Clinical trial NCT02292771
Conditions: Obstetric Labour, Premature
Keywords: Spontaneous Preterm Labor retosiban GSK221149 atosiban
Sponsor: GlaxoSmithKline
Start date: 2015-03-16; Completion date: 2017-08-25
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to demonstrate the superiority of retosiban to prolong pregnancy in females with spontaneous preterm labor compared with atosiban. This objective is based on the hypothesis that prolonging the time to delivery in the absence of harm may benefit the newborn, particularly in women who experience spontaneous preterm labor at early gestational ages (GA). This study is designed to test this hypothesis through a direct comparison with atosiban, a mixed oxytocin vasopressin antagonist indicated for short-term use to delay imminent preterm birth in women between 24\^0/7 and 33\^6/7 weeks' gestation in preterm labor. This is a randomized, double-blind, double-dummy study, which consists of 6 phases: Screening, Inpatient Randomized Treatment, Post Infusion Assessment, Delivery, Maternal Post Delivery Assessment, and Neonatal Medical Review. Approximately 330 females will be randomly assigned to retosiban or atosiban treatment in a 1:1 ratio. The duration of any one subject's (maternal or neonatal) participation in the study will be variable and dependent on GA at study entry and the date of delivery.

Detailed description:

Arms: arm 1: Participants will receive retosiban 6 milligrams (mg) intravenous (IV) loading dose over 5 minutes, followed by a 6mg/hour continuous infusion over 48 hours. For subjects with an inadequate response after the first hour of treatment, investigators will administer another 6mg IV loading dose and increase the infusion rate to 12 mg/hour for the remainder of the 48-hour treatment period. Participants will also receive placebo infusion matched for the atosiban loading (bolus) dose and continuous infusion to ensure blinding. arm 2: Participants will receive atosiban in 3 successive stages: an initial bolus dose (6.75 mg) over 1 minute, immediately followed by a continuous infusion at 18 mg/hour for 3 hours, followed by a 6 mg/hour infusion for the remainder of the 48-hour treatment period. Participants will also receive placebo infusion matched for retosiban loading (bolus) dose and continuous infusion to ensure blinding.
Interventions: intervention 1: Retosiban intervention 2: Atosiban intervention 3: Placebo matching retosiban intervention 4: Placebo matching atosiban
Intervention descriptions: intervention 1: Solution for infusion, consisting of a clear colorless solution of retosiban at a concentration of 15 milligram/milliliter (mg/mL) in 56% volume/volume ethanol/acetate buffer concentrate supplied in 5 mL vial containing 75mg retosiban. intervention 2: Clear, colorless solution for injection in a 0.9-mL vial containing 6.75 mg of atosiban. Clear, colorless concentrate for solution for infusion in a 5-mL vial containing 37.5 mg atosiban. intervention 3: A placebo infusion containing 0.9% sodium chloride (NaCl) matched for retosiban loading (bolus) dose and continuous infusion. intervention 4: A placebo infusion containing 0.9% NaCl matched for the atosiban loading (bolus) dose and continuous infusion.

Protocol documents:
Prot_001.pdf: 
2014N194185_05 
CONFIDENTIAL 
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1 
 
 
 
TITLE PAGE 
Division: Worldwide Development 
Information Type: Protocol Amendment 
 
 
Compound Number: GSK221149 
 
Development Phase: 
III 
 
Effective Date: 
21-DEC-2016 
 
Protocol Amendment Number: 05 
 
 
Authors (PPD): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited. 
Randomized, Double-blind, Multicenter, Phase III Study 
Comparing the Efficacy and Safety of Retosiban Versus 
Atosiban Therapy for Women in Spontaneous Preterm Labor 
Title: 
Authors (GSK): 
PPD 
PPD 
PPD 


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2 
 
 
 
Revision Chronology 
 
GlaxoSmithKline 
Document Number 
Date 
Version 
2014N194185_00 
2014-MAY-14 
Original 
2014N194185_01 
2015-JAN-29 
Country-Specific Protocol 
Amendment for Applicable 
Sites in France 
Inclusion criteria 1 and 2 were amended to specify that subjects must be at least 18 years 
of age to participate in Study 200721, and subjects who participate in Study 200721 must 
also agree to participate in Study 200722, a separate infant follow-up study. Text was 
revised throughout to reflect the change in the subject age criterion and the requirement 
to enroll in the infant follow-up study. Section 9.2 was updated to clarify that the study 
would be conducted using the current version of the Declaration of Helsinki. Finally, an 
appendix was added that categorizes laboratory samples into those supporting study 
conduct and those that may be analyzed at a later date. 
2014N194185_02 
2015-JAN-29 
Country-Specific Protocol 
Amendment for Applicable 
UK Sites 
The text from Section 5.3 has been clarified. The intent of the language remains the same, 
but the clarification confirms there is no requirement for the investigator to discuss 
unblinding with the PPD medical monitor in order to rapidly unblind treatment for a 
study subject if needed. In addition, Section 9.2 was updated to clarify that the study 
would be conducted using the current version of the Declaration of Helsinki. 
2014N194185_03 
2015-FEB-04 
Country-Specific Protocol 
Amendment for Applicable 
Swedish Sites 
An appendix was added to list the medications considered strong, moderate, and weak 
CYP3A4 (cytochrome P450 3A4 enzyme) inhibitors and inducers. 
2014N194185_04 
2016-AUG-22 
Amendment No. 4 
The following changes are reflected in Protocol Amendment No. 4: 
• 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 inclusion criteria for confirming sufficient dilation and effacement at 
Screening. 
• Clarify that co-morbid medical or obstetric conditions that may exclude a subject 


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3 
 
 
 
from the study include known or suspected maternal Zika infection during gestation. 
• Clarify the exclusion criterion for women with a history of substance abuse. 
• Add an exclusion criterion for women for whom the combination of history and 
screening test results is suggestive of abuse or dependency. 
• Clarify that withdrawal from the study will mean that no additional visits can occur or 
procedures performed. 
• 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. 
• Define inadequate treatment response. 
• Clarify in the Time and Events Table the assessments performed at the face-to-face 
post-infusion visit and at the weekly telephone calls during the Post-Infusion 
Assessment Phase. Additionally, the optional retreatment visit was added to the table 
and the assessments that will performed when a subject withdraws from the study 
were clarified. 
• Add definitions for a completed subject and study completion. 
• Update the atosiban preparation instructions. 
• Add procedures that should be followed for managing dose interruptions. 
• Clarify that there is no requirement for the investigator to discuss unblinding with the 
PPD medical monitor in order to rapidly unblind treatment for a study subject if 
needed. 
• 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 presentation of the liver stopping criteria and add that for local laboratory 
results an isolated bilirubin >1.5 × the upper limit of normal is acceptable if bilirubin 
is fractionated and direct bilirubin is <35%. 
• 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 are assessed relative to dosing. Also, added an optional 
measurement of oxygen saturation at Screening only. 
• Revise the timing of the pharmacokinetic (PK) sample taken at the onset of any 
maternal or fetal serious adverse event (SAE) from within 24 hours to within 12 hours 
after completion or discontinuation of investigational product. 
• Clarify that if a subject does not deliver at the investigative center, central laboratory 


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4 
 
 
 
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 and EuroQol 5-dimensional 5-level from ±2 weeks to -2 weeks/+6 weeks. 
• Add as a key secondary endpoint the PK analysis of retosiban clearance and volume 
of distribution and the effect of covariates on these parameters. 
• Remove the listed exploratory endpoints and clarify that exploratory endpoints will 
be provided in the reporting and analysis plan. 
• Remove the follow-up amniotic fluid index (AFI) by abdominal ultrasound as a fetal 
safety endpoint. 
• Remove from the list of disease-related maternal and neonatal events those events 
that are already listed as adverse events (AEs) of special interest. 
• Clarify the time period and frequency of reporting AEs and SAEs. 
• Update the contact information for reporting SAEs. 
• Add information for the follow-up of AEs and SAEs. 
• 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. 
• Remove the requirement for an ultrasound for determination of the AFI within 
12 hours of completion of study treatment. 
• Revise the method used for adjusting multiplicity of the key secondary endpoints 
from a stepwise Holm’s test to a sequential testing method. 
• Add an appendix that provides guidelines for reporting maternal, fetal, and neonatal 
AEs of special interest. 
• Incorporate the changes detailed in the country-specific amendment for sites in 
France (dated 29 Jan 2015). 
• Incorporate the changes detailed in the country-specific amendment for sites in the 
United Kingdom (dated 29 Jan 2015). 
• Incorporate the changes detailed in the country-specific amendment for sites in 
Sweden (dated 04 Feb 2015). 
• Incorporate other administrative changes. 
2014N194185_05 
2016-DEC-21 
Amendment No. 5 
The following changes are reflected in Protocol Amendment No. 5: 
• Remove the 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. 


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• 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 or 
before retreatment unless the most recent ultrasound is within 3 weeks (21 days) 
before the date of randomization or the date of retreatment. 
• Update the list of maternal drug-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. 
• Remove changes detailed in the country-specific amendment for sites in 
France (dated 29 Jan 2015). 
• Incorporate other administrative changes. 


6 
 
 
 
 
 
2014N194185_05 
CONFIDENTIAL 
 
SPONSOR SIGNATORY 
 
 
 
 
 
 
 
---'--------== 
= 
IPP 
=    =    =    =    --    - 
- 
- 
- 
Kathleen  J Beach, M 
flfPH 
Medicine Developm( 
eader, 
Maternal and Neonatal Health Unit 
Alternative Discovery and Development 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
200721 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD 


7 
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SPONSOR INFORMATION PAGE 
Clinical Study Identifier: 200721 (ZINN) 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Contact Address 
GlaxoSmithKline Research & Development Limited 
Five Moore Drive 
P.O. 13398 
Research Triangle Park, NC 27709-3398, USA 
Telephone: PPD 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission. 
Sponsor Medical Monitor Contact Information and Sponsor Serious Adverse 
Events (SAE) Contact Information: 
 
Issue 
Latin America Contact 
Europe/Asia Contact 
Safety Questions 
PPD 
MD 
Medical Director, Medical Affairs and 
Pharmacovigilance 
PPD 
Buenos Aires, Brazil 
Europe: PPD 
MD, MFPM 
Associate Medical Director, Medical 
Affairs and Pharmacovigilance 
PPD 
Warsaw, Poland 
Asia: PPD 
MD 
Associate Medical Director, Medical 
Affairs and Pharmacovigilance 
PPD 
Kuala Lumpur, Malaysia 
24-Hour Safety Hotline: 
PPD 
Safety Fax: 
Safety Hotline: 
PPD 
Safety Fax: 
PPD 
PPD 
SAE Reporting 
24-Hour SAE Hotline: PPD 
SAE Fax: PPD 
 
Regulatory Agency Identifying Number(s): 
IND Number: 73287 
EudraCT Number: 2014-001826-13 


8 
2014N194185_05 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol 200721 (ZINN) 
 
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 
 
LIST OF ABBREVIATIONS ........................................................................................... 13 
PROTOCOL SUMMARY ............................................................................................... 15 
1. 
INTRODUCTION .................................................................................................... 21 
1.1. 
Background ................................................................................................ 21 
1.2. 
Rationale .................................................................................................... 22 
1.3. 
Benefit:Risk Assessment ............................................................................ 23 
1.3.1. 
Risk Assessment ......................................................................... 24 
1.3.2. 
Benefit Assessment ..................................................................... 30 
1.3.3. 
Overall Benefit:Risk Conclusion ................................................... 31 
2. 
OBJECTIVES ......................................................................................................... 31 
2.1. 
Primary Objective ....................................................................................... 31 
2.2. 
Secondary Objectives ................................................................................. 31 
2.3. 
Exploratory Objectives ................................................................................ 31 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 32 
3.1. 
Study Design .............................................................................................. 32 
3.1.1. 
Screening Phase ......................................................................... 35 
3.1.2. 
Inpatient Randomized Treatment Phase ...................................... 36 
3.1.2.1. 
Before Treatment........................................................ 36 
3.1.2.2. 
During Treatment ........................................................ 36 
3.1.2.3. 
End of Treatment ........................................................ 37 
3.1.3. 
Post-Infusion Assessment Phase ................................................. 37 
3.1.3.1. 
Retreatment ................................................................ 37 
3.1.4. 
Delivery Phase ............................................................................. 38 
3.1.5. 
Maternal Post-Delivery Assessment Phase ................................. 39 
3.1.6. 
Neonatal Medical Record Review Phase ..................................... 39 
3.2. 
Discussion of Design .................................................................................. 39 
3.2.1. 
Study Treatments ........................................................................ 39 
3.2.1.1. 
Retosiban ................................................................... 39 
3.2.1.2. 
Active Control ............................................................. 40 
3.2.1.3. 
Corticosteroids and Magnesium Sulfate ..................... 41 
3.2.2. 
Study Population .......................................................................... 41 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 42 
4.1. 
Number of Subjects .................................................................................... 42 
4.2. 
Inclusion Criteria ......................................................................................... 42 
4.3. 
Exclusion Criteria ........................................................................................ 44 
4.4. 
Withdrawal From Study and Discontinuation of IP ....................................... 45 
4.4.1. 
Withdrawal From Study ................................................................ 45 
4.4.1.1. 
Withdrawal From Study Participation After 
Randomization but Prior to Investigational 
Product Administration................................................ 45 
4.4.1.2. 
Withdrawal From Study Participation After 
Beginning Randomized Treatment ............................. 46 
4.4.2. 
Discontinuation of Investigational Product .................................... 47 


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4.5. 
Subject and Study Completion .................................................................... 48 
5. 
STUDY TREATMENTS .......................................................................................... 48 
5.1. 
Investigational Product and Other Study Treatment .................................... 48 
5.1.1. 
Concurrent Administration of Investigational Product With 
Strong CYP3A4 Inhibitors or Strong CYP3A4 Inducers ................ 54 
5.1.1.1. 
Retosiban ................................................................... 54 
5.1.1.2. 
Atosiban ..................................................................... 54 
5.2. 
Managing Dose Interruptions ...................................................................... 54 
5.3. 
Treatment Assignment ................................................................................ 55 
5.4. 
Blinding ....................................................................................................... 55 
5.5. 
Product Accountability ................................................................................ 56 
5.6. 
Treatment Compliance ................................................................................ 56 
5.7. 
Prior Medications and Nondrug Therapies .................................................. 56 
5.8. 
Concomitant Medications and Nondrug Therapies ...................................... 56 
5.8.1. 
Permitted Medications and Nondrug Therapies ........................... 57 
5.8.1.1. 
Antenatal Corticosteroids ............................................ 57 
5.8.1.2. 
Magnesium Sulfate ..................................................... 57 
5.8.1.3. 
Progesterone .............................................................. 57 
5.8.1.4. 
Antibiotics ................................................................... 57 
5.8.1.5. 
Strong CYP3A4 Inhibitors ........................................... 57 
5.8.1.6. 
Strong CYP3A4 Inducers ............................................ 57 
5.8.1.7. 
Breast Cancer Resistance Protein or 
P-Glycoprotein Inhibitors ............................................ 57 
5.8.2. 
Prohibited Medications and Nondrug Therapies ........................... 57 
5.9. 
Treatment After the End of the Study .......................................................... 58 
5.10. Treatment of Study Treatment Overdose .................................................... 58 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 58 
6.1. 
Critical Assessments Prior to Investigational Product Administration........... 66 
6.2. 
Efficacy ....................................................................................................... 66 
6.2.1. 
Time to Delivery ........................................................................... 66 
6.2.2. 
Neonatal Composite and Other Outcomes ................................... 67 
6.2.3. 
Primary Efficacy Endpoint ............................................................ 67 
6.2.4. 
Key Secondary Efficacy Endpoints .............................................. 67 
6.2.5. 
Other Secondary Efficacy Endpoints ............................................ 69 
6.2.6. 
Exploratory Efficacy Endpoints .................................................... 69 
6.3. 
Safety ......................................................................................................... 69 
6.3.1. 
Liver Chemistry Stopping and Follow-Up Criteria ......................... 71 
6.3.1.1. 
Study Treatment Restart or Rechallenge .................... 72 
6.3.2. 
Adverse Events ............................................................................ 72 
6.3.2.1. 
Definition of an AE ...................................................... 72 
6.3.2.2. 
Definition of an SAE ................................................... 73 
6.3.2.3. 
AEs of Special Interest ............................................... 74 
6.3.3. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs ......................................................... 74 
6.3.4. 
Cardiovascular Events ................................................................. 75 
6.3.5. 
Death Events ............................................................................... 75 
6.3.6. 
Congenital Anomalies .................................................................. 75 
6.3.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs ............................................... 76 
6.3.7.1. 
Disease-Related Maternal Events .............................. 76 


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6.3.7.2. 
Disease-Related Neonatal Events (Occurring 
in Infants Born Prior to 37 Completed Weeks) ............ 76 
6.3.8. 
Time Period and Frequency of Detecting AEs and SAEs ............. 78 
6.3.9. 
Method of Detecting AEs and SAEs ............................................. 78 
6.3.10. 
Follow-up of AEs and SAEs ......................................................... 78 
6.3.11. 
Prompt Reporting of SAEs and Other Events to GSK/PPD .......... 79 
6.3.11.1. Regulatory Reporting Requirements for SAEs ............ 80 
6.3.12. 
Other Safety Outcomes................................................................ 80 
6.3.12.1. Physical Examination.................................................. 80 
6.3.12.2. Vital Sign Measurements ............................................ 80 
6.3.12.3. Electronic Fetal Monitoring ......................................... 81 
6.3.12.4. Abdominal Ultrasound ................................................ 82 
6.3.12.5. Laboratory Assessments ............................................ 83 
6.3.12.6. Electrocardiogram ...................................................... 83 
6.3.12.7. Breastfeeding Status .................................................. 83 
6.3.12.8. Maternal Depression .................................................. 84 
6.4. 
Health Outcomes ........................................................................................ 84 
6.4.1. 
Health Outcomes – Maternal........................................................ 84 
6.4.1.1. 
Maternal Health Care Resource Use .......................... 84 
6.4.1.2. 
Maternal       Subject-Reported        Health 
Assessments .............................................................. 85 
6.4.2. 
Health Outcomes – Neonatal ....................................................... 85 
6.4.2.1. 
Neonatal Hospital Admission ...................................... 85 
6.4.2.2. 
Neonatal Health Care Resource Use .......................... 85 
6.5. 
Pharmacokinetics ....................................................................................... 86 
6.5.1. 
Sampling ...................................................................................... 86 
6.5.2. 
Umbilical Cord Blood ................................................................... 86 
6.5.3. 
Retosiban Levels in Breast Milk ................................................... 86 
6.6. 
Cervical Length ........................................................................................... 87 
6.7. 
Fetal Fibronectin ......................................................................................... 87 
6.8. 
Biomarkers ................................................................................................. 87 
6.9. 
Genetic Research ....................................................................................... 87 
7. 
DATA MANAGEMENT ........................................................................................... 88 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 88 
8.1. 
Hypotheses ................................................................................................. 88 
8.2. 
Study Design Considerations ...................................................................... 88 
8.2.1. 
Sample Size Assumptions ........................................................... 88 
8.2.2. 
Sample Size Sensitivity ................................................................ 89 
8.2.3. 
Sample Size Re-estimation .......................................................... 90 
8.3. 
Data Analysis Considerations ..................................................................... 90 
8.3.1. 
Analysis Populations (Maternal) ................................................... 90 
8.3.1.1. 
Maternal Safety Population ......................................... 90 
8.3.1.2. 
Maternal ITT Population ............................................. 90 
8.3.1.3. 
Maternal Per-Protocol Population ............................... 90 
8.3.2. 
Analysis Population (Neonatal) .................................................... 90 
8.3.2.1. 
Neonatal Safety Population ........................................ 90 
8.3.2.2. 
Neonatal ITT Population ............................................. 90 
8.3.2.3. 
Neonatal Per-Protocol Population ............................... 91 
8.3.3. 
Treatment Comparisons............................................................... 91 
8.3.3.1. 
Primary Comparisons of Interest ................................. 91 


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8.3.3.2. 
Other Comparisons of Interest .................................... 91 
8.3.3.3. 
Subgroup Analysis ...................................................... 91 
8.3.3.4. 
Exploratory Covariate Analyses .................................. 91 
8.3.4. 
Interim Analysis ........................................................................... 91 
8.3.5. 
Key Elements of Analysis Plan ..................................................... 92 
8.3.5.1. 
Efficacy Analyses ....................................................... 92 
8.3.5.1.1. 
Primary Analysis ..................................... 92 
8.3.5.1.2. 
Secondary Analysis ................................ 92 
8.3.5.2. 
Safety Analyses .......................................................... 93 
8.3.5.2.1. 
Extent of Exposure (Maternal) ................ 94 
8.3.5.2.2. 
Adverse Events ...................................... 94 
8.3.5.3. 
Health Outcomes Analyses......................................... 94 
8.3.5.4. 
Pharmacokinetic Analyses .......................................... 95 
8.3.5.5. 
Genetic Analyses ........................................................ 95 
9. 
STUDY CONDUCT CONSIDERATIONS ................................................................ 95 
9.1. 
Posting of Information on Publicly Available Clinical Trial Registers ............ 95 
9.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 95 
9.3. 
Quality Control (Study Monitoring) .............................................................. 96 
9.4. 
Quality Assurance ....................................................................................... 96 
9.5. 
Study and Site Closure ............................................................................... 97 
9.6. 
Records Retention ...................................................................................... 97 
9.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication .................... 98 
9.8. 
Independent Data Monitoring Committee .................................................... 98 
10. REFERENCES ....................................................................................................... 99 
11. APPENDICES ...................................................................................................... 103 
11.1. Appendix 1: Genetic Research ................................................................. 103 
11.2. Appendix 2:  Liver Chemistry Stopping and Follow-up Criteria .................. 106 
11.3. Appendix   3:    Cytochrome   P450   3A4   Enzyme   Inhibitors   and 
Inducers .................................................................................................... 109 
11.4. Appendix 4:  Safety Reporting Cheat Sheet .............................................. 111 
11.5. Appendix 5:  Summary of Human Biological Samples ............................... 112 
11.6. Appendix 6: Protocol Changes ................................................................. 115 


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LIST OF ABBREVIATIONS 
 
ACOG 
American College of Obstetricians and Gynecologists 
AE 
adverse event 
AFI 
amniotic fluid index 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
CDC 
Centers for Disease Control and Prevention 
CI 
confidence interval 
CYP 
cytochrome P450 
CYP3A4 
cytochrome P450 3A4 enzyme 
DRE 
disease-related event 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDD 
estimated date of delivery 
EMA 
European Medicines Agency 
EPDS 
Edinburgh Postnatal Depression Scale 
EQ-5D-5L 
EuroQol 5-dimensional 5-level 
EQ VAS 
EuroQol visual analogue scale 
EUROCAT 
European Surveillance of Congenital Anomalies 
fFN 
fetal fibronectin 
GA 
gestational age 
GBS 
group B streptococcal 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
IB 
investigator’s brochure 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
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 
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 
NICU 
neonatal intensive care unit 
pg 
picogram 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PPROM 
preterm premature rupture of membranes 
QTcF 
corrected QT interval using Fridericia formula 
RAP 
reporting and analysis plan 
RCOG 
Royal College of Obstetricians and Gynecologists 
RDS 
respiratory distress syndrome 
SAE 
serious adverse event 
SmPC 
summary of product characteristics 
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 prior to 240/7 weeks’ gestation 
Postmenstrual age 
Determined by adding chronological age to gestational age 
at delivery 
 
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PROTOCOL SUMMARY 
Rationale 
Mortality and morbidity in premature infants are inversely proportional to gestational age 
(GA) at birth; babies born before 320/7 weeks’ gestation have the greatest risk for death 
and poor health outcomes [Saigal, 2008]. The inverse relationship between neonatal 
mortality and morbidity and 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. Tocolytic therapy is recommended for short-term 
delay of delivery in order to administer antenatal corticosteroids, but there is no evidence 
that current tocolytic regimens improve neonatal or infant outcomes beyond the effect of 
antenatal corticosteroids [Sanchez-Ramos, 1999; RCOG, 2011; ACOG, 2012; 
Roos, 2013]. Unfortunately, neonatal mortality and morbidity remain disproportionately 
high for this study population despite antenatal corticosteroids and highlight a critical 
need for new therapies to prolong pregnancy and improve neonatal outcomes. 
 
Results from the OTA105256 Phase II 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, and this difference was consistent across GAs. The emerging safety 
profile for retosiban also appears favorable. All reported adverse events (AEs) (maternal, 
fetal, and neonatal) were generally consistent with either those reported in the 
investigator’s brochure (IB) or in the population under study. A summary of the complete 
results for Study OTA105256 is included in the IB [GlaxoSmithKline Document Number 
CM2006/00201/05]. 
 
No placebo-controlled tocolytic studies have demonstrated an effect of this magnitude in 
spontaneous preterm labor. There is general agreement 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. This study (ZINN) is 
designed to test this hypothesis through a direct comparison with atosiban, a mixed 
oxytocin-vasopressin antagonist indicated for short-term use to delay imminent preterm 
birth in women between 240/7 and 336/7 weeks’ gestation in preterm labor. 
Objectives 
The primary objective is to demonstrate the superiority of retosiban to prolong pregnancy 
compared with atosiban. 
 
The following are the secondary objectives: 
 
• 
To describe the outcomes of newborns during the neonatal period (through 28 days 
post estimated date of delivery [EDD]) for retosiban compared with atosiban 
• 
To describe the maternal, fetal, and neonatal safety profile during and after 
intravenous (IV) retosiban treatment compared with atosiban treatment 


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• 
To determine the effect of retosiban treatment compared with atosiban on health care 
resource use and patient-reported outcomes associated with the maternal and 
neonatal hospitalization 
• 
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 
The following are the exploratory objectives: 
 
• 
To examine the relationship between the baseline fetal fibronectin value, cervical 
length, and other biomarkers and the response to any study treatment 
• 
To examine the relationship between subclinical intrauterine infection and response 
to any study treatment 
• 
To investigate the relationship between genetic variants in the mother and/or fetus 
either with the development or progression of preterm labor or other medically 
related conditions or with treatment response to any study treatment and concomitant 
medications, if indicated 
Study Design 
ZINN is a Phase III, randomized, double-blind, double-dummy, multicenter study. 
Approximately 330 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, will be randomly assigned to retosiban or atosiban in a 1:1 ratio. 
 
• 
Test Treatment: Retosiban 
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 subjects with an 
inadequate response any time after the first hour of treatment, investigators should 
increase the dose by another 6-mg IV loading dose and increase the infusion rate to 
12 mg/hour for the remainder of the 48-hour treatment period (for details see Table 
3). 
• 
Active Control: Atosiban 
Atosiban will be administered in 3 successive stages: an initial bolus dose (6.75 mg) 
over 1 minute, immediately followed by a continuous infusion at 18 mg/hour for 
3 hours, followed by a 6-mg/hour infusion for the remainder of the 48-hour treatment 
period (for details see Table 4). 
For undelivered subjects who are subsequently diagnosed with recurrent preterm labor 
following the Inpatient Randomized Treatment Phase, retreatment with blinded 
investigational product (IP) is permitted. Retreatment is limited to a single repeat course 
of the blinded IP to which the subject was originally randomly assigned, either retosiban 
or atosiban. Retreatment is only permitted if the subject presents prior to 336/7 weeks’ 
gestation and meets the criteria specified in the Time and Events Table. 
 
ZINN will consist of 6 phases: Screening, Inpatient Randomized Treatment, 
Post-Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal 


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Medical Review (see schematic). The duration of any 1 subject’s (maternal or neonatal) 
participation in the study will be variable and dependent on GA at study entry and the 
date of delivery. 
 
 
 
1. 
Stratification (1:1) to retosiban or atosiban 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. 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion assessment 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 atosiban) is allowed. 
 
 
Prior to randomization, each subject will be stratified by progesterone treatment and GA 
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 prior to 240/7 weeks’ gestation. 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. 
The Screening Phase will occur on Day 0 and assessments will primarily focus on 
maternal and fetal safety evaluations prior to dosing. 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 managed per the investigator’s judgment. 


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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 assessment visit for obstetric assessments 1 week (acceptable range: 3 to 
14 days) following the Inpatient Randomized Treatment Phase (Note: study documents 
may reference this visit as the 1-week face-to-face post-infusion assessment visit). The 
subject will then be contacted every week via telephone to determine if birth has 
occurred. If the subject delivers the baby prior to the face-to-face post-infusion 
assessment visit, central laboratory assessments for hematology, chemistry, and liver 
function tests (see Table 5) and the assessments for the Delivery Phase (see Section 3.1.4) 
will be performed. 
 
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. During the Maternal Post-Delivery Assessment Phase, the subject will be 
contacted by telephone within 6 weeks of delivery for a post-delivery assessment. 
 
During the Neonatal Medical Review Phase, the neonatologist subinvestigator will 
conduct a comprehensive review of the newborn’s medical records, including any 
admission to an intensive or specialized care unit and any hospital readmission or 
outpatient surgery, from delivery through 28 days EDD, where EDD is defined as 
400/7 weeks’ gestation for all subjects. 
The subject or other legal guardian for the infant will also be asked to consent to 
participate in a separate 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 
face-to-face post-infusion assessment visit. 
 
An interim analysis will occur after approximately 130 subjects have completed delivery 
and have time-to-delivery results available. At the interim analysis, all available safety 
and efficacy data will be reviewed by an unblinded independent data monitoring 
committee who may make recommendations to terminate the study. 
 
Study Endpoints/Assessments 
The primary efficacy endpoint is time to delivery from the start of IP administration until 
delivery, based on a records review. 
 
The following are the key secondary efficacy endpoints: 
 
• 
Proportion of births prior to 370/7 weeks’ gestation 


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• 
Proportion of births at term (370/7 to 416/7 weeks’ gestation) 
• 
Length of neonatal hospital stay 
• 
Proportion of neonates with any diagnosis from the neonatal morbidity and mortality 
composite determined up to 28 days after EDD (of 400/7 weeks) (details for each 
composite are provided in Section 6.2.4) 
• 
Fetal or neonatal death 
• 
Respiratory distress syndrome (RDS) 
• 
Bronchopulmonary dysplasia 
• 
Necrotizing enterocolitis or isolated perforation 
• 
Sepsis 
• 
Meningitis 
• 
Retinopathy of prematurity 
• 
Intraventricular hemorrhage (IVH) 
• 
White matter injury 
• 
Cerebellar hemorrhage 
• 
Retosiban clearance and volume of distribution and the effect of covariates on these 
parameters 
The following are other secondary efficacy endpoints: 
 
• 
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 
• 
Neonatal admission to a specialized care unit and length of stay 
• 
Newborn hospital readmission and length of stay 
• 
Ambulatory surgery 
• 
Proportion of births prior to 280/7 weeks’ gestation 
• 
Proportion of births prior to 320/7 weeks’ gestation 
• 
Proportion of births ≤7 days 
• 
Proportion of births ≤48 hours 
• 
Proportion of births ≤24 hours 
The following are the safety endpoints (maternal, fetal, and neonatal, as appropriate): 
 
• 
Incidence of reported AEs and serious AEs 
• 
Significant changes in vital signs and clinical laboratory tests 


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• 
Incidence of treatment-limiting toxicities including both clinical and laboratory 
etiology causing subject to discontinue study treatment 
• 
Edinburgh Postnatal Depression Scale 
• 
Fetal acidosis 
• 
Neonatal Apgar scores (at 1 and 5 minutes after birth), growth parameters (weight, 
length, and head circumference) at birth and at discharge, and documentation of any 
complications 
• 
AEs of special interest 
• 
Maternal 
o Death 
o Chorioamnionitis and its complications 
o Placental abruption 
o Postpartum hemorrhage and/or retained placenta 
o Pulmonary edema 
• 
Fetal 
o Intrauterine fetal demise 
o Category II or III fetal heart rate tracing (defined according to American 
College of Obstetricians and Gynecologists Practice Bulletin 106 
[ACOG, 2009]) 
o Fetal inflammatory response syndrome 
• 
Neonatal 
o Neonatal death 
o Asphyxia 
o Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis) 
o RDS 
o Hypotension 
o Intraventricular hemorrhage/periventricular leukomalacia with cysts or 
porencephaly 
o Bronchopulmonary dysplasia 
o Neonatal acidosis 
o Hyperbilirubinemia 
o Necrotizing enterocolitis (any modified Bell’s staging criteria) 
o Hypoxic ischemic encephalopathy 


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1. 
INTRODUCTION 
1.1. 
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]. 
 
