based primarily on the 
analysis of the co-primary key secondary endpoint of time to delivery; however, all 
available safety and efficacy data will be reviewed. 
 
Time to delivery will be analyzed as similarly to analyses described for the primary 
efficacy analyses in Section 9.4.1.1. An estimate of the difference in time to delivery 
between the retosiban and placebo groups will be computed. Additionally, the conditional 
power of rejecting the null hypothesis at the end of the study based on the observed 
difference will be computed. 
 
The second interim analysis will occur after approximately 400 women/newborn pairs 
complete all assessments. The primary objectives of the second interim analysis are to 
determine if the study should be terminated for either lack of efficacy (futility) or for 
greater than expected efficacy (success). The decision to terminate for futility will be 
based on prespecified criteria, the key secondary endpoint of time to delivery, and the 
co primary endpoint of neonatal composite. The decision to stop for success will be 
based on the sequential testing of the null hypotheses for co-primary endpoints (time to 
delivery or treatment failure and then neonatal composite) at the 0.52% significance 
level determined O’Brian-Fleming boundary (the adjusted alpha level will be based on 
an O’Brian-Fleming alpha spending function and the planned actual sample size of 400 
women/newborn pairs at the second interim analysis and 800 women/newborn pairs at 
the end of the study and re-estimated sample size at the end of the study, see 
Section 9.2.3). Decisions will be based on both co-primary endpoints, time to delivery 
and neonatal composite prespecified criteria, although all available safety and efficacy 
data will be reviewed. 
 
Time to delivery or treatment failure and will be analyzed similar to the first interim 
analysis with the addition of calculation of the p-value. Tthe neonatal composite will be 
analyzed as described in Section 9.4.1.1. Point estimate and associated p-value for both 
the difference in time to delivery or treatment failure and the odds ratio of a neonatal 
composite occurring between retosiban and placebo will be computed. Additionally, the 


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conditional power of rejecting the null hypothesis at the end of the study based on the 
observed odds ratio of the neonatal composite will be computed. 
 
Section 9.4.1.1., Primary Analyses 
 
The primary objective of the statistical analysis will be to test the null hypothesis in the 
ITT Population that there is no difference between retosiban and placebo versus the 
alternative hypothesis that there is a difference between the 2 co-primary endpoints. The 
hypotheses tests will be assessed and confidence intervals constructed using the 
adjusted alpha level determined by the O’Brien-Fleming boundaries. 
 
The primary analysis of time to delivery or treatment failure will utilize a finite mixture 
model [McLachlan, 2000] with 2 components, 1 for those women delivering imminently 
and the other for the women delivering at term. The exact weight of each component will 
be determined by the observations from these component and model concomitant 
variables, including treatment, established progesterone use, and GA at randomization. 
Within each component, the expected time to delivery or treatment failure will be 
modeled as a function of treatment as fixed effect and GA at randomization and 
established progesterone use (yes or no) as covariates. The model parameters will be 
estimated using expectation maximization algorithm. Point estimates, associated 100(1 
α)% confidence intervals (CIs), and p values for the overall average difference in time to 
delivery or treatment failure between retosiban and placebo will then be derived using a 
weighted average of model parameter estimates and variance from each subpopulation of 
the mixture model. 
 
Section 9.4.1.2.1., Key Secondary Analyses 
 
The key secondary analysis for this study includes time to delivery, the proportion of 
births prior to 370/7 weeks’ gestation, proportion of births at term (370/7 to 416/7 weeks’ 
gestation), and length of neonatal hospital stay. To preserve the overall type I error rate, 
the key secondary analysis will be performed if and only if the null hypothesis of the 
primary endpoint is rejected. In addition, a stepwise Holm’s test will be used to adjust for 
multiplicity of the key secondary endpoints such that the type I error rate will be 
maintained at 5%. The endpoint of time to delivery will be analyzed as described in 
Section 9.4.1.1. 
 
Section 9.4.3., Health Outcomes Analyses 
 
To further describe the health outcomes of retosiban, the following subgroups may be 
explored: 
 
• 
GA of pregnancy at randomization 
• 
Established progesterone use 
• 
Magnesium sulfate use 
• 
Tocolytic use following IP discontinuation 
• 
Region/sites 


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Section 11., References 
 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Practice Bulletin No. 106. Intrapartum fetal heart rate monitoring:  nomenclature, 
interpretation, and general management principles. Obstet Gynecol. 2009;114(1):192 
202. 
 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Committee Opinion 455. Magnesium sulfate before anticipated preterm birth for 
neuroprotection. Obstet Gynecol. 2010;115:669-71. 
 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Committee Opinion 475. Antenatal corticosteroid therapy for fetal maturation. 
Obstet Gynecol. 2011;117(2 Pt 1):422-4. 
 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Practice Bulletin No. 127. Management of preterm labor. Obstet Gynecol. 
2012;119(6):1308-17. 
 
American College of Obstetricians and Gynecologists on Obstetric Practice Society for 
Maternal-Fetal Medicine. ACOG Committee Opinion No. 573: Magnesium sulfate use 
in obstetrics. Obstet Gynecol. 2013;122(3):727-8. 
 
Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. 
Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, 
infant and child: national clinical practice guidelines. Adelaide: University of Adelaide; 
2010. Available from:  http://www.adelaide.edu.au/arch/MagnesiumSulphate2010.pdf 
(Accessed 05 Nov 2014). 
 
Cregan MD, De Mello TR, Kershaw D, McDougall K, Hartmann PE. Initiation of 
lactation in women after preterm delivery. Acta Obstet Gynecol Scand. 2002;81(9):870 7. 
 
Di Renzo GC, Al Saleh E, Mattei A, Koutras I, Clerici G. Use of tocolytics:  what is the 
benefit of gaining 48 hours for the fetus? BJOG. 2006;113(Suppl 3):72-7. 
 
Fuchs AR, Fuchs F, Husslein P, Soloff MS, Fernstrom MJ. Oxytocin receptors and 
human parturition: a dual role for oxytocin in the initiation of labor. Science. 
1982;215(4538):1396–8. 
 
GlaxoSmithKline Document Number CM2006/00201/03. Investigator's brochure. 
APR 2014. 
 
GlaxoSmithKline Document Number 2015N228508_00. Investigator’s brochure 
supplement 1. FEB-2015. 
 
Meis PJ, Goldenberg RL, Mercer BM, et al. The preterm prediction study:  risk factors 
for indicated preterm births. Maternal-Fetal Medicine Units Network of the National 
Institute of Child Health and Human Development. Am J Obstet Gynecol. 
1998;178(3):562-7. 


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Mercer BM, Merlino AA; Society for Maternal-Fetal Medicine. Magnesium sulfate for 
preterm labor and preterm birth. Obstet Gynecol. 2009;114(3):650-68. 
 
Royal College of Obstetricians and Gynaecologists (RCOG) Green top Guideline No. 1B. 
Tocolytic for women in preterm labour. February 2011a. Available from: 
https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg1b/ (Accessed 05 
Nov 2014). 
 
Royal College of Obstetricians and Gynaecologists (RCOG) Scientific Impact Paper No. 
29. Magnesium sulphate to prevent cerebral palsy following preterm birth. August 2011b. 
 
Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med. 2007;357(5):477 
87. 
 
Society of Obstetricians and Gynaecologists of Canada (SOGC) Clinical Practice 
Guideline 258. Magnesium sulphate for fetal neuroprotection. J Obstet Gynaecol Can. 
2011;33(5):516 29. 
 
Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child 
Health and Human Development Neonatal Research Network. Neonatal outcomes of 
extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 
2010;126(3);443-56. 
 
Stones RW, Paterson CM, Saunders NJ. Risk factors for major obstetric haemorrhage. 
Eur J Obstet Gynecol Reprod Biol. 1993;48(1):15-8. 
 
Tucker JM, Goldenberg RL, Davis RO, Copper RL, Winkler CL, Hauth JC. Etiologies of 
preterm birth in an indigent population:  is prevention a logical expectation? Obstet 
Gynecol. 1991;77(3):343-7. 
 
Section 12.1., Appendix 1: Abbreviations and Trademarks 
Abbreviations 
GBS 
group B streptococcal 
NSAID 
nonsteroidal anti-inflammatory drug 
SOGC 
Society of Obstetricians and Gynaecologists of Canada 


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Section 12.3.5., Evaluating AEs and SAEs 
 
Follow-up of AEs and SAEs: 
 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK/PPD 
to elucidate as fully as possible the nature and/or causality of the AE or SAE. 
• 
The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK/PPD with a copy of any postmortem 
findings, including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE or AE of special interest data to 
GSK/PPD within the designated reporting time frames. 
 
 
 
Section 12.5., Appendix 5: Genetic Research 
 
Study Assessments and Procedures 
 
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response. 
 
• A Two blood samples will be taken for DNA extraction. A blood sample is : one for 
maternal DNA (at all participating investigational centers) and one for cell-free 
fetal DNA (at US and Canadian investigational centers only). These samples will 
be collected at the screening visit, after the subject has provided informed consent for 
genetic research. Instructions for collection and shipping of the genetic sample(s) are 
described in the laboratory manual. The DNA from the blood sample(s) may undergo 
quality control analyses to confirm the integrity of the sample. If there are concerns 
regarding the quality of the sample(s), then the sample(s) may be destroyed. The 
blood sample is genetic samples are collected on a single occasion unless a duplicate 
sample is required due to an inability to use the original sample(s). 
•For those subjects who deliver at the investigative center, a cord blood sample will be 
collected for genetic research. 
The genetic sample(s) is labeled (or “coded”) with the same study-specific number used 
to label other samples and data in the study. This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 


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Section 12.7., Appendix 7: Country-Specific Requirements 
 
No country-specific requirements exist. 
 
At US and Canadian investigational centers only: 
 
One maternal blood sample will be taken for DNA extraction to provide cell-free 
fetal DNA. This sample will be collected at the screening visit, after the subject has 
provided informed consent for genetic research (see Section 7.10 and Appendix 5). 


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Protocol Amendment Number 02 
 
Protocol Amendment Number 02 is applicable to all clinical study centers participating in 
this study. Protocol changes specified in Amendment Number 02 are summarized as 
follows: 
 
• 
Revised the guidance for administration of antenatal corticosteroids to read as 
follows: If not previously administered, antenatal corticosteroid treatment should be 
administered as either (1) two 12-mg doses of betamethasone given intramuscularly 
24 hours apart or (2) four 6-mg doses of dexamethasone administered 
intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is 
permitted if the antecedent treatment was at least 7 days prior to study enrollment. 
• 
Clarified in the Time and Events Table (footnote 15) that hematology, chemistry, 
and liver function tests will only be determined through a central laboratory at the 
screening, Day 2, and the face-to-face post-infusion assessment visits. 
• 
Incorporated other administrative changes. The rationale for these changes is to 
ensure a clear and complete protocol for use at the investigational centers. 
Specific Changes in the Text 
Synopsis, Overall Design: 
• 
If not previously administered, antenatal corticosteroid treatment should be 
administered as either (1) two 12-mg doses of betamethasone given intramuscularly 
24 hours apart or (2) four 6-mg doses of dexamethasone administered 
intramuscularly every 12 hours., if treatment has not been given within A single 
rescue course of antenatal corticosteroids is permitted if the antecedent 
treatment was at least 7 days of prior to study enrollment. 
 
 
 
Section 4.1, Overall Design 
 
If not previously administered, antenatal corticosteroid treatment should be 
administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 
hours apart or (2) four 6-mg doses of dexamethasone administered intramuscularly every 
12 hours., if treatment has not been given within A single rescue course of antenatal 
corticosteroids is permitted if the antecedent treatment was at least 7 days of prior 
to study enrollment. 


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Section 4.2, Treatment Arms and Duration 
Figure 2, Study Design 
1. 
Stratification (1:1) to retosiban or matched placebo based on established progesterone therapy at Screening 
(subjects on established progesterone therapy versus subjects not on established progesterone therapy) and 
gestational age (240/7 to 256/7; 260/7 to 276/7; 280/7 to 306/7; 310/7 to 336/7). 
2. 
If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12- 
mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of dexamethasone 
administered intramuscularly every 12 hours., if treatment has not been given within A single rescue course of 
antenatal corticosteroids is permitted if the antecedent treatment was at least 7 days of prior to study 
enrollment. 
3. 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion visit for obstetric 
assessments 1 week (acceptable range: 3 to 14 days) after the Inpatient Randomized Treatment Phase. The 
subject will then be contacted every week via telephone to determine and record if she has delivered or if she has 
experienced any subsequent episodes of preterm labor. Retreatment with the investigational product (retosiban or 
placebo) is not allowed. 
 
 
 
An adequate response is based on (1) a clinically relevant reduction of contraction 
frequency and/or intensity or (2) no change in the cervical examination. Subjects with an 
inadequate response any time after the first hour of treatment will be administered 
another 6 mg retosiban or matched placebo loading dose and the retosiban or matched 
placebo infusion rate will be increased to 12 mg/hour for the remainder of the 48 hour 
treatment period. A subject’s response should be assessed for at least 1 hour following a 
dose increase before a decision is made to discontinue randomized treatment due to lack 
of response. Investigators will be required to indicate in the electronic case report form 
(eCRF) the reason or reasons for a dose increase. 
 
Section 6.11.1.1, Antenatal Corticosteroids 
 
If not previously administered, antenatal corticosteroid treatment should be 
administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 
hours apart or (2) four 6-mg doses of dexamethasone administered intramuscularly every 
12 hours., if treatment has not been given within A single rescue course of antenatal 
corticosteroids is permitted if the antecedent treatment was at least 7 days of prior 
to study enrollment. 
 
Section 7, Study Assessments and Procedures 
Table 2, Time and Events Table 
8. 
Uterine tocography will be performed prior to dosing to confirm the uterine contraction frequency. If the 
examination reveals a rate that is <4 contractions over a 30-minute interval, the subject cannot be dosed. 
9. 
If not previously administered, antenatal corticosteroid treatment should be administered using as either (1) two 
12-mg doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of 
dexamethasone administered intramuscularly every 12 hours., if treatment has not been given within A single 
rescue course of antenatal corticosteroids is permitted if the antecedent treatment was at least 7 days of 
prior to study enrollment. Investigators have discretion to use a standardized regimen of magnesium sulfate, as 
well as intrapartum antibiotic prophylaxis for perinatal group B streptococcal infection. 
10. Information regarding delivery will be obtained through a review of the hospital and medical records. Growth 
parameters include neonatal weight, length, and head circumference. 
… 


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15.  Hematology, chemistry, and LFTs will be determined through a central laboratory at the screening, Day 2, and 
the face-to-face post-infusion assessment visits. The LFT values from the central laboratory should be 
reviewed for abnormalities (see Section 5.3.3). For subjects who deliver within 24 hours after completion or 
discontinuation of IP and for subjects who deliver at the investigative center after discharge but before the face-to- 
face post-infusion assessment visit, central laboratory assessments for hematology, chemistry, and LFTs should 
be performed. 


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Protocol Amendment Number 03 – Italy Sites Only 
 
The following changes are reflected in the Country-Specific Protocol Amendment for 
Italy: 
• 
Amend inclusion criteria 1 and 2 to specify that subjects must be at least 18 years of 
age to participate in Study 200719. Text was revised throughout to reflect the change 
in the subject age criterion. 
• 
Revise text throughout to indicate that subjects recruited into Study 200719 in Italy 
must not be dosed with the investigational product until the results of their chemical 
parameters have been reviewed by the Investigator and no indicators of altered liver 
function (AST and ALT values and bilirubinemia) are apparent. This check for 
altered liver function must be carried out before the study drug is administered, i.e., 
before initiating randomized treatment. 
The specific text changes for this country-specific amendment are outlined under 
Amendment 04. 


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Protocol Amendment Number 04 
 
Protocol Amendment Number 04 is applicable to all clinical study centers participating in 
this study. Protocol changes specified in Amendment Number 04 are summarized as 
follows: 
 
• 
Added the supportive other secondary endpoints for “the proportion of women 
experiencing subsequent episodes of preterm labor.” This was added to help 
understand the natural history of pregnancy following treatment with retosiban and 
to compare with subsequent use of putative tocolytics. 
• 
Clarified the assessments that should be performed at the 1-week face-to-face 
post-infusion visit and at the weekly telephone calls during the Post-Infusion 
Assessment Phase. Previously, the face-to-face post-infusion visit and weekly 
telephone calls were presented together on the Time and Events Table, which 
resulted in confusion at the sites, as not all assessments indicated in the table are 
performed during the weekly telephone calls. Additionally, the assessments 
performed when a subject withdraws from the study were clarified. 
• 
Clarified the concomitant medications that are considered putative tocolytics and 
added exceptions for putative tocolytic drug use with regard to the definition of 
treatment failure. Putative tocolytic medications may have dual indications, such as 
in the treatment of hypertension, respiratory conditions, or chronic medical 
conditions, for example rheumatoid arthritis. Therefore, specific exceptions for the 
use of putative tocolytic drugs were added, and the definition of treatment failure 
was revised to note the exceptions in putative tocolytic drug use. 
• 
Clarified the language for determining gestational age at screening. 
• 
Added that manual palpations may be used for determining contraction frequency in 
situations where technical difficulties may prohibit accurate measurement. 
• 
Clarified the criteria for confirming sufficient dilation and effacement at Screening. 
• 
Clarified that withdrawal from the study will mean that no additional visits can occur 
or procedures performed after the subject withdraws from study. 
• 
Included a definition of inadequate response. Although previously the protocol 
clearly defined adequate response, a clear definition for inadequate response was not 
included. For maximum understanding of both terms, a definition of inadequate 
response was added. 
• 
Added a section that outlined the procedures that should be followed for managing 
dose interruptions. Previously, instructions for dose interruptions were only included 
in the Study Procedures Manual (SPM), but to ensure sites follow the correct 
procedures, this information was added to the protocol. 
• 
Added that subject use of a pessary is allowed if use began before the current episode 
of preterm labor; otherwise, use of a pessary is prohibited. This text, which is 
included in the SPM, was added to ensure sites were aware of the permitted and 
prohibited use of a pessary. 


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• 
Revised the previous requirements for continuous fetal heart rate monitoring to 
electronic fetal monitoring for a minimum of 6 hours from the start of the infusion or 
from the start of a dose increase as long as the fetal heart rate pattern is consistently 
reassuring throughout the required minimum 6-hour duration of monitoring and the 
contraction frequency is 2 in a 30-minute window within the last hour of 
monitoring. The previous fetal monitoring requirement was for continuous fetal heart 
rate monitoring from Screening until completion of the 48-hour Inpatient 
Randomization Treatment Phase, which proved to be an impediment to subject 
recruitment. 
• 
Clarified that confirmation of uterine contraction eligibility criterion must occur 
within 60 minutes before IP dosing. The protocol previously had not included that 
the 60-minute duration was relative to IP dosing. 
• 
Added respiratory rate to the vital sign measures assessed during the study, and, for 
consistency with the SPM, clarified the frequency that vital sign and oxygen 
saturation measurements are assessed relative to dosing. 
• 
Clarified that if a subject does not deliver at the investigative center, central 
laboratory assessments for hematology, chemistry, and LFTs should be performed at 
the investigative center within 1 week (acceptable range: 3 to 14 days) after 
completion of the study drug infusion. 
• 
Revised the visit window for the administration of the Edinburgh Postnatal 
Depression Scale (EPDS) from 2 weeks to 6 weeks, as the 2-week window 
resulted in protocol deviations and it was determined that it was clinically acceptable 
to use data for the EPDS up to 12 weeks after delivery. 
• 
Clarified that a maternal blood sample for PK analyses may need to be collected at 
the same time as the cord blood sample if the sample time does not already coincide 
with a PK sampling window (i.e., 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 
to 54 hours after the start of the study drug infusion on Day 1). 
• 
Revised the assessment requirement for the first interim analysis. For the first interim 
analysis, the key secondary endpoint, time to delivery, will be used to determine if 
the study should be terminated for lack of efficacy (futility) and the analysis will 
occur when approximately 150 subjects complete delivery; therefore, the protocol 
was updated to reflect this change. 
• 
Clarified that the second interim analysis to specifically state that this analysis will 
occur when approximately 400 women/newborn pairs are followed up to 28 days 
post EDD. 
• 
Added as an appendix guidelines for reporting maternal, fetal, and neonatal adverse 
events of special interest, which is also provided in the SPM. This was added to 
provide sites ready access to these detailed guidelines. 
• 
Clarified that the intensity categories for AEs and serious AEs can be found in the 
SPM. This was changed to provide greater and more granular guidance for the study 
sites when assessing severity. 
• 
Incorporated the changes detailed in the country-specific amendment for sites in Italy 
(dated 19 Apr 2016) 


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• 
Incorporated other administrative changes. The rationale for these changes is to 
ensure a clear and complete protocol for use at the investigational centers. 
Specific Changes in the Text 
 
Title page: 
Authors (GSK): 
 
 
 
PPD 
 
 
 
Synopsis, Type and Number of Subjects: 
 
The study population is women aged 12 to 45 years with an uncomplicated singleton 
pregnancy in preterm labor with intact membranes between 240/7 and 336/7 weeks’ 
gestation. Approximately 900 women (450 per treatment group) will be randomly 
assigned to ensure that approximately 800 women/newborns have recorded birth data 
(assumes approximately 10% missing data). 
 
Italian Subjects: In Italy, the age restriction for study enrollment is 18 to 45 years. 
 
Synopsis, Analysis: 
 
Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 women/newborn pairs subjects have completed delivery and have 
time-to-delivery results available all assessments. The second interim analysis will 
occur after approximately 400 women/newborn pairs are followed up to 28 days post 
EDD complete all assessments. 
 
Section 2.1, Study Rationale 
 
The incidence of birth prior to 37 weeks’ gestation in the retosiban group was 18.7% 
compared with 47.2% in the placebo group (see the investigator’s brochure [IB] Section 
5.3.2.2.2 [GlaxoSmithKline Document Number CM2006/00201/0305]). 
 
A summary of the complete results for Study OTA105256 is included in the IB (Section 
5.3.2.1 [GlaxoSmithKline Document Number CM2006/00201/0305]). 


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Section 3., Objectives and Endpoints 
 
Supportive Other Secondary 
• Proportion of births prior to 320/7 weeks’ 
gestation 
• Proportion of births prior to 280/7 weeks’ 
gestation 
• Proportion of births ≤7 days 
• Proportion of births ≤48 hours 
• Proportion of births ≤24 hours 
• Proportion of neonates with any of the 
co-primary composite neonatal morbidity 
and mortality, excluding RDS 
• Proportion of neonates with each individual 
component of the composite neonatal 
morbidity and mortality endpoints 
• Neonatal admission to a specialized 
care unit and length of stay 
• Newborn hospital readmission and length of 
stay 
• Ambulatory surgery 
• Time to treatment failure 
• Proportion of women receiving any 
putative tocolytic 
• Proportion of women experiencing 
subsequent episodes of preterm labor 
 
 
Section 4.2., Treatment Arms and Duration 
 
For those subjects who deliver at the investigative center within 12 hours of IP (retosiban 
or placebo) completion or discontinuation, a cord blood sample will be collected for 
pharmacokinetic (PK) analysis, and, if required, a corresponding maternal blood 
sample will be collected for PK analysis (see Section 7.6.1). Likewise, a breast 
milk/colostrum sample will be collected for PK analysis in women who deliver at the 
investigative center and produce breast milk within 12 hours after IP completion or 
discontinuation. 
 
During the Maternal Post Delivery Assessment Phase, the subject will be contacted by 
telephone within 6 weeks (±2 weeks) of delivery for a post-delivery assessment, 
including an assessment of AEs (±2 weeks), status of breastfeeding (±2 weeks), and 
completion of the EPDS (±6 weeks). 
 
Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 women/newborn pairs subjects have completed delivery and have 
time-to-delivery results available all assessments. The second interim analysis will 


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occur after approximately 400 women/newborn pairs are followed up to 28 days post 
EDD complete all assessments. 
 
Section 4.3, Type and Number of Subjects: 
 
The study population is women aged 12 to 45 years with an uncomplicated singleton 
pregnancy in preterm labor with intact membranes between 240/7 and 336/7 weeks’ 
gestation. Approximately 900 women (450 per treatment group) will be randomly 
assigned to ensure that approximately 800 women/newborns have recorded birth data 
(assumes ~10% missing data). 
 
Italian Subjects: In Italy, the age restriction for study enrollment is 18 to 45 years. 
 
Section 4.4., Design Justification 
 
To fulfill regulatory requirements to study pediatric subjects, pregnant adolescents aged 
12 to 17 years are allowed to participate in this study, with the exception of sites in 
Italy, where pregnant adolescents are not eligible to enroll in the study (see 
Section 5.1). . . . 
 