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, 2011; ACOG, 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, 2010; ACOG, 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. Retosiban is under development as a 
solution for intravenous (IV) infusion for the treatment of spontaneous preterm labor in 
women with intact membranes. This study is being conducted to demonstrate the 
superiority of retosiban in prolonging pregnancy compared with atosiban, a mixed 
oxytocin and vasopressin antagonist that is a European Medicines Agency 
(EMA)-approved treatment of preterm labor in all member states of the European Union. 


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1.2. 
Rationale 
This study is being conducted based on the results of the OTA10256 study that 
demonstrated significantly longer time to delivery. Specifically, OTA105256 was a 
Phase II study of retosiban for the treatment of spontaneous preterm labor in women with 
singleton pregnancies and intact membranes. This study initially examined the 
pharmacokinetics, dose response, and safety of retosiban in women for whom the 
gestational age (GA) was restricted to 340/7 and 356/7 weeks. Retosiban was given 
intravenously with the loading dose and infusion rate increased in a stepwise fashion 
every 3 hours to achieve target plasma concentrations. Alternate tocolytic drugs were not 
permitted during the study’s IV infusion phase. Twenty-nine adult subjects (ages 18 to 
37 years) were enrolled into Parts A and B. An interim analysis, indicating retosiban 
suppressed contractions and prolonged pregnancy, resulted in an additional cohort (Part C 
with a lowered GA to 300/7 weeks) to evaluate retosiban in a clinical population and 
setting more consistent with current practice guidelines for tocolytic use. Sixty-four adult 
subjects (ages 18 to 41 years) were enrolled, randomly assigned to treatment, and dosed 
in Part C. 
 
Data from Study OTA105256 found that retosiban treatment, at a dosing regimen of 
6-mg load over 5 minutes, then 6 to 12 mg/hour based on response, was associated with a 
higher proportion of females achieving uterine quiescence and a significant difference in 
time to delivery and reduction in preterm births. Uterine quiescence was defined as 4 or 
fewer contractions per hour with no change in cervical dilation greater than 1 cm. Using 
partial informative priors, which partially weighted the Part A/B response rates for 
retosiban and placebo, the posterior mean response rate within the initial 6 hours of 
treatment was 62% in the retosiban group compared with 41% in the placebo group. The 
posterior relative risk of achieving quiescence was 1.53 (95% confidence interval [CI]: 
0.98, 2.48). 
 
Retosiban treatment was also associated with a significant difference in time to delivery 
and births prior to 37 weeks of gestation. The posterior mean difference in time to 
delivery was 8.2 days relative to placebo (95% CI: 2.7, 13.74). The percent of preterm 
births in the retosiban and placebo groups was 18.7% and 47.2%, respectively. The 
posterior relative risk for preterm birth in the retosiban group was 0.38 (95% CI: 0.15, 
0.81). 
 
A comparison of the retosiban and placebo treatment groups for the difference in time to 
delivery is shown in Figure 1. 


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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 consistent with either those 
reported in the investigator’s brochure (IB) or in the population under study. A summary 
of the complete results for Study OTA105256 is included in the IB [GlaxoSmithKline 
Document Number CM2006/00201/05]. 
 
No placebo-controlled tocolytic studies have demonstrated an effect of this magnitude in 
spontaneous preterm labor. There is general agreement 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. This study (ZINN) is 
designed to test this hypothesis through a direct comparison with atosiban, a mixed 
oxytocin vasopressin antagonist indicated for short-term use to delay imminent preterm 
birth in women between 240/7 and 336/7 weeks’ gestation in preterm labor. 
1.3. 
Benefit:Risk Assessment 
Summaries of findings from both clinical and nonclinical studies conducted with 
GSK221149 can be found in the IB [GlaxoSmithKline Document Number 
CM2006/00201/05]. Table 1 and Table 2 outline the risk assessment and mitigation 
strategy for this protocol. 


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1.3.1. 
Risk Assessment 
 
Table 1 
Potential Risks of Clinical Significance 
 
Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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 postpartum hemorrhage (within 24 hours 
of delivery) is estimated to be between 4% to 6% of mothers who 
delivered [ACOG, 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 postpartum hemorrhage are AEs of special 
interest requiring the collection/assessment of risk factors for 
postpartum hemorrhage, eCRFs for any event of postpartum 
hemorrhage, and clinical parameters related to postpartum 
hemorrhage. 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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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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 this 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 on 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 are 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 have 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 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 5.1.1.1 and the IB). Retosiban will only be given for 
48 hours, limiting both maternal and fetal exposure. 


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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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 inducers concomitantly with IP 
requires an adjustment to the retosiban dosing regimen (see 
Section 5.1.1.1 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; CYP3A4 = cytochrome P450 3A4 enzyme; eCRF = electronic case report form; IB = investigator’s brochure; IP = investigational product; IDMC = independent 
data monitoring committee; P-gp = P-glycoprotein. 


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Table 2 
Potential Safety Concerns 
 
Potential Safety Concerns 
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. 
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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1.3.2. 
Benefit Assessment 
 
200721 
 
An estimated 14.9 million babies were born prematurely in 2010, representing 11% of all 
live births worldwide [Blencowe, 2012]. Preterm birth rates ranged from about 5% in 
several European countries to 18% in some African countries. Babies born prematurely 
are at risk for death, short-term medical complications, long-term disabilities, and 
developmental problems; these risks are inversely related to GA. Although babies born 
before 32 weeks have the greatest risk for death and poor health outcomes [Saigal, 2008; 
Lundqvist, 2009; Mathews, 2010], late preterm infants (defined as 340/7 to 366/7 weeks) 
are now known to carry a higher risk of morbidity and mortality than term infants 
[Engle, 2007]. Approximately 40% to 45% of preterm births are preceded by spontaneous 
preterm labor; the remainder is associated with PPROM and clinical indications for 
delivery [Romero, 2000; Goldenberg, 2008]. 
 
Treatment of spontaneous preterm labor is aimed at improving outcomes for the child and 
should be considered in women for whom a delay in delivery will provide benefit to the 
newborn. Tocolytic therapy is currently recommended for short-term delay of delivery in 
order to administer antenatal corticosteroids, which reduce the risks for neonatal 
mortality and morbidity, and transfer the mother to a neonatal specialized care unit. 
However, there is no evidence that current tocolytic regimens improve neonatal or infant 
outcomes beyond the effect of antenatal corticosteroids [RCOG, 2011; ACOG, 2012; 
Roos, 2013]. 
 
Given the inverse relationship between the risks for prematurity complications and GA at 
birth, the development of a treatment that significantly prolongs pregnancy in subjects 
with preterm labor would be invaluable if associated with improved perinatal outcomes. 
Results from the Phase II study OTA105256 offer hope that retosiban may prolong 
pregnancy to such a degree that perinatal outcomes could be favorably affected. 
 
Retosiban is highly selective for the oxytocin receptor. Significant toxicity to major 
end-organ systems has not been detected in preclinical or clinical testing to date. These 
findings indicate the risk for adverse effects related to off-target receptor binding is low. 
Maternal and fetal exposure will be limited to 48 hours, and exposure occurs after fetal 
organogenesis is complete. 
 
The active control in the study, atosiban, is a mixed oxytocin and vasopressin antagonist 
that is an EMA-approved drug marketed in the European Union since 2000. Atosiban is 
indicated to delay imminent preterm birth in pregnant adult women. No benefit to the 
neonate has been demonstrated in clinical trials using atosiban [Tractocile SmPC, 2013]. 
Subjects randomly assigned to this treatment group, therefore, will have the opportunity 
for a treatment benefit that will prolong pregnancy sufficiently to allow for antenatal 
corticosteroid treatment. The label indicates adverse reactions are generally mild, with 
nausea as the most commonly reported adverse maternal effect. Moreover, clinical trials 
did not reveal any specific adverse neonatal effects and long-term effects in the infant 
were in the range of normal variation and comparable with both placebo and β-agonists’ 
rates. 


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1.3.3. 
Overall Benefit:Risk Conclusion 
 
Despite the proven benefit of antenatal corticosteroids, neonatal mortality and morbidity 
remain disproportionately high in the study population. The Phase II program found that 
retosiban treatment significantly increased the time to delivery and reduced preterm 
births. These findings suggest the potential for retosiban to provide additional benefit by 
allowing for continued maturation of fetal organs and systems. 
 
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with retosiban and atosiban are justified 
by the anticipated benefits that may be afforded to subjects with preterm labor. 
 
The overall benefit:risk assessment of retosiban appears favorable 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 [GlaxoSmithKline Document Number CM2006/00201/05]. 
 
2. 
OBJECTIVES 
2.1. 
Primary Objective 
• 
To demonstrate the superiority of retosiban to prolong pregnancy compared with 
atosiban 
2.2. 
Secondary Objectives 
• 
To describe the outcomes of newborns during the neonatal period (through 28 days 
post estimated date of delivery [EDD]) for retosiban compared with atosiban 
• 
To describe the maternal, fetal, and neonatal safety profile during and after IV 
retosiban treatment compared with atosiban treatment 
• 
To determine the effect of retosiban treatment compared with atosiban on health care 
resource use and patient-reported outcomes associated with the maternal and 
neonatal hospitalization 
• 
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 
2.3. 
Exploratory Objectives 
• 
To examine the relationship between the baseline fetal fibronectin (fFN) value, 
cervical length, and other biomarkers and the response to any study treatment 
• 
To examine the relationship between subclinical intrauterine infection and response 
to any study treatment 


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• 
To investigate the relationship between genetic variants in the mother and/or fetus 
either with the development or progression of preterm labor or other medically 
related conditions or with treatment response to any study treatment and concomitant 
medications, if indicated 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
ZINN is a Phase III, randomized, double-blind, double-dummy, multicenter study. This 
study will be conducted in approximately 330 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 
1:1 to receive either retosiban IV infusion over 48 hours or atosiban IV infusion over 
48 hours. 
 
Each investigational site will have an obstetrician with expertise in maternal-fetal 
medicine as the principal investigator who will be responsible for treatment, care, and 
review of data for the mother during the 6 phases of the study and a neonatologist as a 
subinvestigator who will review the newborn hospital records to track and record the 
neonatal information, as required by the study protocol. The specific responsibilities of 
the obstetrician investigator and the neonatologist subinvestigator are outlined in the 
Study Procedures Manual (SPM). 
 
Prior to randomization, each subject will be stratified by progesterone treatment and GA 
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 prior to 240/7 weeks’ gestation. 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. 
ZINN will consist of 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 atosiban 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. 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion assessment 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 atosiban) is allowed. 
 
 
The Screening Phase will occur on Day 0 and assessments and will primarily focus on 
maternal and fetal safety evaluations prior to dosing. 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 managed per the investigator’s judgment. Subjects who 
remain undelivered after 48 hours will be scheduled for a face-to-face post-infusion 
assessment visit for obstetric assessments 1 week (acceptable range: 3 to 14 days) 
following the Inpatient Randomized Treatment Phase (Note: study documents may 
reference this visit as the 1-week face-to-face post-infusion assessment visit). The subject 
will then be contacted every week via telephone to determine if birth has occurred. If the 
subject delivers the baby prior to the face-to-face post-infusion assessment visit, central 
laboratory assessments for hematology, chemistry, and liver function tests (see Table 5) 
and the assessments for the Delivery Phase (see Section 3.1.4) will be performed. 
 
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 


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obstetrician. For those subjects who deliver at the investigative center, a placental tissue 
sample will be obtained at the time of delivery for central histopathology examination 
and a cord blood sample will be collected for potential genetic research and biomarker 
assays. If delivery occurs within 12 hours of investigational product (IP) (retosiban or 
atosiban) completion or discontinuation, the cord blood sample will also be used for the 
pharmacokinetic (PK) assessment, and, if required, a corresponding maternal blood 
sample will be collected for PK analysis (see Section 6.5.1). 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. A maternal post-delivery assessment will be conducted by telephone 
within 6 weeks of delivery. 
 
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) and the EQ-5D-5L (-2 weeks/+6 weeks). 
 
During the Neonatal Medical Review Phase, the neonatologist subinvestigator will 
conduct a comprehensive review of the newborn’s medical records, including any 
admission to an intensive or specialized care unit and any hospital readmission or 
outpatient surgery, from delivery through 28 days EDD, where EDD is defined as 
400/7 weeks’ gestation for all subjects. 
The subject or other legal guardian for the infant will also be asked to consent to 
participate in a separate 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 
face-to-face post-infusion assessment visit. 
 
An interim analysis will occur after approximately 130 subjects have completed delivery 
and have time-to-delivery results available. At the interim analysis, all available safety 
and efficacy data will be reviewed by an unblinded independent data monitoring 
committee (IDMC) who may make recommendations to terminate the study (see 
Section 9.8). Details of the interim analysis are provided in Section 8.3.4. Subjects will 
continue to be enrolled while the interim analysis is being conducted. 
 
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 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 (for details see Table 3). Investigators will be required to 
indicate in the electronic case report form (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 


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response. The duration of the treatment should not exceed 48 hours and the total dose 
should not exceed 582 mg. 
 
Atosiban will be given intravenously in 3 successive stages: an initial bolus dose of 
6.75 mg using atosiban 6.75-mg/0.9-mL solution for injection, immediately followed by 
a continuous high-dose infusion at 18 mg/hour for 3 hours, then a lower 6-mg/hour 
infusion for the remainder of the 48-hour treatment period using the atosiban 
37.5 mg/5-mL concentrate for solution. The duration of the treatment should not exceed 
48 hours and the total dose should not exceed 330 mg. 
 
A single repeat episode of IP treatment may be used if a subject experiences another 
episode of preterm labor 24 hours or more following completion of the Inpatient 
Randomized Treatment Phase, as long as the subject still meets all eligibility criteria (see 
Section 3.1.3.1). 
 
Antenatal corticosteroid treatment should be administered in accordance with national, 
society, or institutional guidelines. Investigators should also follow national, society, or 
institutional guidelines for the use of magnesium sulfate for fetal neuroprotection. 
Antibiotic treatment for group B streptococcal infections (GBS) is allowed per 
institutional guidelines. 
 
Randomized treatment can be discontinued as outlined in Section 4.4.2. Subjects 
discontinuing randomized treatment will be managed according to the standard care and 
asked to remain on study through the Maternal Post-Delivery Assessment Phase. These 
subjects will also be asked to consent to the infant follow-up study. 
 
Retosiban will not be available for compassionate use and will only be available as 
randomized treatment in this study. 
 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM will provide the site staff with 
administrative and detailed technical information that does not impact subject safety. 
 
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 (Table 5), are essential and required for study 
conduct. 
 
3.1.1. 
Screening Phase 
 
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 sign measurements, cervical examination, medical and obstetric 
history, estimated GA). However, 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 the consent having 
been signed. 


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Institutions that routinely perform 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 (see Section 6.7). Likewise, institutions that routinely measure cervical length by 
transvaginal ultrasound should record the result in the eCRF. Cervical length data will not 
be used to determine subject eligibility but will be used in an exploratory analysis (see 
Section 6.6). 
 
The GA will be 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 prior to 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. 
 
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. The screening assessments must include a formal review of 
medical and obstetric history and a review of all eligibility requirements for the study. 
Cardiovascular medical history/risk factors will also be assessed. Concomitant 
medications will be reviewed and the investigator will attempt to obtain a complete 
history of any medications taken during the pregnancy (including trimester of exposure if 
possible). Monitoring for both maternal and fetal AEs will begin. 
 
Additional screening assessments are described in Table 5. 
 
Eligible subjects will be randomly assigned to treatment (see Section 5.3). At 
randomization, the fetus will be issued a separate subject number for tracking of efficacy 
and safety assessments. 
 
3.1.2. 
Inpatient Randomized Treatment Phase 
 
3.1.2.1. 
Before Treatment 
 
Prior to dosing, the investigators must confirm the fetal heart rate pattern remains 
reassuring, that, according to medical discretion, tocolytic therapy is still indicated, and 
the electrocardiogram (ECG) does not have clinically significant abnormalities (see 
Section 6.1). 
 
3.1.2.2. 
During Treatment 
Assessments performed during the treatment period are described in Table 5. 
Antenatal corticosteroid treatment should be administered in accordance with national, 
society, or institutional guidelines. Investigators should also follow national, society, or 
institutional guidelines for the use of magnesium sulfate for fetal neuroprotection. 
Antibiotic treatment for GBS infections is also allowed per institutional guidelines. 
 
Progesterone may be continued for subjects already on established progesterone therapy 


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but should not be initiated in a subject after she has been enrolled in the study. 
 
3.1.2.3. 
End of Treatment 
 
An end-of-treatment examination will be conducted after the subject has completed the 
infusion and before she is released from the acute care setting (either to a nonacute care 
setting or to home). 
 
The subject or other legal guardian for the infant (both delivered and undelivered) will be 
asked to consent to participate in a separate long-term infant follow-up study for safety 
and neurodevelopment, if not already obtained. 
 
The study site staff will schedule the face-to-face post-infusion assessment visit for 
obstetric assessments 1 week (acceptable range: 3 to 14 days) after the end of treatment 
(see Section 3.1.3). 
 
If the subject delivers the baby prior to the face-to-face post-infusion assessment visit, 
central laboratory assessments for hematology, chemistry, and liver function tests (see 
Table 5) and the assessments in Section 3.1.4 will be performed. 
 
3.1.3. 
Post-Infusion Assessment Phase 
 
Subjects who remain undelivered after 48 hours will be scheduled for a face-to-face 
post-infusion assessment 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. See Section 3.1.2.3 for details on 
required assessments when the baby is delivered before the face-to-face post-infusion 
assessment visit. 
 
The subject will then be contacted every week via telephone to determine if she has 
delivered (see Section 3.1.4 for a summary of assessments performed at delivery). Note: 
This assessment should be completed remotely (by telephone); however, 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 a telephone assessment is due, this assessment may be completed 
face-to-face. 
 
3.1.3.1. 
Retreatment 
 
For undelivered subjects who are subsequently diagnosed with recurrent preterm labor 
24 hours or more following completion of the Inpatient Randomized Treatment Phase, 
retreatment with blinded IP is permitted at the discretion of the investigator. Retreatment 
is limited to a single repeat course of the blinded IP to which the subject was originally 
randomly assigned, either retosiban or atosiban. Retreatment is only permitted if the 
subject experiences a spontaneous preterm labor recurrence before 336/7 weeks’ gestation 
and meets the criteria specified in the Time and Events Table (Table 5). Atosiban 
retreatment guidelines are provided in the summary of product characteristics (SmPC) 
[Tractocile SmPC, 2013]. 


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The requirement for a repeat course of antenatal corticosteroid therapy should be 
determined in accordance with national, society, or institutional guidelines (e.g., [RCOG, 
2010; ACOG, 2011]). Investigators should also follow national, society, or institutional 
guidelines for the use of magnesium sulfate for fetal neuroprotection. Antibiotic 
treatment for GBS is also allowed per institutional guidelines. 
 
3.1.4. 
Delivery Phase 
 
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. These procedures include identification at conclusion of 
Inpatient Randomized Treatment Phase of the intended delivery caregiver, ensuring the 
delivery caregiver or neonatal intensive care unit (NICU) staff understand the 
information needed for the study, those events that require rapid communication to 
clinical investigators, and a process that ensures clinical investigators can contact the 
appropriate personnel in case of follow-up questions. 
 
For subjects who deliver at the investigative center, a placental tissue sample will be 
obtained at the time of delivery for central histopathologic examination and a cord blood 
sample will be collected for potential genetic research and biomarker assays. If delivery 
occurs within 12 hours of IP completion or discontinuation, the cord blood sample will 
also be used for the PK assessment (see SPM for information about how these samples 
will be collected), and, if required, a corresponding maternal blood sample will be 
collected for PK analysis (see Section 6.5.1). In addition, 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 (see 
Section 6.5.3). 
 
The following information regarding the delivery and hospitalization for mother and 
newborn will be obtained through a review of the hospital records: 
 
• 
Date and time of delivery 
• 
Mode of delivery 
• 
Indication for delivery 
• 
Concomitant medications 
• 
Maternal AEs and serious AEs (SAEs) (including AEs of special interest; 
Section 6.3.2.3) 
• 
Maternal health care resource use 
The newborn medical records will also be reviewed in order to record the following: 
 
• 
Variables relevant to the composite 
• 
Apgar scores at 1 and 5 minutes 
• 
Length, weight, and head circumference 
• 
Blood gases (when available) 


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• 
Hospital length of stay 
• 
Neonatal health care resource use 
• 
Neonatal AEs and SAEs; in particular, the review will focus on any complications 
requiring intensive or specialized care and information specific to complications of 
prematurity will be collected (see Section 6.3.2 and Section 6.3.7.2). 
 
3.1.5. 
Maternal Post-Delivery Assessment Phase 
 
The subject will be contacted via telephone for the Maternal Post-Delivery Assessment 
Phase to be conducted within 6 weeks following delivery. Maternal assessments 
conducted at this contact will include the following: 
 
• 
Review of concomitant medications and medical/obstetric history (±2 weeks) 
• 
Recording of AEs and SAEs (maternal) (±2 weeks) 
• 
Recording of AEs and SAEs of neonate if discharged from hospital and through 
28 days post EDD (±2 weeks) 
• 
Status of breastfeeding (±2 weeks) 
• 
Postnatal administration of the Edinburgh Postnatal Depression Scale (EPDS) and 
the EuroQol 5-dimensional 5-level (EQ-5D-5L) questionnaire (-2 weeks/+6 weeks) 
• 
Assessment of postpartum bleeding (±2 weeks) 
The subject or other legal guardian will be asked to provide consent for the infant 
(whether delivered or undelivered) to participate in a separate infant follow-up study for 
safety and neurodevelopment, if not already obtained. 
 
3.1.6. 
Neonatal Medical Record Review Phase 
 
Newborns will be followed in this study through 28 days post EDD as outlined in 
Table 5. 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. 
 
3.2. 
Discussion of Design 
3.2.1. 
Study Treatments 
 
3.2.1.1. 
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 treatment 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, investigators should administer another 6-mg loading dose and 


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increase the infusion rate to 12 mg/hour for the remainder of the 48-hour treatment period 
(for details see Table 3). 
 
The retosiban dosing regimen has been informed by animal studies defining retosiban 
concentrations for inhibition of myometrial contractions, evaluations of exposure, safety, 
and tolerability over a wide range of doses in healthy subjects, and forced titration studies 
in pregnant women. The retosiban regimen is designed to yield a mean steady-state 
concentration of 75 ng/mL. The option to double the dose after 1 hour allows for 
between-subject variability in retosiban pharmacokinetics, receptor density, and 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 the Phase III dosing regimen will 
likely yield steady-state concentrations in the range of 50 to 388 ng/mL 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 (see IB [GlaxoSmithKline Document Number 
CM2006/00201/05]). 
 
Retosiban is primarily metabolized by the cytochrome P450 (CYP) 3A4 enzyme 
(CYP3A4). Drug-drug interaction studies indicate retosiban exposure is increased 
approximately 9-fold during co-administration of the potent CYP3A4 inhibitor 
ketoconazole, whereas concomitant administration of the potent CYP3A4 inducer 
efavirenz decreased retosiban exposure 30%. As a result, the retosiban dosing regimen 
requires adjustment in subjects treated concomitantly with drugs that are potent CYP3A4 
inhibitors or CYP3A4 inducers in order to achieve therapeutic retosiban concentrations. 
Refer to Section 5.1.1 for a description of the adjustments to the retosiban loading dose 
and infusion rate during co-administration with potent CYP3A4 inhibitors or CYP3A4 
inducers. 
 
3.2.1.2. 
Active Control 
 
The active control in this study is atosiban, which is a mixed oxytocin/vasopressin 
antagonist approved in the European Union for short-term delay of imminent preterm 
birth in pregnant adult women in preterm labor. Atosiban was chosen as the active 
control because it represents a standard care tocolytic treatment aimed at delaying 
delivery in the targeted study population for at least 48 hours in order to complete 
antenatal corticosteroid treatment (using betamethasone or dexamethasone) and transfer 
of the mother to a specialized care unit [Di Renzo, 2006b; RCOG, 2011]. No current 
evidence indicates that atosiban provides neonatal benefit beyond that of antenatal 
corticosteroids; therefore, the superiority study design will allow for demonstrating the 


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superiority of retosiban compared with atosiban for prolonging pregnancy and improving 
neonatal outcomes. 
 
Atosiban will be administered to a study population and using a dosing regimen in 
accordance with the approved label. Atosiban is administered intravenously as a 6.75-mg 
bolus dose, followed by an 18-mg/hour continuous infusion for 3 hours, after which the 
continuous infusion rate is decreased to 6 mg/hour for the remainder of the 48-hour 
treatment period. The maximum atosiban dose is 330 mg, and the duration of the 
treatment should not exceed 48 hours [Tractocile SmPC, 2013]. 
 
Of note, the different infusion rates for retosiban and atosiban require a double-dummy 
technique in order to maintain blinding (see Section 5.4). 
 
3.2.1.3. 
Corticosteroids and Magnesium Sulfate 
 
Antenatal corticosteroids are associated with a significant reduction in rates for 
respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and neonatal 
death. As a result, practice guidelines recommend a single course of corticosteroids for 
all pregnant women between 24 and 34 weeks’ gestation who are at risk of preterm 
delivery within 7 days [Di Renzo, 2006a; RCOG, 2010; ACOG, 2012]. In this study, 
antenatal corticosteroid treatment should be administered in accordance with national, 
society, or institutional guidelines. 
 
Practice guidelines for the use of magnesium sulfate for fetal neuroprotection have been 
developed by the American College of Obstetricians and Gynecologists (ACOG) 
Committee on Obstetric Practice and Society for Maternal Fetal Medicine [ACOG, 
2010], the Antenatal Magnesium Sulphate for Neuroprotection Guideline Development 
Panel [Antenatal Magnesium Sulphate for Neuroprotection Guideline Development 
Panel, 2010], and the Society of Obstetricians and Gynaecologists of Canada [SOGC, 
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 should administer 
magnesium sulfate for fetal neuroprotection according to national, society, or institutional 
guidelines [ACOG, 2010; Antenatal Magnesium Sulphate for Neuroprotection Guideline 
Development Panel, 2010; SOGC, 2011]. 
 
3.2.2. 
Study Population 
 
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. Preterm birth rates range from approximately 5% in several European countries 
to 18% in some African countries. Birth prior to 34 weeks’ gestation represents roughly 
30% of preterm births in the United States, half of which are preceded by spontaneous 
labor [Tucker, 1991; Berkowitz, 1998; Meis, 1998; Goldenberg, 2008; Martin, 2012;]. 
Premature birth in this group carries a disproportionately high risk for death, neonatal 
complications, and long-term disabilities. The vulnerability of this group for poor infant 
outcomes forms the basis for treatment guidelines aimed at improving neonatal and infant 
outcomes. These include antenatal corticosteroids, short-term tocolysis to complete 
antenatal corticosteroid treatment, and magnesium sulfate for fetal neuroprotection. 


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Pregnant adolescents aged 12 to 17 years are included based on prior discussions with 
regulatory agencies, unless national or local regulations restrict the age for study 
enrollment to subjects 18 to 45 years (see Section 4.2). 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]. The safety and efficacy of atosiban in pregnant women aged less than 
18 years have not been established [Tractocile SmPC, 2013]. 
 
Clinical criteria for the diagnosis of preterm labor is generally based on the presence of 
either regular uterine contractions accompanied by a change in cervical dilation and/or 
effacement or initial presentation of regular contractions and cervical dilation of at least 
2 cm [ACOG, 2012]. Dilation criteria for published studies in a preterm labor population 
generally included contraction criteria and cervical dilation ranging from 0 to 4 cm. 
Based on discussions with maternal fetal medicine specialists, spontaneous preterm labor 
will be based on regular uterine contractions at a rate of ≥4 contractions of at least 
30 seconds duration during a 30-minute interval (confirmed by tocodynamometry) and at 
least one of the following: cervical dilation ≥2 cm and ≤4 cm by digital cervical 
examination or if <2 cm dilation by digital cervical examination, a cervical change 
consisting of an increase of at least 25% effacement or 1 cm dilation. 
 
Subject selection criteria were developed in consultation with maternal-fetal medicine 
specialists and are consistent with practice guidelines advising that tocolysis should not 
be used where there is a contraindication to prolonging pregnancy. These include 
pregnancies with known lethal congenital or chromosomal malformation, intrauterine 
infection, severe pre-eclampsia or eclampsia, placental abruption, advanced cervical 
dilation, and evidence of fetal compromise or placental insufficiency [RCOG, 2011; 
ACOG, 2012]. Women with comorbid medical or obstetric conditions that, in the opinion 
of the investigator, have the potential to complicate the pregnancy course and outcomes 
or predispose the subject to SAEs are also excluded from the study (see Section 4.3). 
 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects 
Approximately 330 women (165 per treatment group) will be randomly assigned to 
ensure that approximately 300 women/newborns have recorded birth data (assumes 10% 
missing data). 
 
4.2. 
Inclusion Criteria 
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK IP or other study treatment that may impact subject 
eligibility is provided in the IB [GlaxoSmithKline Document Number 
CM2006/00201/05], the package insert for atosiban [Tractocile SmPC, 2013], and other 
pertinent documents. 


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Deviations from inclusion 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. 
 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
 
1. 
Signed and dated written informed consent is required prior to a subject’s 
participation in Study 200721 (ZINN) 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: 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.) 
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 
prior to 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 
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: 


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• 
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 
• 
A 1-cm increase in cervical dilation by digital cervical examination 
5. 
Treatment-naïve subjects and subjects not adequately responding to tocolytics other 
than atosiban (e.g., transfers from other care units) during their current episode of 
preterm labor may be eligible for the study. Historical failure of a tocolytic treatment 
in a previous episode of preterm labor is not a required inclusion criterion. Tocolytic 
failure is defined by progressive cervical changes or continuing uterine contractions 
4.3. 
Exclusion Criteria 
Deviations from 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. 
 
Subjects meeting any of the following criteria must not be enrolled in the study: 
 
1. Fever with a temperature greater than 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 
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, 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 


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10. Women with documented active hepatitis B or hepatitis C viral infection, unstable 
liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, 
known biliary abnormalities (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones) 
11. History of sensitivity to the IPs or components thereof or a history of drug or other 
allergy that, in the opinion of the investigator or GSK/PPD medical monitor, 
contraindicates their participation. 
4.4. 
Withdrawal From Study and Discontinuation of IP 
The section describes and distinguishes the following: 
 
• 
Withdrawal of the subject from the study after randomization but before 
administration of IP (Section 4.4.1.1) and after administration of IP (Section 4.4.1.2) 
• 
Discontinuation of the IP (Section 4.4.2), 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. 
4.4.1. 
Withdrawal From Study 
 
4.4.1.1. 
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 ECG cannot be dosed and should 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. 
 
Dosing may be started before local liver function test results are available; however, if 
local laboratory results are available before the start of dosing and ALT is >2 × the upper 
limit of normal (ULN) or 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%. See 
Section 6.3.1 for liver stopping criteria for management of abnormal test results that 
become available after the start of dosing. 


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4.4.1.2. 
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 GSK/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: 
 
• 
Loss to follow-up 
• 
Subject voluntarily withdrew consent 
• 
Investigator decision to withdraw the subject from participation; investigators 
must consult the GSK/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 and 
before the Post-Infusion Assessment Phase will be asked to return and complete the 
assessments specified for the face-to-face post-infusion assessment visit before 
withdrawing from the study (see Section 3.1.3 and Table 5). If the subject withdraws 
after the face-to-face post-infusion assessment visit, the investigator will attempt to 
contact the subject by telephone to determine if she has delivered and to gather the 
information specified in Section 3.1.4. 
 
Withdrawal from this study after beginning randomized treatment does not preclude 
involvement in the separate infant follow-up study. 
 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also 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 based 
on previous noncompliance. 
 
In cases where the subject is deemed “Lost to Follow-up” (e.g., subject does not return 
for the rescheduled visit or cannot be reached to reschedule the missed visit), the 
investigator or designee should 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. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the 


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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. 
 
4.4.2. 
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 
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. 
An abnormal corrected QT interval using 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 
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 
6. 
Abnormal liver function test result detected during standard care of the subject based 
on the criteria detailed in Section 6.3.1. 
Subjects discontinuing the IP for any of the above reasons can and should continue to 
receive antenatal steroids (either betamethasone or dexamethasone) for fetal lung 
maturity if not yet completed and still clinically indicated. 


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Subjects discontinuing the IP who have not yet delivered will continue in the study 
through delivery and the maternal post-delivery assessment. 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. 
 
4.5. 
Subject and Study Completion 
A completed subject is defined as one who has completed all phases of the study (see 
Section 3.1 and Table 5). 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 4.4.2). 
 
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. 
 
5. 
STUDY TREATMENTS 
5.1. 
Investigational Product and Other Study Treatment 
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. The solution for infusion should be stored refrigerated at 2°C to 8°C 
(36°F to 46°F), protected from light. Each single-use 5-mL vial contains 75 mg retosiban 
as solution for infusion (see Table 3). The contents of the label will be in accordance with 
all applicable regulatory requirements. 
 
Under normal conditions of handling and administration, retosiban IP 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. Notify the monitor of any 
unintentional occupational exposure. A Material Safety Data Sheet describing the 
occupational hazards and recommended handling precautions will be provided to site 
staff if required by local laws or will otherwise be available from GSK upon request. 
 
At the clinical study site, the volume required to make up the dose is withdrawn from 1 or 
more drug product vials and aseptically transferred into a 0.9% sodium chloride (NaCl) 
infusion bag to get the required concentration. The final mixture is a clear, colorless to 
slightly colored solution. The infusion solution is chemically stable for up to 48 hours 
under ambient conditions. Chemical stability up to 48 hours has also been established for 
the reconstituted and diluted solution in contact with representative IV administration sets 
under ambient conditions. 
 
Atosiban (Tractocile, Ferring Pharmaceuticals) active comparator will be provided to the 
site. Atosiban is a marketed product that is a clear, colorless solution for infusion that 
contains atosiban at 6.75 mg/0.9 mL. Each single-use, 5-mL vial contains 37.5 mg of 
atosiban. The solution for infusion should be stored at 2°C to 8°C (36°F to 46°F), 
protected from light. Information on atosiban, including list of excipients, can be found in 
the product package inserts found in the summary of characteristics [Tractocile SmPC, 


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2013]. At the clinical study site, the volume required to make up the dose is withdrawn 
from 1 or several drug product vials and aseptically transferred into a 0.9% NaCl infusion 
bag to get the required concentration. The final mixture is a clear, colorless to slightly 
colored solution. The infusion solution is chemically stable for up to 24 hours under 
ambient conditions. 
 
Because the IV dosing instructions for retosiban and atosiban differ, a double-dummy 
technique will be used to ensure blinding. For subjects randomized to retosiban, an 
unblinded pharmacist or other qualified individual will prepare the retosiban IV solution 
and a placebo infusion matched for the atosiban loading (bolus) dose and continuous 
infusion. Likewise, subjects randomized to atosiban will receive the atosiban loading 
(bolus) dose and continuous infusion and a placebo infusion matched for retosiban IV 
administration (see Table 3; detailed instructions are provided in the Study Pharmacy 
Manual). 
 
Atosiban solution for injection will be supplied by the unblinded pharmacist or other 
qualified individual as a prefilled syringe, whereas a prefilled syringe with 0.9% NaCl 
solution will be used for the matched placebo. Normal saline (0.9% NaCl) solution will 
be used for preparing the retosiban or atosiban admixtures for continuous infusion (see 
Table 4). Normal saline (0.9% NaCl) solution will also be used as the placebo solution 
matched to the infusion rates for retosiban or atosiban (see Table 4; detailed instructions 
are provided in the Study Pharmacy Manual). The normal saline solutions will be 
provided by the investigative center. 
 
Details of the dose preparation are described in the Pharmacy Reference Manual. The 
infusion bags and syringes containing the solution for administration will be clearly 
labeled by site staff with the protocol number, subject number, infusion rate, and dosing 
session number. 
 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product. Access to and administration of the IP will be limited to the 
investigator and authorized site staff. Investigational product must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol. 
 
Table 3 and Table 4 summarize the retosiban and atosiban IP, respectively, and other 
study treatment. 


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Table 3 
Retosiban Investigational Product and Other Study Treatment 
 
Product Name 
Retosiban 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 
Preparation instructions 
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 protocol number, subject number, infusion rate, and 
dosing session number. Once the vial has been opened, the dilution must 
be performed immediately. Diluted solution for IV administration should be 
used within 24 hours after preparation. 
If an infusion bag with a different volume is used, a proportional 
calculation should be made for the preparation. 
See the Study Pharmacy Manual for detailed instructions. 
The placebo admixture will consist of a 0.9% NaCl infusion bag, labeled 
with the protocol number, subject number, infusion rate, and dosing 
session number. 
The volume of the 0.9% NaCl infusion bag should be matched to the 
0.9% NaCl infusion bag volume used for the retosiban admixture. 
See Study Pharmacy Manual for detailed instructions. 
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 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, investigators should administer another 6-mg loading dose by 
increasing the infusion rate to 240 mL/hour for 5 minutes, after which the 
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 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, 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. Investigators will be required to indicate 


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Product Name 
Retosiban Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
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. 
For subjects receiving concomitant treatment with a potent 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 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. 
A list of strong, moderate, and weak CYP3A4 inhibitors and inducers is 
provided in Appendix 3. See the Study Pharmacy Manual for detailed 
instructions. 
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. 
For subjects receiving concomitant treatment with a potent 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 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. 
A list of strong, moderate, and weak CYP3A4 inhibitors and inducers is 
provided in Appendix 3. See Study Pharmacy Manual for detailed 
instructions. 
Manufacturer / 
Source of procurement 
GSK 
Not applicable – to be sourced locally 
CYP3A4 = cytochrome P450 3A4 enzyme; eCRF = electronic case report form; IV = intravenous; GSK = GlaxoSmithKline; NaCl = sodium chloride; PTM = placebo to match. 


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Table 4 
Atosiban Investigational Product and Other Study Treatment 
 
Product Name 
Atosiban Solution for Injection and Atosiban Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
Drug product description 
Clear, colorless solution for injection in a 0.9-mL vial containing 6.75 mg 
of atosiban 
Clear, colorless concentrate for solution for infusion in a 5-mL vial 
containing 37.5 mg atosiban 
A placebo-matched 0.9-mL vial is not provided. 
A placebo-matched 5-mL vial is not provided. 
Unit dose strengths / 
Dosage levels 
Atosiban 6.75 mg/0.9 mL (solution for injection) 
Atosiban 7.5 mg/mL (concentrate solution for infusion) 
The total dose given over 48 hours should not exceed 330 mg. 
0.9% NaCl for injection matched for the atosiban loading dose and 
continuous infusion rates 
Route of administration 
IV 
IV 
Preparation instructions 
Withdraw 0.9 mL of a 0.9-mL labeled vial of atosiban 6.75 mg/0.9 mL 
solution for injection into a syringe. Label the syringe with the protocol 
number, subject number, infusion rate, and dosing session number. 
Withdraw 25-mL solution from a 250-mL 0.9% NaCl infusion bag and 
discard the solution. Replace the solution with 25 mL of atosiban 
7.5-mg/mL concentrate solution for infusion from five 5-mL vials to obtain 
a concentration of 0.75 mg/mL (187.5 mg atosiban in 250 mL 0.9% NaCl). 
The reconstituted product is a clear, colorless solution without particles. 
Label the IV bag with protocol number, subject number, infusion rate, and 
dosing session number. 
Prepare new 250-mL bags in the same manner as described to allow the 
infusion to be continued. If an infusion bag with a different volume is 
used, a proportional calculation should be made for the preparation. 
Once the vial has been opened, the dilution must be performed 
immediately. Diluted solution for IV administration should be used within 
24 hours after preparation. 
See the Study Pharmacy Manual for detailed instructions. 
Withdraw 0.9 mL of 0.9% NaCl solution for injection into a syringe. Label 
the syringe with the protocol number, subject number, infusion rate, and 
dosing session number. 
The placebo admixture for continuous infusion will consist of a 0.9% NaCl 
infusion bag, labeled with the protocol number, subject number, infusion 
rate, and dosing session number. 
The volume of the 0.9% NaCl infusion bag should be matched to the 
0.9% NaCl infusion bag volume used for the atosiban admixture. 
See Study Pharmacy Manual for detailed instructions 


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Product Name 
Atosiban Solution for Injection and Atosiban Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
Dosing instructions 
Atosiban is administered in 3 successive stages. 
Administer an initial bolus dose of 6.75 mg slowly over 1 minute using the 
6.75-mg/0.9 mL solution for injection syringe. 
After the bolus dose, administer atosiban at a continuous infusion rate of 
24 mL/hour (18 mg/hour) for 3 hours. 
After 3 hours, the infusion rate is reduced to 8 mL/hour (6 mg/hour) for 
the remainder of the 48-hour treatment period. 
See the Study Pharmacy Manual for detailed instructions. 
The matched placebo is administered in 3 successive stages. 
Using a prefilled syringe, administer 0.9 mL of 0.9% NaCl slowly over 1 
minute. 
After the bolus dose, administer 0.9% NaCl at a continuous infusion rate 
of 24 mL/hour for 3 hours. 
After 3 hours, the infusion rate is reduced to 8 mL/hour for the remainder 
of the 48-hour treatment period. 
See Study Pharmacy Manual for detailed instructions. 
Manufacturer / 
Source of procurement 
To be sourced locally 
Not applicable – to be sourced locally 
IV = intravenous; NaCl = sodium chloride; PTM = placebo to match. 


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5.1.1. 
Concurrent Administration of Investigational Product With 
Strong CYP3A4 Inhibitors or Strong CYP3A4 Inducers 
 
5.1.1.1. 
Retosiban 
 
Retosiban undergoes oxidative metabolism, primarily mediated by CYP3A4 (see 
Section 3.2.1.1). 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 AUC, in the presence of 
ketoconazole, a strong CYP3A4 inhibitor. 
 
To achieve exposures comparable 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 5.8.1.5). Using a 500-mL 
retosiban admixture with a 0.3-mg/mL concentration, the retosiban 3-mg loading dose 
will be administered at an infusion rate of 120 mL/hour for 5 minutes. After 5 minutes, 
the infusion rate will be reduced to 6.7 mL/hour to deliver retosiban at a rate of 
2 mg/hour. If a dose increase is needed due to lack of response, an additional loading 
dose of 1 mg over 5 minutes followed by an increase to 3 mg/hour for the remainder of 
the 48-hour treatment period is an acceptable dosing regimen to use in the presence of a 
strong CYP3A4 inhibitor. 
 
For subjects chronically taking a drug known to be a 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. If a dose increase 
is needed due to lack of response, an additional 3.5-mg loading dose over 5 minutes 
should be administered followed by an increase to 12 mg/hour for the remainder of the 
48-hour treatment period. 
 
A list of strong, moderate, and weak CYP3A4 inhibitors and inducers is provided in 
Appendix 3. 
 
5.1.1.2. 
Atosiban 
 
Atosiban is unlikely to involve CYP-mediated drug-drug interactions, as in vitro 
investigations have shown that atosiban is not a substrate for the CYP system and does 
not inhibit the drug metabolizing CYP enzymes [Tractocile SmPC, 2013]. 
 
5.2. 
Managing Dose Interruptions 
Temporary interruptions of the IP are permitted. The following procedures should be 
followed in the event of a retosiban 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. 


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• 
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. 
For atosiban dose interruptions, resume the infusion at the same rate that was used before 
the dose interruption. 
 
Any changes in the dose rate, corresponding start and stop times, and the reason for an 
interruption must be recorded in the eCRF. 
 
5.3. 
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 24 0/7 to 25 6/7, 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 atosiban using an interactive voice response system 
(IVRS)/interactive web response system (IWRS) in accordance with the randomization 
schedule. 
 
Retosiban and atosiban regimens are described in Table 3 and Table 4. The IP will be 
administered by study personnel during each dosing session. 
 
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. Infusion and dose administration 
information can be found in the SPM and Study Pharmacy Manual. 
 
5.4. 
Blinding 
The pharmacist or other qualified individual will be unblinded, and an unblinded clinical 
research associate will carry out drug 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 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 as part of a formal interim analysis 
and in accordance with the IDMC charter. Unblinded data will be provided by an 
independent statistical data analysis committee. 
 
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). 


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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. 
 
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 clinical investigators in accordance with 
local regulations and/or GSK policy. 
 
5.5. 
Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of IP 
dispensed and/or administered to study subjects, the amount returned by study subjects, 
and the amount received from and returned to GSK, when applicable. Product 
accountability records must be maintained throughout the course of the study. 
 
5.6. 
Treatment Compliance 
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. 
 
5.7. 
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). 
 
5.8. 
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. 


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5.8.1. 
Permitted Medications and Nondrug Therapies 
 
5.8.1.1. 
Antenatal Corticosteroids 
 
Antenatal corticosteroid treatment should be administered in accordance with national, 
society, or institutional guidelines. 
 
5.8.1.2. 
Magnesium Sulfate 
 
Magnesium sulfate for fetal neuroprotection is permitted at the investigator’s discretion 
according to national, society, or local guidelines and/or approved prescribing 
information. 
 
5.8.1.3. 
Progesterone 
 
Progesterone may be continued for subjects already on established progesterone therapy 
but should not be initiated in subjects after they have been enrolled in the study. 
 
5.8.1.4. 
Antibiotics 
 
Antibiotic treatment for GBS is allowed per institutional guidelines. 
 
5.8.1.5. 
Strong CYP3A4 Inhibitors 
 
Drugs that are strong CYP3A4 inhibitors and cannot be temporarily discontinued are 
permitted. Administration of strong CYP3A4 inhibitors concomitantly with IP requires 
an adjustment to the retosiban dosing regimen (see Section 5.1.1). A list of strong, 
moderate, and weak CYP3A4 inhibitors is provided in Appendix 3. 
 
5.8.1.6. 
Strong CYP3A4 Inducers 
 
Drugs that are strong CYP3A4 inducers and cannot be temporarily discontinued are 
permitted. Administration of strong CYP3A4 inducers concomitantly with IP requires an 
adjustment to the retosiban dosing regimen (see Section 5.1.1). A list of strong, moderate, 
and weak CYP3A4 inducers is provided in Appendix 3. 
 
5.8.1.7. 
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. No dose adjustment is required; concomitant use of 
retosiban with inhibitors of BCRP or P-gp will be assessed through AE monitoring. A list 
of BCRP and P-gp inhibitors is provided in the SPM. 
 
5.8.2. 
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 or 30 days after administration of the last dose of IP, 
whichever is longer. 


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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. 
 
5.9. 
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. 
 
Poststudy IP is not provided as part of this protocol. 
 
5.10. 
Treatment of Study Treatment Overdose 
Any signs or symptoms of retosiban overdosage will be treated symptomatically. No 
specific antidote is known. 
 
Few cases of atosiban overdosing have been reported, and these occurred without any 
specific signs or symptoms. There is no known specific treatment in case of an atosiban 
overdose [Tractocile SmPC, 2013]. 
 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
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 pregnancy history, and 
estimated GA). However, the subject will be required to provide 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. A schedule of Time and 
Events is provided in Table 5. 


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Table 5 
Time and Events Table 
 
Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Clinical and Other Assessments 
Written informed 
consent and 
medical releases for 
treatment4 
X 
Discuss and request 
consent for 
participation in the 
infant follow-up study5 
X5 
X 
X 
Inclusion/exclusion 
criteria confirmation 
X 
X 
Subject demography 
X 
Medical history 
(including obstetrics 
history)6 
X 
X 
X 
X 
Physical examination 
(including height and 
weight) 
X 
Cervical examination7 
X 
X 
X 
X 
X 
Estimated fetal weight 
and head 
circumference via 
ultrasound8 
X 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Determine AFI via 
ultrasound9 
X 
X 
Uterine contractions10 
X 
Schedule face-to-face 
post-infusion 
assessment visit 
X 
Investigational Products11 
Investigational product 
(retosiban or atosiban) 
X 
X 
X 
Efficacy Assessments 
Date and time of 
delivery 
X12 
Mode of delivery 
X12 
Indication for delivery 
X12 
Neonatal composite 
outcomes 
X 
Neonatal hospital stay 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Maternal Safety Assessments 
Concomitant 
medications 
X 
X 
X 
ECG 12-lead13 
X 
Vital sign 
measurements (BP, 
pulse rate, respiratory 
rate, and 
temperature)14 
X 
X 
X 
X 
X 
AEs, SAEs, and DREs: 
maternal 
X 
X 
X 
Breastfeeding status 
X 
Edinburgh Postnatal 
Depression Scale15 
(maternal) 
X 
Local laboratory 
assessments (LFTs 
only)16 
X 
X 
Central laboratory 
assessments 
(including hematology, 
chemistry, and LFTs)17 
X 
X 
X 
X17 
Physical examination 
(brief) 
X 
Status of postpartum 
bleeding 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Fetal Safety Assessments 
Electronic fetal 
monitoring 
X18 
X19 
X19 
X19 
X20 
X21 
AEs/SAEs: fetal 
X 
X 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: 
neonatal 
X 
X 
Neonatal Apgar Scores 
(1 and 5 minutes) 
X12 
Neonatal growth 
parameters 
X12 
Neonatal blood gases 
X12 
Health Outcome Assessments 
Maternal and neonatal 
health care resource 
use22 
X 
X 
EQ-5D-5L (maternal) 
X 
X3 
Pharmacokinetic Assessments 
Maternal PK blood 
sample23 
X23 
X23 
Cord blood sample24 
X 
Breast milk/colostrum 
sample25 
X 
Histopathology 
Placental tissue 
sample26 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Biomarker Assessments 
Genetic blood sample 
for maternal DNA27 
X 
Blood sample for 
maternal inflammation 
biomarker 
X 
Biomarker and genetic 
cord blood sample28 
X 
Other Assessments 
Fetal fibronectin 
(optional)29 
X 
X 
Cervical length via 
transvaginal ultrasound 
(optional)30 
X 
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; EPDS = Edinburgh Postnatal Depression Scale; EQ-5D-5L = EuroQol 5-dimensional 5-level questionnaire; IP = investigational 
product; LFT = liver function test; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of normal. 
1. 
For undelivered subjects who are subsequently diagnosed with recurrent preterm labor 24 hours or more following completion of the Inpatient Randomized Treatment Phase, 
retreatment with blinded IP is permitted at the discretion of the investigator (see Section 3.1.3.1). 
2. 
Subjects who remain undelivered after 48 hours will return for a face-to-face post-infusion assessment visit for obstetric assessments 1 week (acceptable range: 3 to 14 days) 
following the Inpatient Randomized Treatment Phase. (Note: study documents may reference this visit as the 1-week face-to-face post-infusion assessment visit). The subject will 
then be contacted every week via telephone to determine 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. 
If the subject delivers the baby prior to the face-to-face post-infusion assessment visit, central laboratory assessments for hematology, chemistry, and LFTs and the assessments 
for the Delivery Phase (see Section 3.1.4) will be performed. 


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3. 
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) and the EQ-5D-5L (-2 weeks/+6 weeks) (see Section 3.1.5 for list of 
assessments and visit windows). 
4. 
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. 
5. 
The subject or other legal guardian for the infant will be asked to consent to participate in a separate long-term study to follow infants for safety and neurodevelopment outcomes. 
The subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant follow-up study at any time during the study that is 
appropriate and convenient. Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude involvement in the infant follow-up study. 
6. 
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. 
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. Additional cervical examinations (Day 1, Day 2, and/or at the 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 4.2), 2 examinations must be documented (either 2 digital cervical examinations or 2 cervical 
length examinations). 
8. 
An ultrasound for estimation of fetal weight and head circumference is needed at Screening or before retreatment 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 or the date of retreatment. 
9. 
The abdominal ultrasound for determination of the AFI will be performed at Screening and before retreatment. The AFI should be measured using the 4-quadrant method. 
10. 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. 
11. Antenatal corticosteroid treatment should be administered in accordance with national, society, or institutional guidelines. Magnesium sulfate for fetal neuroprotection can be given 
at the discretion of the investigator. 
12. Information regarding delivery will be obtained through a review of the hospital and medical records. Growth parameters include neonatal weight, length, and head circumference. 
13. 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. 
14. Vital signs (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, if criteria are met, also during retreatment, and at the post-infusion assessment visit. During the Inpatient Randomized Treatment Phase and during 
retreatment, vital signs will be assessed and recorded within the following windows relative to the start of the infusion: 15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours, at the 
end of the infusion, at the time of any dose changes, and as warranted by a medical condition. It is suggested (but not required) that oxygen saturation also be assessed at 
Screening and recorded in source documents. 
15. Maternal subjects will complete the EPDS, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (-2 weeks/+6 weeks) after delivery. 
16. 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%. 
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 6.3.1 if 
ALT or bilirubin is abnormal. 


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17. 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 6.3.1). 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. 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. 
18. Prior to dosing, if the fetal heart rate pattern is nonreassuring, the subject cannot be dosed. 
19. 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 6.3.12.3). 
20. If the subject has not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate (fetal Doppler heart rate or cardiotocography are both acceptable) 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 6.3.12.3). 
21. 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 6.3.12.3). 
22. 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. 
23. PK samples will be taken at the following sampling windows (relative to the start of the infusion): 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. A maternal blood sample should be 
collected at the same time as the cord blood sample (see Section 6.5.1) if the sample time does not already coincide with one of the PK sampling windows. 
24. In subjects who deliver at an investigative center within 12 hours following completion or discontinuation of the IP, the cord blood sample will also be divided for PK analysis as 
well as genetic (if additional consent is provided; see Appendix 1) and biomarker analyses. 
25. 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. 
26. A placental tissue sample will be collected at delivery in subjects who deliver at an investigative center. 
27. A maternal blood sample for genetic research will only be collected from subjects who provide separate informed consent (see Appendix 1). 
28. A cord blood sample will be collected in subjects who deliver at an investigative center, if additional consent is provided. 
29. Testing for fetal fibronectin will be performed only at those institutions collecting the information as routine practice. Fetal fibronectin will not be used to determine study eligibility. 
30. Cervical length measured by transvaginal ultrasound will be captured only at those institutions collecting the information as routine practice. Cervical length will not be used to 
determine study eligibility. 


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6.1. 
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 
bilirubin is not >1.5 × ULN (>35% direct bilirubin), if available (see Section 6.3.1). 
An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct 
bilirubin is <35%. Dosing may be started prior to the availability of these results. 
• 
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 4.4.1). 
 
6.2. 
Efficacy 
Collection of efficacy endpoint data requires a thorough review of the hospital medical 
records. Review of the maternal hospital record is the responsibility of the investigator 
obstetrician and review of the newborn hospital record is the responsibility of the 
subinvestigator neonatologist. 
 
6.2.1. 
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 
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. 


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6.2.2. 
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. 
 
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 6.2.4) 
• 
Hospital length of stay 
• 
Neonatal admission to a specialized care unit and length of stay 
• 
Newborn hospital readmission and length of stay 
• 
Ambulatory surgery 
6.2.3. 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is time to delivery from the start of IP administration until 
delivery, based on a records review. 
 
6.2.4. 
Key Secondary Efficacy Endpoints 
 
• 
Proportion of births prior to 370/7 weeks’ gestation – ascertain the GA at delivery 
based on a records review 
• 
Proportion of births at term (370/7 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 
• 
Proportion of neonates with any diagnosis from the neonatal morbidity and mortality 
composite determined up to 28 days after EDD (of 400/7 weeks) – proportion of 
infants with any one of the following: 
• 
Fetal or neonatal death 
• 
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 


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• 
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 
 
 
 
 
• 
IVH 
OR 
o Requiring surgical treatment with laser or other surgical intervention 
including cryotherapy or treatment with anti-VEGF (vascular 
endothelial growth factor) 
 
 
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) 


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• 
Retosiban clearance and volume of distribution and the effect of covariates on 
these parameters 
6.2.5. 
Other Secondary Efficacy Endpoints 
 
• 
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 6.2.4 
• 
Neonatal admission to a specialized care unit and length of stay – confirm admission 
to neonatal intensive or 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 
• 
Ambulatory surgery – confirm any neonatal ambulatory surgery and the indication 
for surgery 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 ≤7 days 
• 
Proportion of births ≤48 hours 
• 
Proportion of births ≤24 hours 
6.2.6. 
Exploratory Efficacy Endpoints 
 
A complete list of exploratory endpoints will be provided in the reporting and analysis 
plan (RAP). 
 
6.3. 
Safety 
The timing for all safety assessments is outlined in the Time and Events Schedule 
Table 5. 
 
Maternal: 
 
• 
Incidence of reported AEs and SAEs 
• 
Significant changes in vital signs and clinical laboratory tests 
• 
Incidence of treatment-limiting toxicities including both clinical and laboratory 
etiology causing subject to discontinue study treatment 


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• 
Maternal AEs of special interest 
• 
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 
• 
Incidence of women scoring 12 or higher on the EPDS 
Fetal: 
• 
Incidence of reported AEs, including 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, 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, and documentation of any 
complications 
• 
Incidence of reported AEs and SAEs 
• 
Neonatal AEs of special interest are of interest because of their relationship to 
maternal chorioamnionitis and will include the following: 
• 
Neonatal death 
• 
Asphyxia 
• 
Infections (early onset neonatal sepsis, septic shock, pneumonia, meningitis) 
• 
RDS 
• 
Hypotension 


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• 
IVH/periventricular leukomalacia with cysts or porencephaly 
• 
Bronchopulmonary dysplasia 
• 
Neonatal acidosis 
• 
Hyperbilirubinemia 
• 
Necrotizing enterocolitis (any modified Bell’s staging criteria) 
• 
Hypoxic ischemic encephalopathy 
Maternal and neonatal disease-related events (DREs) to be reported are described in 
Section 6.3.7. 
 
6.3.1. 
Liver Chemistry Stopping and Follow-Up 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 face-to-face 
post-infusion assessment visit for additional liver function testing in order 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. 
 
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 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. 
 
NOTE: The central laboratory report will include results for ALT, aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, and direct bilirubin. 


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Figure 3 
Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
 
 
 
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. 
 
6.3.1.1. 
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. 
 
6.3.2. 
Adverse Events 
 
The investigator or site staff will be responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE. Separate reporting will be done for 
maternal, fetal, and neonatal AEs. 
 
6.3.2.1. 
Definition of an AE 
 
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. For marketed medicinal products, this 
Continue Study Treatment 
No 
Yes 
ALT≥3×ULN 
Plus 
Bilirubin 
≥2×ULN (>35% 
direct) 
or plus 
INR>1.5, if 
measured* 
Possible 
Hy’s Law 
No 
Plus 
Symptoms of 
liver injury 
or        
hypersensitivity 
No 
ALT 
≥8×ULN 
No 
ALT≥3×ULN but 
<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 


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also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or 
misuse. 
 
Events meeting the definition of an AE include: 
 
• 
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/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. 
 
Events that do not meet the definition of an AE include: 
 
• 
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 
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. 
6.3.2.2. 
Definition of an SAE 
 
An SAE is any untoward medical occurrence that, at any dose: 
 
a. 
Results in death (maternal, fetal, or neonatal in this study) 
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 
d. 
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 


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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. 
e. 
Results in disability/incapacity, or 
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. 
f. 
Is a congenital anomaly/birth defect 
g. 
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. 
h. 
All events of possible drug-induced liver injury with hyperbilirubinemia defined as 
ALT 3 × ULN and bilirubin 2 × ULN (>35% direct) (or ALT 3 × ULN and 
international normalized ratio (INR) >1.5, if INR measured) termed “Hy’s Law” 
events (INR measurement is not required and the threshold value stated will not 
apply to subjects receiving anticoagulants). 
NOTE: The central laboratory report will include results for ALT, AST, ALP, total 
bilirubin, and direct bilirubin. 
6.3.2.3. 
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 6.3. Guidelines 
for reporting these events are provided in Appendix 4. 
 
6.3.3. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 


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including those that worsen from baseline values, and felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as AEs or 
SAEs. However, any clinically significant 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, are not to be reported as AEs or SAEs. 
 
6.3.4. 
Cardiovascular Events 
 
Investigators will be required to fill out event specific data collection tools 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 
• 
Revascularisation 
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. 
 
6.3.5. 
Death Events 
 
In addition, all deaths (maternal, fetal, and neonatal) will require a specific death data 
collection tool to be completed. The death data collection tool includes questions 
regarding cardiovascular (including sudden cardiac death) and noncardiovascular death. 
 
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. 
 
6.3.6. 
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 


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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. 
 
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. 
 
6.3.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
 
The DREs listed in Section 6.3.7.1 and Section 6.3.7.2 will be monitored by an internal 
GSK safety review team (reviewing blinded data). 
 