Section 4.5.1, Retosiban 
 
These exposures are significantly less than those studied in the Phase I program, where 
retosiban doses were well tolerated [GlaxoSmithKline Document Number 
CM2006/00201/0305]). 
 
Section 4.6., Benefit:Risk Assessment 
 
Summaries of findings from both clinical and nonclinical studies conducted with 
GSK221149 can be found in the IB. The following section Table 1 and Table 2 outlines 
the risk assessment and mitigation strategy for this protocol: 


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170 
 
 
 
Section 4.6.1., Risk Assessment 
 
Table 1 
Potential Risks of Clinical Significance 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Fetal exposure through placental transfer 
Retosiban is a substrate of P-gp and BCRP 
transporters, which are thought to play a role in 
keeping xenobiotics out of the CNS and out of the fetal 
blood. 
The Ppreclinical data indicate very minimal, if any, 
maternal CNS penetration or placental transfer of retosiban 
as supported by the following: 
• 
In pregnant monkeys, there was no detectable 
retosiban in the cord blood when mothers were dosed 
up to 100 mg/kg (approximately ~7-fold times the 
human exposure). However, approximately 4% of 
circulating drug was detected in the cord blood when 
mothers were dosed at 300 mg/kg (approximately 
~24-fold the human exposure). 
Retosiban is a substrate of P-gp and breast cancer 
resistant protein transporters, which are thought to play a 
role in keeping xenobiotics out of the CNS and out of the 
fetal blood, thereby limiting fetal exposure to retosiban. 
• 
In reproductive toxicology studies in monkeys, where 
retosiban was given to pregnant monkeys, there 
were no adverse mother and or infant behavioral, or 
locomotor effects observed that were suggestive of 
CNS toxicity. 
• 
In rodent neurobehavioral safety studies, there were 
no adverse clinical signs observed at doses up to 
1000 mg/kg. 
Adverse events and serious AEs reported in retosiban 
Analysis of mMaternal blood and cord blood samples will 
be analyzed performed to test for levels of retosiban in 
women who deliver at an investigative center within 
12 hours of the completion or discontinuation of the study 
treatment infusion in this study. 
Surveillance for signals indicating adverse fetal or neonatal 
effects with in utero exposure to retosiban will be 
performed throughout this study. 
Infants exposed to retosiban in utero will be followed for up 
to a minimum of 5 years in a separate follow-up study to 
assess long-term overall safety and neurodevelopmental 
outcomes. 
Unblinded safety data will be monitored by an IDMC. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
clinical trials to date have not indicated that retosiban 
has access to the maternal or fetal CNS; however, this 
has not been rigorously investigated. 
The short half-life of retosiban (~2 hours) is expected 
to minimize any significant risk. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Neonatal exposure via breast milk 
There were no effects on offspring growth and 
development in monkey reproductive toxicology 
studies, where systemic exposure to retosiban 
reached 14-fold the maximum clinical exposures. 
These findings suggest that exposure to retosiban 
during pregnancy had no adverse effect on breast milk 
or feeding. 
While there are no clinical data on the degree of retosiban 
transfer into breast milk, the available data based on 
physiochemical properties suggest retosiban will be 
excreted into breast milk if dosed close to or during the 
time of milk production. Retosiban has a 2-hour elimination 
half-life and is almost completely removed from the body 
12 hours after termination of the infusion. Given the rapid 
clearance of retosiban, the risk for neonatal drug exposure 
via breast milk appears low but could occur in the situation 
where the infant is fed breast milk/colostrum produced 
within 12 hours of the end of the infusion. However, this 
circumstance seems unlikely as prematurity has been 
shown to delay the onset of milk production relative to term 
deliveries [Cregan, 2002; Henderson, 2008]. Since 
lactogenesis is typically delayed 30 to 48 hours 
postpartum in mothers going to term (and is further 
delayed in mothers who deliver preterm), it seems 
unlikely that any drug would be in the plasma 
postpartum to transfer into the milk. 
Breast milk/colostrum samples will be collected for 
measurement of retosiban when delivery occurs and 
lactation has started within 12 hours of receiving study 
treatment infusion. 
• 
When breast milk/colostrum is produced prior to 
4 hours of the completion or discontinuation of the 
study treatment, a sample will be collected for 
evaluation, and consumption by the baby is not 
permitted. 
• 
When breast milk/colostrum is produced between 
4 and 12 hours of the completion or discontinuation 
of the study treatment, a sample will be collected for 
evaluation, and the remainder of the breast milk can 
be consumed if the potential benefits to the infant are 
believed to outweigh the potential risks. The subject 
should be advised on the potential risks associated 
with feeding the infant her breast milk/colostrum that 
was expressed within 12 hours of the completion or 
discontinuation of the study treatment. 
• 
When breast milk is produced more than 12 hours 
after the completion or discontinuation of study 
treatment, no samples will be collected for evaluation 
and there will be no restrictions on consumption, 
given that this time frame is beyond 5 half-lives of 
retosiban. 
Safety monitoring for signals indicating adverse 
effects in infants following exposure to retosiban via 
breastfeeding will be performed throughout the study. 
Unblinded safety data will be monitored by an IDMC, 
including infants exposed to retosiban via 
breastfeeding. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
Uterine atony and postpartum hemorrhage due to oxytocin 
receptor antagonism 
Retosiban is a competitive oxytocin antagonist whose 
effects can be reversed by oxytocin agonists. Retosiban 
has a short elimination half-life (approximately 2 hours) 
and is rapidly removed from the body. 
Given the rapid clearance of retosiban, the risk for 
uterine atony appears low and would most likely occur 
in the situation where delivery occurs within 24 hours 
of treatment. 
The available clinical data for other oxytocin 
antagonists suggest the adverse effects of atony and 
postpartum hemorrhage are limited [Valenzuela, 1995; 
Thornton, 2009]. 
In monkey reproductive toxicology studies, where 
retosiban systemic exposure reached up to 14-fold of the 
maximum clinical exposures, there were no observations 
of postpartum hemorrhage. However, all monkey infants 
whose mothers received retosiban were born about 4 to 5 
days after end of dosing. 
During the Phase II Study, OTA105256, 2 cases of 
postpartum hemorrhage were reported in subjects treated 
with retosiban. Both cases had confounding 
circumstances, as follows: 
One event occurred <48 hours from drug discontinuation 
and 2 hours after delivery in a subject with a prior history of 
retained placenta in a previous 23-week preterm delivery 
of twins. A history of retained placenta is a known risk 
factor for recurrent retained placenta. [Stones, 1993; 
Endler, 2012]. 
The other event occurred >30 days after drug exposure 
discontinuation of retosiban. 
The incidence of primary PPH (within 24 hours of 
Given the rapid clearance of retosiban, the risk for uterine 
atony appears low and would most likely occur in the 
situation where delivery occurs within 24 hours of 
treatment. 
Investigators will be advised to refer to practice guidelines 
for treatment and/or management of postpartum 
hemorrhage, using agents approved for postpartum 
hemorrhage. These include oxytocin agonists and 
prostaglandin analogs. 
Retained placenta and postpartum hemorrhage PPH are 
AEs of special interest requiring the collection/assessment 
of risk factors for PPH, eCRFs for any event of PPH, and 
clinical parameters related to PPH. Evaluations will include 
outcomes such as time from delivery to expulsion of 
placenta and estimated blood loss. 
Unblinded safety data will be monitored by an IDMC. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
delivery) is estimated to be between 4% to 6% of 
mothers who delivered [ACOG Practice Bulletin No. 76, 
2006]. 
Adverse maternal, fetal, or neonatal outcomes due to 
prolonging pregnancy in the presence of subclinical 
intrauterine infection 
The study population includes women, particularly those 
presenting in labor prior to 300/7 weeks of gestation, in 
whom intrauterine infection is implicated as a major 
etiologic factor. Infection may be chronic and 
asymptomatic with the first indication being preterm labor 
or rupture of the membranes. The asymptomatic nature of 
intrauterine infection, including lack of fever, abdominal 
pain, and fetal tachycardia, makes the diagnosis 
challenging. Infection is thought to trigger the labor process 
as a protective means for both the mother and baby 
[Goldenberg, 2002]. 
The protocol will exclude women with a temperature 
>100.4°F (38°C) for more than 1 hour or ≥101°F (38.3°C), 
as well as women with confirmed or suspected 
contraindication for continuation of pregnancy, such as 
chorioamnionitis, premature rupture of membranes, and 
abruption. 
Placental tissue samples will be collected in study 
200721 (ZINN) when delivery occurs at an investigative 
center to examine safety and efficacy outcomes in 
subjects with subclinical intrauterine infection. 
A set of AEs of special interest identified in the literature as 
linked to maternal clinical or subclinical infection has been 
generated and will be used to collect targeted information 
of these AEs. This information will be monitored in stream 
by an IDMC. The unblinded IDMC will review all available 
safety and efficacy data. 
Potential drug-drug interaction with inhibitors of BCRP or P-
gp 
Retosiban is a substrate of murine BCRP and P-gp in vitro. 
Inhibitors of BCRP and P-gp have the potential to increase 
exposure of retosiban when co-administered. 
BCRP and P-gp is expressed in placental membranes and 
the blood-brain barrier, and there is the potential of 
increased maternal CNS and fetal exposure to retosiban 
when co-administered with inhibitors. 
Clinical experience with exposures 10-fold higher than the 
exposure at the planned therapeutic dose has shown 
retosiban to be safe and well tolerated, with no observed 
untoward effects in adult women of childbearing potential. 
Retosiban will only be given for 48 hours, limiting both 
maternal and fetal exposure. The impact of concomitant 
use of retosiban with inhibitors of BCRP or P-gp will be 
assessed through AE monitoring. 
Analysis of maternal serum and cord blood samples will be 
performed when delivery occurs within 12 hours of study 
treatment infusion with co-administration of a BCRP or 
P-gp inhibitor to assess the effect of P-gp inhibition on 
placental transfer of retosiban. 
Potential drug-drug interaction: Increased exposure of 
In a clinical study with healthy subjects, co- 
Administration of strong CYP3A4 inhibitors 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Retosiban [e.g., GSK221149] 
retosiban when co-administered with inhibitors of 
CYP3A4 
administration of retosiban with ketoconazole (a 
strong CYP3A4 inhibitor) increased the Cmax and AUC 
of retosiban, 5.2- and 8.7-fold, respectively. 
concomitantly with IP requires an adjustment to the 
retosiban dosing regimen (see Section 6.3.2 and the 
IB). Retosiban will only be given for 48 hours, limiting 
both maternal and fetal exposure. 
Potential drug-drug interaction: Decreased exposure 
of retosiban when co-administered with inducers of 
CYP3A4 
In healthy, nonpregnant females, co-administration of 
intravenous retosiban with efavirenz (a moderate 
CYP3A4 inducer) increased the clearance of retosiban 
by 42% and reduced total exposure by 30% and peak 
exposure by about 20%. 
Administration of strong CYP3A4 inducer 
concomitantly with IP requires an adjustment to the 
retosiban dosing regimen (see Section 6.3.2 and the 
IB). Retosiban will only be given for 48 hours, limiting 
both maternal and fetal exposure. 
Potential decreased therapeutic effect of drugs 
metabolized by CYP3A4 when co-administered with 
retosiban 
Evidence of metabolic auto-induction has been 
observed with repeat intravenous dosing of retosiban 
in women with preterm labor, as well as in healthy 
nonpregnant women given repeat oral doses of 
retosiban over 2 weeks. 
As 48-hour administration of retosiban has the 
potential to increase the rate of metabolism of drugs 
metabolized by CYP3A4, it is recommended that these 
drugs be monitored for a decrease in their therapeutic 
effect. Details are provided in the IB. Retosiban will 
only be given for 48 hours, limiting both maternal and 
fetal exposure. 
AE = adverse event; AUC = area under the plasma concentration time curve; BCRP = breast cancer resistance protein; Cmax = maximum plasma concentration; CNS = central 
nervous system; eCRF = electronic case report form; CYP3A4 = cytochrome P450 3A4 enzyme; IB = investigator’s brochure; IDMC = independent data monitoring committee; 
P-gp = P-glycoprotein; PPH = postpartum hemorrhage; SPM = Study Procedures Manual. 


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Table 2 
Potential Safety Concerns 
 
Potential Risk of Clinical Significance Safety 
Concern 
Summary of Data/Rationale for Risk Concern 
Mitigation Strategy 
Other 
Pulmonary edema 
Pulmonary edema is a rare but potentially life-threatening 
complication of pregnancy. In the setting of preterm labor, 
pulmonary edema is thought to involve both increased 
hydrostatic pressure and altered vascular permeability. 
Factors associated with pulmonary edema include 
spontaneous preterm labor, multifetal pregnancy, 
chorioamnionitis, pre-eclampsia, cardiac disease, fluid 
overload, blood transfusion, corticosteroid therapy, and 
tocolytic treatment. Magnesium sulfate is implicated 
especially when additional risk factors are present. 
Randomized studies have not shown an increased risk of 
pulmonary edema or other serious maternal complications 
with antenatal magnesium sulfate [Doyle, 2009; Conde- 
Agudelo, 2009; Bain, 2013]. A retrospective chart review 
showed that contributing factors for pulmonary edema 
during magnesium sulfate treatment included high dose, 
high infusion rate, high net positive fluid balance, 
concomitant tocolysis, and multifetal gestations 
[Samol, 2005]. 
Women with identified risk factors for pulmonary edema 
are excluded from the clinical study. These include 
multifetal pregnancies, pre-eclampsia, chorioamnionitis, 
and certain pre-existing cardiovascular conditions. 
Magnesium sulfate will be administered in a standardized 
regimen per the investigator’s discretion (see 
Section 6.11.1.2). Additional information regarding 
appropriate monitoring of magnesium sulfate therapy is 
provided in the SPM. 
Combination administration of a tocolytic is not 
permitted in the clinical studies. 
Maintenance tocolysis is not allowed. 
Guidance is provided to investigators regarding fluid 
balance up to the time of starting treatment and for the 
duration of treatment (see Section 7.4.8). 
Pulmonary edema is designated as an AE of special 
interest requiring the collection and/or assessment of 
specific, relevant history and physical examination 
findings, targeted eCRFs to characterize any reported 
events, and a maximum duration of tocolytic treatment with 
magnesium sulfate of 48 hours. 
AE = adverse event; eCRF = electronic case report form. 


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Section 4.6.3, Overall Benefit:Risk Conclusion 
 
For detailed information on the identified risks and risk-benefit assessment of retosiban, 
refer to the IB and IB supplement 1 [GlaxoSmithKline Document Number 
CM2006/00201/0305; GlaxoSmithKline Document Number 2015N228508_00]. 
 
Section 5.1., Inclusion Criteria 
 
1. Signed and dated written informed consent is required prior to a subject’s 
participation in the study and the performance of any protocol-specific procedures.  
At sites where enrollment of adolescents is allowed, Aadolescents aged 12 to 
17 years must provide written agreement to participate in the study in accordance 
with applicable regulatory and country or state requirements. Subjects will also be 
asked to sign a release for medical records at the time of consenting to allow access 
to both the maternal and neonatal records including information about delivery and 
infant care as well as information collected prior to the consent having been signed 
NOTE: Prescreening alone does not necessarily require consent as this activity may 
be accomplished in the absence of study-specific procedures or assessments. In many 
cases, standard care and standard medical triage will provide sufficient information 
or evidence as to whether or not the subject is eligible for the study 
2. Females aged 12 to 45 years, with an uncomplicated, singleton pregnancy and intact 
membranes in preterm (NOTE: Since local laws, customs, and institutional practice 
vary globally, investigator discretion in the enrollment of pediatric subjects is 
permitted, except in Italy) 
Italian Subjects: In Italy, the age restriction for study enrollment is 18 to 45 
years. 
3. Gestational age between 240/7 and 336/7 weeks as determined by (1) known 
fertilization date, either in vitro fertilization or intrauterine insemination, or (2) a 
best estimated due date last menstrual period confirmed or established by the 
earliest ultrasound prior to performed before 240/7 weeks gestation,. 
or (3) the earliest ultrasound alone prior to 240/7 weeks gestation, whichever is the 
most accurate method available for each subject. In situations where prenatal 
ultrasound records are not available at the time the subject presents, the investigator 
may enroll the subject using the will make every effort to obtain these records 
(either via computer records, directly from the subject’s primary care obstetrician, or 
via telephone). However, in cases in which these records are not readily available 
(e.g., off hours, holiday), it is within the investigator’s discretion to use GA based on 
a verbal history from the subject with the intent of getting confirmation from the 
medical records or from the subject’s primary care obstetrician as soon as 
possible. 
4. Females must be diagnosed with preterm labor according to both of the following 
criteria (a and b): 
a. Regular uterine contractions, confirmed by tocodynamometry, at a rate of 
≥4 contractions of at least 30 seconds’ duration during a 30-minute interval 
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feasible, assessment by manual palpation will be permitted and must be 
documented. 
AND at least 1 of the following: 
b. At least 1 of the following: 
i.Cervical dilation ≥2 cm and ≤4 cm by digital cervical examination OR 
 
cii. If <2 cm dilation by the required initial digital cervical examination, a 
cervical change (2 examinations must be documented) consistent with 
1 of the following: 
 
• 
An absolute consisting of an increase of at least 25% effacement  
(e.g., a change in effacement from 50% to 75%) by digital 
examination or a 10-mm decrease in cervical length by 
transvaginal ultrasound 
OR 
• 
A 1-cm increase in cervical dilation by digital cervical examination 
 
Section 5.3., Withdrawal/ From Study, Discontinuation of IP, and Stopping Criteria 
 
The section describes and distinguishes the following: 
 
• 
Withdrawal of the subject from the study after randomization but before 
administration of IP (5.3.1.1) and after administration of IP (5.3.1.2) 
• 
Discontinuation of the IP (5.3.2), wherein subjects who receive but then 
discontinue from IP will not be considered withdrawn from the study and 
should remain in the study and continue to be followed for efficacy and safety 
• 
Specific stopping criteria before and during dosing, including liver function test 
criteria (5.3.3) and QTc findings (5.3.4). 
 
 
Section 5.3.1.1., Withdrawal From Study Participation After Randomization but 
Prior to Investigational Product Administration 
 
Any subject with a nonreassuring fetal heart rate pattern, a uterine contraction rate less 
than 4 over a 30-minute interval, cervical dilation >4 cm based on digital cervical 
examination, abnormal levels of alanine aminotransferase (ALT) or bilirubin, or a 
clinically significant abnormal finding on an electrocardiogram (ECG) cannot be dosed 
and will be withdrawn from the study. The reasons for not dosing a subject will be 
recorded in the eCRF and source documents. Subjects who are withdrawn prior to 
receiving randomized IP will not be followed. 
 
Sites Not in Italy: If local laboratory results are available before the start of dosing and 
reveal that ALT is ≥2 × the upper limit of normal (ULN) or total bilirubin is >1.5 × ULN 
(>35% direct bilirubin), the subject should not be dosed and should be withdrawn from 


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the study. An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and 
direct bilirubin is <35%. 
 
With the exception of sites in Italy, dosing may be started before local liver function 
test results are available. If the local laboratory results reveal liver abnormalities as 
defined in Section 5.3.3 and Appendix 2, study drug treatment must be discontinued. 
 
Sites in Italy: For sites located in Italy, dosing must not start before local laboratory 
liver function test results are obtained and reviewed by the investigator. If local 
laboratory liver function test results reveal that ALT is ≥2 × ULN or total bilirubin 
is >1.5 × ULN (>35% direct bilirubin), the subject must not be dosed and should be 
withdrawn from the study. An isolated bilirubin >1.5 × ULN is acceptable if 
bilirubin is fractionated and direct bilirubin is <35%. 
 
Section 5.3.1.2., Withdrawal From Study Participation After Beginning 
Randomized Treatment 
 
All subjects who are randomly assigned to and begin treatment (i.e., randomized 
treatment) should be encouraged to complete all phases of the study, including those who 
discontinue randomized treatment. However, a subject may voluntarily withdraw from 
study participation at any time or be withdrawn at any time at the discretion of the 
investigator for any maternal obstetrical or medical complications after consultation with 
the PPD medical monitor. If a subject withdraws from the study, she no additional visits 
can occur or procedures performed, and the subject may request destruction of any 
samples taken and; the investigator must document this request in the site study records. 
 
Subjects who are withdrawn after starting the Inpatient Randomized Treatment Phase but 
before the Post-Infusion Assessment Phase will be asked to return and complete the 
assessments specified for the 1-week face-to-face post-infusion assessment visit before 
withdrawing from the study (Table 5). 
 
Section 5.3.2., Discontinuation of Investigational Product 
 
Subjects who receive but who discontinue from IP will not be considered withdrawn 
from the study and should remain in the study and continue to be followed for 
efficacy and safety. Once delivered, newborns will also continue to be followed for 
safety and outcomes through the 28 days post EDD. 
 
A subject may voluntarily discontinue from the IP at any time. The investigator may also, 
at his or her discretion, discontinue the IP at any time for any medical reason or maternal 
or fetal complications. Subjects who discontinue randomized treatment will be managed 
by the investigator according to standard care. 
 
Subjects who receive but who discontinue from IP will not be considered withdrawn 
from the study and should remain in the study and continue to be followed for efficacy 
and safety. Once delivered, newborns will also continue to be followed for safety and 
outcomes through the 28 days post EDD. Subjects who discontinue the IP will not be 
replaced. Reasons for discontinuation from IP will be recorded in the eCRF and the 
subject’s source documents. 


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Section 5.3.3., Liver Chemistry Stopping Criteria 
 
Blood samples will be collected for central laboratory evaluation at Screening (prior to 
treatment), during Day 2 of the randomized treatment phase, and at the 1-week 
face-to-face post-infusion assessment visit for additional liver function testing to ensure 
subject safety and to evaluate liver event etiology (in alignment with the US Food and 
Drug Administration premarketing clinical liver safety guidance); 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM174090.pdf. 
 
Sites Not in Italy: At Screening, before IP administration, ALT and bilirubin test results 
from a local laboratory should be obtained, although dosing may be started prior to the 
availability of these results. However, if the local laboratory results are available before 
the start of dosing and meet the following criteria, the subject should not be dosed and 
should be withdrawn from the study: 
 
• 
ALT ≥2 × ULN OR total bilirubin >1.5 × ULN (>35% direct bilirubin). An isolated 
bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is 
<35%. 
Phase III-IV liver chemistry stopping criteria are presented in Figure 3 and Appendix 2. 
 
The local and central laboratory liver function test results should be reviewed for the 
abnormalities shown in Figure 3. If the laboratory results are not available at the start of 
dosing and subsequent local OR central laboratory results are abnormal, dosing may be 
continued at the discretion of the investigator, as long as they do not exceed the liver 
chemistry stopping criteria shown in Figure 3 and detailed in Appendix 2. 
 
Sites in Italy: At Screening, before IP administration, ALT and bilirubin test results 
from a local laboratory must be obtained and reviewed by the investigator. If the 
local laboratory liver function test results meet the following criteria, the subject 
must not be dosed and should be withdrawn from the study: 
 
• 
ALT ≥2 × ULN OR total bilirubin >1.5 × ULN (>35% direct bilirubin). An 
isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct 
bilirubin is <35%. 
Phase III-IV liver chemistry stopping criteria are presented in Figure 3 and 
Appendix 2. 
 
The local and central laboratory liver function test results should be reviewed for 
the abnormalities shown in Figure 3. If after the start of dosing, the central 
laboratory results are abnormal, dosing may be continued at the discretion of the 
investigator, as long as they do not exceed the liver chemistry stopping criteria 
shown in Figure 3 and detailed in Appendix 2. 
 
NOTE for All Sites:  The central laboratory report will include results for ALT, aspartate 
aminotransferase (AST), alkaline phosphatase, total bilirubin, and direct bilirubin. 


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Section 6.3.1., Inadequate Response 
 
An adequate response is based on (1) a clinically relevant reduction of contraction 
frequency and/or intensity or (2) no change in the cervical examination. An inadequate 
response is defined as a clinically significant change in the cervical examination or 
no significant reduction in contraction frequency and/or intensity. . . . 
 
Section 6.4., Managing Dose Interruptions 
 
Temporary interruptions of the IP are permitted. The following procedures should 
be followed in the event of a dose interruption: 
 
• 
If the interruption is <60 minutes, restart the IP infusion. 
• 
If the interruption is from 60 to 90 minutes, inclusive, administer a loading dose 
at a rate equal to one-half of the prior loading dose rate. For example, if the 
loading dose rate prior to the interruption was 240 mL/hour over 5 minutes, 
administer the loading dose at 120 mL/hour over 5 minutes, and then resume 
the infusion. 
• 
If the interruption is >90 minutes, administer a loading dose at a rate equal to 
the prior loading dose rate. For example, if the prior loading dose was 
administered at 240 mL/hour over 5 minutes, administer the loading dose at 
240 mL/hour over 5 minutes, and then resume the infusion. 
Any changes in the dose rate, corresponding start and stop times, and the reason for 
an interruption must be recorded in the eCRF. 
 