6.3.7.1. 
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 6.3.7.2 applies 
• 
Hospitalization for delivery, unless prolonged or 1 of the conditions listed at the end 
of Section 6.3.7.2 applies 
 
6.3.7.2. 
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: 


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• 
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 6.3.7.1 and Section 6.3.7.2) 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 an SAE). These events will be recorded on the DRE page in the eCRFs. 
These DREs will be monitored by the internal GSK safety review team. However, if one 
or all of the following conditions apply, then the event should be reported as an 
AE/SAE using the standard process, as summarized in Section 6.3.11: 
 
• 
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. 


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If any of the above conditions are met, then record the event on the SAE page rather than 
the DRE page and report promptly (i.e., expedited reporting, see Section 6.3.11) to 
GSK/PPD. 
 
6.3.8. 
Time Period and Frequency of Detecting AEs and SAEs 
 
The investigator or site staff is responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE. 
 
Adverse events and SAEs will be collected from the start of study treatment and until the 
follow-up contact (see Section 6.3.10) 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 
Section 6.3.11. 
 
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. 
 
6.3.9. 
Method of Detecting AEs and SAEs 
 
Care must 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 the following: 
 
“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?” 
 
6.3.10. 
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 6.3) will be followed until resolution, until the condition stabilizes, 


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until the event is otherwise explained, or until the subject is lost to follow-up (as defined 
in Section 4.4.1.2). 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 the 
SPM. 
 
6.3.11. 
Prompt Reporting of SAEs and Other Events to GSK/PPD 
 
Serious AEs, nonserious AEs related to study treatment, and liver function abnormalities 
meeting predefined criteria will be reported promptly by the investigator to GSK/PPD as 
described in Table 6 once the investigator determines that the event meets the protocol 
definition for that event. Additional details describing DREs not qualifying as SAEs are 
described in Section 6.3.7. 
 
Table 6 
Reporting of Serious Adverse Events and Other Events to GSK/PPD 
 
Initial Reports 
Follow-up Information 
on a Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data collection 
tool 
24 hours 
Updated “SAE” data 
collection tool 
Cardiovascular or 
death event 
Initial and follow-up 
reports to be 
completed within 
1 week of when the 
cardiovascular event 
or death is reported 
“CV events” and/or 
“death” data collection 
tool(s) if applicable 
Initial and follow-up 
reports to be 
completed within 
1 week of when the 
cardiovascular event 
or death is reported 
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable 
Nonserious adverse 
events related to 
study treatment 
5 calendar days 
“Adverse Reaction” 
data collection tool 
2 weeks 
Updated “Adverse 
Reaction” data 
collection tool 
DRE 
2 weeks1 
DRE eCRF 
2 weeks1 
Updated DRE eCRF 
Liver chemistry abnormalities 
ALT3 x ULN and 
bilirubin 2 x ULN 
(>35% direct) (or 
ALT3 x ULN and 
INR>1.5, if INR 
measured)2 
24 hours3 
“SAE” data collection 
tool. “Liver Event 
eCRF” and “Liver 
Imaging” and/or “Liver 
Biopsy” eCRFs, if 
applicable4 
24 hours 
Updated “SAE” data 
collection tool/“Liver 
Event” Documents4 
ALT8 x ULN; 
ALT3 x ULN with 
hepatitis or rash or 
3 x ULN and 
<5 x ULN that persists 
4 weeks 
24 hours3 
“Liver Event” 
Documents (defined 
above)4 
24 hours 
Updated “Liver Event” 
Documents4 
ALT = alanine aminotransferase, CV = cardiovascular; DRE = disease-related event, eCRF = electronic case report 
form; GSK = GlaxoSmithKline; INR = International normalized ratio, SAE = serious adverse event, ULN = upper limit of 
normal. 
1, 
The study review team should determine the appropriate time frame, if one is needed, for completion of DRE 
eCRF pages 
2. 
The INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants. 
3. 
GSK/PPD must be contacted at onset of liver chemistry elevations to discuss subject safety. 
4. 
Liver Event Documents (i.e., “Liver Event eCRF” and “Liver Imaging eCRF” and/or “Liver Biopsy eCRF,” as 
applicable) should be completed as soon as possible 


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The contact information for reporting SAEs is as follows: 
 
Issue 
All Countries/Regions Contact 
Serious Adverse Event Reporting 
24-Hour SAE Hotline: 
PPD 
SAE Fax: 
PPD 
 
The method of recording, evaluating, and following up of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK/PPD are provided in the SPM. 
Procedures for poststudy AEs/SAEs are provided in the SPM. 
 
6.3.11.1. 
Regulatory Reporting Requirements for SAEs 
 
Prompt notification of SAEs by the investigator to GSK/PPD is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 
 
GSK/PPD 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, Institutional Review Board (IRB)/Independent Ethics 
Committee (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 an 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. 
 
6.3.12. 
Other Safety Outcomes 
 
6.3.12.1. 
Physical Examination 
 
An admission physical examination will include at 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 face-to-face post-infusion assessment visit, following conclusion of the treatment 
phase. 
 
6.3.12.2. 
Vital Sign Measurements 
 
Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) will be 
measured at the following time points during the study: Screening, Inpatient Randomized 
Treatment Phase, retreatment (if criteria are met, see Section 3.1.3.1), and at the 


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face-to-face post-infusion assessment visit. During the Inpatient Randomized Treatment 
Phase and during retreatment, vital signs 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. It is suggested (but not required) that oxygen saturation also be assessed at 
Screening and recorded in source documents. 
 
6.3.12.3. 
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 bolus 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 6.3.12.2). The electronic fetal heart rate tracing 
(paper or electronic) must be archived and retained in site records. Fetal heart rate (fetal 
Doppler heart rate or cardiotocography are both acceptable) will be recorded at the 
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, 2009] will be 
reported as an AE of special interest on a specified eCRF in addition to the corresponding 
AE or SAE eCRF: 
 
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 


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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 
6.3.12.4. 
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 4.3). 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 ultrasound-derived 
estimated fetal weight and head circumference within 3 weeks of Screening, with the 
results and date of assessment recorded in the eCRF). 
 
If the investigator determines a subject suitable for retreatment (see Section 3.1.3.1 for 
retreatment criteria), an abdominal ultrasound to assess fetal growth should be performed 
unless records are available documenting ultrasound-derived estimated fetal weight and 


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head circumference within 3 weeks of retreatment, with the results and date of 
assessment recorded in the eCRF. 
 
6.3.12.5. 
Laboratory Assessments 
 
The following laboratory tests will be performed locally: 
 
• 
Liver function tests, including ALT and bilirubin, performed at Screening (see 
Section 6.3.1) 
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 on the subject’s eCRF. Refer to the SPM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws. 
 
With the exception of the above, all protocol-required laboratory assessments, as defined 
in Table 5, must be performed by the central laboratory. For subjects that do 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. 
 
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 biological samples collected over the course of the study that are directly related to 
the conduct and analysis of the study, including hematology and chemistry tests, and liver 
function tests are summarized further in Appendix 5. 
 
6.3.12.6. 
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. Performance of a follow-up ECG after an abnormal finding will be at the 
discretion of the investigator. 
 
6.3.12.7. 
Breastfeeding Status 
 
A questionnaire will be administered at the maternal post-delivery assessment to assess 
the status of breastfeeding, as appropriate. 
 
Details regarding the questionnaire content and administration are provided the SPM. 


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6.3.12.8. 
Maternal Depression 
 
The effect of preterm labor, the prevention of preterm labor, and the impact 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 study center personnel will be notified immediately in order to 
follow-up with the subject to ensure safety. Certain items in the scale also assess anxiety 
and will be used to assess level of anxiety. The EPDS will be administered to mothers 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. 
 
6.4. 
Health Outcomes 
• 
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, 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, 
etc.), and surgical procedures. 
• 
Assess maternal health status (EQ-5D-5L) at time of IP administration and 6 weeks 
(-2 weeks/+6 weeks) after delivery 
6.4.1. 
Health Outcomes – Maternal 
 
6.4.1.1. 
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 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, Cesarean section). 


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6.4.1.2. 
Maternal Subject-Reported Health Assessments 
 
The effect of preterm labor, the prevention of preterm labor, and the impact of preterm 
birth on maternal health status will be assessed using the EQ-5D-5L self-administered 
questionnaire: 
 
• 
The EQ-5D-5L consists of 2 pages (the EQ-5D-5L descriptive system and the EQ 
visual analogue scale [EQ VAS]) plus a cover page. The descriptive system 
comprises mobility, self-care, usual activities, pain/discomfort, anxiety/depression, 
with each dimension having 5 response levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. The respondent is 
asked to indicate her health state by ticking (or placing a cross) in the box against the 
most appropriate statement in each of the 5 dimensions. This decision results in a 
1-digit number expressing the level selected for that dimension. The digits for 
5 dimensions can be combined in a 5-digit number describing the respondent’s 
health state. 
The EQ VAS records the respondent’s self-rated health on a 20-cm vertical, VAS 
with endpoints labeled “the best health you can imagine” and “the worst health you 
can imagine.” 
This information can be used as a quantitative measure of health as judged by the 
individual respondents. The EQ-5D-5L will be administered to mothers early in the 
drug delivery phase (while the mother is still in active preterm labor) and at the 
maternal follow-up assessment 6 weeks (-2 weeks/+6 weeks) after 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. 
 
6.4.2. 
Health Outcomes – Neonatal 
 
6.4.2.1. 
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. 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. 
 
6.4.2.2. 
Neonatal Health Care Resource Use 
 
Details of neonatal health care resource use associated with neonatal comorbidities of 
interest will be 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 


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• 
Use of surfactant and number of doses administered 
• 
Imaging (ultrasound, computed tomography, magnetic resonance imaging, 
radionuclide) 
• 
Other surgical procedures 
6.5. 
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/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. 
 
The samples collected for PK analyses are summarized further in Appendix 5. 
 
6.5.1. 
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. 
 
Additionally, a maternal blood sample should be collected at the same time as the cord 
blood sample (see Section 6.5.2) 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. 
 
6.5.2. 
Umbilical Cord Blood 
 
For those subjects who deliver at the investigative center, a single cord blood sample will 
be collected and divided for biomarker assays (Section 6.8) and potential genetic research 
(Section 6.9). If subjects deliver at the investigative center within 12 hours following 
completion or discontinuation of IP, the cord blood sample will also be used for a PK 
assessment of fetal drug exposure. 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 sampling for the study. 
 
Samples from retosiban-treated subjects with concomitant use of inhibitors of BCRP or 
P-gp will be analyzed for drug-drug interactions. The date and time of the sample should 
be noted in the eCRF. 
 
6.5.3. 
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. 


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• 
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. 
• 
A sample of breast milk/colostrum produced between 4 and 12 hours from receiving 
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. 
6.6. 
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 will not be used 
to determine eligibility but 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. 
 
6.7. 
Fetal Fibronectin 
Institutions that routinely perform 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. 
 
6.8. 
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 maternal 
blood sample for biomarker research will be collected at Screening and a cord blood 
sample for biomarker research will be collected during the Delivery Phase. The samples 
will be stored and may be analyzed for future exploratory research. 
 
The blood samples collected for biomarker analyses are summarized further in 
Appendix 5. 
 
6.9. 
Genetic Research 
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. At Screening (Day 0), a 6-mL blood sample for maternal DNA will be 
collected in subjects who provide informed consent for genetic research. In addition, for 


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those subjects who deliver at the investigative center, a cord blood sample will also be 
collected for potential genetic assays. 
 
Additional information regarding genetic research is included in Appendix 1 and 
Appendix 5. 
 
7. 
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. Adverse events and concomitant medications terms 
will be coded using the MedDRA and an internal validated medication dictionary, 
GSKDrug. 
 
Electronic CRFs (including queries and audit trails) will be retained by GSK, and copies 
will be sent to the investigator to maintain as the investigator copy. In all cases, subject 
initials will not be collected or transmitted to GSK according to GSK policy. 
 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Hypotheses 
The primary endpoint is prolongation of pregnancy as measured by time to delivery 
(days). The following are the null (H0) and alternative (H1) hypotheses for the primary 
endpoint in this study: 
 
• 
H0: The prolongation of pregnancy as measured by time to delivery is equal between 
the women randomized to retosiban versus atosiban 
• 
H1: The prolongation of pregnancy as measured by time to delivery is unequal 
between the women randomized to retosiban versus atosiban 
The hypotheses will be tested at 5% level with a 2-sided test. 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 sequential testing method 
will be used to adjust for multiplicity of key secondary endpoints such that the type I 
error rate will be maintained at 5%. Refer to Section 8.3.5.1.2 for details of key 
secondary analysis. 
 
8.2. 
Study Design Considerations 
8.2.1. 
Sample Size Assumptions 
 
A total of 330 women (165 women per treatment group) will be recruited into the study 
and randomly assigned to treatment to ensure that 300 women/newborns 
(150 women/newborns per treatment group, assuming 10% missing data) have recorded 


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birth data, which provides 86% statistical power to detect an average difference of 
9.5 days between retosiban and atosiban in time to delivery in the proposed adaptive 
design with futility analysis. 
 
The above sample size calculations are based on a 2-sided testing procedure with a type I 
error rate of 5% and an approximate 10% dropout rate. Calculations are based on 
simulations and assumes 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 atosiban 
treatment group will deliver within the 3 weeks of GA at randomization. The details of 
the model assumption and simulation are included in a supplemental simulation report. 
 
Statistical Operating Characteristics 
 
Simulations were carried out to determine the statistical properties for inference about the 
primary hypothesis of the adaptive design with regard to the control of the overall type I 
error and the statistical power under a wide range of efficacy for retosiban, from no effect 
(i.e., null hypotheses) to an increase of 9.5 days in time to delivery (i.e., alternative 
hypothesis) and to greater than expected efficacy. It was shown that the overall type I 
error rate (2.4%) was maintained at a level well below the 5% for the primary hypothesis. 
Furthermore, if the true effect of retosiban is small or zero, there is good probability 
(74%) that the study will be stopped early for lack of efficacy (i.e., futility). If the true 
effect of retosiban is as expected, the statistical power will be 86%, with a 7% probability 
that the study will be stopped for lack of efficacy. The details of model assumption and 
simulation are included in a supplemental simulation report. 
 
Table 7 
Operating Characteristics of the Adaptive Design Under the Null and 
Alternative Hypotheses 
 
Case Hypothesis 
Interim Analysis 
Final 
Futility 
Failure 
Success 
Null (0 day) 
74% 
24% 
2.4% 
Alternative (9.5 days) 
7% 
7% 
86% 
 
 
8.2.2. 
Sample Size Sensitivity 
 
It is expected that the time to delivery will be dependent on the percentage of women 
enrolled into each of the GA strata and the percentage of women that deliver within 
3 weeks of randomization. Subsequently, the power of the study 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 if the 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. If the proportion of women delivering within 
3 weeks is 45%, 10% lower than expected, the power of the study will be approximately 
75% to detect an average difference of 7.7 days between retosiban and atosiban in the 
time to delivery. If it is significantly lower, such as 20% lower, the power of the study 


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could be as low as 53% to detect an average difference of 5.8 days between retosiban and 
atosiban in the time to delivery. Details will be included in a supplemental simulation 
report. 
 
8.2.3. 
Sample Size Re-estimation 
 
Sample size re-estimation is not planned for this study. 
 
8.3. 
Data Analysis Considerations 
8.3.1. 
Analysis Populations (Maternal) 
 
8.3.1.1. 
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. 
 
8.3.1.2. 
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 irrespective of their 
compliance to the planned course of treatment. Subjects who are randomly assigned but 
fail to receive any study treatment (as described in Section 4.4.1.1) 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. 
 
8.3.1.3. 
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 
failure to meet inclusion criteria specified by the protocol. 
 
8.3.2. 
Analysis Population (Neonatal) 
 
8.3.2.1. 
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. 
 
8.3.2.2. 
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 irrespective 


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of their compliance to the planned course of treatment. This is the primary analysis data 
set and will be used for evaluation of all neonatal efficacy endpoints. 
 
8.3.2.3. 
Neonatal Per-Protocol Population 
 
This Neonatal Per-Protocol Population is defined as all subjects in the Neonatal ITT 
Population excluding those who are major protocol violators. 
 
8.3.3. 
Treatment Comparisons 
 
8.3.3.1. 
Primary Comparisons of Interest 
 
The primary comparison of interest is retosiban versus atosiban for time to delivery based 
on the ITT population, at the 2-sided 5% level. 
 
8.3.3.2. 
Other Comparisons of Interest 
 
For each of the secondary endpoints, the comparison of interest is retosiban versus 
atosiban at the 2-sided 5% level. Other comparisons of exploratory endpoints between 
retosiban and atosiban will be discussed in the RAP. 
 
8.3.3.3. 
Subgroup Analysis 
 
Additionally, comparisons of retosiban versus atosiban for 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) 
Other potential subgroup comparisons will be described in the RAP. 
 
8.3.3.4. 
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, other concomitant medications, etc. Details of analysis 
will be included in final RAP. 
 
8.3.4. 
Interim Analysis 
 
To ensure mother and infant safety, an IDMC will be used to periodically monitor the 
benefit:risk profile of subjects in the study. Safety and efficacy summaries will be 
provided to the IDMC by an independent statistical data analysis center. The IDMC will 
review periodic data to monitor potential benefit:risk profiles of the study intervention. 
With considerations for safety, recommendations may be made to modify the protocol or 
discontinue the study if any untoward events or pattern of events are detected. 
 
There will be single planned interim analysis when approximately 130 subjects 
(65 subjects per treatment group) have completed delivery and have time-to-delivery 
results available. The primary objective of the interim analysis will be to determine if the 


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study will be terminated for lack of efficacy (futility) based on prespecified criteria. The 
decision will be based primarily on the analysis of the primary endpoint, time to delivery; 
however, all available safety and efficacy data will be reviewed. 
 
Time to delivery will be analyzed as described in Section 8.3.5.1.1. An estimate of the 
difference in time to delivery between the retosiban and atosiban treatment group 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. 
 
Full details of the statistical analysis and prespecified decision rules will be provided. The 
responsibilities of the IDMC and statistical data analysis center, as well as full details of 
the specific summaries and analyses of safety and efficacy data to be reviewed (including 
tables, listings, and summaries) will be provided in either the IDMC charter or the 
specific RAP for the IDMC. 
 
8.3.5. 
Key Elements of Analysis Plan 
 
8.3.5.1. 
Efficacy Analyses 
 
8.3.5.1.1. 
Primary Analysis 
 
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 atosiban in time to 
delivery versus the alternative hypothesis that there is a difference. 
 
The primary analysis of time to delivery will utilize a finite mixture model [McLachlan, 
2000] with 2 components, 1 for those women that delivery imminently and the other for 
the women delivering at term. The exact weight of each component will be determined 
by the observations from the component and model concomitant variables including 
treatment and GA at randomization. Within each component, the expected time to 
delivery will be modeled as a function of treatment as fixed effect and GA at 
randomization and established progesterone use (yes or no) as a covariate. The model 
parameters will be estimated using expectation-maximization algorithm. Point estimates, 
associated 95% CIs, and p-values for the overall average difference in time to delivery 
between retosiban and atosiban will be derived using the weighted average of model 
parameter estimates and variance from each subpopulation of mixture model. Details of 
mathematical model and analysis will be included in the RAP. 
 
8.3.5.1.2. 
Secondary Analysis 
 
Key Secondary Analysis 
 
The key secondary analysis for this study includes the 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, and composite neonatal morbidity and mortality. 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 sequential testing 
method 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 sequential testing examines the 


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hypothesis testing in a prespecified order, i.e., the testing of the second secondary 
endpoint will be performed only if the first secondary endpoint is significant at 5%, and 
testing of the third secondary endpoint will be performed only if the first and second 
endpoints are significant at 5%. The exact order of sequential testing will be detailed in 
the RAP. 
 
For the endpoints of neonatal composite outcome, proportion of births prior to 
370/7 weeks’ gestation, and proportion of births at term (370/7 to 416/7 weeks’ gestation), a 
logistic regression model will be used for comparing retosiban with atosiban, with GA at 
randomization and established progesterone use (yes or no) as a covariate. 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 atosiban), 95% 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. 
 
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 GA at randomization and established progesterone use (yes or no). 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 atosiban 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. 
 
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. 
 
8.3.5.2. 
Safety Analyses 
 
No formal hypothesis statistical test will be performed for the safety data. All safety 
analyses will be done 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 atosiban treatment. As such, 
maternal, fetal, and neonatal safety data will be summarized by treatment group. 
 
All summary statistics of continuous variables will include: n, 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). 


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To further describe the maternal, fetal, and neonatal safety profile of retosiban, the 
following subgroups may be explored: 
 
• 
GA of pregnancy at randomization 
• 
Established progesterone use 
• 
GA at delivery 
• 
Maternal age 
• 
Region/site 
For each subgroup, maternal, fetal, and neonate safety data will be summarized by 
treatment and subgroup, as described above. 
 
8.3.5.2.1. 
Extent of Exposure (Maternal) 
 
The total volume administered during the infusion and the total volume administered 
overall will be 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 reason for discontinuation and who 
increased study treatment from 6 to 12 mg will be summarized. 
 
8.3.5.2.2. 
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, each phase of the 
study (pretreatment, treatment, and follow-up) will be tabulated 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 6.3.2.3) and DREs (see Section 6.3.7) will 
be similarly summarized. 
 
Full details of all safety analyses including AEs, SAE, clinical laboratory evaluations, 
ECGs, and vital sign measurements will be provided in the RAP. 
 
8.3.5.3. 
Health Outcomes Analyses 
 
Analysis of neonatal length of stay, one of the key secondary endpoints, is described in 
Section 8.3.5.1.2. 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 
atosiban 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: n, mean, median, standard 


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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 
• 
Region/sites 
8.3.5.4. 
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. 
 
8.3.5.5. 
Genetic Analyses 
 
Any genetic analyses may be described in a separate genetic research analysis plan and 
may be reported separately from the main clinical study report. See Appendix 1 for 
details about the genetic research analysis plan. 
 
9. 
STUDY CONDUCT CONSIDERATIONS 
9.1. 
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. 
 
9.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with the International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements. 
 
The study will be conducted in accordance with all applicable regulatory requirements. 
 
The study will 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, including, but not limited to: 
 
• 
IRB/IEC review and favorable opinion/approval of study protocol and any 
subsequent amendments 
• 
Subject informed consent 


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• 
Investigator reporting requirements 
GSK/PPD will provide full details of the above procedures, either verbally, in writing, or 
both. 
 
Written informed consent must be obtained from each subject prior to participation in the 
study. 
 
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., genetic research 
assessments described in Appendix 1, unless otherwise indicated. Where permitted by 
regulatory authorities, approval of the optional assessments can occur after approval is 
obtained for the rest of the study. If so, then the written approval will clearly indicate 
approval of the optional assessments is being deferred and the study, except for the 
optional assessments, can be initiated. When the optional assessments are not approved, 
then the approval for the rest of the study will clearly indicate this and therefore, the 
optional assessments will not be conducted. 
 
9.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, 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 
include identification, agreement, and documentation of data items for which the eCRF 
will serve as the source document. 
 
PPD will monitor the study to ensure 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) agrees to 
allow the monitor direct access to all relevant documents. 
 
9.4. 
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. 


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9.5. 
Study and Site Closure 
Upon completion or termination of the study, the PPD monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK/PPD standard operating procedures. 
 
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance. If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable). When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action. 
 
If a study is suspended or terminated for safety reasons, GSK/PPD will promptly inform 
all investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study. GSK/PPD will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. 
 
9.6. 
Records Retention 
Following closure of the study, the investigator or 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 easily accessible 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must 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. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
 
GSK/PPD will inform the investigator of the time period for retaining the site records in 
order to comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK/PPD standard operating procedures, and/or institutional 
requirements. 
 
The investigator must notify GSK/PPD of any changes in the archival arrangements, 
including, but not limited to, archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site. 


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9.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publicly 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. 
 
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 results summary will be posted to the Clinical Study Register no later than 8 months 
after the final primary completion date, the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary 
outcome. In addition, a manuscript will be submitted to a peer reviewed journal for 
publication no later than 18 months after the last subject’s last visit. When manuscript 
publication in a peer reviewed journal is not feasible, a statement will be added to the 
register to explain the reason for not publishing. 
 
A manuscript will be prepared for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 
 
9.8. 
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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American College of Obstetricians and Gynecologists Committee on Obstetric Practice. 
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Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. 
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Bain ES, Middleton PF, Crowther CA. Maternal adverse effects of different antenatal 
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Berkowitz GS, Blackmore-Prince C, Lapinski RH. Risk factors for preterm birth types. 
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http://www.cdc.gov/ncbddd/birthdefects/documents/macdpcode0807.pdf. (Accessed 
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Lockwood CJ, Kuczynski E. Risk stratification and pathological mechanisms in preterm 
delivery. Paediatr Perinat Epidemiol. 2001;15 Suppl 2:78-89. 
 
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Green-top 1B. Tocolytic drugs for women in preterm labor. Royal College of 
Obstetricians and Gynaecologists. February 2011. 
 
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infancy to adulthood. Lancet. 2008;371(9608):261-9. 
 
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11. 
APPENDICES 
11.1. 
Appendix 1: Genetic Research 
Genetic Research Objectives and Analyses 
 
• 
The objectives of the potential genetic research is to investigate a relationship 
between genetic factors and Response to medicine, including retosiban, atosiban, or 
any concomitant medications 
• 
Preterm labor susceptibility, severity, progression, and related conditions 
This research could include analyses of maternal/fetal gene interactions and the impact of 
genetic associations with preterm labor on drug response. 
 
Genetic data may be generated while the clinical 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 utilize data collected in the 
clinical study and will be limited to understanding the objectives as highlighted here. 
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 the reporting and analysis plan 
(RAP) prior to initiation of any analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical study report or in a separate 
genetics report, as appropriate. 
 
Study Population 
 
Any subject who is enrolled in the clinical 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. After the subject has provided informed 
consent for genetic research, the following procedures will be performed: 
 
• 
Screening: blood samples will be collected for DNA extraction. Instructions for the 
collection and shipment of the genetic sample are described in the laboratory manual. 
The DNA from the blood sample may undergo quality control analyses to confirm 
the integrity of the sample. If there are concerns regarding the quality of the sample, 
then the sample may be destroyed. 
• 
Delivery: an additional sample of cord blood will be collected. 
The genetic sample will be labeled (or “coded”) with the same study-specific number as 
used to label other laboratory samples and data in the study. This number can be traced or 


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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). 
 
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 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 to be destroyed at any time. 
 
Informed Consent 
 
Subjects who do not wish to participate in genetic research may still participate in the 
clinical study. Informed consent specific for genetic research must be obtained before any 
blood sample for genetic research can be obtained. 
 
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 research sample, if already 
collected: 
 
• 
Continue to participate in the genetic research in which case the genetic DNA sample 
will be retained for analysis 
• 
Discontinue participation in genetic research and destroy the genetic DNA sample 
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 clinical study or after completion of the 
clinical study, and it may be analyzed during the clinical study or stored for future 
analysis. If a subject withdraws consent for genetic research and genotype data have not 
been analyzed, the genetic DNA will not be analyzed or used for future research. If a 
subject withdraws consent for genetic research and genetic data have been analyzed, the 
genetic DNA will continue to be stored and used, as appropriate. 
 
If a blood sample for genetic research has been collected and the subject is ultimately not 
dosed (see Section 4.4.1.1), then the investigator should instruct the participant that their 
genetic sample will be destroyed. No forms are required to complete this process as it 


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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. 
 
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 clinical study, then the investigator 
should instruct the participant 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, or 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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11.2. 
Appendix 2: Liver Chemistry Stopping and Follow-up 
Criteria 
 
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. 
AE = adverse event; 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 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. 
 
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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11.3. 
Appendix 3: 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 5.1 and Section 5.1.1.1). 
 
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 
Voriconazole 
Lacidipine 
Omeprazole 
Posaconazole 
Propiverine 


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Strong1 
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
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 
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 the investigational 
product with a strong inhibitor or strong inducer requires an adjustment to the retosiban 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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11.4. 
Appendix 4: Safety Reporting Cheat Sheet 
 
200721 
 
 
 
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; 
PPROM = preterm premature rupture of membranes; RDS = respiratory distress syndrome; SAE = serious adverse event. 
 
 
111 
ZINN SAFETY REPORTING CHEAT SHEET 


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11.5. 
Appendix 5: Summary of Human Biological Samples 
Appendix 5 categorizes human biological samples as 1) those for which the results are 
directly related to the conduct and analysis of the study and 2) those collected and stored 
for future exploratory analyses. Human biological samples directly related to the study 
conduct and analysis include those for eligibility determination and safety, 
pharmacokinetics, and placental pathology. Human biological samples collected and 
stored for biomarker and genetic testing are categorized under future exploratory 
analyses. Appendix 5 also provides information regarding labeling and subject 
anonymization. Shipping location information for each sample is provided in the Study 
Procedures Manual. 
 
The investigator should refer to the laboratory manual for complete information on 
sample collection and preparation, packaging and labeling, and shipping. 
 
Human Biological Samples Directly Related to the Conduct and Analysis of 
the Study: 
 
• 
Hematology and Chemistry: Maternal blood samples for hematology and 
chemistry, including liver function studies, will be collected during Screening, Day 2 
of dosing, at the optional retreatment visit (if applicable), and the face-to-face 
post-infusion assessment visit. Labels will be customized for each test and include 
the protocol number, subject identification number, visit description, and date and 
time of collection. 
• 
Liver Function: A maternal blood sample for liver function studies will be 
collected during Screening and sent to the hospital laboratory for analysis. Normal 
results are required to initiate dosing or continue dosing if dosing has begun before 
results are available. In the event liver function test results from either the local or 
central laboratory reveal abnormalities consistent with the liver chemistry stopping 
criteria defined in Protocol Section 6.3.1 and Appendix 2, additional samples will be 
analyzed for hepatitis A immunoglobulin M (IgM) antibody, hepatitis B surface 
antigen, hepatitis B core antibody (IgM), cytomegalovirus (CMV) IgM antibody, 
hepatitis C RNA, hepatitis E IgM antibody, Epstein-Barr viral (EBV) capsid antigen 
IgM antibody, creatine phosphokinase, lactate dehydrogenase, and complete blood 
count with differential. 
If liver function test results reveal alanine aminotransferase (ALT) ≥3 × the upper 
limit of normal (ULN) AND bilirubin ≥2 × ULN (>35% direct bilirubin; an isolated 
bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is 
<35) samples will also be analyzed for the following: 
• 
Antinuclear antibody, antismooth muscle antibody, type 1 antiliver kidney 
microsomal antibodies, and total immunoglobulin G (IgG) 
• 
If chronic hepatitis B is identified at study entry by a positive hepatitis B surface 
antigen, blood samples will be assayed for hepatitis B DNA and hepatitis delta 
antibody. 
• 
Serum acetaminophen in subjects with definite or likely acetaminophen use in 
the preceding week. 


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Labels will be customized for each test and include the protocol number, subject 
identification number, descriptor as initial liver event assessment or follow-up, and date 
and time of collection. 
 
• 
Pharmacokinetic Samples: 
1. Maternal blood samples for quantification of retosiban plasma concentrations 
will be collected 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 to 54 hours 
after initiation of the infusion. 
2. An umbilical cord blood sample for quantification of retosiban plasma 
concentrations will be collected in subjects who deliver at the investigational 
center within 12 hours of investigation product (IP) completion or 
discontinuation. Additionally, a maternal blood sample should be collected at 
the same time as the cord blood sample (see Section 6.5.2) if the sample time 
does not already coincide with one of the PK sampling windows listed above. 
3. A breast milk/colostrum sample for a semi-quantitative retosiban assay will be 
collected in subjects who deliver at the investigational center within 12 hours of 
IP completion or discontinuation and are expressing breast milk/colostrum. 
4. Maternal blood sample for quantification of retosiban plasma concentration 
within 12 hours of exposure in subjects who meet liver chemistry stopping 
criteria defined in Protocol Section 6.3.1. 
Labels will be customized for each test and include the protocol number, subject 
identification number, visit description, and date and time of collection. 
• 
Placental Pathology: A placental tissue sample will be collected for pathologic 
examination when delivery occurs at an investigational center. Gross examination of 
the intact placenta, umbilical cord, and membranes will be performed by the hospital 
pathology department with gross findings reported in a standardized manner. The 
hospital pathology department will also prepare tissue samples for histologic 
examination of placenta, membranes, and umbilical cord. Labels will be customized 
and include the protocol number, subject identification number, visit description, and 
date and time of collection 
Human Biological Samples for Optional Future Biomarker and 
Genetic Testing: 
 
Biomarker and genetic testing will be performed in relation to the study treatment and 
preterm labor condition. 
 
• 
Biomarker Samples: 
1. Maternal blood samples for biomarker analysis will be collected for all subjects 
during Screening. 
2. An umbilical cord blood sample for biomarker analysis will be collected in 
subjects who deliver at the investigational center. 
Labels will be customized for each test and include the protocol number, subject 
identification number, visit description, and date and time of collection. 


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• 
Genetic Samples: 
1. 
Maternal blood samples for genetic analysis will be collected during Screening 
for subjects who consent to participate. Refer to Appendix 1 for a description of 
genetic testing objectives, assessments and procedures, subject participation, 
and confidentiality of data. Labels will be customized for each test and include 
the protocol number, subject identification number, visit description, and date 
and time of collection. 
2. 
An umbilical cord blood sample for genetic analysis will be collected in 
subjects who deliver at the investigational center. Labels will be customized for 
each test and include the protocol number, subject identification number, visit 
description, and date and time of collection. 


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11.6. 
Appendix 6: Protocol Changes 
Protocol Amendment Number 01 – Sites in France Only 
The following changes are reflected in the Country-Specific Protocol Amendment for 
France: 
 
• 
Inclusion criteria 1 and 2 were amended to specify that subjects must be at least 
18 years of age to participate in Study 200721, and subjects who participate in 
Study 200721 must also agree to participate in Study 200722, a separate infant 
follow-up study. 
• 
Text was revised throughout to reflect the change in the subject age criterion and the 
requirement to enroll in the infant follow-up study. 
• 
Section 9.2 was updated to clarify that the study would be conducted using the 
current version of the Declaration of Helsinki. 
• 
An appendix was added that categorizes laboratory samples into those supporting 
study conduct and those that may be analyzed at a later date. 
The specific text changes for this country-specific amendment are outlined under 
Amendment 04. 
 
Protocol Amendment Number 02 – Sites in United Kingdom Only 
The following changes are reflected in the Country-Specific Protocol Amendment for the 
United Kingdom: 
 
• 
The text from Section 5.3 (Blinding) was clarified. The intent of the language 
remains the same, but the clarification confirms there is no requirement for the 
investigator to discuss unblinding with the PPD medical monitor in order to rapidly 
unblind treatment for a study subject if needed. 
• 
Section 9.2 was updated to clarify that the study would be conducted using the 
current version of the Declaration of Helsinki. 
The specific text changes for this country-specific amendment are outlined under 
Amendment 04. 
 
Protocol Amendment Number 03 – Sites in Sweden Only 
The following changes are reflected in the Country-Specific Protocol Amendment for 
Sweden: 
 
• 
An appendix was added to list the medications considered strong, moderate, and 
weak CYP3A4 (cytochrome P450 3A4 enzyme) inhibitors and inducers. 
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: 
 
• 
Clarified the methods for documentation of 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 inclusion criteria for confirming sufficient dilation and effacement at 
Screening. 
• 
Clarified that co-morbid medical or obstetric conditions that may exclude a subject 
from the study include known or suspected maternal Zika infection during gestation. 
• 
Clarified the exclusion criterion for women with a history of substance abuse. 
• 
Added an exclusion criterion for women for whom the combination of history and 
screening test results is suggestive of abuse or dependency. 
• 
Clarified that withdrawal from the study will mean that no additional visits can occur 
or procedures performed. 
• 
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. 
• 
Included a definition of inadequate treatment 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. 
• 
Clarified the assessments performed at the 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, but this was not accurate as not all assessments 
originally indicated in the table will be performed during the weekly telephone calls. 
Additionally, the optional retreatment visit was added to the Time and Events Table 
and the assessments that will be performed when a subject withdraws from the study 
were clarified. 
• 
Added definitions for a completed subject and study completion. 


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• 
Updated the atosiban preparation instructions for consistency with the pharmacy 
manual. 
• 
Added 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. 
• 
Clarified that there is no requirement for the investigator to discuss unblinding with 
the PPD medical monitor in order to rapidly unblind treatment for a study subject if 
needed. 
• 
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. 
• 
Revised the presentation of the liver stopping criteria to more clearly summarize the 
criteria followed in the study and added that for local laboratory results an isolated 
bilirubin >1.5 × the upper limit of normal is acceptable if bilirubin is fractionated 
and direct bilirubin is <35%. 
• 
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 study drug dosing. The protocol previously had not 
included that the 60-minute duration was relative to investigational product (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 measurements are 
assessed relative to dosing. Also, added an optional measurement of oxygen 
saturation at Screening only. 
• 
Revised the timing of the pharmacokinetic (PK) sample taken at the onset of any 
maternal or fetal serious adverse event (SAE) from within 24 hours to within 
12 hours after completion or discontinuation of IP. 
• 
Clarified 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. 


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• 
Revised the visit window for the administration of the Edinburgh Postnatal 
Depression Scale (EPDS) and EuroQol 5-dimensional 5-level (EQ-5D-5L) from 
±2 weeks to -2 weeks/+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 and EQ-5D-5L up to 12 weeks after delivery. 
• 
Added as a key secondary endpoint the PK analyses of retosiban clearance and 
volume of distribution and the effect of covariates on these parameters. 
• 
Removed the listed exploratory endpoints and clarified that exploratory endpoints 
will be provided in the reporting and analysis plan. 
• 
Removed the follow-up amniotic fluid index (AFI) by abdominal ultrasound as a 
fetal safety endpoint because requirement for an AFI by ultrasound 12 hours after 
completion of study treatment was removed. 
• 
Removed from the list of disease-related maternal and neonatal events those events 
that were already listed as adverse events (AEs) of special interest. 
• 
Clarified the time period and frequency of reporting AEs and SAEs. 
• 
Updated the contact information for reporting SAEs. 
• 
Added information for the follow-up of AEs and SAEs to clarify that all SAEs and 
nonserious AEs of special interest will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost 
to follow-up. Additionally, added that any SAEs and AEs of special interest that are 
unresolved at 28 days post estimated date of delivery (EDD) should be followed to 
stabilization or resolution in those infants participating in the follow-up study. 
• 
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). 
• 
Removed the requirement for an ultrasound for determination of the AFI within 
12 hours of completion of study treatment. 
• 
Revised the method used for adjusting multiplicity of the key secondary endpoints 
from a stepwise Holm’s test to a sequential testing method. 
• 
Added an appendix that provides guidelines for reporting maternal, fetal, and 
neonatal AEs of special interest, which is also provided in the SPM. This was added 
to provide sites ready access to these detailed guidelines. 
• 
Incorporated the changes detailed in the country-specific amendment for sites in 
France (dated 29 Jan 2015). 
• 
Incorporated the changes detailed in the country-specific amendment for sites in the 
United Kingdom (dated 29 Jan 2015). 
• 
Incorporated the changes detailed in the country-specific amendment for sites in 
Sweden (dated 04 Feb 2015). 


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PPD 
• 
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): 
 
 
Sponsor Information Page 
 
Clinical Study Identifier: 200721 (ZINN) 
 
Sponsor Medical Monitor Contact Information and Sponsor Serious Adverse Events 
(SAE) Contact Information: 
 
 
Investigator Protocol Agreement Page 
 
For protocol 200721 (ZINN) 
List of Abbreviations 
IVRS interactive voice response system 
IWRS interactive web response system 
MD 
Europe: 
MD 
PPD 
24-Hour SAE Hotline: PPD 
SAE Fax: PPD 
PPD 
SAE Reporting 
Safety Hotline: 
PPD 
Safety Fax: 
24-Hour Safety Hotline: 
Safety Fax: 
SAE Reporting 
Associate Medical Director, Medical 
Affairs and Pharmacovigilance 
PPD 
Kuala Lumpur, Malaysia 
MD 
Asia: PPD 
Associate Medical Director, Medical 
Affairs and Pharmacovigilance 
PPD 
Sofia, Bulgaria 
Medical Director, Medical Affairs and 
Pharmacovigilance 
PPD 
Buenos Aires, Brazil 
PPD 
PPD 
Safety Questions 
Europe/Asia Contact 
Latin America Contact 
Issue 
PPD 


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PCP phencyclidine 
Definitions 
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) last 
menstrual period a best estimated due date confirmed or 
established by the earliest ultrasound performed prior to 
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 
 
 
Protocol Summary, Rationale 
 
This study (ZINN) is designed to test this hypothesis through a direct comparison with 
atosiban, a mixed oxytocin-vasopressin antagonist indicated for short-term use to delay 
imminent preterm birth in women between 240/7 and 336/7 weeks’ gestation in preterm 
labor. 
 
Protocol Summary, Study Design 
 
This ZINN is a Phase III study will use a, randomized, double-blind, double-dummy, 
multicenter design study. Approximately 330 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, will be randomly assigned to retosiban or atosiban in a 1:1 
ratio. 
 
• 
Test Treatment: Retosiban 
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 subjects with an 
inadequate response any time after the first hour of treatment, investigators should 
increase the dose by another 6-mg IV loading dose and increase the infusion rate to 
12 mg/hour for the remainder of the 48-hour treatment period (for details see 
Table 3). 
• 
Active Control: Atosiban 
Atosiban will be administered in 3 successive stages: an initial bolus dose (6.75 mg) 
over 1 minute, immediately followed by a continuous infusion at 18 mg/hour for 
3 hours, followed by a 6-mg/hour infusion for the remainder of the 48-hour treatment 
period (for details see Table 4). 
 
 
The study ZINN will consist of 6 phases: Screening, Inpatient Randomized Treatment, 
Post-Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal 
Medical Review (see schematic). The duration of any 1 subject’s (maternal or neonatal) 


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participation in the study will be variable and dependent on GA at study entry and the 
date of delivery. 
 
 
 
 
1. 
Stratification (1:1) to retosiban or atosiban 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. 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion assessment 
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 atosiban) is allowed. 
 
 
Prior to randomization, each subject will be stratified by progesterone treatment and GA 
determined by (1) known fertilization date, either in vitro fertilization or intrauterine 
insemination, or (2) last menstrual period a best estimated due date confirmed or 
established by the earliest ultrasound prior to 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. 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. 
The Screening Phase will occur on Day 0 and assessments will primarily focus on 
maternal and fetal safety evaluations prior to dosing. Subjects will be randomly 
assigned to treatment on Day 1 of tThe Inpatient Randomized Treatment Phase. The 


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treatment phase will be 48 hours. Subjects who do not experience labor progression and 
remain undelivered after 48 hours will be managed per the investigator’s judgment. 
 
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. 
 
If a subject has not delivered by the end of treatment, Subjects who remain undelivered 
after 48 hours will be scheduled for a face-to-face post-infusion assessment visit will be 
scheduled for obstetric assessments 1 week (±1 week acceptable range: 3 to 14 days) 
following the Inpatient Randomized Treatment Phase for maternal-fetal assessments 
(Note: study documents may reference this visit as the 1-week face-to-face post- 
infusion assessment visit). The subject will then be contacted every week (±1 week) via 
telephone to determine if birth has occurred. If the subject delivers the baby prior to 
the face-to-face post-infusion assessment visit, central laboratory assessments for 
hematology, chemistry, and liver function tests (see Table 5) and the assessments for 
the Delivery Phase (see Section 3.1.4) will be performed. 
 
In 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. A maternal post-delivery assessment During the Maternal 
Post-Delivery Assessment Phase, the subject will be conducted by telephone within 
6 weeks (±2 weeks) of delivery for a post-delivery assessment. 
 
During the Neonatal Medical Review Phase, tThe neonatologist subinvestigator will 
conduct a comprehensive review of the newborn’s birth hospitalization medical records, 
including any admission to an intensive or specialized care unit and any hospital 
readmission or outpatient surgery, following discharge from an acute care setting from 
delivery through 28 days EDD, where EDD is defined as 400/7 weeks’ gestation for all 
subjects. 
 
The subject or other legal guardian for the infant (both delivered and undelivered) will 
also be asked to consent to participate in a separate long-term study to follow infants for 
safety and neurodevelopmental 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 face-to-face post-infusion assessment visit. 
(Note: In France, consent for the infant study is required during the Screening 
Phase, see Section 4.2 [inclusion criterion 1] and Section 3.1.1). 
 
An interim analysis will occur after 130 mother/infant pairs subjects have completed 
delivery and have time to-delivery results available all assessments. At the interim 
analysis, all available safety and efficacy data will be reviewed by an unblinded 
independent data monitoring committee who may make recommendations to terminate 
the study. 


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Protocol Summary, Study Endpoints/Assessments 
 
The following are the key secondary efficacy endpoints: 
 
• 
Retosiban clearance and volume of distribution and the effect of covariates on 
these parameters 
The following are the safety endpoints (maternal, fetal, and neonatal, as appropriate): 
 
• 
Edinburgh Postnatal Depression Scale 
• 
Follow-up amniotic fluid index determined by abdominal ultrasound 
• 
Fetal acidosis 
• 
AEs of special interest 
• 
Neonatal 
o Intraventricular hemorrhage/periventricular leukomalacia with cysts or 
porencephaly 
 
o Neonatal Necrotizing enterocolitis (any modified Bell’s staging criteria) 
 
 
 
Section 1.1., 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. . . . 
 
 
Section 1.2., Rationale 
 
This study (ZINN) is designed to test this hypothesis through a direct comparison with 
atosiban, a mixed oxytocin vasopressin antagonist indicated for short-term use to delay 
imminent preterm birth in women between 240/7 and 336/7 weeks’ gestation in preterm 
labor. 
 
 
Section 1.3., Benefit:Risk Assessment 
 
Summaries of findings from both clinical and nonclinical studies conducted with 
GSK221149 can be found in the IB [GlaxoSmithKline GSK Document Number 
CM2006/00201/035]. The following section Table 1 and Table 2 outlines the risk 
assessment and mitigation strategy for this protocol. 


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Table 1 
Potential Risks of Clinical Significance 
 
Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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). 
Analysis of mMaternal blood and cord blood samples will be 
performed analyzed 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 a 
minimum of 24 months 5 years in a separate follow-up study to 
assess overall safety and neurodevelopmental outcomes. 
Unblinded safety data will be monitored by an IDMC. 
Retosiban is a substrate of P-glycoprotein 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, 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 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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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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 treatment. 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 from 
receiving 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 from receiving 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 receiving of the completion or discontinuation 
of the study treatment. 
 
When breast milk is produced more than 12 hours after the 
completion or discontinuation of the receiving 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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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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. 
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. 
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 are AEs of 
special interest requiring the collection/assessment of risk factors 
for postpartum hemorrhage, eCRFs for any event of 
postpartum hemorrhage, and clinical parameters related to 
postpartum hemorrhage. Evaluations will include outcomes 
such as time from delivery to expulsion of placenta and estimated 
blood loss. 
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: 
Unblinded safety data will be monitored by an IDMC. 
• 
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 postpartum hemorrhage (within  
24 hours of delivery) is estimated to be between 4% to 6% of 
mothers who delivered [ACOG, 2006]. 


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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
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 this study (200721 
[ZINN]) when delivery occurs at an investigative center to 
examine safety and efficacy outcomes in subjects with subclinical 
intrauterine infection based on histopathologic examination by a 
central laboratory. 
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 onf 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 
iInhibitors 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 are 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 have 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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Retosiban [e.g., GSK221149] 
Potential Risk of Clinical 
Significance 
Summary of Data / Rationale for Risk 
Mitigation Strategy 
Potential drug-drug interaction: 
In a clinical study with healthy subjects, co-administration of 
Administration of strong CYP3A4 inhibitors concomitantly 
Increased exposure of retosiban when 
retosiban with ketoconazole (a strong CYP3A4 inhibitor) 
with IP requires an adjustment to the retosiban dosing 
co-administered with inhibitors of 
increased the Cmax and AUC of retosiban, 5.2- and 8.7 fold, 
regimen (see Section 5.1.1.1 and the IB). Retosiban will only 
CYP3A4 
respectively. 
be given for 48 hours, limiting both maternal and fetal 
exposure. 
Potential drug-drug interaction: 
In healthy, nonpregnant females, co-administration of 
Administration of strong CYP3A4 inducers concomitantly 
Decreased exposure of retosiban 
intravenous retosiban with efavirenz (a moderate CYP3A4 
with IP requires an adjustment to the retosiban dosing 
when co-administered with inducers of 
inducer) increased the clearance of retosiban by 42% and 
regimen (see Section 5.1.1.1 and the IB). Retosiban will only 
CYP3A4 
reduced total exposure by 30% and peak exposure by about 20%. 
be given for 48 hours, limiting both maternal and fetal 
exposure. 
Potential decreased therapeutic effect 
Evidence of metabolic auto-induction has been observed with 
As 48-hour administration of retosiban has the potential to 
of drugs metabolized by CYP3A4 when 
repeat intravenous dosing of retosiban in women with preterm 
increase the rate of metabolism of drugs metabolized by 
co-administered with retosiban 
labor, as well as in healthy nonpregnant women given repeat oral 
CYP3A4, it is recommended that these drugs be monitored 
doses of retosiban over 2 weeks. 
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; CYP3A4 = cytochrome P450 3A4 enzyme; eCRF = electronic case report form; IB = investigator’s brochure; IP = investigational product; IDMC = 
independent data monitoring committee; P-gp = P-glycoprotein. 


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Table 2 
Potential Safety Concerns 
 
Potential Safety Concerns 
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. 
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 3.1., Study Design 
 
ThisZINN is a Phase III, randomized, double-blind, double-dummy, multicenter study. 
This study will be conducted in approximately 330 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. 
Prior to randomization, each subject will be stratified by progesterone treatment and GA 
determined by (1) known fertilization date, either in vitro fertilization or intrauterine 
insemination, or (2) last menstrual period a best estimated due date confirmed or 
established by the earliest ultrasound prior to 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. 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. 
The study ZINN will consist of 6 phases: Screening, Inpatient Randomized Treatment, 
Post-Infusion Assessment, Delivery, Maternal Post-Delivery Assessment, and Neonatal 
Medical Review (see schematic). The duration of any 1 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 
 


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1. 
Stratification (1:1) to retosiban or atosiban 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. 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion assessment 
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 atosiban) is allowed. 
 
 
The Screening Phase will occur on Day 0 and assessments will primarily focus on 
maternal and fetal safety evaluations prior to dosing. Subjects will be randomly 
assigned to treatment on Day 1 of tThe 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 managed per the investigator’s judgment. 
Subjects who do not experience labor progression and remain undelivered after 48 hours 
will be managed per the investigator’s judgment. For Subjects who remain undelivered 
subjects, after 48 hours will be scheduled for a face-to-face post-infusion assessment 
visit will be scheduled for maternal-fetal for obstetric assessments 1 week (±1 week 
acceptable range: 3 to 14 days) following the Inpatient Randomized Treatment Phase 
(Note: study documents may reference this visit as the 1-week face-to-face post- 
infusion assessment visit). The subject will then be contacted every week (±1 week) via 
telephone to determine if birth has occurred. If the subject delivers the baby prior to 
the face-to-face post-infusion assessment visit, central laboratory assessments for 
hematology, chemistry, and liver function tests (see Table 5) and the assessments for 
the Delivery Phase (see Section 3.1.4) will be performed. 
 
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. For those subjects who deliver at the investigative center, a 
placental tissue sample will be obtained at the time of delivery for central histopathology 
examination and a cord blood sample will be collected for potential genetic research and 
biomarker assays; if. If delivery occurs within 12 hours of investigational product (IP) 
(retosiban or atosiban) completion or discontinuation, the cord blood samples will also 
be used for the pharmacokinetic (PK) assessment, and, if required, a corresponding 
maternal blood sample will be collected for PK analysis (see Section 6.5.1). 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. A maternal post-delivery assessment will be conducted 
by telephone within 6 weeks (±2 weeks) of delivery. 
 
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) and the EQ-5D-5L (-2 weeks/+6 weeks). 
 
During the Neonatal Medical Review Phase, tThe neonatologist subinvestigator will 
conduct a comprehensive review of the newborn’s medical records, including any 
admission to an intensive or specialized care unit and any hospital readmission or 


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outpatient surgery, following discharge from an acute care setting from delivery through 
28 days EDD, where EDD is defined as 400/7 weeks’ gestation for all subjects. 
The parent/ subject or other legal guardian of the infant will also be asked to provide 
consent to participate in for a separate infant follow-up study to assess 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 face to-face post-infusion 
assessment visit (Note: In France, consent for the infant study is required during the 
Screening Phase, see Section 4.2 [inclusion criterion 1] and Section 3.1.1). 
 
An interim analysis will occur after 130 mother/infant pairs subjects have completed 
delivery and have time to-delivery results available all assessments. At the interim 
analysis, all available safety and efficacy data will be reviewed by an unblinded 
independent data monitoring committee (IDMC) who may make recommendations to 
terminate the study (see Section 9.8). Details of the interim analysis are provided in 
Section 8.3.4. Subjects will continue to be enrolled while the interim analysis is being 
conducted. 
 
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 based on (1) a clinically relevant reduction in the of contraction 
frequency of contractions without an increase in and/or intensity or (2) no change in 
the cervical dilation 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 (for details see Table 3). Investigators will be required to indicate in 
the electronic case report form (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 response. The 
duration of the treatment should not exceed 48 hours and the total dose should not exceed 
582 mg. 
 
Randomized treatment can be discontinued as outlined in Section 4.4.2. Subjects 
discontinuing randomized treatment will be managed according to the standard care and 
asked to remain on study through the Maternal Post-Delivery Assessment Phase. These 
subjects will also be asked to consent to the infant follow-up study, with the exception of 
subjects in France (see Section 4.2 and Section 3.1.1). 
 
 
Section 3.1.1., Screening Phase 
 
However, 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 the consent having been signed. Additionally, in 
France, subjects providing consent to participate in ZINN at Screening must also 
provide signed and dated written consent for their infant to participate in the infant 


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follow-up study (200722 [ARIOS]) (see Section 4.2). 
 
The GA will be determined by (1) known fertilization date, either in vitro fertilization or 
intrauterine insemination, or (2) last menstrual period a best estimated due date 
confirmed or established by the earliest ultrasound performed prior to 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 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 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. 
 
 
Section 3.1.2.1., Before Treatment 
 
Prior to dosing, the investigators must confirm the fetal heart rate pattern remains 
reassuring, the uterine contraction rate is not less than 4 contractions over a 30-minute 
interval, and the electrocardiogram (ECG) does not have clinically significant 
abnormalities (see Section 6.1). 
 
 
Section 3.1.2.3., End of Treatment 
 
If not already obtained, tThe subject or other legal guardian for the infant (both delivered 
and undelivered) will be asked to consent to participate in a separate long-term infant 
follow-up study for safety and neurodevelopment, if not already obtained. Note: In 
France, consent for the infant study is required during the Screening Phase (see 
Section 4.2 and Section 3.1.1). 
 
The study site staff will schedule the face-to-face post-infusion assessment visit for 
maternal-fetal obstetric assessments 1 week (±1 week acceptable range: 3 to 14 days) 
after the end of treatment (see Section 3.1.3). 
 
If the subject delivers the baby prior to the outpatient face-to-face post-infusion 
assessment visit, central laboratory assessments for hematology, chemistry, and liver 
function tests (see Table 5) and the assessments in Section 3.1.4 will be performed 
followed. 
 
 
Section 3.1.3., Post-Infusion Assessment Phase 
 
For sSubjects who have not delivered, the subject remain undelivered after 48 hours 
will return be scheduled for a face-to-face post-infusion assessment visit for maternal- 


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fetal obstetric assessments as part of the Post-Infusion Assessment Phase. The visit 
will be scheduled 1 week (±1 week acceptable range: 3 to 14 days) following her 
release from the acute care setting per the investigator’s judgment Inpatient 
Randomized Treatment Phase. See Section 3.1.2.3 for details on required 
assessments when the baby is delivered before the face-to-face post-infusion 
assessment visit. 
 
The subject will then be contacted every week (±1 week) via telephone to determine if 
she has delivered (see Section 3.1.4 for a summary of assessments performed at 
delivery). Note: This assessment should be completed remotely (by telephone); 
however, 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 a telephone assessment is due, this 
assessment may be completed face-to-face. 
 
 
Section 3.1.4., Delivery Phase 
 
For subjects who deliver at the investigative center, a placental tissue sample will be 
obtained at the time of delivery for central histopathologic examination and a cord blood 
sample will be collected for potential genetic research and biomarker assays; if. If 
delivery occurs within 12 hours of IP completion or discontinuation, the cord blood 
samples will also be used for the PK assessment (see SPM for information about how 
these samples will be collected), and, if required, a corresponding maternal blood 
sample will be collected for PK analysis (see Section 6.5.1). In addition, if a breast 
milk/colostrum sample will be collected for PK analysis in women who deliver at the 
delivery was investigative center and produce breast milk within 12 hours of after IP 
completion or discontinuation, a sample of breast milk/colostrum will be obtained if 
lactogenesis has occurred (see Section 6.5.3). 
 
 
Section 3.1.5., Maternal Post-Delivery Assessment Phase 
 
The subject will be contacted via telephone for the Maternal Post-Delivery Assessment 
Phase to be conducted within 6 weeks (±2 weeks) following delivery. Maternal 
assessments conducted at this contact will include the following: 
 
• 
Review of concomitant medications and medical/obstetric history (±2 weeks) 
• 
Recording of AEs and SAEs (maternal) (±2 weeks) 
• 
Recording of AEs and SAEs of neonate if discharged from hospital and through 
28 days post EDD (±2 weeks) 
• 
Status of breastfeeding (±2 weeks) 


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• 
Postnatal administration of the Edinburgh Postnatal Depression Scale (EPDS) and 
the EuroQol 5-dimensional 5-level (EQ-5D-5L) questionnaire (-2 weeks/+6 weeks) 
• 
Assessment of postpartum bleeding (±2 weeks) 
If not already obtained, tThe subject or other legal guardian will be asked to provide 
consent for the infant (whether delivered or undelivered) to participate in a separate 
infant follow-up study for safety and neurodevelopment, if not already obtained. Note: 
In France, consent for the infant study is required during the Screening Phase (see 
Section 4.2 and Section 3.1.1). 
 
 
Section 3.2.1.1., 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 treatment response is defined 
as based on (1) a clinically relevant reduction in the of contraction frequency of 
contractions without an increase in and/or intensity or (2) no change in the cervical 
dilation 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, 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 
(for details see Table 3). 
 
 
Section 3.2.2., Study Population 
 
Pregnant adolescents aged 12 to 17 years are included based on prior discussions with 
regulatory agencies, unless national or local regulations restrict the age for study 
enrollment to subjects 18 to 45 years (see Section 4.2). 
 
 
Section 4.2. Inclusion Criteria 
 
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK IP or other study treatment that may impact subject 
eligibility is provided in the IB and IB supplement(s) [GlaxoSmithKline Document 
Number CM2006/00201/05], the package insert for atosiban [Tractocile SmPC, 2013], 
and other pertinent documents. 
 
1. 
Signed and dated written informed consent is required prior to a subject’s 
participation in the study Study 200721 (ZINN) 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 


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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. 
 
French Subjects: Participation in Study 200721 (ZINN) also requires that the 
subject provide signed and dated written consent for her infant to participate 
in Study 200722 (ARIOS), a follow-up study assessing long-term safety and 
outcomes in infants born to mothers participating in retosiban treatment 
studies. 
 
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 labor (Note: This protocol includes pregnant adolescents, 
aged 12 to 17 years, as appropriate, unless based on national or local regulations 
restrict the age for study enrollment to subjects aged 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) last 
menstrual period a best estimated due date confirmed or established by the 
earliest ultrasound prior to 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 a 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 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 
 
4. 
SubjectsFemales must be diagnosed with preterm labor according to both of the 
following criteria (a or 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. 
confirmed by tocodynamometry Where tocodynamometry is not technically 
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: 


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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) consistenting of 
an increase of at least 25% effacement or 1 cm dilation 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 
 
• 
A 1-cm increase in cervical dilation by digital cervical 
examination 
 
 
 
Section 4.3., 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, 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 urine drug 
screen findings suggestive positive for of substance abuse that may either be 
implicated as the cause of preterm labor (e.g., abuse of cocaine, phencyclidine 
(PCP), or methamphetamines, or amphetamine) or have the potential to 
complicate the pregnancy outcome (e.g., alcohol abuse or opioid addiction) 
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 positive findings 
for substances other than cocaine, PCP, methamphetamine, or amphetamine 
is at the investigator’s discretion (examples include alcohol, cannabinoids, 
and opiates) 
910. 
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 
112. 
Women with documented active hepatitis B or hepatitis C viral infection, unstable 
liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones) 


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123. 
History of sensitivity to the IPs or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or GSK/PPD medical monitor, 
contraindicates their participation. 
 
 
Section 4.4., Withdrawal Criteria From Study and Discontinuation of IP 
The section describes and distinguishes the following: 
• 
Withdrawal of the subject from the study after randomization but before 
administration of IP (Section 4.4.1.1) and after administration of IP 
(Section 4.4.1.2) 
• 
Discontinuation of the IP (Section 4.4.2), 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. 
 
 
Section 4.4.1.1., 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 ECG cannot be dosed. and should 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. 
 
Dosing may be started before local liver function test results are available; however, if 
local laboratory results are available before the start of dosing and ALT is >2 × the upper 
limit of normal (ULN) or 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%. 
See Section 6.3.1 for liver stopping criteria for management of abnormal test results that 
become available after the start of dosing. 
 
 
Section 4.4.1.2., 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 GSK/PPD medical monitor. If a subject withdraws from the study, no additional 
visits can occur or procedures performed, and the subject may request destruction 


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of any samples taken; the investigator must document this request in the site study 
records. 
 
Subjects who are withdrawn after starting the Inpatient Randomized Treatment Phase and 
before the Post-Infusion Assessment Phase will be asked to return and complete the 
assessments specified for the face-to-face post-infusion assessment visit before 
withdrawing from the study (see Section 3.1.3 and Table 35). If the subject withdraws 
after the face-to-face post-infusion assessment visit, the investigator will attempt to 
contact the subject by telephone to determine if she has delivered and to gather the 
information specified in Section 3.1.4. 
 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also 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 based 
on previous noncompliance. 
 