Section 6.6., Preparation/Handling/Storage/Accountability 
 
The following are the preparation instructions for the retosiban solution for infusion: 
 
•Withdraw 10 mL solution from a 500 mL 0.9% NaCl infusion bag and discard the 
solution 
•Replace discarded solution with 10 mL retosiban 15 mg/mL concentrate solution for 
infusion from two 5 mL vials to obtain a concentration of 0.3 mg/mL (150 mg 
retosiban in 500 mL 0.9% NaCl). The reconstituted product is a clear, colorless 
solution without particles 
•Label the IV bag with the following information: subject number, date, protocol 
number, dosing session number, investigator’s name, and the statement, “use as 
directed per pharmacy manual” (for details see the Study Pharmacy Manual). 
Once the vial of retosiban solution has been opened, the dilution must be performed 
immediately. The diluted solution for IV administration should be used within 24 hours 
after preparation in order to minimize the risk for microbial growth. The volume for the 
infusion bag must be 500 mL to avoid proportional calculations. 
 
The unblinded pharmacist or other qualified individual will prepare the placebo 
admixture, which will consist of a 500-mL 0.9% NaCl infusion bag, labeled with the 
following information: subject number, date, protocol number, dosing session number, 


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investigator’s name, and the statement, “use as directed per pharmacy manual.” The 
volume of the 0.9% NaCl infusion bag should 500 mL to match the 0.9% NaCl infusion 
bag volume used for the retosiban admixture (for details see the Study Pharmacy 
Manual). 
 
A description of the methods and materials required for preparation of the retosiban 
solution and the matching placebo are detailed in the Study Pharmacy Manual. 
 
The following considerations must be made with regard to IP preparation, handling, 
storage, and accountability in this study: . . . 
 
Section 6.12., Concomitant Medications and Nondrug Therapies 
 
All concomitant medications taken by the mother during the study will be recorded in 
the eCRF; the indication for the concomitant medication must be specified. 
Prespecified concomitant medications of interest will be assessed. Concomitant 
medications taken during time of delivery and hospitalization will be obtained through a 
review of the hospital records. 
 
Section 6.12.1.2., Magnesium Sulfate 
 
Investigators have the option to use magnesium sulfate. Magnesium sulfate should be 
given intravenously using a 4- to 6-g loading dose and 1- to 2-g/hour infusion rate. The 
total duration of magnesium sulfate administration should not exceed 48 hours. Doses 
exceeding this range will be considered a putative tocolytic and will be classified as a 
treatment failure. 
 
Section 6.12.2. 
Prohibited Medications and Nondrug Therapies 
 
Except for IP administered during this study, no additional investigational drugs or 
investigational devices are permitted for the mother from the time of study entry through 
completion of the follow-up visit (i.e., the maternal post-delivery assessment) or 30 days 
after administration of the last dose of IP, whichever is longer. 
 
The use of a pessary may be continued for subjects who were using a pessary prior 
to the current episode of preterm labor; however, initiating use of a pessary during 
the study is prohibited. 


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Section 6.11.2.1., Tocolytic Drugs 
 
Concomitant use of calcium-channel blockers, nonsteroidal anti-inflammatory drugs 
(NSAIDs), or -agonists for tocolysis during IP administration is prohibited. The 
concomitant medications listed below will be considered putative tocolytics when 
administered for active preterm labor or for the prevention of preterm labor. Apart 
from the exceptions listed in Table 4, use of any of the following putative tocolytics 
at any time prior to delivery will be considered a treatment failure: 
 
• 
Calcium-channel blockers:  nifedipine 
• 
-agonists: ritodrine, terbutaline, and salbutamol 
• 
NSAIDs: celecoxib, ibuprofen, indomethacin, ketorolac, naproxen 
Likewise, subjects administered any the use of the calcium-channel blockers, NSAIDs, 
or -agonists medications listed above for maintenance tocolysis (prevention of 
recurrent preterm labor) in subjects who remained undelivered following the Inpatient 
Treatment Phase is prohibited will be considered a treatment failure. Subjects 
administered doses of magnesium sulfate that exceed the dose specified in Section 
6.12.1.2 (i.e., any dose that exceeds a 4- to 6-g IV loading dose and then a 1- to 
2-g/hour infusion rate, with total duration of magnesium sulfate administration up 
to 48 hours) will also be considered a treatment failure. 


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Table 4 
Guidelines for Exceptions to Putative Tocolytic Drug Use 
 
Drug Class 
Example Drugs 
Exceptions for Use 
Calcium-channel 
blockers 
nifedipine 
• Administration for chronic or pregnancy- 
induced hypertension will not be considered 
a treatment failure if the indication is 
provided when documenting concomitant 
medications. 
• Administration for new onset of hypertension 
would not be considered a treatment failure. 
The new onset must be recorded on the 
AE/SAE page of the eCRF. 
• A dose increase due to exacerbation of 
hypertension will be not considered a 
treatment failure. Exacerbation must be 
recorded on the AE/SAE page of the eCRF. 
-agonists 
ritodrine, salbutamol, and 
terbutaline 
• Administration for chronic or new onset 
respiratory indications is permitted. Acute 
short-term courses for respiratory conditions 
will not be considered a treatment failure if 
the indication is provided when documenting 
concomitant medications. 
• New onset of a respiratory condition would 
not be considered a treatment failure. The 
new onset must be recorded on the AE/SAE 
page of the eCRF. 
• A dose increase due to exacerbation of a 
respiratory condition will be not considered a 
treatment failure. Exacerbation to be 
recorded on the AE/SAE page of the eCRF. 
NSAIDs1 
celecoxib, ibuprofen, 
indomethacin, ketorolac, and 
naproxen 
• Administration for chronic medical 
conditions, such as rheumatoid arthritis, will 
not be considered a treatment failure if the 
indication is provided when documenting 
concomitant medications. 
• Single doses of NSAIDs not taken for 
treatment of preterm labor (e.g., taken for 
headache, dysmenorrhea, or fever) will not 
be considered a putative tocolytic. 
NSAID = nonsteroidal anti-inflammatory drug. 
1.    Subjects should be discouraged from using NSAIDs without first discussing with the investigator. 


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Time and Events Table 
185 
 
 
 
 
Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
(±2 weeks) 
after delivery2 
Delivery to 
28 days post 
EDD 
Clinical and Other Assessments 
Written informed consent 
and medical releases for 
treatment23 
X 
Discuss and request 
consent for participation in 
the infant follow-up study34 
X
X 
X 
Inclusion/exclusion criteria 
confirmation 
X 
Baseline characteristics 
and demographic data 
X 
Medical history (including 
obstetrics history)45 
X 
Drug and alcohol 
screening56 
X 
Physical examination 
(including height and 
weight) 
X 
Cervical examination67 
X 
X 
X 
X 
Estimated fetal weight via 
ultrasound 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
(±2 weeks) 
after delivery2 
Delivery to 
28 days post 
EDD 
Determine AFI via 
ultrasound78 
X 
Uterine contractions89 
X 
Schedule post-infusion 
assessment visit 
X 
Investigational Products910 
Retosiban or placebo 
X 
X 
Efficacy Assessments 
Date and time of 
delivery1011 
X 
Mode of delivery1011 
X 
Indication for delivery1011 
X 
Neonatal composite 
outcomes 
X 
Neonatal hospital stay 
X 
Maternal Safety Assessments 
Concomitant medications 
X
X 
X 
ECG 12-lead1112 
X 
Vital sign measurements 
(BP, pulse rate, 
temperature, respiratory 
rate, and oxygen 
saturation) 1213 
X 
X 
X 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
(±2 weeks) 
after delivery2 
Delivery to 
28 days post 
EDD 
AEs, SAEs, and DREs : 
maternal 
X
X 
X 
Monitor fluid balance 
intake and output 
X 
X 
X 
Breastfeeding status 
X 
Edinburgh Postnatal 
Depression 
Scale1314(maternal) 
X 
Local laboratory 
assessments (LFTs 
only)1415 
X 
Central laboratory 
assessments (including 
hematology, chemistry, 
and LFTs)1516 
X 
X 
X1516 
Physical examination 
(brief) 
X 
Status of postpartum 
bleeding 
X 
Fetal Safety Assessments 
Electronic fetal heart rate 
monitoring16 
X17 
X18 
X18 
X19 
X20 
AEs, SAEs, and DREs: 
fetal 
X
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
(±2 weeks) 
after delivery2 
Delivery to 
28 days post 
EDD 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: 
neonatal 
X
X 
Neonatal Apgar Scores 
(1 and 5 minutes)1011 
X 
Neonatal growth 
parameters1011 
X 
Neonatal umbilical cord 
blood gases1011 
X 
Health Outcome Assessments 
Maternal and neonatal 
health care resource 
use1721 
X 
X 
Pharmacokinetic Assessments 
Maternal PK blood 
sample1822 
X1821 
X 
Cord blood sample1923 
X 
Breast milk/colostrum 
sample2024 
X 
Genetic and Biomarker Assessments 
Genetic blood sample for 
maternal DNA2125 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
Every week 
(or early 
termination/ 
withdrawal) 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
(±2 weeks) 
after delivery2 
Delivery to 
28 days post 
EDD 
Biomarker maternal blood 
sample2226 
X 
Genetic blood sample for 
cell-free fetal DNA2327 
X 
X 
Other Assessments 
Fetal fibronectin 
(optional)2428 
X 
Cervical length via 
transvaginal ultrasound 
(optional)2529 
X 
Confirm no other study 
participation for infant2630 
X 
AE = adverse event; AFI = amniotic fluid index; ALT = alanine aminotransferase; BP = blood pressure; DRE = disease-related event; ECG = electrocardiogram; eCRF = electronic case 
report form; EDD = estimated date of delivery; IP = investigational product; LFT = liver function test; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of 
normal. 
1. 
Subjects who remain undelivered after 48 hours will return for a face-to-face post-infusion visit for obstetric assessments 1 week (acceptable range: 3 to 14 days) following 
the Inpatient Randomized Treatment Phase. The subject will then be contacted every week via telephone to determine and record if she has delivered or experienced any 
subsequent episodes of preterm labor. Note: If the subject is scheduled to visit the clinic for reasons not required by this protocol and/or she happens to be present at the 
time the telephone assessment is due, this assessment may be completed face-to-face. 
2. 
During the Maternal Post Delivery Assessment Phase, subjects will be contacted by telephone within 6 weeks of delivery for a post-delivery assessment, 
including an assessment of AEs (±2 weeks), status of breastfeeding (±2 weeks), and completion of the EPDS (±6 weeks). 
23. 
Prestudy screening information that is collected by the study site may need to come from records that are obtained before the subject has signed the informed consent. The 
subject will be required to provide written informed consent before any study-specific procedures are performed, and the consent will request permission for use of any 
information collected prior to its having been signed. 


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34. 
During the study, the subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant to participate in a separate 
long-term infant follow-up study for safety and neurodevelopment. Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude 
involvement in the infant follow-up study. 
45. 
Medical history will be collected at Screening. If a condition with a start date predating Day 0 (Screening) is subsequently discovered, the condition should be recorded in the 
Medical History eCRF. For obstetrics history, the investigator will make every effort to obtain this information either via computer records, directly from the subject’s primary 
care obstetrician, or via telephone. However, in cases in which these records are not readily available (e.g., off hours, holiday), it is within the investigator’s discretion to can 
use gestational age based on the verbal history from the subject with the intent of getting confirmation from the medical records or from the subject’s primary care 
obstetrician as soon as possible. 
56. 
The urine drug screen will be performed using a point-of-care qualitative testing device. A point-of-care breath analyzer for alcohol will be used in some countries in addition 
to the urine drug screen. 
67. 
A cervical examination (including dilation, effacement, and station) will occur at Screening, and an additional cervical examination may be performed before dosing based on 
investigator discretion. If a predosing cervical examination reveals dilation >4 cm, the subject cannot be dosed. Additional cervical examinations (Day 1, Day 2, and/or at the  
1-week face-to-face post-infusion assessment visit) will be performed based on investigator discretion. 
78. 
The abdominal ultrasound for determination of the AFI will be performed at Screening for all subjects. 
89. 
Uterine tocography or manual palpation (if necessary) will be performed prior to dosing to confirm the persistent uterine contractions frequency. If the examination reveals 
in the 60 minutes before IP dosing a rate that is <4 contractions of a least 30 seconds’ duration over a 30-minute interval, the subject cannot be dosed. Manual 
palpations will be permitted if there are technical challenges with measuring contraction frequency. 
910. 
If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours 
apart or (2) four 6-mg doses of dexamethasone administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the  
antecedent treatment was at least 7 days prior to study enrollment. Investigators have discretion to use a standardized regimen of magnesium sulfate, as well as intrapartum 
antibiotic prophylaxis for perinatal group B streptococcal infection. 
1011. 
Information regarding delivery will be obtained through a review of the hospital and medical records. Growth parameters include neonatal weight, length, and head 
circumference. 
1112. 
A 12-lead ECG will be performed prior to dosing. If the results are interpreted by the investigator to have clinically significant abnormalities, the subject cannot be dosed. 
1213. 
Blood pressure, pulse rate, respiratory rate, and temperature will be assessed at Screening once every 4 to 8 hours, as part of maternal safety monitoring during the 
Inpatient Randomized Treatment Phase, and at the post-infusion assessment visit. Oxygen saturation will be assessed by pulse oximetry at Screening and once every 4 to 8 
hours Dduring the Inpatient Randomized Treatment Phase, vital signs and oxygen saturation will be assessed and recorded within the following windows relative to 
the start of the infusion: 15 to 30 minutes, 4 to 8 hours, 20 to 24 hours, at the end of the infusion, at the time of any dose changes, and as warranted by a medical 
condition.; oOxygen saturation less than 92% should be recorded as an AE or SAE, as appropriate. 
1314. 
Maternal subjects will complete the Edinburgh Postnatal Depression Scale, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (±26 weeks) after 
delivery. 
1415. 
The LFTs should be ordered from the local laboratory to confirm that ALT is not ≥2 × ULN OR total bilirubin is not >1.5 × ULN (>35% direct bilirubin) before dosing with the 
IP. An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%. With the exception of sites in Italy, Sscreening LFT laboratory 
results do not need to be available for the subject to be randomly assigned to treatment; however, see Section 5.3.3 if ALT or bilirubin is abnormal. Sites in Italy: Subjects 
must not be dosed before local laboratory LFT results are obtained and reviewed by the investigator, see Section 5.3.1.1 and Section 5.3.3 for details. 
1516. 
Hematology, chemistry, and LFTs will be determined through a central laboratory at the screening, Day 2, and the 1-week face-to-face post infusion assessment visits. The 
LFT values from the central laboratory should be reviewed for abnormalities (see Section 5.3.3). For subjects who deliver within 24 hours after completion or discontinuation 


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of IP and for subjects who deliver at the investigative center after discharge but before the 1-week face-to-face post-infusion assessment visit, central laboratory   
assessments for hematology, chemistry, and LFTs should be performed. For subjects that do not deliver at the investigative center, central laboratory assessments   
for hematology, chemistry, and LFTs should be performed at the investigative center within 1 week (acceptable range: 3 to 14 days) after completion of the study 
drug infusion. 
1617. 
Prior to dosing, if the fetal heart rate pattern is nonreassuring, the subject cannot be dosed. 
18.Electronic fetal heart rate monitoring is required for a minimum of 6 hours from the start of the infusion or from the start of a dose increase will be continuous throughout the 
Inpatient Randomized Treatment Phase. The fetal heart rate will be recorded in the eCRF once every 4 to 8 hours in conjunction with maternal vital signs. If  the subject has 
not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate will be recorded at the face-to-face post-infusion assessment visit. Any fetal heart rate 
assessment of Category II or III will be reported as an AE of special interest on a specified eCRF (details in Section 7.4.4). As long as the fetal heart rate pattern is 
consistently reassuring throughout the required 6-hour duration of monitoring and the contraction frequency is 2 in a 30-minute window within the  last hour of 
monitoring, continuous monitoring may be discontinued and nonstress tests initiated at a minimum of every 8 hours and as needed. Electronic fetal monitoring, 
including the fetal heart rate and fetal heart rate category, will be recorded in the eCRF with maternal vital signs. Any fetal heart rate assessment of Category II or 
III will be reported as an AE of special interest on a specified eCRF (details in Section 7.4.4). 
19. 
If the subject has not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate will be recorded at the 1-week face-to-face post-infusion 
assessment visit. Any fetal heart rate assessment of Category II or III will be reported as an AE of special interest on a specified eCRF (details in Section 7.4.4). 
20. 
During the Delivery Phase, fetal heart rate just prior to delivery will be collected, if available, from review of delivery records. Any fetal heart rate assessment of 
Category II or III will be reported as an AE of special interest on a specified eCRF (details in Section 7.4.4). 
1721. 
Maternal and neonatal health care resource use may include, but is not limited to, neonatal complications requiring intensive or specialized care, neonatal hospital 
readmission, and neonatal ambulatory surgery. 
1822. 
PK samples will be taken at each of the following sampling windows (relative to the start of the infusion on Day 1): 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 to 
54 hours. In addition, a PK sample should be taken at the onset of any maternal or fetal SAE that occurs within 12 hours after completion or discontinuation of IP. 
1923. 
In subjects who deliver at an investigative center within 12 hours following completion or discontinuation of the IP, a single cord blood sample will be collected for PK 
analysis. Additionally, a maternal blood sample should be collected at the same time as the cord blood sample if the sample time does not already coincide with a 
PK sampling window (see Section 7.6.1). 
2024. 
A breast milk/colostrum sample is only to be collected in women who deliver and produce breast milk within 12 hours after completion or discontinuation of the IP. 
2125. 
All participating investigational centers will collect a blood sample for maternal DNA in women who provide informed consent for genetic research. 
2226. 
All participating investigational centers will collect a maternal blood sample for biomarker research. 
2327. 
Only US and Canadian investigational centers will collect a maternal blood sample for cell-free fetal DNA in women who provide informed consent for genetic research.   
2428. 
Fetal fibronectin results will be collected only at those institutions that perform fetal fibronectin testing as routine practice. Fetal fibronectin will not be used to determine study 
eligibility. 
2529. 
Cervical length determined by transvaginal ultrasound will be collected only at those institutions that measure cervical length as routine practice. Cervical length will not be 
used to determine study eligibility. 
2630. 
Obtain confirmation from the subject or the legal guardian for the infant that the infant is not participating in any other study. 


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Section 7.2., Screening and Critical Assessments Prior to Investigational Product 
Administration 
 
The following assessments are required before dosing (i.e., before initiating randomized 
treatment): 
 
• 
Electronic Ffetal heart rate monitoring to confirm that the fetal heart rate pattern 
remains reassuring 
• 
Cervical examination to ensure cervical dilation continues to meets eligibility 
criteria at the discretion of the investigator, as clinically indicated 
• 
Uterine tocography or manual palpation (if necessary) to confirm persistent 
uterine contractions (see Section 5.1). A that the uterine contraction frequency that 
exceeds the threshold for eligibility (see Section 5.1) should be clearly 
documented, specifically demonstrating within the 60 minutes before IP 
administration that there is an observed 30-minute interval with 
≥4 contractions of at least 30 seconds’ duration. Manual palpations of 
contractions will be permitted if there are technical challenges with measuring 
contraction frequency; use of manual palpations must be documented. Dosing 
should not be started if contraction frequency decreases. 
• 
Liver function tests from a local laboratory to confirm that ALT is not ≥2 × ULN OR 
total bilirubin is not >1.5 × ULN (>35% direct bilirubin), if available; dosing may be 
started prior to the availability of these results. An isolated bilirubin >1.5 × ULN is 
acceptable if bilirubin is fractionated and direct bilirubin is <35% (see Section 5.3.3). 
With the exception of sites in Italy, dosing may be started prior to the 
availability of these results. 
Sites in Italy:  Dosing must not be started prior to the availability of liver 
function tests results from a local laboratory (see Section 5.3.3). 
• 
Electrocardiogram that is interpreted by the investigator to not have any significant 
abnormalities that may place the subject at risk for a cardiopulmonary complication 
during the study 
If the fetal heart rate pattern is nonreassuring, the uterine contraction rate is less than 
4 contractions over a 30-minute interval, cervical dilation exceeds 4 cm, levels of ALT or 
bilirubin are abnormal, or the ECG has been interpreted to have clinically significant 
abnormalities, the subject cannot be dosed and will be withdrawn from the study (see 
Section 5.3.1). 
 
Section 7.3.1.2., Time to Treatment Failure 
 
Treatment failure will be defined as the administration of any putative tocolytic 
medication for active preterm labor or as prevention of preterm labor, such as 
calcium-channel blockers, NSAIDs, or -agonists, apart from the exceptions listed in 
Table 4, and magnesium sulfate doses that exceed a 4- to 6-g IV loading dose and 1- 
to 2-g/hour infusion rate and total duration of magnesium sulfate administration 
greater than 48 hours (see Section 6.12.1.2). The time to treatment failure will be 


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assessed from the start of study treatment administration (time 0) in the Inpatient 
Randomized Treatment Phase until a putative tocolytic is administered. 
 
Treatment failure will be considered to have occurred in the following situations: 
 
• 
Administration of a putative tocolytic following IP discontinuation during the 
Inpatient Randomized Treatment Phase. 
• 
Administration of a putative tocolytic in an undelivered subject for the management 
of recurrent preterm labor. 
• 
Maintenance tocolysis is prohibited (Section 6.12.2.1); however, any subject treated 
with a tocolytic as maintenance treatment during the Post-infusion Assessment Phase 
will be considered a treatment failure. 
For this efficacy assessment, the following information will be collected: 
 
• 
Date and time of administration of any putative tocolytics 
• 
Name and dose of the putative tocolytics 
• 
Reason for administration of putative tocolytics 
Operational procedures will be instituted to optimize data collection and reporting 
consistency in those situations when the subject is administered an alternative putative 
tocolytic by her referring primary care obstetrician. Details of these procedures are 
provided in the SPM. 
 
Section 7.4.1.4., AEs of Special Interest 
 
Maternal, fetal, and neonatal AEs of special interest are listed in Section 3 and in 
Appendix 4. Guidelines for reporting these events are provided in Appendix 5. 
 
Section 7.4.2., Physical Examinations 
 
An admission physical examination will include at a minimum maternal height, weight, 
and assessment of heart, lungs, abdomen, and cervical examination including dilation, 
effacement, and station. 
 
A brief physical examination, assessing heart, lungs, and abdomen, at a minimum, and, 
if undelivered, a cervical examination at a minimum the discretion of the investigator 
will be performed at the 1-week face-to-face post-infusion assessment visit, following 
conclusion of the treatment phase. 
 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 
Section 7.4.3., Vital Signs and Oxygen Saturation 
 
Blood pressure, pulse rate, respiratory rate, and temperature will be measured at the 
following time points during the study:  Screening, Inpatient Randomized Treatment 
Phase (once every 4 to 8 hours and as warranted by a medical condition or AE), and at 


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the 1-week face-to-face post-infusion assessment visit. During the Inpatient 
Randomized Treatment Phase, vital signs and oxygen saturation will be assessed 
and recorded within the following windows relative to the start of the infusion: 15 to 
30 minutes, 4 to 8 hours, 20 to 24 hours, at the end of the infusion, at the time of any 
dose changes, and as warranted by a medical condition. Subjects may be either in a 
semirecumbent or seated position. In addition, oxygen saturation will be assessed by 
pulse oximetry at Screening and during the Inpatient Randomized Treatment Phase (once 
every 4 to 8 hours with the other vital sign assessments). Clinically relevant abnormal 
findings, including oxygen saturation less than 92%, should be recorded as an AE or 
SAE, as appropriate. 
 
Section 7.4.4., Electronic Fetal Heart Rate Monitoring 
 
Electronic fetal monitoring is required for a minimum of 6 hours from the start of 
the infusion or from the start of a dose increase if the following are confirmed 
during monitoring: 
 
• 
The fetal heart rate pattern is consistently reassuring throughout the required 
minimum 6-hour duration of monitoring 
• 
The contraction frequency is 2 in a 30-minute window within the last hour of 
monitoring. 
A reassuring nonstress test (defined as meeting Category I criterion), accounting for 
GA expectations, is required at a minimum of every 8 hours and as needed. An 
additional 6 hours of electronic fetal monitoring will be required for dose 
interruptions that are sufficiently long as to require an additional infusion of the IP. 
 
Electronic fetal monitoring, including the Ffetal heart rate and fetal heart rate 
category, will be monitored continuously from Screening until completion of the 48-hour 
Inpatient Randomized Treatment Phase. Subjects will be allowed breaks of up to 1 hour 
if fetal heart rate monitoring up to that point has been reassuring. Fetal heart rate should 
be recorded in the eCRF once every 4 to 8 hours at approximately the same time that 
maternal vital sign measurements are collected (Section 7.4.3). The electronic fetal 
heart rate tracing (paper or electronic) must be archived and retained in site 
records. Fetal heart rate also will be recorded at the 1-week face-to-face post-infusion 
assessment visit if the subject remains undelivered. During the Delivery Phase, fetal heart 
rate just prior to delivery monitoring information will be collected summarized, if 
available, from review of medical delivery records. Any fetal heart rate assessment of 
Category II or III according to the following criteria and based on ACOG guidelines 
[ACOG Practice Bulletin No. 106, 2009] will be reported as an AE of special interest on 
a specified eCRF in addition to the corresponding AE or SAE eCRF: 
 
Section 7.4.6., Clinical Safety Laboratory Assessments 
 
With the exception of the above, all protocol-required laboratory assessments must be 
performed by the central laboratory. For subjects that do not deliver at the 
investigative center, central laboratory assessments for hematology, chemistry, and 
LFTs should be performed at the investigative center within 1 week (acceptable 
range: 3 to 14 days) after completion of the study drug infusion. 


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Section 7.4.8., Fluid Management 
 
Care should be taken to assess for fluid overload by monitoring the total fluid balance  
intake and output from the Screening Phase through Inpatient Randomized Treatment 
Phase and assessing for signs and symptoms of fluid overload. Details regarding this 
assessment are provided in the SPM. 
 
Section 7.4.10., Maternal Depression 
 
Maternal subjects will complete the EPDS at the maternal follow-up assessment 6 weeks 
(±26 weeks) post-delivery (Table 5). 
 
Section 7.6.1, Sampling 
 
Maternal blood samples for the quantification of retosiban in plasma will be taken at the 
following sampling windows (relative to the start of the infusion on Day 1):  2 to 4 hours, 
10 to 14 hours, 22 to 26 hours, and 48 to 54 hours, the last point being after the end of the 
infusion. Samples may be taken at any time within these windows, but the exact time of 
the sample should be recorded in the eCRF. The volume of blood required for PK 
sampling, as specified in the Time and Events Table (Table 5), is approximately 8 mL. 
 
Additionally, a maternal blood sample should be collected at the same time as the 
cord blood sample (see Section 7.6.2) if the sample time does not already coincide 
with one of the PK sampling windows listed above. 
 
In addition A blood sample also should be taken at the onset of any maternal or fetal SAE 
that occurs within 12 hours after completion or discontinuation of IP 
 
Section 9.3.3.3., Subgroup Analysis 
 
Additionally, comparisons of retosiban versus placebo for co-primary and key secondary 
endpoints may also be performed for the following subgroups: 
 
• 
GA strata 240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7, or 310/7 to 336/7 
• 
Established progesterone use (yes or no) 
• 
Magnesium sulfate use 
• 
Putative Ttocolytic use following IP discontinuation 
Other potential subgroup comparisons will be described in the RAP. 
 
Section 9.3.4., Interim Analyses 
 
Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 women/newborn pairs subjects have completed delivery and have 
time-to-delivery results available all assessments. The primary objective of the first 
interim analysis is to determine if the study should be terminated for lack of efficacy 
(futility) based on prespecified criteria. The decision will be based primarily on the 


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analysis of the key secondary endpoint of time to delivery; however, all available safety 
and efficacy data will be reviewed. 
 
. . . 
 
The second interim analysis will occur after approximately 400 women/newborn pairs 
are followed up to 28 days post EDD complete all assessments. . . 
 
Section 9.4.3., Health Outcomes Analyses 
 
To further describe the health outcomes of retosiban, the following subgroups may be 
explored: 
 
• 
GA of pregnancy at randomization 
• 
Established progesterone use 
• 
Magnesium sulfate use 
• 
Putative Ttocolytic use following IP discontinuation 
• 
Region/sites 
Section 11., References 
 
American College of Obstetricians and Gynecologists Committee on Obstetric 
Practice. ACOG Practice Bulletin No. 76. Postpartum hemorrhage. Obstet Gynecol. 
2006;108(4):1039-47. 
 
Cregan MD, De Mello TR, Kershaw D, McDougall K, Hartmann PE. Initiation of 
lactation in women after preterm delivery. Acta Obstet Gynecol Scand. 2002;81(9):870 7. 
 
GlaxoSmithKline Document Number CM2006/00201/035. Investigator's brochure 
Version 3. APR-2014. 
 
Henderson JJ, Hartmann PE, Newnham JP, Simmer K. Effect of preterm birth and 
antenatal corticosteroid treatment of lactogenesis II in women. Pediatrics. 
2008;121(1):e92-100. 
 
Thornton S, Goodwin TM, Greisen G, Hedegaard M, Arce JC. The effect of 
barusiban, a selective oxytocin antagonist, in threatened preterm labor at late 
gestational age: a randomized, double-blind, placebo-controlled trial. Am J Obstet 
Gynecol. 2009;200(6):627e1-627e10. 
 
Valenzuela GJ, Craig J, Bernhardt MD, Holland ML. Placental passage of the 
oxytocin antagonist atosiban. Am J Obstet Gynecol.l 1995;172(4 Pt 1):1304-6. 
 
Section 12.1., Appendix 1: Abbreviations and Trademarks 


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Definitions 
 
Chronological age 
Defined as the time elapsed after birth; it is usually 
described in days, months, and years 
Estimated date of delivery 
Defined as 400/7 weeks’ gestation for all subjects 
Gestational age 
Determined by (1) known fertilization date, either in vitro 
fertilization or intrauterine insemination, or (2) a best 
estimated due date last menstrual period confirmed or 
established by the earliest ultrasound prior to performed 
before 240/7 weeks’ gestation, or (3) the earliest ultrasound 
alone prior to 240/7 weeks’ gestation, whichever is the most 
accurate method available for each subject. 
Postmenstrual age 
Determined by adding chronological age to gestational age 
at delivery 
 
 
Section 12.3.5, Evaluating AEs and SAEs 
 
Assessment of intensity: 
 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to an intensity category. Refer to the SPM for 
details on assessing intensity of maternal and fetal AEs and SAEs. one of the 
following categories: 
 
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities. 
 Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severity is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
 Note: An event is defined as “serious” when it meets at least one of the predefined 
outcomes as described in the definition of an SAE. 


 
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Section 12.5., Appendix 5: Safety Reporting Cheat Sheet 
 
 
NEWBORN 1 SAFETY REPORTING CHEAT SHEET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; ARDS = adult respiratory distress syndrome, BDP = bronchopulmonary dysplasia; DIC = Disseminated Intravascular Coagulation; DRE = disease- 
related event; GERD = gastroesophageal reflux disease, IP = investigational product; IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; PDA = patent 
ductus arteriosus; RDS = respiratory distress syndrome; SAE = serious adverse event. 
 
 
 
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Section 12.6., Appendix 56: Genetic Research 
 
Section 12.7., Appendix 67: Cytochrome P450 3A4 Enzyme Inhibitors and Inducers 
 
Strong1  
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
Inhibitors 
Amprenavir 
Aprepitant 
Amlodipine 
Atazanavir 
Cimetidine 
Atomoxetine 
Clarithromycin 
Darunavir 
Atorvastatin 
Conivaptan 
Diltiazem 
Azithromycin 
Fosamprenavir 
Erythromycin 
Bicalutamide 
Grapefruit juice4 
Fluconazole 
Chlorzoxazone 
Indinavir 
Imatinib 
Cilostazol 
Itraconazole 
Nifedipine 
Cyclosporine 
Ketoconazole 
Tofisopam 
Darifenacin 
Nefazodone 
Verapamil 
Dasatinib 
Nelfinavir 
Ezetimibe 
Ritonavir 
Fentanyl 
Saquinavir 
Fluvoxamine 
Telithromycin 
Gemfibrozil 
Troleandomycin 
Isoniazid 
Voriconazole 
Lacidipine 
Omeprazole 
Posaconazole 
Propiverine 
Propofol 


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Strong1  
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
Quinidine 
Ranitidine 
Ranolazine 
Roxithromycin 
Tabimorelin 
Inducers 
Strong1  
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
Carbamazepine 
Bosentan 
Aprepitant 
Efavirenz 
Etravirine 
Amprenavir 
Phenytoin 
Nafcillin 
Avasimibe 
Rifampin 
Nevirapine 
Dexamethasone 
St. Johns Wort 
Phenobarbital 
Glycyrrhizin 
Modafinil 
Oxcarbazepine 
Pioglitazone 
Prednisone 
Rifabutin 
Rufinamide 
1. 
Strong inhibitor: >5 AUCi/AUC (area of the curve of substrate in the presence of an inhibitor/area under the curve 
of substrate in a control condition); strong inducer: <0.2 AUCi/AUC. Co-administration of study drug with a 
strong inhibitor or strong inducer requires an adjustment to the study drug dosing regimen. 
2. 
Moderate inhibitor: 2 to 5 AUCi/AUC; moderate inducer: 0.2 to 0.5 AUCi/AUC. 
3. 
Weak inhibitor: <2 AUCi/AUC; weak inducer: 0.5 to 0.8 AUCi/AUC. 
4. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation- 
dependent. However, no dose adjustment is needed for retosiban, as grapefruit juice is not expected to cause an 
interaction given that retosiban is administered intravenously. 


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Section 12.8., Appendix 78: Country-Specific Requirements 
 
Section 12.9., Appendix 89: Protocol Changes 


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Protocol Amendment Number 05 
 
Protocol Amendment Number 05 is applicable to all clinical study centers participating in 
this study. Protocol changes specified in Amendment Number 05 are summarized as 
follows: 
 
• 
Removed screening urine drug and alcohol tests. Women with a history of overt 
substance abuse during the pregnancy or dependency that may have the potential to 
complicate the pregnancy outcome are still ineligible for the study, but instead of 
mandating a drug and alcohol test at the time of Screening, the investigator will be 
allowed to use medical discretion and knowledge of the subject to decide whether or 
not the subject is eligible. 
• 
Removed the requirement that investigator confirm uterine contraction rate and 
cervical dilation after randomization and just before study drug administration. In 
place of this requirement, added that after randomization and prior to study drug 
administration investigators will re-assess that tocolytic therapy is still indicated, 
according to their medical discretion. This change has been made to simplify the 
Inpatient Randomized Treatment Phase and to allow the investigator to use medical 
judgement about whether or not the subject requires tocolysis immediately prior to 
study drug administration. 
• 
Clarified that an abdominal ultrasound to assess fetal growth is needed at Screening 
unless the most recent ultrasound is within 3 weeks (21 days) before the date of 
randomization. This change has been made to avoid a repeat ultrasound if an 
abdominal ultrasound has already been completed within 3 weeks of the study 
treatment. 
• 
Updated the list of maternal disease-related events to clarify the reporting process for 
events of subsequent preterm labor and hospitalization for delivery that are not worse 
than expected. 
• 
Added that the amniotic fluid index should be measured using the 4-quadrant 
method. 
• 
Incorporated other administrative changes. The rationale for these changes is to 
ensure a clear and complete protocol for use at the investigational centers. 
 
 
 
Specific Changes in the Text 
Title Page 
Authors (GSK): PPD 


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Medical Monitor/Sponsor Information Page 
Medical Monitor/SAE Contact Information: 
Role 
Name 
Day Time 
Phone 
Number 
After-Hours 
Phone/Cell/ 
Pager 
Number 
Fax Number 
Site Address 
Primary 
Medical 
Monitor 
PPD 
PPD 
PPD 
PPD 
PPD 
Pharmacovigilance 
MD 
PPD 
PPD 
PPD 
Secondary 
Medical 
Monitor 
PPD 
PPD 
PPD 
PPD 
PPD 
Pharmacovigilance 
PPD 
PPD 
PPD 
PPD 
PPD 
MD 
SAE Fax 
Number 
PPD 
PPD 


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Section 4.2., Treatment Arms and Duration 
 
NEWBORN-1 will comprise 6 phases:  Screening, Inpatient Randomized Treatment, Post 
Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal 
Medical Review (Figure 2). The duration of any subject’s (maternal or neonatal) 
participation in the study will be variable and dependent on GA at study entry and the 
date of delivery. 
 
Figure 2 
Study Design 
 
 
 
 
 
During the Maternal Post Delivery Assessment Phase, the subject will be contacted by 
telephone within 6 weeks of delivery for a post-delivery assessment, including an 
assessment of AEs (±2 weeks), status of breastfeeding (±2 weeks), and completion of the 
EPDS (-2 weeks/+±6 weeks). 
 
During the Neonatal Medical Review Phase, the neonatologist subinvestigator will 
conduct a comprehensive review of the newborn’s medical records from delivery through 
28 days EDD (400/7 weeks’ gestation) for all subjects. During this phase, the subject or 
other legal guardian for the infant should also confirm that the infant is not participating 
in any other study. 
 
Two interim analyses are planned. The first interim analysis will occur after 
approximately 150 subjects have completed delivery and have time-to-delivery results 
available. The second interim analysis will occur after approximately 
400 women/newborn pairs are followed up to 28 days post EDD. At each interim 
analysis, all available safety and efficacy data will be reviewed by the unblinded 


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independent data monitoring committee (IDMC) who may make recommendations to 
terminate the study based on prespecified criteria. At the second interim analysis, the 
IDMC may also make recommendations to increase the sample size of the study based on 
prespecified criteria. Additionally, the IDMC may make recommendations to terminate 
the study at any time for an unfavorable benefit:risk profile. Subjects will continue to be 
enrolled while the interim analyses are being conducted. 
 
Section 4.6.3., Overall Benefit:Risk Conclusion 
 
For detailed information on the identified risks and risk-benefit assessment of retosiban, 
refer to the IB and IB supplement 1 [GlaxoSmithKline Document Number 
CM2006/00201/05; GlaxoSmithKline Document Number 2015N228508_00]. 
 
Section 5., Selection of Study Population and Withdrawal Criteria 
 
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GlaxoSmithKline (GSK) IP or other study treatment that 
may affect subject eligibility is provided in the IB, IB Supplement 1, and other pertinent 
documents [GlaxoSmithKline Document Number CM2006/00201/05; GlaxoSmithKline 
Document Number 2015N228508_00]. 
 
Section 5.1, Inclusion Criteria 
 
2. 
Females aged 12 to 45 years, with an uncomplicated, singleton pregnancy and 
intact membranes in spontaneous preterm labor (Note: This protocol includes 
pregnant adolescents, aged 12 to 17 years, as appropriate, unless national or local 
regulations restrict the age for study enrollment to subjects aged 18 to 45 years.) 
 
Section 5.2, Exclusion Criteria 
 
7. 
Women with co-morbid medical or obstetric conditions that in the opinion of the 
investigator have the potential to complicate the pregnancy course and outcomes, 
such as uncontrolled hypertension or uncontrolled diabetes (if known, history of 
glycosylated hemoglobin >8% at any time during pregnancy), known or 
suspected maternal Zika infection during gestation (see SPM for details), or 
compromise the safety of the subject, such as underlying cardiovascular disorder 
(specifically ischemic cardiac disease, congenital heart disease, pulmonary 
hypertension, valvular heart disease, arrhythmias, and cardiomyopathy) 
 
8. 
Women with a history of substance abuse during the pregnancy or dependency 
that may have the potential to complicate the pregnancy outcome urine drug 
screen positive for cocaine, phencyclidine (PCP), methamphetamine, or 
amphetamine 
 
9. 
Women in whom the combination of history and screening test results is 
suggestive of abuse or dependency that may have the potential to complicate the 
pregnancy outcome. NOTE:  Exclusion of a subject with a positive findings for 
substances other than cocaine, PCP, methamphetamine, or amphetamine is at the 
investigator’s discretion (examples include alcohol, cannabinoids, and opiates) 


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109. 
Women with any diagnosis, condition, treatment, or other factor that, in the 
opinion of the investigator, has the potential to affect or confound assessments of 
efficacy or safety 
 
110. 
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment) 
 
NOTES: 
 
• Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or 
gastric varices, or persistent jaundice, or cirrhosis 
 
• Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(or positive hepatitis C antibody test result at Screening or within 3 months 
prior to first dose of study treatment) are acceptable if subject otherwise meets 
entry criteria 
 
112. 
History of sensitivity to any of the IPs or components thereof or a history of drug 
or other allergy that, in the opinion of the investigator or PPD medical monitor, 
contraindicates the subject’s participation 
 
Section 5.3.1.1., Withdrawal From Study Participation After Randomization but 
Prior to Investigational Product Administration 
 
Any subject with a nonreassuring fetal heart rate pattern, a re-assessment that 
determines tocolytic therapy is no longer indicated (according to investigator’s 
medical discretion), uterine contraction rate less than 4 over a 30-minute interval, 
cervical dilation >4 cm based on digital cervical examination, abnormal levels of alanine 
aminotransferase (ALT) or bilirubin (if results are available), or a clinically significant 
abnormal finding on an electrocardiogram (ECG) cannot be dosed and will be withdrawn 
from the study. The reasons for not dosing a subject will be recorded in the eCRF and 
source documents. Subjects who are withdrawn prior to receiving randomized IP will not 
be followed. 
 
Section 6.5., Blinding 
 
The IDMC will review unblinded data periodically in addition to 2 formal interim 
analyses in accordance with the IDMC charter. Unblinded data will be provided by an 
independent statistical data analysis committee center. 


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Section 7.1., Time and Events Table 
Table 5 Time and Events Table 
Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Clinical and Other Assessments 
Written informed consent 
and medical releases for 
treatment3 
X 
Discuss and request 
consent for participation in 
the infant follow-up study4 
X
X 
X 
Inclusion/exclusion criteria 
confirmation 
X 
Baseline characteristics 
and demographic data 
X 
Medical history (including 
obstetrics history)5 
X 
Drug and alcohol 
screening6 
X 
Physical examination 
(including height and 
weight) 
X 
Cervical examination76 
X 
X 
X 
X 
Estimated fetal weight and 
head circumference via 
ultrasound7 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Determine AFI via 
ultrasound8 
X 
Uterine contractions9 
X 
Schedule post-infusion 
assessment visit 
X 
Investigational Products10 
Retosiban or placebo 
X 
X 
Efficacy Assessments 
Date and time of delivery11 
X 
Mode of delivery11 
X 
Indication for delivery11 
X 
Neonatal composite 
outcomes 
X 
Neonatal hospital stay 
X 
Maternal Safety Assessments 
Concomitant medications 
X
X 
X 
ECG 12-lead12 
X 
Vital sign measurements 
(BP, pulse rate, 
temperature, respiratory 
rate, and oxygen 
saturation)13 
X 
X 
X 
X 
AEs, SAEs, and DREs : 
maternal 
X
X 
X 
Monitor fluid intake and 
output 
X 
X 
X 
Breastfeeding status 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Edinburgh Postnatal 
Depression 
Scale14(maternal) 
X 
Local laboratory 
assessments (LFTs only)15 
X 
Central laboratory 
assessments (including 
hematology, chemistry, 
and LFTs)16 
X 
X 
X16 
Physical examination 
(brief) 
X 
Status of postpartum 
bleeding 
X 
Fetal Safety Assessments 
Electronic fetal monitoring 
X17 
X18 
X18 
X19 
X20 
AEs, SAEs, and DREs: 
fetal 
X
X 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: 
neonatal 
X
X 
Neonatal Apgar Scores 
(1 and 5 minutes)11 
X 
Neonatal growth 
parameters11 
X 
Neonatal umbilical cord 
blood gases11 
X 


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Procedures 
Screening 
Phase 
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week face-
to-face post-
infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Health Outcome Assessments 
Maternal and neonatal 
health care resource use21 
X 
X 
Pharmacokinetic Assessments 
Maternal PK blood 
sample22 
X21 
X 
Cord blood sample23 
X 
Breast milk/colostrum 
sample24 
X 
Genetic and Biomarker Assessments 
Genetic blood sample for 
maternal DNA25 
X 
Biomarker maternal blood 
sample26 
X 
Genetic blood sample for 
cell-free fetal DNA27 
X 
Other Assessments 
Fetal fibronectin 
(optional)28 
X 
Cervical length via 
transvaginal ultrasound 
(optional)29 
X 
Confirm no other study 
participation for infant30 
X 
. . . 


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2. 
During the Maternal Post Delivery Assessment Phase, subjects will be contacted by telephone within 6 weeks of delivery for a post-delivery assessment, including an assessment 
of AEs (±2 weeks), status of breastfeeding (±2 weeks), and completion of the EPDS (-2 weeks/+±6 weeks). 
3. 
Prestudy screening information that is collected by the study site may need to come from records that are obtained before the subject has signed the informed consent. The  
subject will be required to provide written informed consent before any study-specific procedures are performed, and the consent will request permission for use of any information 
collected prior to its having been signed. 
4. 
During the study, the subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant to participate in a separate long-term 
infant follow up study for safety and neurodevelopment. Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude involvement in the 
infant follow-up study. 
5. 
Medical history will be collected at Screening. If a condition with a start date predating Day 0 (Screening) is subsequently discovered, the condition should be recorded in the 
Medical History eCRF. For obstetrics history, the investigator will make every effort to obtain this information either via computer records, directly from the subject’s primary care 
obstetrician, or via telephone. However, in cases in which these records are not readily available (e.g., off hours, holiday), the investigator can use gestational age based on the 
verbal history from the subject with the intent of getting confirmation from the medical records or from the subject’s primary care obstetrician as soon as possible. 
6. 
The urine drug screen will be performed using a point-of-care qualitative testing device. A point-of-care breath analyzer for alcohol will be used in some countries in addition to the 
urine drug screen. 
76.  A cervical examination (including dilation, effacement, and station) will occur at Screening, and an additional cervical examination may be performed before dosing based on 
investigator discretion. If a predosing cervical examination reveals dilation >4 cm, the subject cannot be dosed. Additional cervical examinations (Day 1, Day 2, and/or at the 1 
week face to-face post-infusion assessment visit) are not required but will may be performed based on investigator discretion. If inclusion criteria are based on cervical 
change (see Section 5.1), 2 examinations must be documented (either 2 digital cervical examinations or 2 cervical length examinations). 
7. 
An ultrasound for estimation of fetal weight and head circumference is needed at Screening unless the date of the most recent ultrasound that includes fetal weight 
and head circumference is within 3 weeks (21 days) of the date of randomization. 
8. 
The abdominal ultrasound for determination of the AFI will be performed at Screening for all subjects. The AFI should be measured using the 4-quadrant method. 
9. 
Uterine tocography or manual palpation (if necessary) will be performed at Screening prior to dosing to confirm persistent uterine contractions. If the examination reveals in the 60 
minutes before IP dosing a rate that is <4 contractions of a least 30 seconds’ duration over a 30-minute interval, the subject cannot be dosed. Manual palpations will be permitted 
if there are technical challenges with measuring contraction frequency. 
. . . 
14. Maternal subjects will complete the Edinburgh Postnatal Depression Scale, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (-2 weeks/+±6 weeks) 
after delivery. 
15. The LFTs should be ordered from the local laboratory before dosing with the IP. If the local laboratory results are available before the start of dosing, to confirm that ALT is 
not ≥2 × ULN OR total bilirubin is not >1.5 × ULN (>35% direct bilirubin) before dosing with the IP. An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and  
direct bilirubin is <35%. With the exception of sites in Italy, screening LFT laboratory results do not need to be available for the subject to be randomly assigned to treatment or for 
the start of dosing with IP; however, see Section 5.3.3 if ALT or bilirubin is abnormal. Sites in Italy: Subjects must not be dosed before local laboratory LFT results are obtained 
and reviewed by the investigator, see Section 5.3.1.1 and Section 5.3.3 for details. 
. . . 
30.  Obtain confirmation from the subject or the legal guardian for the infant that the infant is not participating in any other study. 