In cases where the subject is deemed “Lost to Follow-up” (e.g., subject does not return 
for the rescheduled visit or cannot be reached to reschedule the missed visit), the site 
investigator or designee should 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) so that they can appropriately be 
withdrawn from the study. These contact attempts should be documented in the subject’s 
medical record. Should the subject continue to be unreachable, then and only then will 
he/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. 
 
 
Section 4.4.2., 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. 
 
The investigator should consult the PPD medical monitor prior to discontinuing any 
subject from the IP based on urine drug screen results that become available after the IP 
has been initiated. 
 
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 


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and safety. Once delivered, newborns will also continue to be followed for safety and 
outcomes through the 28 days post EDD. 
 
5. An abnormal corrected QT interval using 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 
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 
6. Abnormal liver function test result detected during standard care of the subject based 
on the criteria detailed in Section 6.3.1 the following criteria: 
 
• 
ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) 
• 
ALT ≥8 × ULN 
• 
ALT ≥3 × ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, or jaundice) or hypersensitivity (such as fever, rash, or 
eosinophilia) 
NOTE: The central laboratory report will include results for ALT, aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, and direct 
bilirubin. 
Subjects discontinuing the IP who have not yet delivered will continue in the study 
through delivery and the maternal post-delivery assessment. 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. Note: In France, consent 
for the infant study is required during the Screening Phase (see Section 4.2 and 
Section 3.1.1). 
 
 
 
Section 4.5., Subject and Study Completion 
 
A completed subject is defined as one who has completed all phases of the study (see 
Section 3.1 and Table 5). 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 4.4.2). 
 
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. 


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Section 5.1., Investigational Product and Other Study Treatment 
 
Table 3 
Retosiban Investigational Product and Other Study Treatment 
 
Product Name 
Retosiban Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
. . . 
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 based on (1) clinically 
relevant reduction in the 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 
intensityof 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. 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. 
For subjects receiving concomitant treatment with a potent 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. 
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 based on (1) clinically 
relevant reduction in the 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 
intensityof 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. 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. 
For subjects receiving concomitant treatment with a potent 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 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 


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Product Name 
Retosiban Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
For subjects receiving concomitant treatment with a 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. 
A list of strong, moderate, and weak CYP3A4 inhibitors and inducers 
is provided in Appendix 3. See the Study Pharmacy Manual for detailed 
instructions. 
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. 
A list of strong, moderate, and weak CYP3A4 inhibitors and inducers 
is provided in Appendix 3. See Study Pharmacy Manual for detailed 
instructions. 
CYP3A4 = cytochrome P450 3A4 enzyme; eCRF = electronic case report form; IV = intravenous; GSK = GlaxoSmithKline; NaCl = sodium chloride; PTM = placebo to match. 


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Table 4 
Atosiban Investigational Product and Other Study Treatment 
 
Product Name 
Atosiban Solution for Injection and Atosiban Solution for Infusion 
PTM 
IV Solution (0.9% NaCl) 
. . . 
Preparation instructions 
Withdraw 0.9 mL of a 0.9 mL labeled vial of atosiban 6.75 mg/0.9 mL 
solution for injection into a syringe. Label the syringe with the protocol 
number, subject number, infusion rate, and dosing session number. 
Withdraw 1025-mL solution from a 100250- mL 0.9% NaCl infusion bag 
and discard the solution. Replace the solution with 1025 mL of atosiban 
7.5 mg/mL concentrate solution for infusion from two five 5 mL vials to 
obtain a concentration of 0.75 mg/mL (187.5 mg atosiban in 100250 mL 
0.9% NaCl (0.75 mg/mL). The reconstituted product is a clear, colorless 
solution without particles. 
Label the IV bag with protocol number, subject number, infusion rate, and 
dosing session number. 
Prepare new 100250-mL bags in the same manner as described to allow 
the infusion to be continued. If an infusion bag with a different volume is 
used, a proportional calculation should be made for the preparation. 
Once the vial has been opened, the dilution must be performed 
immediately. Diluted solution for IV administration should be used within 
24 hours after preparation. 
See the Study Pharmacy Manual for detailed instructions. 
Withdraw 0.9 mL of 0.9% NaCl solution for injection into a syringe. Label 
the syringe with the protocol number, subject number, infusion rate, and 
dosing session number. 
The placebo admixture for continuous infusion will consist of a 0.9% NaCl 
infusion bag, labeled with the protocol number, subject number, infusion 
rate, and dosing session number. 
The volume of the 0.9% NaCl infusion bag should be matched to the 
0.9% NaCl infusion bag volume used for the atosiban admixture. 
See Study Pharmacy Manual for detailed instructions 


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Section 5.1.1.1., Retosiban 
 
A list of strong, moderate, and weak CYP3A4 inhibitors and inducers is provided in 
Appendix 3. 
 
 
 
Section 5.2., Managing Dose Interruptions 
 
Temporary interruptions of the IP are permitted. The following procedures should 
be followed in the event of a retosiban 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. 
For atosiban dose interruptions, resume the infusion at the same rate that was used 
before the dose interruption. 
 
Any changes in the dose rate, corresponding start and stop times, and the reason for 
an interruption must be recorded in the eCRF. 
 
 
 
Section 5.23., Treatment Assignment 
 
Subjects within each stratum will be randomly assigned in 1:1 ratio to receive either 
retosiban or atosiban using an interactive voice response system (IVRS)/interactive web 
response system (IWRS) in accordance with the randomization schedule. 
 
 
Section 5.34., Blinding 
 
The principal investigator or treating physician may unblind a subject’s treatment 
assignment only 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). 


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The principal It is preferred (but not required) that the investigator must first contact 
discuss options with the GSK/PPD medical monitor or appropriate GSK/PPD study 
personnel to discuss options before unblinding the subject’s treatment assignment. The 
PPD medical monitor will authorize the unblinding, and the treatment assignment will be 
provided. The date and reason for the unblinding must be recorded in the appropriate data 
collection tool. 
 
The PPD medical monitor may unblind the treatment assignment after discussing the 
rationale for unblinding with the principal investigator. However, in the event of an 
emergency, when it is not possible to contact the medical monitor, the investigator may 
contact the interactive voice response system and obtain subject-specific randomization 
information. Notification of unblinding will be sent to GSK, PPD, and the study center. 
 
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. 
 
 
Section 5.78., 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                5.78.1.5.,                 Strong                 CYP3A4                 Inhibitors 
A list of strong, moderate, and weak CYP3A4 inhibitors is provided in Appendix 3. 
 
 
Section                5.78.1.6.,                 Strong                 CYP3A4                 Inducers 
A list of strong, moderate, and weak CYP3A4 inducers is provided in Appendix 3. 
 
 
Section 5.78.2., Prohibited Medications and Nondrug Therapies 
 
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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Table 35 
Time and Events Table 
 
Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase12 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Every week 
(±1 week) (or 
early 
termination/ 
withdrawal) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks (±2 
weeks) after 
delivery3 
Delivery 
to 
28 days 
post EDD 
Clinical and Other Assessments 
Written informed 
consent and 
medical releases for 
treatment24 
X 
Discuss and request 
cConsent for 
participation in the 
infant follow-up study5 
X5 
X 
X 
Inclusion/exclusion 
criteria confirmation 
X 
X 
Subject demography 
X 
Medical history 
(including obstetrics 
history3) 6 
X 
X 
X 
X 
Urine drug screen47 
X 
X 
Physical examination 
(including height and 
weight) 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase12 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Every week 
(±1 week) (or 
early 
termination/ 
withdrawal) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks (±2 
weeks) after 
delivery3 
Delivery 
to 
28 days 
post EDD 
Cervical dilation based 
on digital 
examination58 
X 
X 
X 
X 
X 
Estimated fetal weight 
and head 
circumference via 
ultrasound 
X 
Determine AFI via 
ultrasound69 
X 
X 
Uterine contractions710 
X 
Schedule face-to-face 
post-infusion 
assessment visit 
X 
Investigational Products811 
Investigational product 
(retosiban or atosiban) 
X 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase12 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Every week 
(±1 week) (or 
early 
termination/ 
withdrawal) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks (±2 
weeks) after 
delivery3 
Delivery 
to 
28 days 
post EDD 
Efficacy Assessments 
Date and time of 
delivery 
X912 
Mode of delivery 
X912 
Indication for delivery 
X912 
Neonatal composite 
outcomes 
X 
Neonatal hospital 
stay 
X 
Maternal Safety Assessments 
Concomitant 
medications 
X 
X 
X 
ECG 12-lead1013 
X 
Vital sign 
measurements (BP, 
pulse rate, respiratory 
rate, and 
temperature)1114 
X 
X 
X 
X 
AEs/, SAEs, and 
DREs: maternal 
X 
X 
X 
Breastfeeding status 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase12 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Every week 
(±1 week) (or 
early 
termination/ 
withdrawal) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks (±2 
weeks) after 
delivery3 
Delivery 
to 
28 days 
post EDD 
Edinburgh Postnatal 
Depression Scale1215 
(maternal) 
X 
Local laboratory 
assessments (LFTs 
only)16 
X 
X 
Central laboratory 
assessments 
(including hematology, 
chemistry, and 
LFTs)1317 
X 
X 
X 
X17 
Local laboratory 
assessments (LFTs 
only)13 
X 
X 
Physical examination 
(brief) 
X 
Status of postpartum 
bleeding 
X 
Fetal Safety Assessments 
Electronic fetal heart 
rate monitoring14 
X18 
X19 
X19 
X19 
X20 
X21 
AEs/, SAEs, and 
DREs: fetal 
X 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase12 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Every week 
(±1 week) (or 
early 
termination/ 
withdrawal) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks (±2 
weeks) after 
delivery3 
Delivery 
to 
28 days 
post EDD 
Neonatal Safety Assessments 
AEs/, SAEs, and 
DREs: neonatal 
X 
X 
Neonatal Apgar Scores 
(1 and 5 minutes) 
X712 
Neonatal growth 
parameters 
X712 
Neonatal blood gases 
X712 
Health Outcome Assessments 
Maternal and neonatal 
health care resource 
use1522 
X 
X 
EQ-5D-5L (maternal) 
X 
X3 
Pharmacokinetic Assessments 
Maternal PK blood 
sample1623 
X1623 
X1623 
Cord blood sample1724 
X 
Breast milk/colostrum 
sample1825 
X 
Histopathology 
Placental tissue 
sample1926 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase12 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Every week 
(±1 week) (or 
early 
termination/ 
withdrawal) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks (±2 
weeks) after 
delivery3 
Delivery 
to 
28 days 
post EDD 
Biomarker Assessments 
Genetic research 
maternal blood sample 
for maternal DNA2027 
X 
Fetal fibronectin 
(optional)21 
X 
Blood sample for 
maternal inflammation 
biomarker 
X 
Biomarker and genetic 
cord blood sample2228 
X 
Other Assessments 
Fetal fibronectin 
(optional)2127 
X 
X 
Cervical length via 
transvaginal ultrasound 
(optional)2330 
X 
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; EPDS = Edinburgh Postnatal Depression Scale; EQ-5D-5L = EuroQol 5-dimensional 5-level questionnaire; IP = 
investigational product; LFT = liver function test; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of normal. 
1. 
For undelivered subjects who are subsequently diagnosed with recurrent preterm labor 24 hours or more following completion of the Inpatient Randomized 
Treatment Phase, retreatment with blinded IP is permitted at the discretion of the investigator (see Section 3.1.3.1). 
12. Subjects who remain undelivered after 48 hours Conducted when subject is discharged from an acute care setting, either to home or to a nonacute care setting; the subject will 
return for a face-to-face post-infusion assessment visit for maternal-fetal obstetric assessments 1 week (±1 week acceptable range: 3 to 14 days) following the Inpatient 


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Randomized Treatment Phase her release from the acute care setting. (Note: study documents may reference this visit as the 1-week face-to-face post-infusion 
assessment visit). The subject will then be contacted every week (±1 week) via telephone to determine 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. If the subject delivers the baby prior to the face-to-face post-infusion assessment visit, central laboratory 
assessments for hematology, chemistry, and LFTs and the assessments for the Delivery Phase (see Section 3.1.4) will be performed. 
3. 
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) and the EQ-5D-5L (-2 weeks/+6 weeks) (see 
Section 3.1.5 for list of assessments and visit windows). 
24.  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. 
5. 
The subject or other legal guardian for the infant will be asked to consent to participate in a separate long-term study to follow infants for safety and 
neurodevelopment outcomes. The subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant follow-up 
study at any time during the study that is appropriate and convenient. (Note: In France, consent for the infant study is required during the Screening Phase [see 
Section 4.2 and Section 3.1.1]). Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude involvement in the infant 
follow-up study. 
36. 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, tThe 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. 
47.   The urine drug screen will be performed locally using a point-of-care, qualitative testing device. 
58. 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. 
69. The abdominal ultrasound for determination of the AFI will be performed at Screening and within 12 hours of study treatment for all subjects. 
710. Uterine tocography or manual palpation (if necessary) will be performed prior to dosing to confirm the uterine contraction 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. 
811. Antenatal corticosteroid treatment should be administered in accordance with national, society, or institutional guidelines. Magnesium sulfate for fetal neuroprotection can be given 
at the discretion of the investigator. 
912. Information regarding delivery will be obtained through a review of the hospital and medical records. Growth parameters include neonatal weight, length, and head 
circumference. 
103. 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. 
114. 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, All vital signs will be assessed and recorded within the 
following windows relative to the start of the infusion: every 15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the time of any dose changes, 


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at the end of the infusion, at the time of any dose changes, and as warranted by a medical condition or AE as part of maternal safety monitoring during the treatment phase. It is 
suggested (but not required) that oxygen saturation also be assessed at Screening and recorded in source documents. 
125. Maternal subjects will complete tThe Edinburgh Postnatal Depression Scale EPDS, a self-reported questionnaire, must be administered to mothers at the maternal follow-up 
assessment 6 weeks(±2 weeks-2 weeks/+6 weeks) after delivery. 
136. 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 of 
the investigational product 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 6.3.1) if ALT or bilirubin is abnormal. In addition, laboratory values for 
hematology, chemistry, and LFTs will be determined through a central laboratory. 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 post-infusion visit, central laboratory assessments for hematology, chemistry, and LFTs should be 
performed. 
17. 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 6.3.1). 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. 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. 
148. Prior to dosing, if the fetal heart rate pattern is nonreassuring, the subject cannot be dosed. Fetal heart rate monitoring will be continuous throughout the Inpatient Randomized 
Treatment Phase. If the subject has not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate monitoring will occur at the face-to-face post-infusion 
assessment visit. 
19. 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 02 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 6.3.11.3). 
20. If the subject has not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate (fetal Doppler heart rate or cardiotocography are both 
acceptable) 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 6.3.11.3). 
21. 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 6.3.11.3). 
1522. 
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. 
1623. 
PK samples will be taken at the following sampling windows (relative to the start of the infusion): 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 to 504 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. A maternal 
blood sample should be collected at the same time as the cord blood sample (see Section 6.5.1) if the sample time does not already coincide with one of the PK 
sampling windows. 
1724. 
In subjects who deliver at an investigative center within 12 hours following completion or discontinuation of the investigational product IP, the cord blood sample will also be 
divided for PK analysis as well as genetic (if additional consent is provided; see Appendix 1) and biomarker analyses. 


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1825. 
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 investigational 
product IP. 
1926. 
A placental tissue sample will be collected at delivery in subjects who deliver at an investigative center. 
207. A maternal blood sample for genetic research will only be collected from subjects who provide separate informed consent (see Appendix 1). 
28. A cord blood sample will be collected in subjects who deliver at an investigative center, if additional consent is provided. 
219. Testing for fetal fibronectin will be performed only at those institutions collecting the information as routine practice. 
22. A cord blood sample will be collected in subjects who deliver at an investigative center. 
230. Cervical length measured by transvaginal ultrasound will be captured only at those institutions collecting the information as routine practice. Cervical length will not be used to 
determine study eligibility. 


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Section 6.1., 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 4.2). A that the 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 (see Section 4.2). 
• 
Liver function tests from a local laboratory to confirm that ALT is not ≥2 × ULN OR 
bilirubin is not >1.5 × ULN (>35% direct bilirubin), if available (see Section 6.3.1). 
An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and 
direct bilirubin is <35%. Dosing may be started prior to the availability of these 
results. 
• 
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 4.4.1). 
 
 
Section 6.2., Efficacy 
 
Collection of efficacy endpoint data requires a thorough review of the hospital medical 
records. Review of the maternal hospital record is the responsibility of the investigator 
obstetrician and review of the newborn hospital record is the responsibility of the 
subinvestigator neonatologist. 


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Section 6.2.1., 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 
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. 
 
 
 
Section 6.2.2., 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. 
 
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 6.2.4) 
• 
Hospital length of stay 
• 
Neonatal admission to a specialized care unit and length of stay 
• 
Newborn hospital readmission and length of stay 
• 
Ambulatory surgery 
 
 
Section 6.2.4., Key Secondary Efficacy Endpoints 
 
• 
Retosiban clearance and volume of distribution and the effect of covariates on 
these parameters 


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Section 6.2.4., Exploratory Efficacy Endpoints 
 
• 
Proportion of subjects requiring increase in infusion rate 
• 
Proportion of subjects receiving retreatment 
• 
Proportion of subjects with improved health status based on the EQ-5D-5L 
A complete list of exploratory endpoints will be provided in the reporting and 
analysis plan (RAP). 
 
 
 
Section 6.3., Safety 
 
Fetal: 
 
• 
Follow-up AFI determined by abdominal ultrasound 
• 
Incidence of reported AEs, including SAEs 
• 
Fetal acidosis 
Neonatal: 
 
• 
IVH/periventricular leukomalacia with cysts or porencephaly 
• 
Necrotizing enterocolitis (any modified Bell’s staging criteria) 
 
 
Section 6.3.1., Liver Chemistry Stopping and Follow-Up Criteria 
 
Blood samples draws will be collected obtained for central laboratory evaluation at 
Screening (prior to treatment,) during Day 2 of the randomized treatment phase, and at 
the face-to-face post-infusion assessment visit for additional liver function testing in 
order to ensure assure subject safety and to evaluate liver event etiology consistent (in 
alignment with the US Food and Drug Administration premarketing clinical liver safety 
guidance); 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ 
Guidances/UCM174090.pdf. 
 
At Screening, before IP administration, ALT and bilirubin test results liver function 
tests from a local laboratory, including ALT and bilirubin, 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: 
 
• 
1. ALT ≥2 × ULN OR 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 1 to 3 are defined below and are presented 
in Figure 3 and a figure in Appendix 2. 


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The local and central laboratory liver function test results should be reviewed for the 
abnormalities shown in Figure 3 listed below. 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 following liver chemistry stopping criteria shown in Figure 3 and detailed in 
Appendix 2.: 
 
NOTE: The central laboratory report will include results for ALT, aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, and direct 
bilirubin. 
 
Figure 3 
Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
 
 
 
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. 
 
1. ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) 
2. ALT ≥8 × ULN 
3. ALT ≥3 × ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 
NOTE: The central laboratory report will include results for ALT, AST, ALP, total 
bilirubin, and direct bilirubin. 
Continue Study Treatment 
No 
Yes 
ALT≥3×ULN 
Plus 
Bilirubin 
≥2×ULN (>35% 
direct) 
or plus 
INR>1.5, if 
measured* 
Possible 
Hy’s Law 
No 
Plus 
Symptoms of 
liver injury 
or        
hypersensitivity 
No 
ALT 
≥8×ULN 
No 
ALT≥3×ULN but 
<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 


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In the event liver function test results from either the local or central laboratory reveal 
abnormalities consistent with the liver chemistry stopping criteria 1 to 3 listed above 
during the randomized treatment phase, investigators should complete the following 
actions: 
 
• 
Immediately discontinue study treatment in the unlikely event that subject is 
receiving the IP 
• 
Report the event to GSK/PPD within 24 hours of learning its occurrence (see 
Table 3 and Section 6.3.8) 
• 
Complete the liver event and SAE eCRFs, where applicable (see Section 6.3.10). All 
events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct), termed “Hy’s 
Law,” must be reported as an SAE. 
• 
Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed 
• 
Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below 
• 
Do            not            restart             IP 
In addition, for criterion 1, do the following: 
• 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring 
• 
A specialist or hepatology consultation is recommended 
• 
Monitor subjects twice weekly until liver chemistries (ALT, AST, ALP, bilirubin) 
resolve, stabilize, or return to within baseline values 
For those subjects meeting criteria 2 or 3, do the following: 
 
• 
Make every reasonable attempt to have subjects return to clinic within 24 to 72 hours 
for repeat liver chemistries and liver event follow up 
• 
Monitor subjects weekly until liver chemistries (ALT, AST, ALP, bilirubin) resolve, 
stabilize, or return to within baseline values; criterion 3 subjects should be monitored 
as frequently as possible. 
For those subjects with ALT ≥3 × ULN but <5 × ULN and bilirubin <2 × ULN without 
hepatitis symptoms or rash and who can be monitored weekly for 4 weeks: 
 
• 
Notify the GSK/PPD medical monitor within 24 hours of learning of the abnormality 
to discuss subject safety and determine if the subject should be excluded from the 
option for retreatment (see Section 3.1.3.1) 
• 
Must return weekly for repeat liver chemistries (ALT, AST, ALP, bilirubin) until 
they resolve, stabilize, or return to within baseline values 
• 
If at any time these subjects meet the liver chemistry stopping criteria, proceed with 
the follow up procedures as described above 


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• 
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 
values 
For criteria 1 to 3, make every attempt to carry out the liver event follow up assessments 
described below: 
 
• 
Viral hepatitis serology including: 
• 
Hepatitis A immunoglobulin M (IgM) antibody 
• 
Hepatitis B surface antigen and hepatitis B core antibody (IgM) 
• 
Hepatitis C RNA 
• 
Hepatitis E IgM antibody 
• 
Cytomegalovirus IgM antibody 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing) 
• 
Blood samples for PK analysis will be taken at the following sampling windows 
(relative to the start of the infusion): 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 
48 to 50 hours. Record the date/time of the PK blood sample draw and the date/time 
of the last dose of IP prior to blood sample draw in 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 SPM 
• 
Serum creatine phosphokinase and lactate dehydrogenase 
• 
Fractionate bilirubin, if total bilirubin 2 × ULN 
• 
Obtain complete blood count with differential to assess eosinophilia 
• 
Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia as relevant on the AE eCRF 
• 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
eCRF 
• 
Record alcohol use on the liver event alcohol intake eCRF 
The following are required for subjects with ALT 3 × ULN and bilirubin 2 × ULN 
(>35% direct) but are optional for other abnormal liver chemistries: 
 
• 
Antinuclear antibody, antismooth muscle antibody, and type 1 anti-liver kidney 
microsomal antibodies 
• 
Serum acetaminophen adduct high performance liquid chromatography assay 
(quantifies potential acetaminophen contribution to liver injury in subjects with 
definite or likely acetaminophen use in the preceding week [James, 2009]) 


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• 
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 antibody. NOTE: 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] 
• 
Liver imaging (ultrasound, magnetic resonance, or computed tomography) to 
evaluate liver disease 
 
 
Section 6.3.1.1., 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. 
 
 
 
Section 6.3.2.3., 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 AE eCRFs pages unless they are already captured on 
specifically designated in addition to the AE/SAE eCRF pages such as those to capture 
additional details for the efficacy safety analyses. 
 
Maternal, fetal, and neonatal AEs of special interest are listed in Section 6.3. Guidelines 
for reporting these events are provided in Appendix 4. 
 
 
 
Section 6.3.4., Cardiovascular Events 
 
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. This The cardiovascular information should be recorded 
on in the specific cardiovascular section of the eCRF within 1 week of receipt of a 
cardiovascular event data query prompting its completion when the AE/SAE(s) are 
first reported. 
 
 
Section 6.3.5., Death Events 
 
This information should be recorded on the specific 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 first 
reported. 


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Section 6.3.7.1., 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) 
• 
PPROM 
 
 
Section 6.3.7.2., 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 
• 
RDS 
• 
Bronchopulmonary dysplasia 
• 
Apnea (severe) 
• 
Respiratory failure due to fatigue, hypoxia, or air leak from alveolar injury 
• 
Cardiovascular 
• 
Patent ductus arteriosus 
• 
Bradycardia 
• 
Hypotension 
• 
Neurological 
• 
IVH (all grades) 
• 
Periventricular leukomalacia with cysts or porencephaly 
• 
Ventriculomegaly 
• 
Cerebellar hemorrhage 
• 
Hydrocephalus other than congenital 
• 
Hypoxic ischemic encephalopathy 
• 
Gastrointestinal 
• 
Necrotizing enterocolitis (any modified Bell’s staging criteria) 
• 
Gastroesophageal reflux 
• 
Aspiration pneumonia 
• 
Hematologic 
• 
Anemia (severe) 


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• 
Vision 
• 
Retinopathy of prematurity (all stages) 
• 
Auditory 
• 
Hearing disorder 
• 
Other 
• 
Temperature instability 
• 
Hypoglycemia 
• 
Hyperbilirubinemia 
Because these events (Section 6.3.7.1 and Section 6.3.7.2) 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 an SAE). 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 team. However, if one or all of the following conditions apply, then the 
event should be reported as an AE/SAE using the standard process, as summarized in 
Section 6.3.11: 
 
 
Section 6.3.8., Time Period and Frequency of Detecting AEs and SAEs 
 
The investigator or site staff is responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE. 
 
Adverse events and SAEs will be collected from the start of study treatment and until the 
follow up contact (see Section 6.3.10) 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. 
 
Serious AEs will be collected over the same time period as stated above for AEs. 
However, aAny SAEs assessed as related to study participation (e.g., study treatment, 
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product concomitant medication, 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 
Section 6.3.101. 
 
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 


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event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK/PPD. 
 
 
 
Section 6.3.10., 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 6.3) 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 4.4.1.2). 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 the SPM. 
 
 
 
Section 6.3.101., Prompt Reporting of SAEs and Other Events to GSK/PPD 
 
Table 6 
Reporting of Serious Adverse Events and Other Events to 
GSK/PPD 
 
ALT = alanine aminotransferase, CV = cardiovascular; DRE = drug disease-related event, eCRF = electronic case 
report form; GSK = GlaxoSmithKline; INR = International normalized ratio, SAE = serious adverse event, ULN = 
upper limit of normal. 
The contact information for reporting SAEs is as follows: 
 
Issue 
Latin America All 
Countries/Regions Contact 
Europe/Asia Contact 
Serious Adverse Event 
Reporting 
24-Hour Safety SAE Hotline: 
PPD 
PPD 
Safety SAE Fax: 
Safety Hotline: 
PPD 
Safety Fax: 
PPD 
PPD 
PPD 
 
Section 6.3.112.1., Physical Examination 
 
An admission physical examination will include at 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 face-to-face post-infusion assessment visit, following conclusion 
of the treatment phase. 


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Section 6.3.112.2.,Vital Sign Measurements 
 
Blood pressure, pulse rate, respiratory rate, and temperature will be measured at the 
following time points during the study: 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 time of any dose changes, at the end of the infusion, and as warranted by a medical 
condition  or  AE),  and  at  the  face-to-face  post-infusion  assessment  visit.:  15  to    
30 minutes, 4 to 8 hours, and 20 to 24 hours after the start of the infusion, at the 
time of any dose changes, at the end of the infusion, and as warranted by a medical 
condition. Subjects may be either in a semirecumbent or seated position. It is suggested 
(but not required) that oxygen saturation also be assessed at Screening and recorded 
in source documents. 
 
 
 
Section 6.3.112.3., 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 bolus of 
the IP. 
 
Electronic fetal monitoring, including the Ffetal 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 6.3.11.2). The electronic 
fetal heart rate tracing (paper or electronic) must be archived and retained in site 
records. Fetal heart rate (fetal Doppler heart rate or cardiotocography are both 
acceptable) will be recorded, will be monitored continuously from Screening to time of 
delivery or discharge from the acute care setting. 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 
monitoring will also be performed at the 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, 2009] will be reported as an AE of special interest on a 
specified eCRF in addition to the corresponding AE or SAE eCRF: 
 
Category II fetal heart rate tracings include all fetal heart rate tracings not categorized as 
Category I or III. Category III tracings may represent an appreciable fraction of those 


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encountered in clinical care. Examples of Category II fetal heart rate tracings include any 
of the following: 
 
 
Section 6.3.112.4., 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 4.3) and within 12 hours of study 
treatment for all subjects. If a subject discontinues IP before the end of the treatment 
phase, the follow-up abdominal ultrasound for AFI determination should be performed 
within 4 hours of IP discontinuation. If a subject delivers or membranes rupture during IP 
administration and before the follow-up AFI has been completed, a follow-up abdominal 
ultrasound is no longer applicable, and the reason for not determining the AFI will be 
captured in the eCRF. An abdominal ultrasound to assess fetal growth will be done at 
Screening (unless records are available documenting an ultrasound derived estimated 
fetal weight within 1 week of Screening, with the results and date of assessment recorded 
in the eCRF). 
 
 
Section 6.3.112.5., Laboratory Assessments 
 
With the exception of the above, all protocol required laboratory assessments, as defined 
in Table 3, must be performed by the central laboratory. For subjects that do 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. 
 
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 biological samples collected over the course of the study that are directly 
related to the conduct and analysis of the study, including hematology and 
chemistry tests, liver function tests, and urine drug screening are summarized 
further in Appendix 5. 
 
 
 
Section 6.3.112.6., 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 


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significant ECG abnormality, the subject will not be dosed and will be withdrawn from 
the study. Performance of a follow-up ECG after an abnormal finding will be at the 
discretion of the investigator. 
 
 
Section 6.3.112.8., Maternal Depression 
 
A score of 12+ indicates an increased probability of depression and investigators or 
designated study center personnel will be notified immediately in order to follow-up 
with the subject to ensure safety. Certain items in the scale also assess anxiety and will 
be used to assess level of anxiety. The EPDS will be administered to mothers at the 
maternal follow-up assessment 6 weeks (2 -2 weeks/+6 weeks) post-delivery 
(Table 35). 
 
 
Section 6.4., Health Outcomes 
 
• 
Assess maternal health status (EQ-5D-5L) at time of IP administration and 6 weeks 
(2 -2 weeks/+6 weeks) after delivery 
 
 
Section 6.4.1.2., Maternal Subject Reported Health Assessments 
 
This information can be used as a quantitative measure of health as judged by the 
individual respondents. The EQ-5D-5L will be administered to mothers early in the drug 
delivery phase (while the mother is still in active preterm labor) and at the maternal 
follow-up assessment 6 weeks (2 -2 weeks/+6 weeks) after delivery (Table 35). 
 
 
Section 6.5., 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-DMPK Drug Metabolism and Pharmacokinetics/Scinovo, the 
details of which are included in the SPM. Concentrations of retosiban will be determined 
in plasma samples using the currently approved bioanalytical methodology. Raw data 
will be archived at the bioanalytical site (detailed in the SPM). 
 
The samples collected for PK analyses are summarized further in Appendix 5. 
 