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Section 7.2., Screening and Critical Assessments Prior to Investigational Product 
Administration 
 
The following assessments are required before dosing (i.e., before initiating randomized 
treatment): 
 
• 
Electronic fetal monitoring to confirm that the fetal heart rate pattern remains 
reassuring 
• 
Re-assess that tocolytic therapy is still indicated, according to the investigator’s 
medical discretion. 
•Cervical examination to ensure cervical dilation continues to meet eligibility criteria at 
the discretion of the investigator, as clinically indicated 
•Uterine tocography or manual palpation (if necessary) to confirm persistent uterine 
contractions (see Section 5.1). A uterine contraction frequency that exceeds the 
threshold for eligibility should be clearly documented, specifically demonstrating 
within the 60 minutes before IP administration that there is an observed 30-minute 
interval with ≥4 contractions of at least 30 seconds’ duration. Manual palpations of 
contractions will be permitted if there are technical challenges with measuring 
contraction frequency; use of manual palpations must be documented. Dosing should 
not be started if contraction frequency decreases. 
• 
Liver function tests from a local laboratory to confirm that ALT is not ≥2 × ULN OR 
total bilirubin is not >1.5 × ULN (>35% direct bilirubin), if available. An isolated 
bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is 
<35% (see Section 5.3.3).With the exception of sites in Italy, dosing may be started 
prior to the availability of these results. 
Sites in Italy:  Dosing must not be started prior to the availability of liver function 
tests results from a local laboratory (see Section 5.3.3). 
• 
Electrocardiogram that is interpreted by the investigator to not have any significant 
abnormalities that may place the subject at risk for a cardiopulmonary complication 
during the study 
If the fetal heart rate pattern is nonreassuring, tocolytic therapy is no longer indicated  
the uterine contraction rate is less than 4 contractions over a 30 minute interval, cervical 
dilation exceeds 4 cm, levels of ALT or bilirubin are abnormal (if results are available), 
or the ECG has been interpreted to have clinically significant abnormalities, the subject 
cannot be dosed and will be withdrawn from the study (see Section 5.3.1). 
 
Section 7.4.1.7., Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
 
The DREs listed in Section 7.4.1.7.1 and Section 7.4.1.7.2 will be monitored by a safety 
review team made up of an internal GSK safety review team (reviewing blinded data) 
and the IDMC (reviewing unblinded data). 


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Section 7.4.1.7.1., Disease-Related Maternal Events 
 
The following DREs are common maternal events during pregnancy, labor, and delivery: 
 
• 
Signs and symptoms of labor discomfort (e.g., cramping, backache, muscle aches, 
nausea) 
• 
Subsequent episodes of preterm labor (even if hospitalization is required) unless 
1 of the conditions listed at the end of Section 7.4.1.7.2 applies 
• 
Hospitalization for delivery, unless prolonged or 1 of the conditions listed at the 
end of Section 7.4.1.7.2 applies 
 
 
 
Section 7.4.1.7.2., Disease-Related Neonatal Events (Occurring in Infants Born Prior 
to 37 Completed Weeks) 
 
Because these events (Section 7.4.1.7.1 and Section 7.4.1.7.2) are typically associated 
with preterm labor and prematurity, they will not be reported according to the standard 
process for expedited reporting of SAEs to GSK/PPD (even though the event may meet 
the definition of a SAE). These events will be recorded on the DRE page in the eCRFs, 
and additional data will be recorded for any DREs related to study endpoints (see Section 
3). These DREs will be monitored by the IDMC and internal GSK safety review team. 
 
Section 7.4.5., Abdominal Ultrasound 
 
An abdominal ultrasound for determination of the AFI will be performed at Screening for 
confirmation that subject does not have evidence of polyhydramnios or oligohydramnios 
(per exclusion criterion 6, Section 5.2). The AFI should be measured using the 4- 
quadrant method (see SPM for details). An abdominal ultrasound to assess fetal 
growth will be done at Screening (unless records are available documenting an ultrasound 
derived estimated fetal weight and head circumference within 13 weeks of Screening, 
with the results and date of assessment recorded in the eCRF). 
 
Section 7.4.6., Clinical Safety Laboratory Assessments 
 
The following laboratory tests will be performed locally: 
 
• 
Liver function tests, including ALT and bilirubin, performed at Screening (see 
Section 5.3.3) 
•Urine drug screen using a point-of-care, qualitative testing device 
•Alcohol screen using point-of-care breath analyzer; in some countries this will be in 
addition to the urine drug screen 


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Section 7.4.10., Maternal Depression 
 
The effect of preterm birth on maternal health status will be assessed using the EPDS. 
The EPDS is a 10-item self-reported assessment of depression, validated for 
administration during both the antenatal and the post-natal periods. Items are rated on a 
4-point variable Likert scale, ranging from 0 to 3. A score of 12+ indicates an increased 
probability of depression and investigators or designated investigative center personnel 
will be notified immediately. Certain items in the scale also assess anxiety and will be 
used to assess level of anxiety. Maternal subjects will complete the EPDS at the maternal 
follow-up assessment 6 weeks (-2 weeks/+±6 weeks) post-delivery (Table 5). 
 
Section 9.1., Hypotheses 
 
No further adjustments to the type I error rate are planned for the co-primary endpoints. 
Details of the methodologies to control the type I error will be included in the IDMC  
charter and study reporting and analysis plans (RAPs). 
 
Section 11, References 
 
GlaxoSmithKline Document Number 2015N228508_00. Investigator’s brochure 
Version 3 Supplement 1. FEB-2015. 
 
GlaxoSmithKline Document Number CM2006/00201/05. Investigator's brochure 
Version 3. APR-2014 GSK716755. 29-Jun-2016. 
 
Section 12.1, Appendix 1: Abbreviations and Trademarks 
 
PCP 
phencyclidine 

SAP_000.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
GSK200719 
 
1 
 
 
Division 
: Worldwide Development 
Information Type      : Reporting and Analysis Plan 
 
Title 
: Randomized, Double-Blind, Multicentre, Phase III Study 
Comparing the Efficacy and Safety of Retosiban Versus 
Placebo for Women in Spontaneous Preterm Labor 
Compound Number 
: GSK221149 
Effective Date  
: 08-SEP-2017 
 
Description: 
• The purpose of this reporting and analysis plan (RAP) is to describe the final planned 
analyses and output to be included in the Clinical Study Report for Protocol 200719.   
• This RAP is intended to describe the planned efficacy (primary, secondary and 
exploratory) and safety analyses required for the study.  
• This document will be provided to the study team members to convey the content of 
the final Statistical Analysis Complete (SAC) Deliverable. 
 
Author’s Name and Functional Area:  
 
08-SEP-2017 
Manager, Biostatistics, PPD 
  
08-SEP-2017 
Biostatistician, PPD 
 
Approved by:  
  
08-SEP-2017 
Manager Statistics, GlaxoSmithKline 
Signature: 
08-SEP-2017 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNOPSIS ......................................................... 5 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 7 
2.3. 
Study Design .............................................................................................. 10 
2.4. 
Statistical Hypotheses................................................................................. 11 
3. 
PLANNED ANALYSES .......................................................................................... 11 
3.1. 
Interim Analyses ......................................................................................... 11 
3.2. 
Final Analyses ............................................................................................ 12 
4. 
ANALYSIS POPULATIONS ................................................................................... 13 
4.1. 
Protocol Deviations ..................................................................................... 14 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS .................................................................................. 14 
5.1. 
Subgroups .................................................................................................. 14 
5.2. 
Multiplicity Adjustment ................................................................................ 14 
6. 
STUDY POPULATION ANALYSES ....................................................................... 15 
6.1. 
Planned Analyses Overview ....................................................................... 15 
6.2. 
Disposition of Subjects ................................................................................ 15 
6.3. 
Demographic and Baseline Characteristics ................................................. 16 
6.4. 
Medical Conditions (Current/Past) .............................................................. 17 
6.5. 
Concomitant Medication ............................................................................. 17 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 19 
7.1. 
Efficacy Analyses ........................................................................................ 19 
7.1.1. 
Overview of Planned Efficacy Analyses ....................................... 19 
7.1.2. 
Planned Statistical Analyses ........................................................ 20 
8. 
SECONDARY AND EXPLORATORY ANALYSES ................................................. 21 
8.1. 
Secondary Efficacy Analyses ...................................................................... 21 
8.1.1. 
Overview of Planned Efficacy Analyses ....................................... 21 
8.1.2. 
Planned Key Secondary Efficacy Statistical Analyses .................. 23 
8.1.3. 
Planned Other Secondary Efficacy Statistical Analyses ............... 24 
8.2. 
Safety Analyses .......................................................................................... 25 
8.2.1. 
Overview of Planned Analyses .................................................... 25 
8.2.2. 
Extent of Exposure (Maternal) ..................................................... 27 
8.2.3. 
Adverse Events............................................................................ 27 
8.2.3.1. 
All Adverse Events ..................................................... 27 
8.2.3.2. 
Relationship of Adverse Events to Study Drug ........... 28 
8.2.3.3. 
Most Common Adverse Events .................................. 28 
8.2.3.4. 
Serious Adverse Events ............................................. 28 
8.2.3.5. 
Adverse Events of Special Interest ............................. 28 
8.2.3.6. 
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................ 30 
8.2.3.7. 
Death ......................................................................... 31 


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8.2.4. 
Health Outcome ........................................................................... 32 
8.2.4.1. 
Neonatal Health Care ................................................. 32 
8.2.4.2. 
Maternal Health Care ................................................. 32 
8.2.5. 
Clinical Laboratory ....................................................................... 32 
8.2.6. 
Vital Signs .................................................................................... 32 
8.2.6.1. 
Maternal Vital Signs .................................................... 32 
8.2.6.2. 
Fetal Heart Rate ......................................................... 33 
8.2.7. 
Neonatal Birth Record.................................................................. 33 
8.3. 
Pharmacokinetic Analyses .......................................................................... 33 
8.4. 
Biomarker Analyses .................................................................................... 33 
9. 
DEVIATION OF PLANNED ANALYSES FROM PROTOCOL................................. 33 
10. REFERENCES ....................................................................................................... 35 
11. APPENDICES ........................................................................................................ 36 
11.1. 
Appendix 1: Protocol Deviation Definitions .................................................. 37 
11.2. 
Appendix 2: Time and Events ..................................................................... 38 
11.3. 
Appendix 3: Treatment States and Phases ................................................. 44 
11.3.1. 
Treatment Phases ....................................................................... 44 
11.3.2. 
Treatment States ......................................................................... 44 
11.3.3. 
Treatment States for AE Data ...................................................... 45 
11.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 46 
11.4.1. 
Study Treatment & Sub-group Display Descriptors ...................... 46 
11.4.2. 
Baseline Definition & Derivations ................................................. 46 
11.4.2.1. Baseline Definitions .................................................... 46 
11.4.2.2. Derivations and Handling of Missing Baseline 
Data ........................................................................... 46 
11.4.3. 
Reporting Process & Standards ................................................... 47 
11.5. 
Appendix 5: Derived and Transformed Data ............................................... 49 
11.5.1. 
General ........................................................................................ 49 
11.5.2. 
Study Population .......................................................................... 49 
11.5.3. 
Safety .......................................................................................... 50 
11.5.4. 
Efficacy ........................................................................................ 51 
11.6. 
Appendix 6: Premature Withdrawals & Handling of Missing Data ............... 54 
11.6.1. 
Premature Withdrawals ................................................................ 54 
11.6.2. 
Handling of Missing Data ............................................................. 54 
11.6.2.1. Handling of Missing Stratification ................................ 54 
11.6.2.2. Handling of Missing/Partial Dates ............................... 54 
11.7. 
Appendix 7: Primary and Sensitivity Analyses for Co-Primary 
Endpoints with Missing Data ....................................................................... 58 
11.7.1. 
Co-Primary Endpoints with Missing Data ..................................... 58 
11.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 59 
11.8.1. 
Laboratory Values for Pregnant Women ...................................... 59 
11.8.2. 
Vital Signs for Pregnant Women .................................................. 60 
11.8.3. 
Fetal Heart Rate .......................................................................... 60 
11.9. 
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses ..................................................................................................... 61 
11.10. Appendix 10: Abbreviations & Trade Marks ................................................ 61 
11.10.1. Abbreviations ............................................................................... 61 
11.10.2. Trademarks ................................................................................. 62 
11.11. Appendix 11: List of Data Displays.............................................................. 63 


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11.11.1. Data Display Numbering .............................................................. 63 
11.11.2. Study Population Tables .............................................................. 64 
11.11.3. Efficacy Tables ............................................................................ 65 
11.11.4. Safety Tables ............................................................................... 66 
11.11.5. ICH Listings ................................................................................. 69 
11.11.6. Non-ICH  Listings ......................................................................... 74 
 


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1. 
REPORTING & ANALYSIS PLAN SYNOPSIS 
Overview 
Key Elements of the RAP   
Purpose 
• This Reporting and Analysis Plan (RAP) details all planned efficacy and safety 
analyses and outputs required for the final Clinical Study Report (CSR) of study 
200719.  
Protocol 
• This RAP is based on the original protocol (Dated: 26-Nov-2014), original 
protocol republished to make Section 6.4 (Blinding) consistent with the protocol 
template(Dated: 17-Feb-2015), protocol amendment 01(Dated: Aug-13-2015), 
protocol amendment 02 (Dated 14-Sep-2015), country-specific amendment 03 
(Italy; Dated: 19-Apr-2016 ) and protocol amendment 04 (Dated: 20-Jun-2016) 
for study GSK200719 [GlaxoSmithKline Document Numbers: 2014N194467_00, 
2014N194467_01, 2014N194467_02, 2014N194467_03, 2014N194467_04 and 
2014N194467_05 
Primary 
Objective  
• To test the null hypothesis in the ITT Population that there is no difference 
between retosiban and placebo versus the alternative hypothesis that there is a 
difference between the 2 co-primary endpoints. 
Primary 
Endpoint 
• Time to delivery or treatment failure, whichever occurs first 
• Proportion of neonates with any diagnosis from the neonatal morbidity and 
mortality composite determined up to 28 days after the estimated date of delivery 
(EDD) of 40 0/7 weeks 
Study 
Design 
• Phase III, randomized, double-blind, double-dummy, placebo-controlled, parallell-
group, multicenter study to investigate efficacy and safety of 6-mg IV loading 
dose of retosiban over 5 minutes, followed by a 6-mg/hour continuous infusion 
over 48 hours in women aged 18 to 45 years (Sweden) or aged 12 to 45 years 
(all other countries) with an uncomplicated singleton pregnancy in preterm labor 
with intact membranes between 240/7 and 336/7 weeks’ gestation. 
• The study was terminated due to fesibility reason.  The study enrolled 25 patients 
and patients were randomly assigned to one active arm (retosiban) and one 
control arm(placabo). 
Planned 
Analyses 
• Interim analyses are described in Independent Data Monitoring Committee 
(IDMC) RAP. 
• Final efficacy and safety analyses are detailed within Section 3.2. 
• All decisions regarding final analyses, as defined in this RAP document, will be 
made prior to Database Freeze (unblinding) of the study data.  
Primary 
Analysis 
Population 
• The Maternal and Neonatal Safety Analysis Population will be used to evaluate 
safety. 
• The Intent-to-treat (ITT) Maternal and Neonatal Analysis Populations will be used 
to evaluate efficacy. 
Hypothesis • Due to the early termination of this study, no formal statistical analysis will be 
performed for the time to delivery or treatment failure endpoints.  
Primary 
Analyses 
• Due to the early termination of this study, no formal statistical analysis will be 
performed for the co-primary endpoints. But, summary statistics by treatment 
group will be provided.  


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Secondary 
Analyses 
• Safety data will be presented in tabular format and summarized descriptively 
according to GSK’s Integrated Data Standards Library (IDSL) standards.  
• Due to the early termination of this study, no formal statistical analysis will be 
performed for the secondary endpoints. But, summary statistics by treatment 
group will be provided.  


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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
This study was terminated due to feasibility.  Due to the low number of subjects involved, the 
analysis is modified and certain analysis won’t be performed. Please refer to below section for 
more details.   
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary  
Primary 
• To demonstrate the superiority 
of retosiban to prolong 
pregnancy compared with 
placebo. 
• Time to delivery or treatment failure, whichever occurs 
first. Time to delivery will be calculated from the start of 
study treatment administration until delivery. Time to 
treatment failure will be calculated from the start of study 
treatment administration to the administration of any 
putative tocolytic medication 
 
• Proportion of neonates with any diagnosis from the 
neonatal morbidity and mortality composite determined 
up to 28 days after the estimated date of delivery (EDD) 
of 400/7 weeks 
 
Supportive Key Secondary 
• Time to delivery 
 
• Proportion of births prior to 370/7 weeks’ gestation – 
ascertain the GA at delivery based on a records review 
• Proportion of births at term (37 0/7 to 416/7 weeks’ 
gestation) – ascertain the GA at delivery based on a 
records review 
• Length of neonatal hospital stay – confirm duration (in 
days) of neonatal hospital admission from the medical 
records 
Supportive Other Secondary 
• Proportion of neonates with each individual component of 
the composite neonatal morbidity and mortality  
• Neonatal admission to a specialized care unit and length 
of stay – confirm admission to neonatal intensive or 


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Objectives 
Endpoints 
specialized care unit from the medical records 
• Newborn hospital readmission and length of stay – 
confirm any neonatal hospital readmission following the 
birth hospitalization, the reason for admission, and the 
length of stay from the medical records 
• Proportion of births prior to 280/7 weeks’ gestation 
• Proportion of births prior to 320/7 weeks’ gestation  
• Proportion of births prior to 350/7 weeks’ gestation 
• Proportion of births ≤7 days from the first study treatment  
• Proportion of births ≤48 hours from the first study 
treatment 
• Proportion of births ≤24 hours from the first study 
treatment 
Secondary  
Secondary  
• To describe the maternal, 
fetal, and neonatal safety 
profile during and after IV 
retosiban treatment compared 
with placebo 
Endpoints for Mother 
• Incidence of maternal Adverse Events (AEs) and Serious 
Adverse Events (SAEs) 
• Significant changes in maternal vital signs and maternal 
clinical laboratory tests 
• Incidence of treatment-limiting toxicities including both 
clinical and laboratory etiology causing subject to 
discontinue study treatment 
• Maternal AEs of special interest 
• Maternal disease-related events 
 
Endpoints for Fetus 
• Incidence of fetal AEs and SAEs 
• Fetal acidosis 
• Fetal AEs of special interest 
 
Endpoints for Neonate 
• Neonatal APGAR scores, growth parameters at birth and 
at discharge 
• Incidence of neonatal AEs and SAEs 
• Neonatal AEs of special interest 
• Neonatal disease-related events 
 
• To determine the effect of 
retosiban treatment compared 
with placebo on health care 
resource use for the maternal 
and neonatal hospitalizations 
• Maternal hospital admission (e.g., length of stay, hospital 
unit and type) and resource use (e.g., use of transport 
services, admission to extended stay facility) 


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Objectives 
Endpoints 
• To obtain further data on the 
pharmacokinetics of 
retosiban in pregnant 
women, including the effect 
of covariates such as age, 
weight, race/ethnicity, and 
GA on retosiban clearance 
and volume of distribution 
• 
Population PK analysis is not performed.   
 


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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
1. Stratification (1:1) to retosiban or matched placebo based on established progesterone therapy at Screening 
(subjects on established progesterone therapy versus subjects not on established progesterone therapy) and 
gestational age (240/7 to 256/7; 260/7 to 276/7; 280/7 to 306/7; 310/7 to 336/7). 
2 
If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg 
doses of betamethasone given intramuscularly 24 hours apart or (2) four 6-mg doses of dexamethasone 
administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the 
antecedent treatment was at least 7 days prior to study enrollment. Investigators have discretion to use a 
standardized regimen of magnesium sulfate, as well as intrapartum antibiotic prophylaxis for perinatal group B 
streptococcal infection.  
3 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion visit for obstetric 
assessments 1 week (acceptable range: 3 to 14 days) after the Inpatient Randomized Treatment Phase. The 
subject will then be contacted every week via telephone to determine and record if she has delivered or if she has 
experienced any subsequent episodes of preterm labor. Retreatment with the investigational product (retosiban or 
placebo) is not allowed. 


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Overview of Key Study Design Features 
Design 
Features: 
• Phase III, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study 
• Subjects are females, aged 12 to 45 years (all other countries including UK, 
Japan and US), with an uncomplicated, singleton pregnancy and intact 
membranes in preterm labor between 240/7 and 336/7 weeks of gestation. 
Dosing: 
• Retosiban treatment will be administered as a 6-mg IV loading dose over 
5 minutes, followed by a 6-mg/hour continuous infusion over 48 hours. 
• Normal saline 0.9% NaCl administered intravenously will serve as the 
placebo control. The normal saline infusion will be matched for the retosiban 
volume, IV loading dose over 5 minutes, and continuous infusion rate, 
including a dose increase in subjects with an inadequate response any time 
after the first hour of treatment. 
Treatment 
Assignment: 
• A total of 25 patients were blindly randomly assigned to retosiban or placebo 
in a 1:1 ratio.  
• Subjects were stratified by established progesterone treatment (Yes/No) and 
gestational age at randomization (240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7 
and 310/7 to 336/7. 
• Subjects within each stratum were randomly assigned in 1:1 ratio to receive 
either retosiban or placebo using an IVRS in accordance with the 
randomization schedule. 
Interim 
Analysis  
• There was no interim analysis  being conducted since there study was 
terminated before inteirm analysis.   
 
2.4. 
Statistical Hypotheses 
The co-primary endpoints assess prolongation of pregnancy using time to delivery or 
treatment failure, whichever comes first, and neonatal outcomes using a morbidity and 
mortality composite.  
Due to the early termination of this study, no formal statistical analysis will be performed 
for the time to delivery or treatment failure endpoints. But summary statistics will be 
provided.  
3. 
PLANNED ANALYSES 
All planned analyses will be done using SAS version 9.3 or higher.  The Analysis Data 
Model (ADaM) will be created per ADaM implementation guide version 1.1. Details on 
derivation of variables will be specified in the specification document of ADaM. All 
analysis tables, listings and figures will be generated based on ADaM and/or Study Data 
Tabulation Model (SDTM). 
3.1. 
Interim Analyses 
No interim analysis was conducted.  


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3.2. 
Final Analyses 
The final planned analyses will be performed after the completion of the following 
sequential steps: 
1. All subjects have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and the final database 
release and database freeze has been declared by Data Management. 
3. All criteria for unblinding the study have been met. 
4. Randomization codes have been distributed. 


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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All 
Randomized  
• Consists of all mothers randomly assigned to 
treatment regardless of whether they actually are 
treated. 
• Subjects will be presented by their planned 
randomized treatment 
• Subject Disposition 
Randomized 
but not dosed 
• Consists of all mothers that are randomized but 
fail to receive any study treatment. 
• Subjects will be presented by their planned 
randomized treatment. 
• Subject Disposition 
Maternal 
Safety 
• Mothers randomly assigned to treatment who 
have been exposed to study treatment.  
• Randomly assigned subjects will only be excluded 
if there is clear evidence the subject did not 
receive IP. 
• Subjects will be analyzed according to their actual 
treatment. Any subject who received both 
treatments (retosiban and placebo) will be 
assigned to retosiban group for actual treatment. 
• Maternal and fetal 
safety 
 
Neonatal 
Safety 
• Consists of neonates whose mothers received 
randomized treatment. 
• Subjects are analyzed according to the actual 
treatment their mothers received.  
• Any subject who received both treatments 
(retosiban and placebo) will be assigned to 
retosiban group for actual treatment. 
• Neonatal safety 
Maternal ITT  
• Consists of all mothers randomly assigned to 
treatment who have been exposed to study 
treatment irrespective of their compliance to the 
planned course of treatment. 
• Subjects who are randomly assigned but fail to 
receive any study treatment will be presented 
separately. 
• Maternal and fetal 
efficacy endpoints 
Neonatal ITT 
• Dataset comprises all neonates whose mothers 
are the randomized Subjects who have been 
exposed to study drug, i.e., mothers from the ITT 
Population. 
• Neonatal efficacy 
endpoints 
NOTE :  
• 
Please refer to Section 11.11 Appendix 11: List of Data Displays which details the population to be used for each 
display being generated. 
 


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4.1. 
Protocol Deviations 
• 
Significant protocol deviations (including deviations related to study 
inclusion/exclusion criteria, study treatment, conduct of the trial, patient 
management or patient assessment) will be listed. 
• 
Protocol deviations are tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan (Reference).   
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
significant protocol deviations and non-significant deviations which may lead to 
exclusion from the analysis are captured and categorised on the protocol 
deviations dataset.  
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
AND DATA HANDLING CONVENTIONS 
5.1. 
Subgroups 
There will be no subgroup analysis due to limited number of subjects enrolled because of 
early termination of the study. 
5.2. 
Multiplicity Adjustment 
There will be no multiplicity adjustment due to early termination of the study.  
 
No formal tests of hypothesis will be performed on safety data. 
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 1 
Overview of Appendices 
Section Component 
11.1 
Appendix 1: Protocol Deviation Definitions  
11.2 
Appendix 2: Time and Events 
11.3 
Appendix 3: Treatment States and Phases 
11.4 
Appendix 4: Data Display Standards & Handling Conventions 
11.5 
Appendix 5: Derived and Transformed Data 
11.6 
Appendix 6: Premature Withdrawals & Handling of Missing Data 
11.7 
Appendix 7: Primary and Sensitivity Analyses for Co-Primary Endpoints with Missing 
Data 
11.8 
Appendix 8: Values of Potential Clinical Importance 
11.9 
Appendix 9: Model Checking and Diagnostics for Statistical Analyses 
11.10 
Appendix 10: Abbreviations & Trade Marks 
11.11 
Appendix 11: List of Data Displays 


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6. 
STUDY POPULATION ANALYSES 
6.1. 
Planned Analyses Overview 
The study population analyses will be based on the population specified in Section 0. 
Table 2 provides an overview of the planned study population analyses with full details 
of data displays being presented in Appendix 11: List of Data Displays. 
Table 2 
Overview of Planned Study Population Analyses 
Display Type 
Data Display’s Generated 
Table 
Figure 
Listing 
Randomization 
Randomization 
 
 
Y 
Subject Disposition 
Study Populations [1] 
Y 
 
Y  
Subject Disposition [1] 
Y 
 
Y 
Reasons for Withdrawals [2] 
Y 
 
Y 
Significant Protocol Deviations [2] 
Y 
 
Y 
Subjects by Site [3] 
Y 
 
Y 
Demography 
Demographics and Baseline Characteristics [2] 
Y 
 
Y 
Race & Racial Combinations [2] 
Y 
 
Y 
Medical Condition & Concomitant  Medications 
Medical History/Conditions (Obstetrical/Prenatal) [2] 
Y 
 
Y 
Prior/Concomitant Medication [3] 
 
 
Y 
Obstetrical Medication, Magnesium Sulfate and 
Antenatal Corticosteroids [3] 
Y 
 
Y 
NOTES: 
1. 
Displays generated using the all randomized subjects. 
2. 
Displays generated using the ITT population. 
3. 
Displays generated using the Safety population. 
6.2. 
Disposition of Subjects 
Subject status with respect to the infusion of the investigational product (IP) will be 
summarized in relation to:  
• Randomized and not dosed 
• Study completion and withdrawal 


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• IP Discontinuation 
• Dose increase 
• The number and percentage of subjects who complete or withdraw from the study 
will be summarized by treatment group. Reasons for withdrawal from the study will 
also be summarized. 
The number and percentage of subjects with the above IP status will be reported by 
treatment group. Reasons for IP discontinuation will be presented. Also, the number and 
percentage of subjects who are randomized to IP but not dosed will be reported by 
treatment group.  
A completed subject is defined as one who has completed all phases of the study 
including the post-delivery assessment and neonatal medical review phase. Subjects who 
receive but who discontinue from IP will not be considered withdrawn from the study and 
should remain in the study and continue to be followed for efficacy and safety. Also, the 
number and percentage of subjects withdrawn prior to IP completion and after IP 
completion will be reported. 
Subject disposition data will also be listed. All disposition summaries will be performed 
using all randomized subjects.  
6.3. 
Demographic and Baseline Characteristics 
For mothers, continuous variables, such as age (years), weight (kg), height (cm), BMI 
(kg/m2), gestational age at randomization (weeks/day), contraction frequency, cervical 
dilation (cm), cervical length (mm), fFN (continuous) and other baseline characteristics 
as needed will be summarized using descriptive statistics by treatment group. Since only 
year of birth is collected and the month and day of birth are not collected, a mother’s age 
will be calculated using below algorithm.  
• The day and month is imputed as ‘30th June’.  
• The age of mother is calculated as the difference of the date of the first study 
treatment and the date of birth divided by 365.25. For example, if the date of the 
randomization was at 00:00 am on 20 March 2015 and date of birth was 1987, the 
age is 27. 
• If no inclusion deviation in age requirement, the age is between 12 and 45 year 
old based on study entry criteria. 
• The mother is recorded as an adolescent in CRF if she is adolescent (12 to < 18 
years of age), so age will be adjusted. For example, the calculated age is 18.2 but 
a subject is marked as an adolescent in CRF, a subject’s age is to 18.  
 
GA at randomization in weeks/days will be obtained from CRF and will be converted 
into numeric value as covariate in the statistical analysis of primary and secondary 
endpoint. Please refer to Appendix 11.6.2 for missing GA at randomization.  


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The following categorical variables will be summarized by reporting the number and 
percentage of subjects in each category by treatment group: 
• Race 
• Ethnicity 
• GA at randomization (4 strata)  
• Established progesterone use 
• Country 
• Prior tocolytic use in current episode (Beta-mimetics, Magnesium Sulfate, 
Calcium channel Blockers, NSAIDs, and Oxytocin receptor antagonists) 
• Adolescent (between 12-<18 years) and adult (>= 18 years) patients. 
• fFN (positive or negative) 
 
For fetus, continuous variables, such as estimated weight (g) and AFI results (cm) 
measured using the 4-quadrant method will be summarized.  
Demographic and baseline characteristics data will also be listed. Summaries will be 
performed using ITT population. For mothers/fetus, demographic and baseline 
characteristics will be presented in a separate table. Additional baseline characteristics 
which are not listed above can be included in the final analysis. 
Races and racial combinations will be presented in a separate table following GSK race 
reporting standards. 
6.4. 
Medical Conditions (Current/Past) 
The number and percentages of subjects with obstetrical history, and prenatal history will 
be presented.  
In addition, subject level listings of, obstetrical history and prenatal history will be listed. 
All summaries will be performed using the Maternal ITT Population. 
6.5. 
Concomitant Medication 
Any prior and concomitant medication used during the study will be recorded and coded 
using World Health Organization Drug Dictionary (WHODRUG), which will be updated 
whenever available throughout the life of the study. Summary of all medications by 
treatment group and preferred term will be provided in relation to treatment phase (prior 
medication or concomitant medication). Prior medications are those started before the 
first study treatment. Concomitant medications are those taken at any time on or after the 
day of the first treatment during the study period, including those medications that were 
started prior to randomization but were continued into the study period. If the medication 
are taken prior to start of IP and continue into the study period, the medication will be 
included as both prior and concomitant medication.  
For mothers, all prior and concomitant medications will be listed using verbatim and 
preferred terms. All summaries will be performed using the Maternal Safety Population. 


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In addition, obstetrical medication, magnesium sulphate, and antenatal corticosteroids 
used during the study will be summarized and listed separately for the Maternal Safety 
Population. 


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7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Efficacy Analyses 
7.1.1. 
Overview of Planned Efficacy Analyses 
There is no hypothesis testing for the co-primary endpoints - time to delivery or treatment 
failure and neonatal composite outcome.  The co-primary endpoint will be summarised 
and listed by treatment in the ITT Population.    
Table 3 provides an overview of the planned efficacy analyses with full details of data 
displays being presented in Appendix 11: List of Data Displays. 
 
Table 3 
Overview of Planned Efficacy Analyses 
 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Time to delivery or treatment failure [1] 
 
 
 
Y 
 
 
Y 
Neonatal composite endpoint [1] 
 
 
 
Y 
 
 
Y 
Individual neonatal composite 
endpoint[1]t  
 
 
 
Y 
 
 
Y 
Neonatal composite endpoint without 
RDS [1] 
 
 
 
Y 
 
 
Y 
Neonatal composite endpoint without 
RDS and mortality [1]  
 
 
 
Y 
 
 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
1. 
Displays generated using the ‘ITT’ population. 
 
Following review of the data, additional analyses may be conducted to further support the 
evaluation and interpretation of the data. 


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7.1.2. 
Planned Statistical Analyses 
The time to delivery is calculated as the days between the delivery and start time of the 
infusion of IP using the formula below: 
Time to delivery (days) = date/time of delivery – date/time of start of infusion 
The exact date/time of delivery and infusion will be used to determine the time to 
delivery.   
Time to delivery is a continuous numeric value with one decimal place (e.g. expressed as 
xx.x days) and the exact date/time of delivery and infusion will be used to determine the 
time to delivery.  For example, if the date/time of delivery was at 00:00 am on 20 March 
2015 and date/time of start of infusion was at 12:00 pm on 01 March 2015 APR2015, 
time to delivery is 19.5 (days). 
Treatment failure will be defined as the administration of any putative tocolytic 
medication for active preterm labor or as prevention of preterm labor, such as 
calcium-channel blockers, NSAIDs, or -agonists, apart from the exceptions listed in 
Protocol Section 6.12.1.2.1 Error! Reference source not found., and magnesium sulfate 
doses that exceed a 4- to 6-g IV loading dose and 1- to 2-g/hour infusion rate and total 
duration of magnesium sulfate administration greater than 48 hours (see Protocol Section 
Error! Reference source not found.). The time to treatment failure will be assessed 
from the start of study treatment administration (time 0) in the Inpatient Randomized 
Treatment Phase until a putative tocolytic is administered.  
Times to deliver or treatment failure is defined as time to delivery or time to treatment 
failure whichever occurs first. 
No formal statistical analysis will be performed but summary statistics will be provided. 


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8. 
SECONDARY AND EXPLORATORY ANALYSES 
8.1. 
Secondary Efficacy Analyses 
8.1.1. 
Overview of Planned Efficacy Analyses 
The secondary efficacy analyses will be based on the Maternal and Neonatal ITT 
Populations.   
 


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Table 4 provides an overview of the planned efficacy analyses with further details of data 
displays presented in Appendix 11: List of Data Displays. 


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Table 4 
Overview of Planned Efficacy Analyses 
 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Supportive Key Secondary Endpoints 
Time to delivery 
 
 
 
Y 
 
 
Y 
Proportion of births prior to 370/7 weeks’ 
gestation – ascertain the GA at delivery 
based on a records review 
 
 
 
Y 
 
 
 
Proportion of births at term (370/7 to 
416/7 weeks’ gestation) – ascertain the 
GA at delivery based on a records 
review 
 
 
 
Y 
 
 
 
Length of neonatal hospital stay –
duration (in days) of neonatal hospital 
admission from the medical records 
 
 
 
Y 
 
 
Y 
 
Newborn hospital readmission and 
length of stay  
 
 
 
 
 
 
Y 
Proportion of births prior to 280/7 weeks’ 
gestation 
 
 
 
Y 
 
 
 
Proportion of births prior to 320/7 weeks’ 
gestation 
 
 
 
Y 
 
 
 
Proportion of births prior to 350/7 weeks’ 
gestation 
 
 
 
Y 
 
 
 
Proportion of births ≤7 days of IP 
administration 
 
 
 
Y 
 
 
 
Proportion of births ≤48 hours of IP 
administration 
 
 
 
Y 
 
 
 
Proportion of births ≤24 hours of IP 
administration 
 
 
 
Y 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  
1. 
Will be presented in the integrated analysis. 
 
Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data. 
 
8.1.2. 
Planned Key Secondary Efficacy Statistical Analyses  
No formal statistical analysis will be performed but summary statistics will be provided. 
 


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8.1.3. 
Planned Other Secondary Efficacy Statistical Analyses 
Other Secondary Efficacy Statistical Analysis 
Endpoint 
• Proportion of neonates with any of the composite neonatal morbidity and mortality 
excluding RDS 
• Proportion of neonates with each individual component of the composite neonatal 
morbidity and mortality endpoints listed in Section 11.5.4. 
• Proportion of births prior to 280/7 weeks’ gestation 
• Proportion of births prior to 320/7 weeks’ gestation 
• Proportion of births prior to 350/7 weeks’ gestation 
• Proportion of births ≤7 days from the first study treatment 
• Proportion of births ≤48 hours from the first study treatment 
• Proportion of births ≤24 hours from the first study treatment 
Results Presentation 
• Data will be summarized by treatment group. 
 
  


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8.2. 
 Safety Analyses 
All safety summaries will be performed for the Safety Population as defined in Section 0 
of this document.  A listing of all safety data will be presented. 
8.2.1. 
Overview of Planned Analyses 
The safety analyses will be based on the Maternal and Neonatal Safety Populations, 
unless otherwise specified. 
Table 5Error! Not a valid bookmark self-reference. provides an overview of the 
planned analyses with further details of data displays being presented in Appendix 11: 
List of Data Displays. 


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Table 5 
Overview of Planned Safety Analyses 
Endpoints 
Observed 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Exposure 
Extent of Exposure 
Y 
 
 
Y 
 
 
 
 
Maternal Endpoints 
Adverse Events 
 
 
 
 
 
 
 
 
  All AEs 
 
Y 
 
 
Y 
 
 
 
 
  Most Common AEs 
Y 
 
 
 
 
 
 
 
  Serious AEs 
Y 
 
 
Y 
 
 
 
 
  AEs of special interest  
Y 
 
 
Y 
 
 
 
 
  Disease-related AEs 
Y 
 
 
Y 
 
 
 
 
Clinical Laboratory 
Y 
 
 
Y 
Y 
 
 
Y 
Maternal Vital Signs 
Y 
 
 
Y 
Y 
 
 
Y 
Maternal Health Care Resource Use 
 
 
 
Y 
 
 
 
 
Fetal Endpoints 
Adverse Events 
 
 
 
 
 
 
 
 
  All AEs 
 
Y 
 
 
Y 
 
 
 
 
  Most Common AEs 
Y 
 
 
Y 
 
 
 
 
  Serious AEs 
Y 
 
 
Y 
 
 
 
 
  AEs of special interest  
Y 
 
 
Y 
 
 
 
 
Fetal Heart Rate 
Y 
 
 
Y 
Y 
 
 
Y 
Neonatal Endpoints 
Adverse Events 
 
 
 
 
 
 
 
 
  All AEs 
 
Y 
 
 
Y 
 
 
 
 
  Most Common AEs 
Y 
 
 
Y 
 
 
 
 
  Serious AEs 
Y 
 
 
Y 
 
 
 
 
  AEs of special interest  
Y 
 
 
Y 
 
 
 
 
  Disease-related AEs  
Y 
 
 
Y 
 
 
 
 
Neonatal Health Care Resource Use 
 
 
 
Y 
 
 
 
 
Neonatal Birth Record 
Y 
 
 
Y 
 
 
 
 
  APGAR  scores 
Y 
 
 
Y 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.  


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8.2.2. 
Extent of Exposure (Maternal) 
Summaries will be presented only for mothers by initial treatment.  
Duration of exposure (hour) is defined as the total number of hours a subject is exposed 
to any study drug and will be presented as the total number of hours from the first dose 
date/time (Day 1) to the last dose date/time (date/time of last dose - the date/time of first 
dose). 
The duration of exposure to study drug by treatment will be summarized using 
descriptive statistics for Maternal Safety Population. The duration of exposure will then 
be classified into one of the following categories: 0 to ≤1 hour, >1 and ≤6 hours,>6 and 
≤12 hours, >12 and ≤24 hours, >24 and ≤36 hours, >36 and ≤48 hours and >48 hours and 
will be presented as the number and percentage of subjects in each duration category.  
The total volume administered during the infusion and the number of infusion 
interruptions will be summarized using descriptive statistics.   
In addition, reasons for IP deviation, escalation and interruption will also be listed. 
Details of IP deviation will be finalized before DBF. 
Also, inadequate therapeutic response will be summarized and listed. 
A summary of each subject exposure will be presented in a listing.  
8.2.3. 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary.  A mapping of the MedDRA primary system organ class (SOC) and 
preferred term (PT) that each verbatim term has been coded to will be provided in a 
listing.  In general, AEs will be presented in descending order from the SOC with the 
highest total incidence (that is, summed across all treatment groups) for any adverse 
event within the class to the SOC with the lowest total incidence. Within the SOC level, 
AEs will be presented in descending order from the PT with the highest total incidence to 
the PT with the lowest total incidence. If the total incidence for any two or more PTs 
within an SOC is equal, the PTs will be presented in alphabetical order. A PT will not be 
presented if no adverse events occur within the level. At each level of summarization, a 
subject is counted only once if the subject reported one or more events. 
The number and percentage of subjects with any AE started on or after the first study 
treatment will be summarized by treatment group in the tables. All AEs will be listed. 
8.2.3.1. 
All Adverse Events 
The number and percentage of subjects reporting at least one AE for each SOC and PT 
will be reported by treatment group.  The summary will include both non-serious and 
serious AEs. A listing of all adverse events will be provided.  
The AE will be summarized by maternal, fetal and neonatal events, separately. 


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8.2.3.2. 
Relationship of Adverse Events to Study Drug 
AEs by relationship to study drug (as assessed by the investigator) will be presented in 
listing. The investigator will provide an assessment of the relationship of the event to the 
study drug. The relationships are recorded as “Yes” or “No” on the CRF page. AEs that 
are missing a relationship will be presented with a missing relationship.  
The AE will be listed by maternal, fetal and neonatal events, separately. 
8.2.3.3. 
Most Common Adverse Events 
A summary of most common on-treatment adverse events (>2% incidence rate among 
retosiban and placebo group) by treatment will be produced. 
Most common AEs will be reported in the similar manner as all AEs. 
The AE will be summarized by maternal, fetal and neonatal events, separately. 
8.2.3.4. 
Serious Adverse Events 
The seriousness of an AE should be assessed by the Investigator independently from the 
severity of the AE. A serious AE (SAE) is defined as any untoward medical occurrence 
that at any dose results in death, is life-threatening, requires hospitalization or 
prolongation of existing hospitalization, results in disability/incapacity, is a congenital 
anomaly/birth defect, or is possible of drug-induced liver injury with hyperbilirubinemia. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
 
SAEs will be reported in the similar manner as all AEs. A listing of SAEs will be 
provided. 
The SAEs will be summarized by maternal, fetal and neonatal events, separately.  
8.2.3.5. 
Adverse Events of Special Interest 
Adverse Events of Special Interest (AESIs) are AEs potentially related to treatment 
administration (direct or indirect) and are of special interest for evaluating and 
characterizing the outcomes of women, fetuses, and neonates participating in this study. 
AESIs will be reported in the similar manner as all AEs. A listing of AESIs will be 
provided.  
The AESIs will be summarized by maternal, fetal and neonatal events, separately if there 
are more than 3 subjects reported AESIs. If the number of subjects with AESIs is less 
than or equal to 3 subjects, only listings will be provided. Also, individual listing for each 
type of AESIs will be provided if there are any events. 


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Maternal, fetal and neonatal AESIs are as follows: 
Maternal AESIs: 
• Maternal death 
• Chorioamnionitis and its complications 
o Clinical chorioamnionitis, PPROM, endomyometritis, wound infection, pelvic 
abscess, bacteremia, septic shock, disseminated intravascular coagulation, and 
adult RDS 
• Placental abruption 
• Postpartum hemorrhage - postpartum hemorrhage and/or retained placenta (as 
assessed by AEs, time to expulsion of the placenta, assessment of uterotonic 
agents used, and change in hemoglobin from baseline value to 24 to 48 hours 
post-delivery adjusting for mode of delivery) 
• Pulmonary edema 
Fetal AESIs: 
• Intrauterine fetal demise 
• Category II or III fetal heart rate tracing (defined according to ACOG Practice 
Bulletin 106 [ACOG, 2009]) 
• Fetal inflammatory response syndrome characterized by cord blood interleukin-6 
>11 pg/mL, funisitis, or chorionic vasculitis  
Neonatal AESIs: 
• Neonatal death 
• Asphyxia 
• Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis) 
• RDS 
• Hypotension 
• IVH/periventricular leukomalacia 
• Bronchopulmonary dysplasia 
• Neonatal acidosis 


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• Hyperbilirubinemia 
• Neonatal enterocolitis 
• Hypoxic ischemic encephalopathy 
8.2.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
Maternal and neonatal disease-related events (DREs) described below will be reported in 
a similar manner as all AEs. A listing of DREs will be provided.  
The DREs will be summarized by maternal and neonatal events, separately if there are 
more than 3 subjects with reported DREs. If the number of subjects with DREs is less 
than or equal to 3 subjects, only listings will be provided. Also, individual listing for each 
type of DREs will be provided if there are any events. 
The following DREs are common maternal events during pregnancy, labor, and delivery: 
• Signs and symptoms of labor discomfort (e.g., cramping, backache, muscle aches, 
nausea) 
• Subsequent episodes of preterm labor (even if hospitalization is required) unless 1 
of the conditions listed at the end of Protocol Section 7.4.1.7.2 applies 
• Hospitalization for delivery, unless prolonged or 1 of the conditions listed at the 
end of Protocol Section 7.4.1.7.2 applies Signs and symptoms of labor discomfort 
(e.g., cramping, backache, muscle aches, nausea) 
The following DREs are common neonatal events related to prematurity and can be 
serious or life threatening: 
• Lungs and respiratory system 
o 
Apnea (severe) 
o 
Respiratory failure due to fatigue, hypoxia, or air leak from alveolar injury 
• Cardiovascular 
o 
Patent ductus arteriosus 
o 
Bradycardia 
• Neurological 
o 
Ventriculomegaly 
o 
Cerebellar hemorrhage 


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o 
Hydrocephalus other than congenital 
• Gastrointestinal 
o 
Gastroesophageal reflux 
o 
Aspiration pneumonia 
• Hematologic 
o 
Anemia (severe) 
• Vision 
o 
Retinopathy of prematurity (all stages) 
• Auditory 
o 
Hearing disorder 
• Other 
o 
Temperature instability 
o 
Hypoglycemia 
These events will be recorded on the DRE page in the maternal or neonatal eCRFs. These 
DREs will be monitored by the IDMC and internal safety review committee. However, if 
one or all of the following conditions apply, then the event should be reported as an 
AE/SAE using the standard process: 
• The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject,  
• The investigator considers that there is a reasonable possibility that the event was 
related to treatment with the IP, or 
• An event defined as a disease-related neonatal event is reported in an infant born 
≥ 37 completed weeks. 
If any of the above conditions are met, then record the event on the SAE page rather than 
the DRE page and report promptly. 
8.2.3.7. 
Death 
A listing of death will be provided by maternal, fetal and neonatal events, separately.  


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8.2.4. 
Health Outcome  
8.2.4.1. 
Neonatal Health Care 
Neonatal health care will be summarized using Neonatal Safety Population. 
Descriptive statistics will be summarized for cumulative length of Neonatal Hospital Stay 
in days and log (length of Hospital Stay) for neonates at birth by treatment. 
A listing of all data available for neonatal health care utilization both at birth and 
readmission will be provided for Neonatal Safety population. 
8.2.4.2. 
Maternal Health Care  
A listing of all data available for maternal pre-term labor related and at delivery health 
care resource utilization will be provided for maternal safety population. 
8.2.5. 
Clinical Laboratory 
Summaries for hematology and chemistry parameters will be performed using the 
Maternal Safety Population. 
Summary tables presenting observed values and changes from baseline will be presented 
for clinical laboratory tests with numeric values by treatment group. Changes from 
baseline to each scheduled post-baseline visit will be presented. 
The number and percentages of subjects with laboratory values below or above normal 
ranges for pregnant women will be summarized by treatment groups (hematology).   
The subjects with potential clinically important laboratory data (hematology and 
chemistry) will be listed. The criteria for laboratory values outside of normal ranges are 
detailed in Appendix 11.8.1. If there are only the lower or upper ranges, only the lower or 
upper changes will be calculated for direction of interests.  
8.2.6. 
Vital Signs 
8.2.6.1. 
Maternal Vital Signs 
Summaries for maternal vital signs will be performed using the Maternal Safety 
Population  
Summary tables will be presented for vital sign data including weight (kg), height (cm), 
systolic blood pressure (mmHg), diastolic blood pressure (mmHg), temperature (°C), 
heart rate (beats/min), and respiration rate (breaths/minute), by treatment group. 
Observed results at each scheduled timepoint (Screening, Inpatient Randomized 
Treatment Phase (15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the 
infusion, at the end of the infusion), and at the face-to-face post-infusion assessment 
visit), will be presented. Changes from baseline to each scheduled post-baseline visit will 
be presented.  


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All maternal vital sign data below and above normal ranges will be presented in a listing.  
The criteria for vital signs values with potential clinical importance are detailed in 
Appendix 11.8.2. 
8.2.6.2. 
Fetal Heart Rate 
Summaries for fetal heart rate will be performed using the Maternal Safety Population. 
A table will summarize categorical fetal heart rate results by treatment group during 
treatment phase and post-treatment phase. Categories to be presented are Category I, II 
and III based on ACOG guidelines [ACOG, 2009]. 
All fetal heart rate data by subject will be presented in a listing.  
8.2.7. 
Neonatal Birth Record 
Continuous variables, such as weight (g) and head circumference (cm) at neonatal birth 
record will be summarized. Also, APGAR at 1 and 5 minutes at birth will be summarized 
by reporting the number and percentage of subjects by treatment group. In addition, 
Neonatal Apgar scores at 1 and 5 minutes at birth will presented categorically (>=7 or 
<7) 
All neonatal birth record data will be listed.  
8.3. 
Pharmacokinetic Analyses 
The PK concentration data will be listing for plasma, cord blood and blood milk samples. 
8.4. 
Biomarker Analyses 
fFN results and cervical length will be presented in the baseline characteristics table. 
Also, the results will be listed.   If applicable, inflammatory biomarker such as IL-6 will 
be summarized and listed. 
Whenever applicable, the details of these additional analyses to explore the correlation of 
biomarker and the study effect will be described in a separate document. 
 