 
 
Section 6.5.1., Sampling 
 
Maternal Bblood samples (approximately 2 mL) for the quantification of retosiban in 
plasma will be taken at the following sampling windows (relative to the start of the 


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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. In 
addition, a PK sample (approximately 2 mL) should be taken at the onset of any maternal 
or fetal SAE that occurs within 24 hours after the end of the infusion. 
 
Additionally, a maternal blood sample should be collected at the same time as the 
cord blood sample (see Section 6.5.2) 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. 
 
 
 
Section 6.5.2., Umbilical Cord Blood 
 
For those subjects who deliver at the investigative center, a single cord blood sample will 
be collected and divided for biomarker assays (Section 6.8) and for potential genetic 
research and biomarker assays (Section 6.9). If subjects deliver at the investigative 
center; if delivery occurs within 12 hours following of the IP completion or 
discontinuation of IP, a the cord blood sample will also be used for a PK assessment of 
fetal drug exposure. 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 sampling for the study. 
 
Samples from retosiban-treated subjects with concomitant use of inhibitors of BCRP 
breast cancer resistance protein or P-gp p-glycoprotein will be analyzed for drug-drug 
interactions. The date and time of the sample should be noted in the eCRF. 
 
 
Section 6.5.3., Retosiban Levels in Breast Milk 
 
If breast milk/colostrum is expressed within 12 hours of receiving the completion or 
discontinuation of the 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 within prior to 4 hours of receiving the completion 
or discontinuation of the study treatment will not be permitted to be consumed but 
will be collected for evaluation. 
• 
A sample of breast milk/colostrum produced between 4 and 12 hours from receiving 
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 receiving the 
completion or discontinuation of the study treatment. 


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• 
Breast milk produced more than 12 hours after receiving 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. 
 
Section 6.6., 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 will not be used 
to determine eligibility but 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. 
 
 
Section 6.7., Biomarkers 
 
Section 6.7.1., Fetal Fibronectin 
Section 6.87.2., Other Biomarkers 
Other biomarkers as measured at the screening assessment in the maternal serum (such as 
interleukin-6) that may predict the relationship of time to delivery or inflammation in the 
fetus and outcomes based on treatment may be obtained. 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 maternal blood sample 
for biomarker research will be collected at Screening and a cord blood sample for 
biomarker research will be collected during the Delivery Phase. The samples will be 
stored and may be analyzed in the for future for exploratory laboratory biomarkers 
research. 
 
The blood samples collected for biomarker analyses are summarized further in 
Appendix 5. 
 
 
 
Section 6.98., Genetic Research 
 
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. At Screening (Day 0), a 6-mL maternal blood sample for maternal 
DNA will be collected in subjects who provide informed consent for potential genetic 
sampling research. In addition, for those subjects who deliver at the investigative center, 
a cord blood sample will also be collected for potential genetic assays. 


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Additional information regarding genetic research is included in Appendix 1 and 
Appendix 5. 
 
 
Section 8.1., Hypotheses 
 
The hypotheses will be tested at 5% level with a 2-sided test. 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 
sequential testing method will be used to adjust for multiplicity of key secondary 
endpoints such that the type I error rate will be maintained at 5%. Refer to Section 
8.3.5.1.2 for details of key secondary analysis. 
 
 
Section 8.3.5.1.2., Secondary Analysis 
Key Secondary Analysis 
The key secondary analysis for this study includes the 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, and composite neonatal morbidity and mortality. 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 
sequential testing method 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 sequential testing 
examines the hypothesis testing in a prespecified order, i.e., the testing of the second 
secondary endpoint will be performed only if the first secondary endpoint is 
significant at 5%, and testing of the third secondary endpoint will be performed 
only if the first and second endpoints are significant at 5%. The exact order of 
sequential testing will be detailed in the RAP. 
 
 
 
Section 9.2., Regulatory and Ethical Considerations, Including the Informed 
Consent Process 
 
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical guiding principles that are outlined in the of the current 
version of Declaration of Helsinki 2008, including, but not limited to: 
 
 
Section 10., 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. 


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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. 
 
 
 
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. 
 
 
 
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. 
 
 
 
GlaxoSmithKline Document Number CM2006/00201/035 Investigator’s brochure. 
GSK716755. 29-Jun-20164. 
 
 
Samol JM, Lambers DS. Magnesium sulfate tocolysis and pulmonary edema: the 
drug or the vehicle? Am J Obstet Gynecol. 2005;192(5):1430-2. 
 
 
 
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-e10. 
 
 
 
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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Yes 
Continue IP 
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values 
Yes ALT<3xULN 
+ bilirubin 
<2xULN 
after ≤ 4 
wks? 
 
No 
 
Notify GSK within 24h 
to discuss subject 
safety; continue IP; 
check liver chemistry 
weekly for 4 weeks 
Yes 
Able to 
monitor 
weekly for 
4 weeks? 
Yes 
No 
ALT>3xULN 
plus 
bilirubin >2x 
ULN (>35% 
No 
direct) (or plus No Hepatitis 
INR >1.5, if 
measured)* 
symptoms 
or rash? 
No 
ALT 
>8xULN 
ALT 
No >5xULN 
but 
<8xULN 
Yes 
ALT >5 
Able to 
and 
monitor 
Yes <8xULN No 
Yes   weekly for  
for > 2 
> 2 wks? 
wks 
No** 
 
Yes 
ALT>3xULN 
but <5xULN + 
bilirubin 
<2xULN+no 
symptoms 
No 
Yes
Yes 
• Instruct subject to stop investigational product (IP) 
• Notify GSK and arrange clinical followup within 24h 
• Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
• Report as SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed. 
• Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values 
• Consultation with hepatologist/specialist recommended 
• Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug 
• Instruct subject to stop investigational product (IP) 
• Notify GSK within 24h and arrange clinical followup 
within 24-72h 
• Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
• Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if 
tests performed. 
• Obtain weekly liver chemistries [**as far as possible in 
these subjects] until resolved, stabilised or returned to 
baseline 
• Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug 
*INR value not applicable to subjects on anticoagulants 
Section 11.2., Appendix 2: Liver Chemistry Stopping and Follow-up Criteria 
OLD 
Phase III-IV Liver Safety Algorithms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NEW 
 
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 


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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 
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, 
• 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 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 


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AE = adverse event; 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 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. 
 
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 
• 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 
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 
resonance, or computed tomography) 
and/or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms. 


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monitored weekly for 4 weeks. 
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. 
 
 
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. 
 
 
 
Section 11.3., Appendix 3: 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  5.1  and 
Section 5.1.1.1). 
 
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. 


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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 
Quinidine 
Ranitidine 


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Strong1 
(Requires Adjustment to 
Dosing Regimen) 
Moderate2 
Weak3 
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 the 
investigational product with a strong inhibitor or strong inducer requires an adjustment to the retosiban 
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 11.4., Appendix 4: 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; PPROM = preterm premature rupture of membranes; RDS = respiratory distress syndrome; SAE = serious adverse event. 
 
 
178 
ZINN SAFETY REPORTING CHEAT SHEET 


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11.5. Appendix 5: Summary of Human Biological Samples 
 
Appendix 5 categorizes human biological samples as 1) those for which the results 
are directly related to the conduct and analysis of the study and 2) those collected 
and stored for future exploratory analyses. Human biological samples directly 
related to the study conduct and analysis include those for eligibility determination 
and safety, pharmacokinetics, and placental pathology. Human biological samples 
collected and stored for biomarker and genetic testing are categorized under future 
exploratory analyses. Appendix 5 also provides information regarding labeling and 
subject anonymization. Shipping location information for each sample is provided 
in the Study Procedures Manual. 
 
The investigator should refer to the laboratory manual for complete information on 
sample collection and preparation, packaging and labeling, and shipping. 
 
Human Biological Samples Directly Related to the Conduct and Analysis of the 
Study: 
 
• 
Hematology and Chemistry: Maternal blood samples for hematology and 
chemistry, including liver function studies, will be collected during Screening, 
Day 2 of dosing, at the optional retreatment visit (if applicable), and the face-to- 
face post-infusion assessment visit. Labels will be customized for each test and 
include the protocol number, subject identification number, visit description, 
and date and time of collection. 
• 
Liver Function: A maternal blood sample for liver function studies will be 
collected during Screening and sent to the hospital laboratory for analysis. 
Normal results are required to initiate dosing or continue dosing if dosing has 
begun before results are available. In the event liver function test results from 
either the local or central laboratory reveal abnormalities consistent with the 
liver chemistry stopping criteria defined in Protocol Section 6.3.1 and  
Appendix 2, additional samples will be analyzed for hepatitis A 
immunoglobulin M (IgM) antibody, hepatitis B surface antigen, hepatitis B core 
antibody (IgM), cytomegalovirus (CMV) IgM antibody, hepatitis C RNA, 
hepatitis E IgM antibody, Epstein-Barr viral (EBV) capsid antigen IgM 
antibody, creatine phosphokinase, lactate dehydrogenase, and complete blood 
count with differential. 
If liver function test results reveal alanine aminotransferase (ALT) ≥3 × the 
upper limit of normal (ULN) AND bilirubin ≥2 × ULN (>35% direct bilirubin; 
an isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and 
direct bilirubin is <35) samples will also be analyzed for the following: 
• 
Antinuclear antibody, antismooth muscle antibody, type 1 antiliver kidney 
microsomal antibodies, and total immunoglobulin G (IgG) 
• 
If chronic hepatitis B is identified at study entry by a positive hepatitis B 
surface antigen, blood samples will be assayed for hepatitis B DNA and hepatitis 
delta antibody. 


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• 
Serum acetaminophen in subjects with definite or likely acetaminophen use in 
the preceding week. 
Labels will be customized for each test and include the protocol number, subject 
identification number, descriptor as initial liver event assessment or follow-up, 
and date and time of collection. 
• 
Urine Drug Screen: A urine sample will be collected during Screening in order 
to assay for ethanol and other substances of abuse for eligibility determination. 
The urine drug screen will be performed locally using a point-of-care, 
qualitative testing device. 
• 
Pharmacokinetic Samples: 
1. Maternal blood samples for quantification of retosiban plasma concentrations 
will be collected 2 to 4 hours, 10 to 14 hours, 22 to 26 hours, and 48 to 54 hours 
after initiation of the infusion. 
2. An umbilical cord blood sample for quantification of retosiban plasma 
concentrations will be collected in subjects who deliver at the investigational 
center within 12 hours of investigation product (IP) completion or 
discontinuation. Additionally, a maternal blood sample should be collected at 
the same time as the cord blood sample (see Section 6.5.2) if the sample time 
does not already coincide with one of the PK sampling windows listed above. 
3. A breast milk/colostrum sample for a semi-quantitative retosiban assay will be 
collected in subjects who deliver at the investigational center within 12 hours of 
IP completion or discontinuation and are expressing breast milk/colostrum. 
4. Maternal blood sample for quantification of retosiban plasma concentration 
within 12 hours of exposure in subjects who meet liver chemistry stopping 
criteria defined in Protocol Section 6.3.1. 
Labels will be customized for each test and include the protocol number, subject 
identification number, visit description, and date and time of collection. 
 
• 
Placental Pathology: A placental tissue sample will be collected for pathologic 
examination when delivery occurs at an investigational center. Gross 
examination of the intact placenta, umbilical cord, and membranes will be 
performed by the hospital pathology department with gross findings reported in 
a standardized manner. The hospital pathology department will also prepare 
tissue samples for histologic examination of placenta, membranes, and umbilical 
cord. Labels will be customized and include the protocol number, subject 
identification number, visit description, and date and time of collection 
Human Biological Samples for Optional Future Biomarker and Genetic Testing: 
 
Biomarker and genetic testing will be performed in relation to the study treatment 
and preterm labor condition. 
 
• 
Biomarker Samples: 
1. Maternal blood samples for biomarker analysis will be collected for all subjects 


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during Screening. 
2. An umbilical cord blood sample for biomarker analysis will be collected in 
subjects who deliver at the investigational center. 
Labels will be customized for each test and include the protocol number, subject 
identification number, visit description, and date and time of collection. 
• 
Genetic Samples: 
1. Maternal blood samples for genetic analysis will be collected during Screening 
for subjects who consent to participate. Refer to Appendix 1 for a description of 
genetic testing objectives, assessments and procedures, subject participation, 
and confidentiality of data. Labels will be customized for each test and include 
the protocol number, subject identification number, visit description, and date 
and time of collection. 
2. An umbilical cord blood sample for genetic analysis will be collected in subjects 
who deliver at the investigational center. Labels will be customized for each test 
and include the protocol number, subject identification number, visit 
description, and date and time of collection. 
 
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 the 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. 
• 
Clarify that an abdominal ultrasound to assess fetal growth is needed at Screening or 
before retreatment unless the most recent ultrasound is within 3 weeks (21 days) 
before the date of randomization or the date of retreatment. 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 or retreatment. 


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• 
Updated the list of maternal drug-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. 
• 
Removed changes detailed in the country-specific amendment for sites in France 
because subjects in this country will not be recruited for this study. 
• 
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 
Sponsor Information Page 
Sponsor Medical Monitor Contact Information and Sponsor Serious Adverse 
Events (SAE) Contact Information: 
 
Issue 
Latin America Contact 
Europe/Asia Contact 
Safety Questions 
PPD 
MD 
Medical Director, Medical Affairs and 
Pharmacovigilance 
PPD 
Buenos Aires, Brazil 
Europe: PPD 
MD, 
MFPM 
Associate Medical Director, Medical 
Affairs and  Pharmacovigilance 
PPD 
Sofia, Bulgaria Warsaw, Poland 
Asia: PPD 
MD 
Associate Medical Director, Medical 
Affairs and Pharmacovigilance 
PPD 
Kuala Lumpur, Malaysia 
24-Hour Safety Hotline: 
PPD 
Safety Fax: 
Safety Hotline: 
PPD 
Safety Fax: 
PPD 
PPD 
SAE Reporting 
24-Hour SAE Hotline: PPD 
SAE Fax: PPD 
 
List of Abbreviations 
PCP phencyclidine 
Protocol Summary, Study Design 
 
For undelivered subjects who are subsequently diagnosed with recurrent preterm labor 
following the Inpatient Randomized Treatment Phase, retreatment with blinded 
investigational product (IP) is permitted. Retreatment is limited to a single repeat course 


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of the blinded IP to which the subject was originally randomly assigned, either retosiban 
or atosiban. Retreatment is only permitted if the subject presents prior to 336/7 weeks’ 
gestation and meets all the eligibility criteria specified in the Time and Events Table. 
 
The subject or other legal guardian for the infant will also be asked to consent to 
participate in a separate 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 face 
to-face post-infusion assessment visit. (Note: In France, consent for the infant study is 
required during the Screening Phase, see Section 4.2 [inclusion criterion 1] and  
Section 3.1.1). 
 
An interim analysis will occur after approximately 130 subjects have completed delivery 
and have time to-delivery results available. At the interim analysis, all available safety 
and efficacy data will be reviewed by an unblinded independent data monitoring 
committee who may make recommendations to terminate the study. 
 
 
Section 3.1., Study Design 
 
The subject or other legal guardian for the infant will also be asked to consent to 
participate in a separate 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 face 
to-face post-infusion assessment visit. (Note: In France, consent for the infant study is 
required during the Screening Phase, see Section 4.2 [inclusion criterion 1] and  
Section 3.1.1). 
 
An interim analysis will occur after approximately 130 subjects have completed delivery 
and have time to-delivery results available. At the interim analysis, all available safety 
and efficacy data will be reviewed by an unblinded independent data monitoring 
committee (IDMC) who may make recommendations to terminate the study (see 
Section 9.8). Details of the interim analysis are provided in Section 8.3.4. Subjects will 
continue to be enrolled while the interim analysis is being conducted. 
 
Randomized treatment can be discontinued as outlined in Section 4.4.2. Subjects 
discontinuing randomized treatment will be managed according to the standard care and 
asked to remain on study through the Maternal Post Delivery Assessment Phase. These 
subjects will also be asked to consent to the infant follow-up study, with the exception of 
subjects in France (see Section 4.2 and Section 3.1.1). 


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Section 3.1.1., Screening Phase 
 
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 sign measurements, cervical examination, medical and obstetric 
history, estimated GA). However, 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 the consent having 
been signed. Additionally, in France, subjects providing consent to participate in ZINN at 
Screening must also provide signed and dated written consent for their infant to 
participate in the infant follow-up study (200722 [ARIOS]) (see Section 4.2). 
 
 
 
Section 3.1.2.1., Before Treatment 
 
Prior to dosing, the investigators must confirm the fetal heart rate pattern remains 
reassuring, the uterine contraction rate is not less than 4 contractions over a 30-minute 
interval that, according to medical discretion, tocolytic therapy is still indicated, and 
the electrocardiogram (ECG) does not have clinically significant abnormalities (see 
Section 6.1). In addition, at the discretion of the investigator and as clinically indicated, a 
cervical examination may be performed to ensure that cervical dilation does not exceed  
4 cm. 
 
 
Section 3.1.2.3., End of Treatment 
 
The subject or other legal guardian for the infant (both delivered and undelivered) will be 
asked to consent to participate in a separate long-term infant follow up study for safety 
and neurodevelopment, if not already obtained. Note: In France, consent for the infant 
study is required during the Screening Phase (see Section 4.2 and Section 3.1.1). 
 
 
Section 3.1.3.1., Retreatment 
 
For undelivered subjects who are subsequently diagnosed with recurrent preterm labor 24 
hours or more following completion of the Inpatient Randomized Treatment Phase, 
retreatment with blinded IP is permitted at the discretion of the investigator. Retreatment 
is limited to a single repeat course of the blinded IP to which the subject was originally 
randomly assigned, either retosiban or atosiban. Retreatment is only permitted if the 
subject experiences a spontaneous preterm labor recurrence before 336/7 weeks’ gestation 
and meets all the eligibility criteria specified in the Time and Events Table (Table 5). 
Atosiban retreatment guidelines are provided in the summary of product characteristics 
(SmPC) [Tractocile SmPC, 2013]. 


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Section 3.1.5., Maternal Post-Delivery Assessment Phase 
 
The subject or other legal guardian will be asked to provide consent for the infant 
(whether delivered or undelivered) to participate in a separate infant follow up study for 
safety and neurodevelopment, if not already obtained. Note: In France, consent for the 
infant study is required during the Screening Phase (see Section 4.2 and Section 3.1.1). 
 
 
Section 4.2., Inclusion Criteria 
 
1.   Signed and dated written informed consent is required prior to a subject’s 
participation in Study 200721 (ZINN) 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. 
French Subjects: Participation in Study 200721 (ZINN) also requires that the 
subjects provide signed and dated written consent for her infant to participate in 
Study 200722 (ARIOS), a follow-up study assessing long-term safety and outcomes 
in infants born to mothers participating in retosiban treatment studies. 
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. 
3. 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 4.3., Exclusion Criteria 
 
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 positive findings for 
substances other than cocaine, PCP, methamphetamine, or amphetamine is at the 
investigator’s discretion (examples include alcohol, cannabinoids, and opiates) 
10 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 


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110. 
Women with documented active hepatitis B or hepatitis C viral infection, unstable 
liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones) 
121. 
History of sensitivity to the IPs or components thereof or a history of drug or 
other allergy that, in the opinion of the investigator or GSK/PPD medical monitor, 
contraindicates their participation. 
 
Section 4.4.1.1., 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 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 ECG cannot be dosed and should 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 4.4.2., Discontinuation of Investigational Product 
 
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. 
The investigator should consult the PPD medical monitor prior to discontinuing any 
subject from the IP based on urine drug screen results that become available after the IP 
has been initiated. 
Subjects discontinuing the IP who have not yet delivered will continue in the study 
through delivery and the maternal post-delivery assessment. 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. Note: In France, consent for 
the infant study is required during the Screening Phase (see Section 4.2 and Section 
3.1.1). 
 
 
Section 5.1., Investigational Product and Other Study Treatment 
 
Atosiban (Tractocile, Ferring Pharmaceuticals) active comparator will be provided by to 
the site. Atosiban is a marketed product that is a clear, colorless solution for infusion that 
contains atosiban at 6.75 mg/0.9 mL 


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Section 6., Study Assessments and Procedures 
Table 5, Time and Events Table 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Clinical and Other Assessments 
Written informed 
consent and 
medical releases for 
treatment4 
X 
Discuss and request 
consent for 
participation in the 
infant follow-up study5 
X5 
X 
X 
Inclusion/exclusion 
criteria confirmation 
X 
X 
Subject demography 
X 
Medical history 
(including obstetrics 
history)6 
X 
X 
X 
X 
Urine drug screen7 
X 
X 
Physical examination 
(including height and 
weight) 
X 
Cervical examination87 
X 
X 
X 
X 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Estimated fetal weight 
and head 
circumference via 
ultrasound8 
X 
X 
Determine AFI via 
ultrasound9 
X 
X 
Uterine contractions10 
X 
Schedule face-to-face 
post-infusion 
assessment visit 
X 
Investigational Products11 
Investigational product 
(retosiban or atosiban) 
X 
X 
X 
Efficacy Assessments 
Date and time of 
delivery 
X12 
Mode of delivery 
X12 
Indication for delivery 
X12 
Neonatal composite 
outcomes 
X 
Neonatal hospital stay 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Maternal Safety Assessments 
Concomitant 
medications 
X 
X 
X 
ECG 12-lead13 
X 
Vital sign 
measurements (BP, 
pulse rate, respiratory 
rate, and 
temperature)14 
X 
X 
X 
X 
X 
AEs, SAEs, and DREs: 
maternal 
X 
X 
X 
Breastfeeding status 
X 
Edinburgh Postnatal 
Depression Scale15 
(maternal) 
X 
Local laboratory 
assessments (LFTs 
only)16 
X 
X 
Central laboratory 
assessments 
(including hematology, 
chemistry, and LFTs)17 
X 
X 
X 
X17 
Physical examination 
(brief) 
X 
Status of postpartum 
bleeding 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Fetal Safety Assessments 
Electronic fetal 
monitoring 
X18 
X19 
X19 
X19 
X20 
X21 
AEs/SAEs: fetal 
X 
X 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: 
neonatal 
X 
X 
Neonatal Apgar Scores 
(1 and 5 minutes) 
X12 
Neonatal growth 
parameters 
X12 
Neonatal blood gases 
X12 
Health Outcome Assessments 
Maternal and neonatal 
health care resource 
use22 
X 
X 
EQ-5D-5L (maternal) 
X 
X3 
Pharmacokinetic Assessments 
Maternal PK blood 
sample23 
X23 
X23 
Cord blood sample24 
X 
Breast milk/colostrum 
sample25 
X 
Histopathology 
Placental tissue 
sample26 
X 


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Procedures 
Screening 
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal 
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Biomarker Assessments 
Genetic blood sample 
for maternal DNA27 
X 
Blood sample for 
maternal inflammation 
biomarker 
X 
Biomarker and genetic 
cord blood sample28 
X 
Other Assessments 
Fetal fibronectin 
(optional)29 
X 
X 
Cervical length via 
transvaginal ultrasound 
(optional)30 
X 
X 
 
5. 
The subject or other legal guardian for the infant will be asked to consent to participate in a separate long-term study to follow infants for safety and neurodevelopment outcomes. 
The subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant follow-up study at any time during the study that is 
appropriate and convenient. (Note: In France, consent for the infant study is required during the Screening Phase [see Section 4.2 and Section 3.1.1]). Withdrawal from the study 
after beginning randomized treatment or discontinuing IP does not preclude involvement in the infant follow-up study. 
6. 
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. 
7. 
The urine drug screen will be performed locally using a point-of-care, qualitative testing device. 
87. 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 


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to-face post-infusion assessment visit) will are not required but may be performed based on investigator discretion. If inclusion criteria is based on cervical change (see 
Section 4.2), 2 examinations must be documented (either 2 digital cervical examinations or 2 cervical length examinations). 
8. 
An ultrasound for estimation of fetal weight and head circumference is needed at Screening or before retreatment unless the date of the most recent ultrasound that 
includes fetal weight and head circumference is within 3 weeks (21 days) before the date of randomization or retreatment. 
9. 
The abdominal ultrasound for determination of the AFI will be performed at Screening and before retreatment. The AFI should be measured using the 4-quadrant method. 
10. Uterine tocography or manual palpation (if necessary) will be performed at Screening prior to dosing to confirm the uterine contraction 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. 
14. Vital signs (bBlood 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, if criteria are met, also during retreatment, and at the post-infusion assessment visit. During the Inpatient Randomized Treatment Phase and during 
retreatment, vital signs will be assessed and recorded within the following windows relative to the start of the infusion: 15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours, at the 
end of the infusion, at the time of any dose changes, and as warranted by a medical condition. It is suggested (but not required) that oxygen saturation also be assessed at 
Screening and recorded in source documents. 
15. Maternal subjects will complete the EPDS, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (-2 weeks/+6 weeks) after delivery. 
16. 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%. 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 6.3.1 if ALT or bilirubin is abnormal. 


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Section 6.1., 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 4.2). 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 
bilirubin is not >1.5 × ULN (>35% direct bilirubin), if available (see Section 6.3.1). 
An isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct 
bilirubin is <35%. Dosing may be started prior to the availability of these results. 
• 
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 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 4.4.1). 
 
 
Section 6.3.7., Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
 
The DREs listed in Section 6.3.7.1 and Section 6.3.7.2 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 6.3.7.1, 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 6.3.7.2 applies 
• 
Hospitalization for delivery, unless prolonged or one of the conditions listed at 
the end of Section 6.3.7.2 applies 
 
 
 
Section 6.3.7.2., Disease-Related Neonatal Events (Occurring in Infants Born Prior 
to 37 Completed Weeks) 
 
Because these events (Section 6.3.7.1 and Section 6.3.7.2) 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 an SAE). These events will be recorded on the DRE page in the eCRFs. 
These DREs will be monitored by the IDMC and internal GSK safety review team. 
However, if one or all of the following conditions apply, then the event should be 
reported as an AE/SAE using the standard process, as summarized in Section 6.3.11: 
 
 
Section 6.3.12.2., Vital Sign Measurements 
 
Vital signs (bBlood pressure, pulse rate, respiratory rate, and temperature) will be 
measured at the following time points during the study: Screening, Inpatient Randomized 
Treatment Phase, retreatment (if criteria are met, see Section 3.1.3.1), and at the face 
to face post-infusion assessment visit. During the Inpatient Randomized Treatment Phase 
and during retreatment, vital signs 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. It is 
suggested (but not required) that oxygen saturation also be assessed at Screening and 
recorded in source documents. 
 
 
Section 6.3.12.4., 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 4.3). 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 


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ultrasound-derived estimated fetal weight and head circumference within 13 weeks of 
Screening, with the results and date of assessment recorded in the eCRF). 
 
If the investigator determines a subject suitable for retreatment (see Section 3.1.3.1 
for retreatment criteria), an abdominal ultrasound to assess fetal growth should be 
performed unless records are available documenting ultrasound-derived estimated 
fetal weight and head circumference within 3 weeks of retreatment, with the results 
and date of assessment recorded in the eCRF. 
 
 
 
Section 6.3.12.5., Laboratory Assessments 
 
The following laboratory tests will be performed locally: 
 
• 
Liver function tests, including ALT and bilirubin, performed at Screening (see 
Section 6.3.1) 
• 
Urine drug screen using a point-of-care, qualitative testing device 
The biological samples collected over the course of the study that are directly related to 
the conduct and analysis of the study, including hematology and chemistry tests, and 
liver function tests, and urine drug screening are summarized further in Appendix 5. 
 
 
Section 11.5., Appendix 5: Summary of Human Biological Samples 
 
Labels will be customized for each test and include the protocol number, subject 
identification number, descriptor as initial liver event assessment or follow-up, and date 
and time of collection. 
 
• 
Urine Drug Screen: A urine sample will be collected during Screening in order to 
assay for ethanol and other substances of abuse for eligibility determination. The 
urine drug screen will be performed locally using a point-of-care, qualitative testing 
device. 