9. 
DEVIATION OF PLANNED ANALYSES FROM 
PROTOCOL 
No changes will be made to the planned analyses after the breaking of the study blind; 
however, due to the early termination of the study and the resultant low number of 
subjects enrolled in the study, not all originally planned data analyses, as outlined in the 
protocol, will be performed.  
The following changes will be made to the planned analyses from the protocol: 


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• The co-primary endpoints (time to delivery or treatment failure, whichever came 
first, and neonatal composite outcome) will not statistically analysed but will be 
summarized with descriptive statistics for each treatment group. 
• Sample size re-estimation was not performed. 
• The key secondary endpoints of time to delivery, proportion of preterm births 
(<370/7 weeks’ gestation), proportion of births ≥370/7 weeks’ gestation, and 
neonatal length of hospital stay will not analysed but will be summarized with 
descriptive statistics for each treatment group. 
• Time to delivery by preterm labor criteria (IC #4) will be summarized with 
descriptive statistics for each treatment group. No other subgroup analyses for the 
co-primary endpoints and key secondary endpoints will not be performed. 
• Other exploratory covariate analyses will not be performed to examine the 
relationship between the treatment response and potential covariates including 
baseline fFN value, subclinical intrauterine infection, and other concomitant 
medications. 
• Maternal and neonatal health outcomes will not be analysed but will be presented 
in data listings and analysis by subgroups will not be explored.  
• Data will not be presented for neonatal ambulatory surgery as part of neonatal 
health care resource use results. 
• No formal interim analyses will be performed. 
• The PK data will be not analysed but will be listed for plasma, cord blood and 
blood milk samples.  
• No analysis for retosiban clearance and volume of distribution and the effect of 
covariates on these parameters will be performed. 
• Newborn hospital readmission and length of stay will not be analysed but will be 
listed. 
• Incidence of treatment-limiting toxicities including both clinical and laboratory 
etiology causing subject to discontinue study treatment will not analysed. 
• No analysis for Edinburgh Postnatal Depression Scale and EQ-5D-5L will be 
performed.  
• No analysis using per-protocol (PP) population will be performed. 
 


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10. 
REFERENCES 
American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
ACOG Practice Bulletin No. 106. Intrapartum fetal heart rate monitoring: nomenclature, 
interpretation, and general management principles. Obstet Gynecol. 2009;114(1):192-
202. 
GlaxoSmithKline Document Number 2014N194467_05: Randomized, Double-Blind, 
Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus 
Placebo for Women in Spontaneous Preterm Labor. Effective date: 20-Jun-2016 
 


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11. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 11.1 
Appendix 1: Protocol Deviation Definitions  
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 11.2 
Appendix 2: Time and Events 
Section 11.3 
Appendix 3: Treatment States and Phases 
Section 11.4 
Appendix 4: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 11.5 
Appendix 5: Derived and Transformed Data 
• General, Study Population & Safety 
• Efficacy 
Section 11.6 
Appendix 6: Premature Withdrawals & Handling of Missing Data 
• Premature Withdrawals 
• Handling of Missing Data  
Section 11.7 
Appendix 7: Primary and Sensitivity Analyses for Co-Primary Endpoints with 
Missing Data 
Section 11.8 
Appendix 8: Values of Potential Clinical Importance 
• Laboratory Values for Pregnant Women 
• Vital Signs for Pregnant Women 
• Fetal Heart Rate 
Section 11.9 
Appendix 9: Model Checking and Diagnostics for Statistical Analyses 
Other RAP Appendices 
Section 11.10 
Appendix 10: Abbreviations & Trade Marks 
Section 11.11 
Appendix 11: List of Data Displays 
 


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11.1. 
Appendix 1: Protocol Deviation Definitions  
Subject compliance to the protocol will be evaluated prior to database freeze and 
unblinding the study and subjects with significant protocol deviations will be identified. 
Specific criteria for what constitutes a major protocol violation will be determined by the 
study team and the following criteria will be considered:   
Maternal Major Protocol Violation 
• 
Not meeting inclusion criteria 3 (Gestational age between 240/7 and 336/7 weeks as 
determined by (1) known fertilization date, either in vitro fertilization or intrauterine 
insemination or (2) a best estimated due date confirmed or established by the earliest 
ultrasound performed before 240/7 weeks gestation.) 
   


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11.2. 
Appendix 2: Time and Events 
 
Procedures 
Screening  
Phase  
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Clinical and Other Assessments 
Written informed consent 
and medical releases for 
treatment3 
X 
 
 
 
 
 
 
 
 
Discuss and request 
consent for participation in 
the infant follow-up study4 
 
X
X 
X 
Inclusion/exclusion criteria 
confirmation 
X 
 
 
 
 
 
 
 
 
Baseline characteristics 
and demographic data 
X 
 
 
 
 
 
 
 
 
Medical history (including 
obstetrics history)5 
X 
 
 
 
 
 
 
 
 
Drug and alcohol 
screening6 
X 
 
 
 
 
 
 
 
 
Physical examination 
(including height and 
weight) 
X 
 
 
 
 
 
 
 
 
Cervical examination7 
X 
X 
X 
X 
 
 
 
 
 
Estimated fetal weight via 
ultrasound 
X 
 
 
 
 
 
 
 
 
Determine AFI via 
ultrasound8 
X 
 
 
 
 
 
 
 
 
Uterine contractions9 
X 
 
 
 
 
 
 
 
 


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Procedures 
Screening  
Phase  
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Schedule post-infusion 
assessment visit 
 
 
X 
 
 
 
 
 
 
Investigational Products10 
Retosiban or placebo 
 
X 
X 
 
 
 
 
 
 
Efficacy Assessments 
Date and time of delivery11 
 
 
 
 
 
X 
 
 
 
Mode of delivery11 
 
 
 
 
 
X 
 
 
 
Indication for delivery11 
 
 
 
 
 
X 
 
 
 
Neonatal composite 
outcomes 
 
 
 
 
 
 
 
X 
 
Neonatal hospital stay 
 
 
 
 
 
 
 
X 
 
Maternal Safety Assessments 
Concomitant medications 
 
X
X 
 
X 
ECG 12-lead12 
X 
 
 
 
 
 
 
 
 
Vital sign measurements 
(BP, pulse rate, 
temperature, respiratory 
rate, and oxygen 
saturation)13 
X 
X 
X 
X 
 
 
 
 
 
AEs, SAEs, and DREs :  
maternal 
 
X
X 
 
X 
Monitor fluid intake and 
output 
X 
X 
X 
 
 
 
 
 
 
Breastfeeding status 
 
 
 
 
 
 
X 
 
 
Edinburgh Postnatal 
Depression 
Scale14(maternal) 
 
 
 
 
 
 
X 
 
 


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Procedures 
Screening  
Phase  
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Local laboratory 
assessments (LFTs only)15 
X 
 
 
 
 
 
 
 
 
Central laboratory 
assessments (including 
hematology, chemistry, 
and LFTs)16 
X 
 
X 
X16 
 
 
 
 
 
Physical examination 
(brief) 
 
 
 
X 
 
 
 
 
 
Status of postpartum 
bleeding 
 
 
 
 
 
 
X 
 
 
Fetal Safety Assessments 
Electronic fetal monitoring 
X17 
X18 
X18 
X19 
 
X20 
 
 
 
AEs, SAEs, and DREs:  
fetal 
 
X
X 
 
 
 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: 
neonatal 
 
 
 
 
 
X
X 
 
Neonatal Apgar Scores 
(1 and 5 minutes)11 
 
 
 
 
 
X 
 
 
 
Neonatal growth 
parameters11 
 
 
 
 
 
X 
 
 
 
Neonatal umbilical cord 
blood gases11 
 
 
 
 
 
X 
 
 
 


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Procedures 
Screening  
Phase  
Inpatient Randomized 
Treatment 
Phase 
Post-Infusion Assessment 
Phase1 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
1-week 
face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone call 
Information 
collected via 
medical 
records review 
6 weeks 
after delivery2 
Delivery to 
28 days post 
EDD 
Health Outcome Assessments 
Maternal and neonatal 
health care resource use21 
 
 
 
 
 
X 
 
X 
 
Pharmacokinetic Assessments 
Maternal PK blood 
sample22 
 
X21 
X 
 
 
 
 
 
 
Cord blood sample23 
 
 
 
 
 
X 
 
 
 
Breast milk/colostrum 
sample24 
 
 
 
 
 
X 
 
 
 
Genetic and Biomarker Assessments 
Genetic blood sample for 
maternal DNA25 
X 
 
 
 
 
 
 
 
 
Biomarker maternal blood 
sample26 
X 
 
 
 
 
 
 
 
 
Genetic blood sample for 
cell-free fetal DNA27 
X 
 
 
 
 
 
 
 
 
Other Assessments 
Fetal fibronectin 
(optional)28 
X 
 
 
 
 
 
 
 
 
Cervical length via 
transvaginal ultrasound 
(optional)29 
X 
 
 
 
 
 
 
 
 
Confirm no other study 
participation for infant30 
 
 
 
 
 
 
 
X 
 
 
AE = adverse event; AFI = amniotic fluid index; ALT = alanine aminotransferase; BP = blood pressure; DRE = disease-related event; ECG = electrocardiogram; eCRF = electronic case 
report form; EDD = estimated date of delivery; IP = investigational product; LFT = liver function test; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of normal. 


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1. 
Subjects who remain undelivered after 48 hours will return for a face-to-face post-infusion visit for obstetric assessments 1 week (acceptable range: 3 to 14 days) following the 
Inpatient Randomized Treatment Phase. The subject will then be contacted every week via telephone to determine and record if she has delivered or experienced any subsequent 
episodes of preterm labor. Note:  If the subject is scheduled to visit the clinic for reasons not required by this protocol and/or she happens to be present at the time the telephone 
assessment is due, this assessment may be completed face-to-face. 
2. 
During the Maternal Post Delivery Assessment Phase, subjects will be contacted by telephone within 6 weeks of delivery for a post-delivery assessment, including an assessment 
of AEs (±2 weeks), status of breastfeeding (±2 weeks), and completion of the EPDS (±6 weeks). 
3. 
Prestudy screening information that is collected by the study site may need to come from records that are obtained before the subject has signed the informed consent. The 
subject will be required to provide written informed consent before any study-specific procedures are performed, and the consent will request permission for use of any information 
collected prior to its having been signed. 
4. 
During the study, the subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant to participate in a separate long-term 
infant follow-up study for safety and neurodevelopment. Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude involvement in the 
infant follow-up study. 
5. 
Medical history will be collected at Screening. If a condition with a start date predating Day 0 (Screening) is subsequently discovered, the condition should be recorded in the 
Medical History eCRF. For obstetrics history, the investigator will make every effort to obtain this information either via computer records, directly from the subject’s primary care 
obstetrician, or via telephone. However, in cases in which these records are not readily available (e.g., off hours, holiday), the investigator can use gestational age based on the 
verbal history from the subject with the intent of getting confirmation from the medical records or from the subject’s primary care obstetrician as soon as possible. 
6. 
The urine drug screen will be performed using a point-of-care qualitative testing device. A point-of-care breath analyzer for alcohol will be used in some countries in addition to the 
urine drug screen. 
7. 
A cervical examination (including dilation, effacement, and station) will occur at Screening, and an additional cervical examination may be performed before dosing based on 
investigator discretion. If a predosing cervical examination reveals dilation >4 cm, the subject cannot be dosed. Additional cervical examinations (Day 1, Day 2, and/or at the 
1-week face-to-face post-infusion assessment visit) will be performed based on investigator discretion. 
8. 
The abdominal ultrasound for determination of the AFI will be performed at Screening for all subjects. 
9. 
Uterine tocography or manual palpation (if necessary) will be performed prior to dosing to confirm persistent uterine contractions. If the examination reveals in the 60 minutes 
before IP dosing a rate that is <4 contractions of a least 30 seconds’ duration over a 30-minute interval, the subject cannot be dosed. Manual palpations will be permitted if there 
are technical challenges with measuring contraction frequency. 
10. If not previously administered, antenatal corticosteroid treatment should be administered as either (1) two 12-mg doses of betamethasone given intramuscularly 24 hours apart or 
(2) four 6-mg doses of dexamethasone administered intramuscularly every 12 hours. A single rescue course of antenatal corticosteroids is permitted if the antecedent treatment 
was at least 7 days prior to study enrollment. Investigators have discretion to use a standardized regimen of magnesium sulfate, as well as intrapartum antibiotic prophylaxis for 
perinatal group B streptococcal infection. 
11. Information regarding delivery will be obtained through a review of the hospital and medical records. Growth parameters include neonatal weight, length, and head circumference. 
12. A 12-lead ECG will be performed prior to dosing. If the results are interpreted by the investigator to have clinically significant abnormalities, the subject cannot be dosed. 
13. Blood pressure, pulse rate, respiratory rate, and temperature will be assessed at Screening, as part of maternal safety monitoring during the Inpatient Randomized Treatment 
Phase, and at the post-infusion assessment visit. During the Inpatient Randomized Treatment Phase, vital signs and oxygen saturation will be assessed and recorded within the 
following windows relative to the start of the infusion: 15 to 30 minutes, 4 to 8 hours, 20 to 24 hours, at the end of the infusion, at the time of any dose changes, and as warranted 
by a medical condition. Oxygen saturation less than 92% should be recorded as an AE or SAE, as appropriate. 
14. Maternal subjects will complete the Edinburgh Postnatal Depression Scale, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (±6 weeks) after delivery. 


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15. The LFTs should be ordered from the local laboratory to confirm that ALT is not ≥2 × ULN OR total bilirubin is not >1.5 × ULN (>35% direct bilirubin) before dosing with the IP. An 
isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%. With the exception of sites in Italy, screening LFT laboratory results do not need to 
be available for the subject to be randomly assigned to treatment; however, see Protocol Section 5.3.3 if ALT or bilirubin is abnormal. Sites in Italy: Subjects must not be dosed 
before local laboratory LFT results are obtained and reviewed by the investigator, see Protocol Section 5.3.1.1Error! Reference source not found. and Protocol Section Protocol 
5.3.3 for details. 
16. Hematology, chemistry, and LFTs will be determined through a central laboratory at the screening, Day 2, and the 1-week face-to-face post infusion assessment visits. The LFT 
values from the central laboratory should be reviewed for abnormalities (see Protocol Section 5.3.3). For subjects who deliver within 24 hours after completion or discontinuation of 
IP and for subjects who deliver at the investigative center after discharge but before the 1-week face-to-face post-infusion assessment visit, central laboratory assessments for 
hematology, chemistry, and LFTs should be performed. For subjects that do not deliver at the investigative center, central laboratory assessments for hematology, chemistry, and 
LFTs should be performed at the investigative center within 1 week (acceptable range: 3 to 14 days) after completion of the study drug infusion. 
17. Prior to dosing, if the fetal heart rate pattern is nonreassuring, the subject cannot be dosed. 
18. Electronic fetal monitoring is required for a minimum of 6 hours from the start of the infusion or from the start of a dose increase. As long as the fetal heart rate pattern is 
consistently reassuring throughout the required 6-hour duration of monitoring and the contraction frequency is 2 in a 30-minute window within the last hour of monitoring, 
continuous monitoring may be discontinued and nonstress tests initiated at a minimum of every 8 hours and as needed. Electronic fetal monitoring, including the fetal heart rate 
and fetal heart rate category, will be recorded in the eCRF with maternal vital signs. Any fetal heart rate assessment of Category II or III will be reported as an AE of special 
interest on a specified eCRF (details in Protocol Section 7.4.4). 
19. If the subject has not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate will be recorded at the 1-week face-to-face post-infusion assessment visit. 
Any fetal heart rate assessment of Category II or III will be reported as an AE of special interest on a specified eCRF (details in Protocol Section 7.4.4). 
20. During the Delivery Phase, fetal heart rate just prior to delivery will be collected, if available, from review of delivery records. Any fetal heart rate assessment of Category II or III 
will be reported as an AE of special interest on a specified eCRF (details in Protocol Section 7.4.4). 
21. Maternal and neonatal health care resource use may include, but is not limited to, neonatal complications requiring intensive or specialized care, neonatal hospital readmission, 
and neonatal ambulatory surgery. 
22. PK samples will be taken at each of the following sampling windows (relative to the start of the infusion on Day 1):  2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 to 
54 hours. In addition, a PK sample should be taken at the onset of any maternal or fetal SAE that occurs within 12 hours after completion or discontinuation of IP. 
23. In subjects who deliver at an investigative center within 12 hours following completion or discontinuation of the IP, a single cord blood sample will be collected for PK analysis. 
Additionally, a maternal blood sample should be collected at the same time as the cord blood sample if the sample time does not already coincide with a PK sampling window (see 
Protocol Section 7.6.1). 
24. A breast milk/colostrum sample is only to be collected in women who deliver and produce breast milk within 12 hours after completion or discontinuation of the IP. 
25. All participating investigational centers will collect a blood sample for maternal DNA in women who provide informed consent for genetic research.  
26. All participating investigational centers will collect a maternal blood sample for biomarker research. 
27. Only US and Canadian investigational centers will collect a maternal blood sample for cell-free fetal DNA in women who provide informed consent for genetic research. 
28. Fetal fibronectin results will be collected only at those institutions that perform fetal fibronectin testing as routine practice. Fetal fibronectin will not be used to determine study 
eligibility. 
29. Cervical length determined by transvaginal ultrasound will be collected only at those institutions that measure cervical length as routine practice. Cervical length will not be used to 
determine study eligibility. 
30. Obtain confirmation from the subject or the legal guardian for the infant that the infant is not participating in any other study 
 
 


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11.3. 
Appendix 3: Treatment States and Phases 
 
Study treatment start date/time and/or stop date/time are determined by the infusion of IP 
administered.   
11.3.1. 
Treatment Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment, unless otherwise specified.  
Treatment Phase 
Definition 
Pre-treatment 
Date/Time < Initial Study Treatment Start Date/Time  
On-treatment 
Study Treatment Start Date Time ≤  Date Time ≤ Study Treatment Stop 
Date Time + 12 hours  
Post-treatment 
Date/Time > Study Treatment Stop Date/Time + 12 hours 
 
 
11.3.2. 
Treatment States 
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date/time of the study treatment. 


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11.3.3. 
Treatment States for AE Data 
Treatment State 
Definition 
AE = Pre-treatment 
AE Start Date < Study Treatment Start Date 
AE = On-treatment 
If AE onset date is on or after the treatment start date and on or before the 
treatment stop date. 
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date 
+ 1 
AE = Post-
treatment 
If AE onset date is after the treatment stop date. 
AE Start Date > Study Treatment Stop Date + 1 
AE Onset Time 
Since 1st  Dose 
(Days) 
If Study Treatment Start Date > AE Onset Date :  
= AE Onset Date – Study Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date :  
= AE Onset Date – Study Treatment Start Date + 1 
Missing otherwise  
AE Duration (Days)  AE Resolution Date – AE Onset Date + 1 
AE = Drug-related 
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing. 
NOTES:  
• 
If the study treatment stop date is missing then the AE will be considered to be On-Treatment if there are no post-
infusion assessments and delivery. 
 


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11.4. 
Appendix 4: Data Display Standards & Handling 
Conventions 
11.4.1. 
Study Treatment & Sub-group Display Descriptors 
Study Treatment Descriptions 
Code 
Description 
Order of Table Presentation 
1 
Retosiban 
2 
2 
Placebo 
1 
 
11.4.2. 
Baseline Definition & Derivations 
11.4.2.1. 
Baseline Definitions 
For all endpoints (expect as noted) baseline value will be the latest pre-dose assessment.  
Parameter 
Study Assessments Considered As 
Baseline 
Baseline Used in Data 
Display 
Screening 
Day 1  (Pre 
Dose) 
Safety 
Vital Signs  
X 
X 
Last value to prior to start 
of IP 
Laboratory  
X 
 
Screening 
 
11.4.2.2. 
Derivations and Handling of Missing Baseline Data 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
NOTE : 
• 
Unless otherwise specified, the baseline definitions specified in 11.4.2.1Baseline Definitions will be used for 
derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data are missing no derivation will be performed and baseline value will be set 
to missing. 
• 
The baseline definition will be footnoted on all change from baseline displays. 
 
The baseline is defined as last assessment prior of start of IP administration.  The value 
will be missing if the baseline data are missing.  For lab parameters, last assessment prior 
to IP will be used as baseline if there are multiple assessment at screening or day 1. 


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11.4.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• The currently supported versions of SAS software will be used to perform all data analyses, 
generate tables, figures, and listings.  
Reporting Area 
Analysis Datasets  
• Analysis datasets will be created according to ADaM implementation guide version xx. 
• RTF files will be generated. 
• All datasets are CDISC compliance. 
 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
• 4.03 to 4.23: General Principles 
• 5.01 to 5.08: Principles Related to Data Listings 
• 6.01 to 6.11: Principles Related to Summary Tables 
• 7.01 to 7.13: Principles Related to Graphics  
Formats 
• For study population and efficacy analyses, all data will be reported according to the planned 
treatment the subject was randomized unless otherwise stated.  
• For safety analyses, all data will be reported according to the actual treatment the subject 
received unless otherwise stated. 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.  


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Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses : 
• Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as 
appropriate. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the subject’s listings.  
• Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses. 
Unscheduled Visits 
• Unscheduled visits will not be included in by-visit summary tables or figures except ‘any visit 
post-baseline category’, unless otherwise stated. 
• All unscheduled visits will be listed. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principles 7.01 to 7.13. 
 


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11.5. 
Appendix 5: Derived and Transformed Data 
11.5.1. 
General 
Multiple Measurements at One Time Point 
• Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented. 
• For laboratory assessment and vital signs’ descriptive summary statistics and other endpoints, 
if there are multiple assessments within a same scheduled visit, the last assessment within the 
visit will be used. 
• For laboratory assessment and vital signs with potential clinical importance, if there are two 
values within a time window, the worst value (i.e. the most extreme value from the normal 
range) will be used.  
• Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. Unscheduled visit will be included. This will also be 
applicable to relevant Potential Clinical Importance summary tables. 
Study Day 
• Calculated as the number of days from the first study treatment date : 
[1] Ref Date = Missing                                  → Study Day = Missing (none displayed) 
[2] Ref Date < First Study Treatment Date   → Study Day = Ref Date – First Study Treatment 
Date     
[3] Ref Data ≥ First Study Treatment Date   → Study Day = Ref Date – (First Study 
Treatment Date) + 1     
 
11.5.2. 
Study Population 
Demographics  
Age for Mother 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
[1] Date of birth of any subject will have this imputed as ‘30th June’. 
[2] If a subject is recorded as an adolescence in CRF and imputed date of birth in [1] is > 18 
years old, the last possible date to be 18 years old will be assigned. For example, an 
adolescence’s randomization date is 30Jun2016 and birth year is 1998. Imputed date of 
birth in [1] is 30Jun1998 and age is 19 years old. Then 29Jun1998 will be used as birth date 
to keep the subject in adolescence category.  
• Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
• Calculated as Weight (kg) / [Height (m)]2 
 
Extent of Exposure 
• Number of hours of exposure to study drug will be calculated using dates from the trial 
medication form. The duration of exposure in days will be based on the formula:   


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Duration of Exposure in Hours = (Treatment Stop Date/Time (in minutes) – Start Date/Time (in 
minutes))/60 
• If there are any treatment interruption during the study, then the exposure data will be adjusted 
accordingly. 
11.5.3. 
Safety 
Laboratory Parameters  
• If a laboratory value, which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with '<x' or '>x' (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value.  
• Example 1: 2 Significant Digits =  '< x ' becomes x - 0.01 
• Example 2: 1 Significant Digit   =  '> x' becomes x + 0.1 
• Example 3: 0 Significant Digits = '< x' becomes x - 1.     
• If there is more than one value of a particular parameter for a subject for a visit, the last 
assessment will be used in summary; all values will be listed.   
 
 


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11.5.4. 
Efficacy 
Calculation of Time to Delivery and Time to Delivery or Treatment Failure 
• Once delivery is confirmed, the maternal delivery and hospitalization records will be reviewed 
for data collection by the investigator obstetrician. The time to delivery is calculated as the 
days between the delivery and start time of the infusion of IP using the formula below: 
Time to delivery (days) = (date/time of delivery – date/time of start of infusion)/(24*60) 
The exact date/time of delivery and infusion will be used to determine the time to delivery.   
• Time to delivery or treatment failure is defined as the days between the delivery or treatment 
failure and start time of the infusion of IP in a similar fashion to the time to delivery.   
 
 
Calculation of Neonatal Composite Endpoint 
Neonatal Composite Endpoint 
The presence of any of the following endpoints determined from review of medical records will lead 
to a value of 1 for the neonatal composite endpoint and 0 otherwise: 
• Fetal or neonatal death  
• Respiratory Distress Syndrome (RDS) 
o Requiring continuous positive airway pressure or mechanical ventilation. 
Diagnosis requires a chest radiograph consistent with RDS (reticulogranular 
appearance to the lung fields or air bronchograms) within the first 24 hours of life 
 
OR 
o Received surfactant for a clinical picture of RDS within the first 24 hours of life 
• Bronchopulmonary dysplasia at ≥36 weeks postmenstrual age (determined by adding 
chronological age to GA at delivery), defined as follows: 
o >21% supplemental oxygen requirement 
 
OR 
o Use of high flow nasal cannula at ≥1 L (21% oxygen) 
• Necrotizing enterocolitis or isolated perforation 
o Diagnosed by radiographic evidence of Stage II or higher according to Bell’s 
staging criteria (fixed/unchanging bowel loops, pneumatosis intestinalis, portal 
venous gas, pneumoperitoneum) 
 
OR 
o Pneumatosis intestinalis, bowel necrosis, or perforation noted at surgery 
• Sepsis based on positive blood culture with clinical features of sepsis 
• Meningitis based on positive cerebrospinal fluid culture performed as part of infection 
workup 
• Retinopathy of prematurity 
o    Confirmed by an ophthalmologist based on international committee Stage 4  or 5 


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OR 
o Requiring surgical treatment with laser or other surgical intervention 
including cryotherapy or treatment with anti-VEGF (vascular endothelial growth 
factor) 
• Intraventricular Hemorrhage (IVH) 
o Grade 3 or 4 (severe IVH) 
 
OR 
o Any grade of IVH with posthemorrhagic hydrocephalus requiring a shunt 
• White matter injury, documented on cranial ultrasound or magnetic resonance imaging, as 
indicated by the following: 
o Multiple cystic lucencies in periventricular white matter (may be bilateral or 
unilateral, may vary in size, and be diffuse or focal in distribution) 
OR 
o Porencephalic cyst (not including subependymal or choroid plexus cysts) 
OR 
o Persistent ventriculomegaly, moderate to severe 
• Cerebellar hemorrhage (unilateral or bilateral) 
 
Individual Neonatal Composite Endpoint 
• This will be derived for all the conditions included under the composite endpoint.  For each 
individual condition, the variable will be 1 if the condition is satisfied, otherwise, 0. 
 
Neonatal Composite Endpoint without RDS 
• Same as the composite endpoint without the RDS condition. 
 
Neonatal Composite Endpoint without RDS and mortality  
• Same as the composite endpoint without the RDS and fetal/neonatal death conditions. 
 
Modified Neonatal Composite Endpoint 
• Same as the composite endpoint and include the all reported neonatal events. For 
example, a subject is considered as experience a RDS even without record of CPAP, 
ventilation or Surfactant. . 
 
 


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Calculation of Gestational Age at Birth and Proportion of Pre-term Births 
• Gestational age at birth (weeks) is defined as the gestational age when the baby is born 
and is captured in the eCRF. If the data are missing, the GA at birth can be calculated as 
follows: 
 GA at Birth (weeks) = (GA at Randomization x 7 + Time to delivery) / 7 
             GA at randomization will be converted to 1 decimal place (i.e. 30.2 weeks GA at   
             randomization) prior the calculation.   
• Proportion of births prior to 370/7 , 350/7 , 320/7 , or 280/7 week’s gestation (preterm) 
Subjects are considered to have delivered prior to 370/7 weeks if the gestational age at   
birth is less than 370/7 weeks (e.g.: < 37.0 weeks). Other proportions also will be calculated 
in a similar fashion. For proportion of births prior to 320/7 and 280/7 week’s gestation, only 
mothers who were randomized prior to 320/7 and 280/7 week’s gestation will be included 
respectively.  
• Proportion of births at term (≥ 370/7 week’s gestation) 
Subjects are considered to have delivered at term if the gestational age is ≥ 370/7 (e.g., ≥ 
37.0 weeks) 
 
Calculation of Neonatal Hospital Admission  
• For the delivery visit hospitalization, the length of the hospital stay (days) and associated 
hospital unit (NICU, nursery level, or level of care 1 to 4) will be recorded. The length of 
stay is calculated as the days between the delivery date/time and discharge date/time.  
• In addition, whether the baby was transported to a different hospital or extended stay 
facility and length of stay (days) and number of hospital readmissions in the month 
following discharge from the delivery visit hospitalization will also be captured and 
reported. 
 
 
 
 
 


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11.6. 
Appendix 6: Premature Withdrawals & Handling of Missing 
Data 
11.6.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion status was defined as subjects who either prematurely 
withdrawn.  
• Those subjects that are randomized and not dosed are not considered as 
prematurely withdrawn. 
• Subjects who are withdrawn from study participation after starting randomized 
treatment will not be replaced. 
• Subjects who receive but who discontinue from IP will not be considered 
withdrawn from the study and should remain in the study and continue to be 
followed for efficacy and safety. 
 
11.6.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument : 
[1] These data will be indicated by the use of a “blank” in subject listing 
displays.  
[2] Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such. 
 
11.6.2.1. 
Handling of Missing Stratification 
Element 
Reporting Detail 
GA at 
Randomization 
• 
If GA at randomization in weeks/days obtained from CRF is missing, the 
upper bound of the GA strata assigned at randomization will be used as a 
numeric value. For example, a subject in 24 0/7 to 25 6/7 group, 25 weeks and 
6 days will be converted into numeric value.  
Established 
Progesterone 
Use 
• 
Established progesterone use will be derived using mediations which are 
taken prior to the study treatment and recorded in obstetrical medications 
CRF page. If a subject is stratified as progesterone user at the randomization 
but no progesterone medication prior to the study treatment was recorded in 
obstetrical medications CRF page, the subject will be considered as 
established progesterone user for analysis.  
 
11.6.2.2. 
Handling of Missing/Partial Dates 
Element 
Reporting Detail 


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Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Concomitant 
Medication 
Partial start dates of prior and concomitant medications will be assumed to be the 
earliest possible date consistent with the partial date. In the case of a missing year, 
the year will be assumed to be the year part of informed consent date of that 
subject. In the case of a completely missing start date, the start date will be 
assumed to be prior to date of the first administration of study medication. Partial 
stop dates of prior and concomitant medications will be assumed to be the latest 
possible date consistent with the partial date. In the case of a completely missing 
stop date, the medication will be assumed to be ongoing. 
Time to 
Delivery and 
Time to 
Delivery or 
Treatment 
Failure 
For the delivery and delivery or failure date/time, 
• Missing data with respect to time to delivery and time to delivery or treatment 
failure endpoints is unlikely to occur. If it occurs and the dates are missing, the 
last assessment date of a mother prior to delivery phase will be used.  
• If the times are missing, a “00:00” will be used for the time. 
Length of 
neonatal 
hospital stay 
• For neonates have the data of hospital stay at birth, if date/time of hospital 
admission is not missing but date/time of discharge is missing, the date/time of 
discharge will be imputed using EDD + 28 days in calculation of length of stay. 
Adverse 
Events 
(General) 
• If the dates are missing for on-treatment, or post-treatment AEs, imputation of 
AE dates may be performed if needed. The eCRF allows for the possibility of 
partial dates (i.e., only month and year) to be recorded for AE start and end 
dates; that is, the day of the month may be missing. 
• Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied. 
• There will be no imputation for AE data listings 
Adverse 
Events 
(Mother) 
• Any partial dates for adverse events will be flagged to data management. If the 
full date cannot be ascertained, the following assumptions will be made whether 
the AE occurred on-treatment or post- treatment : 
Start Date 
• If the partial date is a start date, a '01' will be used for the 
day and 'Jan' will be used for the month.  
o For AEs which can occur only during or after 
labor/delivery (ex. postpartum hemorrhage), if these 
results in a date are prior to the delivery date, then the 
delivery date will be assumed to be the start date. 
Applicable AEs will be identified by PPD/GSK medical 
monitor. 
o For other AEs that occur prior to labor or delivery, if 
these results in a date are prior to the first study 
treatment date, then the first study treatment date will 
be assumed to be the start date.   
• The AE will then be considered to start on-treatment (worst 
case). 


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Element 
Reporting Detail 
End Date 
• If the partial date is a stop date, a '28/29/30/31' will be used 
for the day (dependent on the month and year) and 'Dec' 
will be used for the month.  
o For AEs which can occur only during the pregnancy 
(ex. gestational diabetes), if these results in a date are 
after the delivery date, then the delivery date will be 
assumed to be the end date. Applicable AEs will be 
identified by PPD/GSK medical monitor. 
o For other AEs that occur only during or after 
labor/delivery, if these results in a date are after the last 
assessment date or contact date, then the last 
assessment date or contact date will be assumed to be 
the end date.   
Adverse 
Events 
(Neonate) 
• Any partial dates for adverse events will be flagged to data management. If the 
full date cannot be ascertained, the following assumptions will be made: 
Start Date 
• If the partial date is a start date, a '01' will be used for the 
day and 'Jan' will be used for the month.  
• However, if these results in a date are prior to the birth 
date, then the birth date will be assumed to be the start 
date.  
• The AE will then be considered to start on-treatment (worst 
case). 
End Date 
• If the partial date is a stop date, a '28/29/30/31' will be used 
for the day (dependent on the month and year) and 'Dec' 
will be used for the month. 
• If these results in a date are after neonatal death date, then 
neonatal death date will be assumed to be the end date. 
• If the dates are after the last assessment date or contact 
date, then the last assessment date in medical record or 
contact date will be assumed to be the end date. 
• However, if these results in a date are more than 28 days 
after EDD, then 28 days after EDD will be assumed to be 
the end date.   
Adverse 
Events 
(Fetus) 
• Any partial dates for adverse events will be flagged to data management. If the 
full date cannot be ascertained, the following assumptions will be made: 
Start Date 
• If the partial date is a start date, a '01' will be used for the 
day and 'Jan' will be used for the month.  
• However, if these results in a date are prior to the first study 
treatment date, then the first study treatment date will be 
assumed to be the start date.  
• The AE will then be considered to start on-treatment (worst 


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Element 
Reporting Detail 
case). 
End Date 
• If the partial date is a stop date, a '28/29/30/31' will be used 
for the day (dependent on the month and year) and 'Dec' 
will be used for the month. 
• However, if these results in a date are after the birth date or 
fetal death date, then the birth date or fetal death date will 
be assumed to be the end date.   
 


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11.7. 
Appendix 7: Primary and Sensitivity Analyses for Co-
Primary Endpoints with Missing Data 
11.7.1. 
Co-Primary Endpoints with Missing Data 
Missing data will not be imputed for primary and sensitivity analyses for co-primary 
endpoints. 


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11.8. 
Appendix 8: Values of Potential Clinical Importance 
11.8.1. 
Laboratory Values for Pregnant Women 
For laboratory parameters not listed below, the normal range defined in Quest will be 
used for analysis. 
Haematology 
Laboratory Parameter 
 
SI Units 
Normal Range 
Low Flag (< x) 
High Flag (>x) 
Eosinophils 
GI/L 
0 
0.6 
Hematocrit 
1 
0.28 
 
Hemoglobin 
G/L 
95 
 
Lymphocytes, Abs 
GI/L 
1.0 
3.6 
Lymphocytes 
% 
16 
46 
Total Neutrophil, Abs 
GI/L 
3.9 
13.1 
Platelet Count 
GI/L 
146 
 
Red Blood Cell Count (RBC) 
TI/L 
12.7 
15.3 
While Blood Cell Count (WBC) 
GI/L 
5.9 
16.9 
 
Clinical Chemistry 
Laboratory Parameter 
 
SI Units 
Normal Range 
Low Flag (< x) 
High Flag (>x) 
Alanine transaminase (ALT) 
U/L 
 
25 
Aspartate transaminase (AST) 
U/L 
 
32 
Albumin 
G/L 
23 
42 
Bilirubin, total 
UMOL/L 
 
18.8 
Chloride 
MMOL/L 
97 
109 
CO2 CONTENT 
MMOL/L 
20 
32 
Creatinine 
UMOL/L 
 
68.6 
Glucose 
MMOL/L 
3.9 
10 
Magnesium 
MMOL/L 
0.45 
0.90 


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Clinical Chemistry 
Laboratory Parameter 
 
SI Units 
Normal Range 
Low Flag (< x) 
High Flag (>x) 
Phosphorus, INORG 
MMOL/L 
0.90 
1.49 
Potassium 
MMOL/L 
3.3 
5.1 
Sodium 
MMOL/L 
130 
 
Uric acid 
UMOL/L 
 
375 
 
 
11.8.2. 
Vital Signs for Pregnant Women 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 160 
Diastolic Blood Pressure 
mmHg 
< 45 
> 100 
Heart Rate 
bpm 
< 40 
> 110 
 
11.8.3. 
Fetal Heart Rate 
Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Heart Rate 
bpm 
< 110 
> 160 
 


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11.9. 
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses 
 
Endpoint(s) • Length of hospital stay 
Analysis 
• Analysis of Covariance for the Length of hospital stay 
• Length of hospital stay will be log-transformed prior to the model fitting. 
 
11.10. 
Appendix 10: Abbreviations & Trade Marks 
11.10.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AFI 
Aniotic Fluid Index 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
AST 
Aspartate aminotransferase (SGOT) 
BMI 
Body mass index 
BPM 
Beat Per Minute 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
DRE 
Disease-related Event 
eCRF 
electronic Case Report Form 
EDD 
Estimated Date of Delivery 
EM 
Expectation-maximization 
EP 
Established Progesterone Use 
EPDS  
Edinburgh Postnatal Depression Scale 
EQ-5D-5L  
EuroQol 5-dimensional 5-level 
fFN  
fetal Fibronectin 
FMM 
Finite Mixture Models 
GA  
Gestational Age 
GSK 
GlaxoSmithKline 
HR 
Heart rate 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IDMC  
Independent Data Monitoring Committee 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
ITT 
Intent-to-treat 
Kg 
Kilogram 
MedDRA  
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Description 
NICU  
Neonatal Intensive Care Unit 
PK  
Pharmacokinetic 
PP 
 
PPROM 
Preterm Premature Rupture of Membranes 
RAP 
Reporting and Analysis Plan 
RDS  
Respiratory Distress Syndrome 
SAC 
Statistical Analysis Complete 
SAE  
Serious Adverse Event 
SAS 
Statistical Analysis Software 
SI 
System Independent  
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operating Procedure 
TRT 
Treatment 
ULN 
Upper limit of normal 
 
11.10.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 


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11.11. 
Appendix 11: List of Data Displays 
 
A separate document for shells contains all table, listing and figures’ (TLFs) for the 
planned final analysis. However, due to early termination of the study, only TLFs listed 
in this appendix will be generated.  
11.11.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Study Population 
1.01 to 1.xx 
Efficacy 
2.01 to 2.xx 
Safety 
3.01 to 3.xx 
Other Analysis 
 
Section 
Listings 
ICH Listings 
1 to 200 
Other Listings 
From 201  
 


 
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11.11.2. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition  
1.01 
All Randomized 
 
Summary of Subject Disposition  
 
 
1.03 
Maternal ITT 
 
Summary of Significant Protocol Deviations 
 
 
Demographics 
1.11 
Maternal ITT 
 
Summary of Maternal/Fetal Demographic  
 
 
1.12 
Maternal ITT 
 
Summary of Maternal/Fetal Baseline 
Characteristics  
 
 
1.13 
Neonatal ITT 
 
Summary of Neonatal Birth Data 
 
 
1.15 
Maternal ITT 
 
Summary of Maternal Race and Racial 
Combinations  
 
 
Medical Condition & Con Meds 
1.23 
Maternal ITT 
 
Summary of Obstetrical History 
 
 
1.24 
Maternal ITT 
 
Summary of Prenatal History 
 
 
1.29 
Maternal ITT 
 
Summary of Maternal Obstetrical Medications 
 
 
1.30 
Maternal ITT 
 
Summary of Maternal Magnesium Sulfate 
 
 
1.31 
Maternal ITT 
 
Summary of Maternal Antenatal Corticosteroids 
 
 


 
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11.11.3. 
Efficacy Tables 
Efficacy Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Time to Delivery 
2.01 
Maternal ITT 
 
Summary of Time to Delivery 
 
 
2.02 
Maternal ITT 
 
Summary of Time to Delivery or Treatment Failure 
 
 
2.53 
Maternal ITT 
 
Summary Statistics for Time to Delivery by Preterm Labor 
Criteria (IC #4) 
 
 
Neonatal Composite Endpoint 
2.101 
Neonatal ITT 
 
Proportion of Neonatal Composite Endpoint 
 
 
2.102 
Neonatal ITT 
 
Proportion of Modified Neonatal Composite Endpoint 
 
 
Proportion of Births 
2.181 
Maternal ITT 
 
Proportion of Births 
 
 
Neonatal Hospital Admission: Length of Neonatal Hospital Stay 
2.301 
Neonatal ITT 
 
Summary of Neonatal Hospital Stay  
 
 
 


 
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11.11.4. 
Safety Tables 
Safety Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Exposure 
3.01 
Maternal 
Safety 
 
Summary of Extent of Study Drug Exposure 
 
 
3.02 
Maternal 
Safety 
 
Summary of Inadequate Therapeutic Response 
 
 
Maternal Adverse Events 
3.11 
Maternal 
Safety 
 
Summary of Maternal Adverse Events 
 
 
3.41 
Maternal 
Safety 
 
Summary of Most Common Maternal Adverse 
Events 
 
 
3.51 
Maternal 
Safety 
 
Summary of Maternal Serious Adverse Events 
 
 
Fetal Adverse Events 
3.111 
Maternal Safety 
 
Summary of Fetal Adverse Events 
 
 
3.141 
Maternal Safety 
 
Summary of Most Common Fetal Adverse Events 
 
 
3.151 
Maternal Safety 
 
Summary of Fetal Serious Adverse Events 
 
 


 
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Safety Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
3.171 
Maternal Safety 
 
Summary of Fetal Adverse Events of Special 
Interest 
 
 
Neonatal Adverse Events 
3.211 
Neonatal 
Safety 
 
Summary of Neonatal Adverse Events 
 
 
3.241 
Neonatal 
Safety 
 
Summary of Most Common Neonatal Adverse 
Events 
 
 
3.251 
Neonatal 
Safety 
 
Summary of Neonatal Serious Adverse Events 
 
 
3.271 
Neonatal 
Safety 
 
Summary of Neonatal Adverse Events of Special 
Interest 
 
 
3.281 
Neonatal 
Safety 
 
Summary of Neonatal Disease-Related Adverse 
Events 
 
 
Labs 
3.401 
Maternal Safety 
 
Summary of Observed Value and Change from 
Baseline in Hematology by Visit 
 
 
3.402 
Maternal Safety 
 
Summary of Hematology Results Outside the 
Reference Ranges by Visit 
 
 
3.403 
Maternal Safety 
 
Summary of Observed Value and Change from 
Baseline in Clinical Chemistry by Visit 
 
 


 
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Safety Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Vital Signs  
3.421 
Maternal Safety 
 
Summary of Observed Value and Change from 
Baseline in Maternal Vital Signs by Visit 
 
 
3.424 
Maternal Safety 
 
Summary of Fetal Heart Rate Category 
 
 
 


 
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11.11.5. 
ICH Listings 
ICH Listings 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Randomization 
1 
All Randomized 
 
Randomised and Actual Treatments 
 
 
8 
All Randomized 
 
Randomised and Actual Treatments by Center 
 
 
9 
All Randomized 
 
Randomised and Actual Treatments by Center for 
Subjects not Enrolled in ARIOS at Study 
Completion 
 
 
Subject Disposition 
2 
All Randomized 
 
Reasons for Study Withdrawal 
 
 
3 
All Randomized 
 
Reasons for Study Treatment Discontinuation 
 
 
4 
All Randomized 
 
Study Disposition 
 
 
5 
All Randomized 
 
Significant Protocol Deviations 
 
 
Demographics 
11 
Maternal ITT 
 
Maternal Demographic Characteristics 
 
 
12 
Maternal ITT 
 
Maternal Baseline Characteristics I 
 
 
13 
Maternal ITT 
 
Maternal Baseline Characteristics II 
 
 


 
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ICH Listings 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
14 
Maternal ITT 
 
Maternal Race 
 
 
15 
Neonatal ITT 
 
Neonatal Birth Data 
 
 
Exposure 
21 
Maternal Safety 
 
Study Drug Exposure 
 
 
30 
Maternal Safety 
 
Inadequate Therapeutic Response 
 
 
Medical Condition & Con Meds 
23 
Maternal ITT 
 
Prior and Concomitant Medications 
 
 
24 
Maternal ITT 
 
Obstetrical Medications 
 
 
25 
Maternal ITT 
 
Magnesium Sulfate 
 
 
26 
Neonatal ITT 
 
Antenatal Corticosteroids 
 
 


 
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ICH Listings 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
41 
Maternal Safety 
 
All Maternal Adverse Events 
 
 
42 
Maternal Safety 
 
Maternal Serious Adverse Events 
 
 
43 
Maternal Safety 
 
Maternal Adverse Events of Special Interest 
 
 
44 
Maternal Safety 
 
Maternal Adverse Events of Special Interest: 
Chorioamnionitis 
 
 
56 
Maternal Safety 
 
Fetal Adverse Events of Special Interest: Category 
II-III FHR Event 
 
 
57 
Maternal Safety 
 
Maternal Disease-Related Adverse Events 
 
 
62 
Maternal Safety 
 
Maternal Deaths 
 
 
76 
Maternal Safety 
 
All Fetal Adverse Events 
 
 
77 
Maternal Safety 
 
Fetal Serious Adverse Events 
 
 
78 
Maternal Safety 
 
Fetal Adverse Events of Special Interest 
 
 
79 
Maternal Safety 
 
Fetal Deaths 
 
 
82 
Neonatal Safety 
 
All Neonatal Adverse Events 
 
 
83 
Neonatal Safety 
 
Neonatal Serious Adverse Events 
 
 


 
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ICH Listings 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
84 
Neonatal Safety 
 
Neonatal Adverse Events of Special Interest 
 
 
86 
Neonatal Safety 
 
Neonatal Adverse Events of Special Interest: 
Respiratory Distress Syndrome 
 
 
87 
Neonatal Safety 
 
Neonatal Adverse Events of Special Interest: 
Hypotension 
 
 
89 
Neonatal Safety 
 
Neonatal Adverse Events of Special Interest: 
Intraventricular Hemorrhage 
 
 
90 
Neonatal Safety 
 
Neonatal Adverse Events of Special Interest: 
Bronchopulmonary Dysplasia 
 
 
92 
Neonatal Safety 
 
Neonatal Adverse Events of Special Interest: 
Hyperbilirubinemia 
 
 
93 
Neonatal Safety 
 
Neonatal Adverse Events of Special Interest: 
Infant Infections Event 
 
 
96 
Neonatal Safety 
 
Neonatal Disease-Related Adverse Events 
 
 
97 
Neonatal Safety 
 
Neonatal Deaths 
 
 
108 
Neonatal Safety 
 
Neonatal Disease-Related Adverse Events: 
Hydrocephalus 
 
 
111 
Neonatal Safety 
 
Neonatal Disease-Related Adverse Events: 
Retinopathy of Prematurity 
 
 


 
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ICH Listings 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
LABS 
113 
Maternal Safety 
 
Haematology Laboratory Data Outside the 
Reference Ranges 
 
 
116 
Maternal Safety 
 
Clinical Chemistry Laboratory Data Outside the 
Reference Ranges 
 
 
Vital Signs 
121 
Maternal Safety 
 
Vital Signs for Subjects with Abnormalities of 
Potential Clinical Importance 
 
 
123 
Maternal Safety 
 
Fetal Heart Rate 
 
 


 
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11.11.6. 
Non-ICH  Listings 
Non-ICH Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Screening Visit 
203 
All 
 
Obstetrical History at Screening 
 
 
204 
All 
 
Prenatal History at Screening 
 
 
Efficacy 
301 
Maternal 
ITT 
 
Time to Delivery or Treatment Failure 
 
 
302 
Neonatal 
ITT 
 
Neonatal Composite Endpoints 
 
 
303 
Neonatal 
ITT 
 
Neonatal Health Care Resource Utilization at Birth 
 
 
304 
Neonatal 
ITT 
 
Neonatal Heath Care Resource Utilization at 
Readmission 
 
 
309 
Neonatal 
ITT 
 
Modified Neonatal Composite Endpoints 
 
 
Safety 
403 
Maternal 
Safety 
 
Maternal Health Care Resource Utilisation (In-
patient) 
 
 


 
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Non-ICH Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
407 
Maternal 
Safety 
 
Subsequent Preterm Labor 
 
 
PK 
461 
Maternal 
Safety 
 
Retosiban Concentration in Plasma 
 
 
462 
Maternal 
Safety 
 
Retosiban concentration in Umbilical Cord Blood 
 
 
463 
Maternal 
Safety 
 
Retosiban concentration in Breast Milk