SAP_000.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 GSK200721 
 
1 
 
 
Division 
: Worldwide Development 
Information Type      : Reporting and Analysis Plan 
 
Title 
: Randomized, Double-blind, Multicenter, Phase III Study 
Comparing the Efficacy and Safety of Retosiban Versus 
Atosiban Therapy for Women in Spontaneous Preterm Labor 
Compound Number 
: GSK221149 
Effective Date  
: 04-OCT-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 200721.   
 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:  
 
04-OCT-2017 
Manager, Biostatistics, PPD 
  
04-OCT-2017 
Biostatistician II, PPD 
  
04-OCT-2017 
Biostatistician, PPD 
 
Approved by:  
  
04-OCT-2017 
Manager Statistics, GlaxoSmithKline 
Signature: 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
2 
 
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 ........................................................................................... 12 
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 
5.1.1. 
Efficacy Analyses .......................................................................... 14 
5.1.2. 
Safety Analyses ............................................................................ 14 
5.2. 
Multiplicity Adjustment .................................................................................. 14 
6. 
STUDY POPULATION ANALYSES ......................................................................... 15 
6.1. 
Planned Analyses Overview......................................................................... 15 
6.2. 
Disposition of Subjects ................................................................................. 16 
6.3. 
Demographic and Baseline Characteristics ................................................. 16 
6.4. 
Medical Conditions (Current/Past) ............................................................... 18 
6.5. 
Concomitant Medication ............................................................................... 18 
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 .................................................. 22 
8.1. 
Secondary Efficacy Analyses ....................................................................... 22 
8.1.1. 
Overview of Planned Efficacy Analyses ........................................ 22 
8.1.2. 
Planned Key Secondary Efficacy Statistical Analyses .................. 24 
8.1.3. 
Planned Other Secondary Efficacy Statistical Analyses ............... 27 
8.2. 
Safety Analyses ........................................................................................... 27 
8.2.1. 
Overview of Planned Analyses ..................................................... 28 
8.2.2. 
Extent of Exposure (Maternal) ...................................................... 30 
8.2.3. 
Adverse Events ............................................................................. 30 
8.2.3.1. 
All Adverse Events ...................................................... 31 
8.2.3.2. 
Adverse Events by Maximum Grade or 
Intensity ....................................................................... 31 
8.2.3.3. 
Most Common Adverse Events ................................... 31 
8.2.3.4. 
Serious Adverse Events .............................................. 31 


 
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GSK200721 
 
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8.2.3.5. 
Adverse Events Leading to Treatment 
Discontinuation ............................................................ 32 
8.2.3.6. 
Adverse Events of Special Interest ............................. 32 
8.2.3.7. 
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................ 33 
8.2.3.8. 
Death ........................................................................... 35 
8.2.4. 
Health Outcome ............................................................................ 35 
8.2.4.1. 
Neonatal Health Care .................................................. 35 
8.2.4.2. 
Maternal Health Care .................................................. 36 
8.2.5. 
Clinical Laboratory ........................................................................ 36 
8.2.6. 
Vital Signs ..................................................................................... 37 
8.2.6.1. 
Maternal Vital Signs .................................................... 37 
8.2.6.2. 
Fetal Heart Rate .......................................................... 37 
8.2.7. 
Neonatal Birth Record ................................................................... 37 
8.2.8. 
Placental Data ............................................................................... 37 
8.3. 
Pharmacokinetic Analyses ........................................................................... 38 
8.4. 
Biomarker Analyses ..................................................................................... 38 
9. 
DEVIATION OF PLANNED ANALYSES FROM PROTOCOL ................................. 38 
10.  REFERENCES ........................................................................................................ 40 
11.  APPENDICES .......................................................................................................... 41 
11.1. 
Appendix 1: Protocol Deviation Definitions .................................................. 42 
11.2. 
Appendix 2: Time and Events ...................................................................... 43 
11.3. 
Appendix 3: Treatment States and Phases .................................................. 50 
11.3.1. 
Treatment Phases ......................................................................... 50 
11.3.2. 
Treatment States .......................................................................... 50 
11.3.3. 
Treatment States for AE Data ....................................................... 51 
11.4. 
Appendix 4: Data Display Standards & Handling Conventions .................... 53 
11.4.1. 
Study Treatment & Sub-group Display Descriptors ...................... 53 
11.4.2. 
Baseline Definition & Derivations .................................................. 53 
11.4.2.1.  Baseline Definitions ..................................................... 53 
11.4.2.2.  Derivations and Handling of Missing Baseline 
Data ............................................................................. 53 
11.4.3. 
Reporting Process & Standards .................................................... 54 
11.5. 
Appendix 5: Derived and Transformed Data ................................................ 56 
11.5.1. 
General ......................................................................................... 56 
11.5.2. 
Study Population ........................................................................... 56 
11.5.3. 
Safety ............................................................................................ 57 
11.5.4. 
Efficacy ......................................................................................... 58 
11.6. 
Appendix 6: Premature Withdrawals & Handling of Missing Data ................ 61 
11.6.1. 
Premature Withdrawals ................................................................. 61 
11.6.2. 
Handling of Missing Data .............................................................. 61 
11.6.2.1.  Handling of Missing Stratification ................................ 61 
11.6.2.2.  Handling of Missing/Partial Dates ............................... 61 
11.7. 
Appendix 7: Primary and Sensitivity Analyses for Primary and Key 
Secondary Endpoints with Missing Data ...................................................... 65 
11.7.1. 
Time to Delivery ............................................................................ 65 
11.7.2. 
Neonatal Composite Outcome ...................................................... 65 
11.7.3. 
Proportional of Preterm Birth <37 weeks or ≥ 37 weeks ............... 67 
11.7.4. 
Length of Hospital Stay ................................................................. 67 


 
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4 
 
11.8. 
Appendix 8: Values of Potential Clinical Importance .................................... 69 
11.8.1. 
Laboratory Values for Pregnant Women ....................................... 69 
11.8.2. 
Vital Signs for Pregnant Women ................................................... 70 
11.8.3. 
Fetal Heart Rate ............................................................................ 70 
11.9. 
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses ....................................................................................................... 71 
11.10.  Appendix 10: Abbreviations & Trade Marks ................................................. 71 
11.10.1.  Abbreviations ................................................................................ 71 
11.10.2.  Trademarks ................................................................................... 72 
11.11.  Appendix 11: List of Data Displays ............................................................... 73 
11.11.1.  Data Display Numbering ............................................................... 73 
11.11.2.  Study Population Tables ............................................................... 74 
11.11.3.  Efficacy Tables .............................................................................. 76 
11.11.4.  Efficacy Figures ............................................................................ 78 
11.11.5.  Safety Tables ................................................................................ 79 
11.11.6.  ICH Listings ................................................................................... 83 
11.11.7.  Non-ICH  Listings .......................................................................... 88 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
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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 
200721.  
Protocol 
 This RAP is based on the original protocol (Dated: 14-May-2014), country-
specific amendment 02 (France; dated 29-Jan-2015, country-specific amendment 
02 (United Kingdom; dated 29-Jan-2015) and country-specific amendment 03 
(Sweden; dated 04-Feb-2015), protocol amendment 04 (Dated: 22-Aug-2016), 
and protocol amendment 05 (Dated: 21-Dec-2016) for study GSK200721 
[GlaxoSmithKline Document Numbers: 2014N194185_00, 2014N194185_01, 
2014N194185_02, 2014N194185_03, 2014N194185_04 and 2014N194185_05]. 
 
Primary 
Objective  
 Demonstrate the superiority of retosiban to prolong pregnancy compared with 
atosiban. 
Primary 
Endpoint 
 Time to delivery (in days) from the start of investigational product (IP) 
administration until delivery, based on a records review. 
Study 
Design 
 Phase III, randomized, double-blind, double-dummy, 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 97 patients 
and patients were randomly assigned to one active arm (retosiban) and one 
active control arm (atosiban). 
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  The study is designed to test the following hypotheses: 
o Null hypothesis:  The prolongation of pregnancy as measured by time to 
delivery is equal between the women randomized to retosiban versus 
atosiban. 
o Alternative hypothesis:  The prolongation of pregnancy as measured by 
time to delivery is unequal between the women randomized to retosiban 
versus atosiban. 


 
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Primary 
Analyses 
 Time to delivery will be analyzed using a two-component normal mixture model, 
where the components pertain to women who deliver imminently and to women 
who deliver at term.  The exact weight of each component will be determined by 
the observations from the component and model concomitant variables including 
treatment and Gestational Age (GA) at randomization. Within each component, 
the expected time to delivery will be modeled as a function of treatment as fixed 
effect and GA at randomization and established progesterone use (yes or no) as 
a covariate.  Comparison of the two treatments will be performed through mean 
point estimates and their corresponding 95% confidence intervals derived from 
the finite mixture model. 
Secondary 
Analyses 
 Safety data will be presented in tabular format and summarized descriptively 
according to GSK’s Integrated Data Standards Library (IDSL) standards.  
 Key secondary efficacy endpoints such as proportion of births prior to 370/7 
weeks’ gestation, proportion of births at term (370/7 to 416/7 weeks’ gestation) and 
the neonatal composite endpoint will be analyzed using logistic regression 
models to facilitate comparison between the two treatments. 
 Key secondary efficacy endpoint length of neonatal hospital stay will be log-
transformed prior to analysis. Log-transformed length of hospital stay will be 
analyzed using an analysis of covariance model adjusting for the covariates of 
GA at randomization and established progesterone use (yes or no). Other 
covariates may be added appropriate. The model-adjusted length of stay will be 
presented for each treatment group.  
 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 analyses are 
provided in the body of the RAP. 


 
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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 
atosiban. 
 Time to delivery from the start of IP administration until 
delivery, based on a records review.  
Secondary  
Secondary  
 To describe the outcomes of 
nwborns during the neonatal 
period (through 28 days post 
estimated date of delivery 
[EDD]) for retosiban compared 
with atosiban. 
 
 
 
 
 
Key Secondary Endpoints 
 Proportion of births prior to 370/7 weeks’ gestation – 
ascertain the GA at delivery based on a record review 
 Proportion of births at term (37 0/7 to 416/7 weeks’ 
gestation) – ascertain the GA at delivery based on a 
record review 
 Length of neonatal hospital stay – confirm duration (in 
days) of neonatal hospital admission from the medical 
records 
 Proportion of neonates with any diagnosis from the 
neonatal morbidity and mortality composite determined 
up to 28 days after estimated date of delivery (EDD) (of 
400/7 weeks) 
Other Secondary Endpoints 
 Proportion of neonates with any of the composite 
neonatal morbidity and mortality excluding Respiratory 
Distress Syndrome (RDS) 
 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 
 To describe the maternal, 
fetal, and neonatal safety 
profile during and after IV 
retosiban treatment compared 
with atosiban treatment. 
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 atosiban on health care 
resource use and patient-
reported outcomes associated 
with the maternal and 
 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) 
 Neonatal interventions of interest (e.g., parenteral 
nutrition, surfactants, blood products), procedures (e.g., 
imaging, such as ultrasound, computed tomography, 


 
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Objectives 
Endpoints 
neonatal hospitalization. 
etc.), and surgical procedures. 

 
 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 concentration in plasma, cord blood and 
breast milk. 
 Population PK analysis is not performed in the protocol.   
 


 
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2.3. 
Study Design 
 
Overview of Study Design and Key Features 
1. 
Stratification (1:1) to retosiban or atosiban 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. 
Subjects who have not delivered after 48 hours will return for a face-to-face post-infusion assessment 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 atosiban) is allowed. 


 
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Overview of Key Study Design Features 
Design 
Features: 
 Phase III, randomized, double-blind, double-dummy, multicenter design 
 Subjects are females, aged 18 to 45 years (Sweden) or aged 12 to 45 years 
(all other countries including UK, Germany, Italy, Israel, South Korea, 
Belgium, Mexico, Spain and Brazil), 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. 
 Atosiban will be given intravenously in 3 successive stages: an initial bolus 
dose of 6.75 mg using atosiban 6.75 mg/0.9 mL solution for injection, 
immediately followed by a continuous high dose infusion at 18 mg/hour for 
3 hours, then a lower 6 mg/hour infusion for the remainder of the 48-hour 
treatment period using the atosiban 37.5 mg/5 mL concentrate for solution. 
Treatment 
Assignment: 
 A total of 97 patients were blindly randomly assigned to retosiban or atosiban 
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 will be randomly assigned in 1:1 ratio to receive 
either retosiban or atosiban using an IVRS in accordance with the 
randomization schedule. 
Interim 
Analysis  
 There study was terminated before inteirm analysis due to feasibility.   
 Details of the interim analysis were written in the IDMC RAP. 
2.4. 
Statistical Hypotheses 
The primary endpoint is prolongation of pregnancy as measured by time to delivery 
(days). The following are the null (H0) and alternative (H1) hypotheses for the primary 
endpoint in this study: 
 
H0: The prolongation of pregnancy as measured by time to delivery is equal between 
the women randomized to retosiban versus atosiban 
 
H1: The prolongation of pregnancy as measured by time to delivery is unequal 
between the women randomized to retosiban versus atosiban 
The primary objective of the statistical analysis will be to test the null hypothesis in 
intent-to-treat (ITT) Population that there is no difference between retosiban and atosiban 
and the alternative hypothesis that there is a difference for the primary endpoint.  The 
hypotheses will be tested at 5% level in a 2-sided test. 
3. 
PLANNED ANALYSES 
All planned analyses will be done using SAS version 9.2 or higher.  The Analysis Data 
Model (ADaM) will be created per ADaM implementation guide version 1.1. Details on 


 
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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.  
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 atosiban) 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 atosiban) 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 
5.1.1. 
Efficacy Analyses 
The comparison of the treatment groups for the primary and selected secondary efficacy 
endpoints (i.e., prolongation of pregnancy, neonatal composite) will be analyzed by the 
following subgroups if applicable: 
 
GA at randomization with 4 categories: 24 0/7 to 25 6/7, 26 0/7 to 27 6/7, 28 0/7 to 30 6/7 
and 31 0/7 to 33 6/7 
 
Established progesterone group with categories “Yes” and “No” 
In addition, for the primary efficacy endpoint, there are no per-protocol population 
defined, so additional subgroup analyses based on major protocol deviations or violation 
of PTL criteria (inclusion criteria #4) may be performed as appropriate. Also, additional 
subgroup analysis based on the status of spontaneous onset delivery will be performed. 
5.1.2. 
Safety Analyses 
Safety data will be summarized by the following subgroups if applicable: 
 
GA at randomization with 4 categories: 24 0/7 to 25 6/7, 26 0/7 to 27 6/7, 28 0/7 to 30 6/7 
and 31 0/7 to 33 6/7 
Additional subgroup analyses may be performed as appropriate. 
5.2. 
Multiplicity Adjustment 
There will be no multiplicity adjustment sue 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.  


 
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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 Primary and Key Secondary 
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 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Planned Analyses Overview 
The study population analyses will be based on the population specified in Section 4. 
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 
Demography 
Demographics and Baseline Characteristics [2] 
Y 
 
Y 
Race & Racial Combinations [2] 
Y 
 
Y 


 
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Medical Condition & Concomitant  Medications 
Medical History/Conditions (Obstetrical/Prenatal) [2] 
Y 
 
Y 
Prior/Concomitant Medication [3] 
Y 
 
Y 
Obstetrical Medication, Magnesium Sulfate and 
Antenatal Corticosteroids [3] 
Y 
 
Y 
NOTES: 
1. 
Listing of subjects 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 
 IP Discontinuation 
 Dose increase 
 Re-treatment  
 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 and plotted. All disposition summaries will be 
performed using the 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 


 
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dilation (cm), cervical length (mm), percentage of women who failed PTL criteria 
(inclusion criteria #4), 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.  
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 GA strata: 240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7 and 
310/7 to 336/7)  
 Established progesterone use 
 Region 
 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. 


 
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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 
is 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. 
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 
The primary objective of the statistical analysis will be to test the null hypothesis in the 
ITT Populations that there is no difference between retosiban and atosiban in time to 
delivery versus the alternative hypothesis that there is a difference.   
 
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 [1] 
Y 
 
Y 
Y 
Y 
 
Y 
Time to delivery, retreatment or 
subsequent preterm labor) [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, with the exception of individual listings. 
 
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 
Primary Statistical Analysis 
Endpoint 
 Time to delivery (days in 1 decimal point) from the start of IP administration until delivery  
 
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). 
 
Model Specification 
 The primary endpoint of time to delivery will be statistically analyzed using a two-component 
finite mixture regression model.  Time to delivery (y) is assumed to follow a mixture of two-
components with normal densities.  Within each component, the expected time to delivery will 
be modeled as a function of treatment (TRT) as fixed effect, and GA at randomization (GA) 
and established progesterone use (EP) as covariates., 
 
where k = 2 to denote the 2 groups of mothers namely those who deliver preterm and those 
who deliver at term. 
The component normal distributions depend on the regressors: TRT, GA and EP thru the 
means 
, i.e., 
 
The mixing probabilities 
, which are non-negative and sum to one, are modeled using a 
logistic regression model with TRT, GA and EP and corresponding parameters, 
, i.e,  
 
 
 
The patient assignment of each component is determined by the mixture model described 


 
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Primary Statistical Analysis 
above and some patients are pre-assigned to each component to stabilize the model, i.e. the 
first component includes those deliveries within 1 week of GA at randomization and the second 
component includes the patients who deliver after 38 weeks of GA. 
The model parameters can then be estimated using PROC FMM from SAS 9.4 by maximizing 
the likelihood. Point estimate, associated 95% confidence intervals and p-values for the overall 
average difference between Retosiban and Atosiban is then derived using weighted average of 
model parameter estimates and variance from each sub-population of mixture model.   
 Additionally, treatment by GA at randomization interaction and treatment by progesterone use 
interaction will also be investigated. 
 Terms fitted in the FMM model will include: 
 
Fixed Categorical: 
TRT, EP and their interaction term (TRT*EP). Interaction will 
be included only if the interaction is statistically significant 
(at 0.05 level of significance). 
 
Fixed Continuous Covariates:  
GA and interaction term (TRT*GA). Interaction will be 
included only if both interaction are statistically significant (at 
0.05 level of significance). 
 
Repeated: 
None 
SAS Code 
proc fmm data=xxx TECHNIQUE=xxx. partial=xxx ; 
  class TRT EP; 
  model T2D =  TRT EP GA TRT*GA TRT*EP/ k=2; 
  probmodel TRT EP GA TRT*GA TRT*EP; 
run; 
Model Checking & Diagnostics 
 Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
 Point estimates of the treatment means and standard deviation will be presented, together with 
the estimate of the treatment mean differences (retosiban – atosiban), the corresponding 95% 
confidence intervals and p-value.  
Summary Results Presentation 
 The following plot of the time to delivery per treatment will be generated.    
- 
Kaplan-Meier Plot of Time to Delivery 
 Observed values using descriptive statistics will be presented for each treatment group. 
 In addition, time to delivery or retreatment/subsequent preterm labor will be summarized using 
descriptive statistics. 


 
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Primary Statistical Analysis 
Sensitivity and Support Statistical Analysis 
 Time to delivery will be analyzed using an analysis of covariance adjusting for the covariate of 
GA at randomization and established progesterone use (yes or no).  Additionally, interactions 
between GA at randomization and treatment and established progesterone use and treatment 
will also be investigated. 
 Observed values using descriptive statistics will be presented within defined subgroups in 
Section 5.1. 
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.   
 
Table 4 provides an overview of the planned efficacy analyses with further details of data 
displays presented in Appendix 11: List of Data Displays. 
Table 4 
Overview of Planned Efficacy Analyses 
 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Key Secondary Endpoints 
Proportion of births prior to 370/7 weeks’ 
gestation – ascertain the GA at delivery 
based on a records review 
Y 
 
 
Y 
 
 
 
Proportion of births at term (370/7 to 
416/7 weeks’ gestation) – ascertain the 
GA at delivery based on a records 
review 
Y 
 
 
Y 
 
 
 
Length of neonatal hospital stay –
duration (in days) of neonatal hospital 
admission from the medical records 
Y 
 
 
Y 
 
 
Y 
Neonatal composite endpoint 
Y 
 
 
Y 
 
 
Y 
Other Secondary Endpoints 
Individual neonatal composite endpoint 
 
 
 
Y 
 
 
Y 
Neonatal composite endpoint without 
RDS 
Y 
 
 
Y 
 
 
Y 
Neonatal composite endpoint without 
RDS and mortality 
Y 
 
 
Y 
 
 
Y 
Neonatal admission to a specialized 
 
 
 
Y 
 
 
Y 


 
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Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
care unit and length of stay  
Newborn hospital readmission and 
length of stay  
 
 
 
Y 
 
 
Y 
Proportion of births prior to 280/7 weeks’ 
gestation 
Y 
 
 
Y 
 
 
 
Proportion of births prior to 320/7 weeks’ 
gestation 
Y 
 
 
Y 
 
 
 
Proportion of births prior to 350/7 weeks’ 
gestation 
Y 
 
 
Y 
 
 
 
Proportion of births ≤7 days of IP 
administration 
Y 
 
 
Y 
 
 
 
Proportion of births ≤48 hours of IP 
administration 
Y 
 
 
Y 
 
 
 
Proportion of births ≤24 hours of IP 
administration 
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. 
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. 


 
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8.1.2. 
Planned Key Secondary Efficacy Statistical Analyses 
Key Secondary Efficacy Statistical Analysis 
Endpoint 
 Proportion of births prior to 370/7 weeks’ gestation 
 Proportion of births at term (≥ 370/7 weeks’ gestation) 
 Length of neonatal hospital stay 
 Proportion of neonates with any diagnosis from the neonatal morbidity and mortality 
composite determined up to 28 days after EDD (of 400/7 weeks) (details for each composite 
are provided in Section 11.5.4.) 
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 sequential testing method 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 sequential testing examines the hypothesis testing in a pre-specified 
order, i.e., the testing of the second secondary endpoint will be performed only if the first 
secondary endpoint is significant at 5%, and testing of the third secondary endpoint will be 
performed only if the first and second endpoints are significant at 5%.  
Order of sequential testing is 
1) Length of neonatal hospital stay 
2) Proportion of births prior to 370/7 weeks’ gestation and Proportion of births at term 
3) Neonate composite outcome 
 
Model Specification 
 For the endpoints of neonatal composite outcome, proportion of births prior to 370/7 weeks’ 
gestation, and proportion of births at term (370/7 to 416/7 weeks’ gestation), a logistic regression 
model will be used for comparing retosiban with atosiban, with GA at randomization and 
established progesterone use (yes or no) 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. Additionally, 
interactions between GA at randomization and treatment and established progesterone use 
and treatment will also be investigated. 
 Length of hospital stay will be log-transformed (at base 10) prior to analysis. Log-transformed 
length of hospital stay will be analyzed using an analysis of covariance adjusting for the 
covariate of GA at randomization and established progesterone use (yes or no).  Additionally, 
interactions between GA at randomization and treatment and established progesterone use 
and treatment will also be investigated. Wilcoxon rank sum test will also be performed to 
compare the two treatments if length of hospital stay is not log normal. 
 Terms fitted in the model will include: 
 
Fixed Categorical: 
TRT, EP and their interaction term (TRT*EP). Interaction will 


 
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Key Secondary Efficacy Statistical Analysis 
be included only if the interaction is statistically significant 
(at 0.1 level of significance). 
 
Fixed Continuous Covariates: 
GA and interaction term (TRT*GA). Interaction will be 
included only if the interaction is statistically significant (at 
0.1 level of significance). 
 
Repeated: 
None 
SAS Code 
 Analysis of Covariance: 
ods output lsmeans=means diffs=diffs tests3=tests; 
proc mixed data=xxx;   
     class EP TRT; 
     model log_LoS= TRT EP GA TRT*EP TRT*GA/ddfm=kr s; 
     lsmeans TRT /pdiff cl alpha=0.05;  
run; 
 Wilcoxon rand sum test: 
proc npar1way data=xxx Wilcoxon; 
 
class TRT; 
 
var log_LoS; 
 
ods output wilcoxontest=wtest; 
run; 
Model Checking & Diagnostics 
 Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
 For binary endpoints, the number and percentage of subjects in each treatment group, the 
relative risk (RR) and 95% CIs, the odds ratio (OR) of response rates (retosiban versus 
atosiban) and 95% CIs, and p-value will be presented.   
 The model-adjusted length of stay will be presented for each treatment group. In addition, the 
treatment difference between retosiban and atosiban and associated 95% CIs and p-values 
will be presented. 
 Observed values using descriptive statistics for length of stay will be presented for each 
treatment group. 
 For proportion of neonates with any of the composite component, neonates with any of the 
composite component w/o RDS, neonates with any of the composite component w/o RDS and 
mortality, and individual composite component, RR and 95% CIs, OR and 95% CIs, and p-
values will be provided. 
Sensitivity and Support Statistical Analysis 
 For length of stay, data will be analyzed in a similar fashion as described in Section 7.1.2. 


 
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Key Secondary Efficacy Statistical Analysis 
 Treatment effects within defined subgroups in Section 5.1 will be explored. 


 
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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. 
 Neonatal admission to a specialized care unit and length of stay – confirm admission to 
neonatal intensive or 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 
 Ambulatory surgery – confirm any neonatal ambulatory surgery and the indication for 
surgery 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 
Model Specification 
 Binary endpoints will be analyzed in a similar fashion to the neonatal composite analysis in 
Section 8.1.2.  
 Neonatal admission to a specialized care unit and length of stay, and ambulatory surgery will 
be explored in the integrated analysis separately. 
Model Results Presentation 
 Data will be analyzed in a similar fashion as described in Section 8.1.2. 
 Treatment effects within defined subgroups in Section 5.1 will be explored.  
8.2. 
Safety Analyses 
All safety summaries will be performed for the Safety Population as defined in Section 4 
of this document.  A listing of all safety data will be presented. 


 
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8.2.1. 
Overview of Planned Analyses 
The safety analyses will be based on the Maternal and Neonatal Safety Populations, 
unless otherwise specified. 
Table 5 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 
 
 
 
 
  AEs by Maximum Grade or Intensity 
Y 
 
 
Y 
 
 
 
 
  Most Common AEs 
Y 
 
 
Y 
 
 
 
 
  Serious AEs 
Y 
 
 
Y 
 
 
 
 
  AEs of special interest  
Y 
 
 
Y 
 
 
 
 
  Disease-related AEs 
Y 
 
 
Y 
 
 
 
 
  AEs leading to Deaths 
 
 
 
Y 
 
 
 
 
Clinical Laboratory 
Y 
 
 
Y 
Y 
 
 
Y 
Maternal Vital Signs 
Y 
 
 
Y 
Y 
 
 
Y 
Maternal Health Care Resource Use 
Y 
 
 
Y 
 
 
 
 
Fetal Endpoints 
Adverse Events 
 
 
 
 
 
 
 
 
  All AEs 
 
Y 
 
 
Y 
 
 
 
 
  AEs by Maximum Grade or Intensity 
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 
 
 
 
 
  AEs by Maximum Grade or Intensity 
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 
 
 
Y 
 
 
 
 
Neonatal Birth Record 
Y 
 
 
Y 
 
 
 
 


 
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Endpoints 
Observed 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
  APGAR  scores 
Y 
 
 
Y 
 
 
 
 
  Any Complications 
 
 
 
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.  
 
8.2.2. 
Extent of Exposure (Maternal) 
Summaries will be presented only for mothers by initial treatment, retreatment and total.  
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 DBL. 
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 


 
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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. Also, the above summary 
will be produced by subgroups defined in Section Error! Reference source not found.. 
The AE will be summarized by maternal, fetal and neonatal events, separately. Also, the 
maternal AE by treatment phase (on-treatment, post-treatment) defined in Section 11.3.3 
will be summarized. 
8.2.3.2. 
Adverse Events by Maximum Grade or Intensity 
A summary of AEs by grade or intensity will be presented in a table. The grade or 
intensity that will be presented represents the most extreme grade or intensity captured on 
the CRF page. The possible grades or intensities are “Not applicable”, “Mild or Grade 1”, 
“Moderate or Grade 2”, “Severe or Grade 3” and “Grade 4”. In the grade or intensity 
table, if a patient reported multiple occurrences of the same AE, only the most severe will 
be presented. AEs that are missing grade or intensity will be presented in tables as “Grade 
4” but will be presented in the data listing with a missing grade or intensity. 
The AE will be summarized 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 atosiban 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. 


 
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SAEs will be reported in the similar manner as all AEs. A listing of SAEs will be 
provided. Also, the above summary will be produced by subgroups as defined in Section 
Error! Reference source not found.. 
The SAEs will be summarized by maternal, fetal and neonatal events, separately. Also, 
the maternal SAEs by treatment phase (on-treatment, post-treatment) defined in Section 
11.3.3 will be summarized. 
8.2.3.5. 
Adverse Events Leading to Treatment Discontinuation 
A listing of all AEs leading to permanent discontinuation of study drug and/or 
withdrawal from the study will be produced if applicable. 
The AEs leading to permanent discontinuation will be summarized only for maternal 
events if applicable. 
8.2.3.6. 
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. Also, the above summary will be produced by subgroups defined in Section 
Error! Reference source not found.. 
The AESIs will be summarized by maternal, fetal and neonatal events, separately. 
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 


 
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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 
 Hyperbilirubinemia 
 Neonatal enterocolitis 
 Hypoxic ischemic encephalopathy 
8.2.3.7. 
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. Also, the above 
summary will be produced by subgroups defined in Section Error! Reference source 
not found.. 
The DREs will be summarized by maternal and neonatal events, separately. 
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) 


 
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 Subsequent episodes of preterm labor (even if hospitalization is required) unless 1 
of the conditions listed at the end of Protocol Section 6.3.7.2 applies 
 Hospitalization for delivery, unless prolonged or 1 of the conditions listed at the 
end of Protocol Section 6.3.7.2 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 
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 


 
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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. 
8.2.3.8. 
Death 
Deaths will be reported in the similar manner as all AEs. If applicable, a listing of death 
will be provided by maternal, fetal or neonatal events, separately.  
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 length of Intensive Care Unit (ICU) or 
Neonatal Intensive Care Unit (NICU) in days for neonates at birth by treatment. 
The following variables will be summarized with number and percentage for neonates 
with hospital unit utilization at birth by treatment: 
 Total number of neonates with hospital unit utilization at birth 
 Hospital unit type (Accident and emergency (observation), General ward, High 
dependency unit/step down unit, Intensive care unit, etc.) 
 ICU or NICU admissions (yes, no) 
 Number of ICU or NICU admissions (1, 2, 3, >3) 
 Length of hospital stay in days (<=3, > 3-<=7, >7). 


 
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RR and 95% CI, OR and 95% CI, and corresponding p-value for ICU or NICU 
admissions will be provided. ICU or NICU admissions will be analyzed in a similar 
fashion to the neonatal composite analysis in Section 8.1.2. 
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  
Maternal health care will be summarized using Maternal Safety Population. 
Descriptive statistics will be summarized for cumulative length of hospital stays in days 
for pre-term labor related hospital admission and hospital admission at delivery by 
delivery status (Pre-Term Delivery (<37 Weeks of GA), Term Delivery >=37 Weeks of 
GA)) by treatment. The following variables will be summarized with number and 
percentage for pre-term labor related hospital admission by treatment: 
 Total number of subjects with pre-term labor related hospital admission 
 Number of hospital admissions (1, 2, 3, >3) 
 Cumulative length of hospital stay in days (<=3, >3-<=7, >7) 
 Hospital unit type (Accident and emergency (observation), General ward, High 
dependency unit/step down unit, Intensive care unit, etc.). 
The following variables will be summarized with number and percentage for hospital 
admission at delivery by delivery status (Pre-Term Delivery (<37 Weeks of GA), Term 
Delivery >=37 Weeks of GA)) by treatment: 
 Number of subjects with hospital admission at delivery; 
 Cumulative length of hospital stay in days (<=3, >3-<=7, >7); 
 Maternal hospital unit type (Accident and emergency (observation), General 
ward, High dependency unit/step down unit, Intensive care unit, etc.). 
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. 


 
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The number and percentages of subjects with laboratory values outside the reference 
ranges will be summarized by treatment groups (hematology).   
The subjects with laboratory values outside the reference ranges (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.  
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.  


 
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8.2.8. 
Placental Data 
Placental data including chronic chorio, acute chorio, acute vasculitis, acute funisitis, 
remote infarction, recent infarction, post mature, intervillous thromb, villous infarctions, 
chronic villitis, acute villitis, inflammation, meconium will be summarized by treatment 
group. Also, the summary by GA category at randomization and time from start of IP 
until delivery will be presented.  
All placental 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: 
 The following subgroup analyses for the primary and key secondary endpoints 
will not be performed. 
- Magnesium sulfate use 
- Putative tocolytic use following IP discontinuation 
 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.  


 
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 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 2014N194185_00: Randomized, Double-blind, 
Multicenter, Phase III Study Comparing the Efficacy and Safety of Retosiban Versus 
Atosiban Therapy for Women in Spontaneous Preterm Labor. Effective date: 14-MAY-
2014 
McLachlan and Peel, 2000, Finite Mixture model Wiley Series in Probability and 
Statistics 
Carpenter JR1, Roger JH, Kenward MG., 2013, Analysis of longitudinal trials with 
protocol deviation: a framework for relevant, accessible assumptions, and inference via 
multiple imputation 
Little, R.J.A. and Rubin, D.B., 1987, Statistical Analysis with Missing Data, New York: 
John Wiley & Sons, Inc.  


 
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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 Primary and Key Secondary 
Endpoints with Missing Data 
 Time to Delivery 
 Neonatal Composite Outcome 
 Proportional of Preterm Birth <37 weeks or ≥ 37 weeks 
 Length of Hospital Stay 
 Error! Reference source not found. 
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 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Clinical and Other Assessments 
Written informed 
consent and 
medical releases for 
treatment4 
X 
 
 
 
 
 
 
 
 
 
Discuss and request 
consent for 
participation in the 
infant follow-up study5 
 
X5
X 
X 
Inclusion/exclusion 
criteria confirmation 
X 
 
 
X 
 
 
 
 
 
 
Subject demography 
X 
 
 
 
 
 
 
 
 
 
Medical history 
(including obstetrics 
history)6 
X 
 
 
 
X 
 
X 
X 
 
 
Physical examination 
(including height and 
weight) 
X 
 
 
 
 
 
 
 
 
 
Cervical examination7 
X 
X 
X 
X 
X 
 
 
 
 
 
Estimated fetal weight 
and head 
circumference via 
ultrasound8 
X 
 
 
X 
 
 
 
 
 
 


 
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Procedures 
Screening  
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Determine AFI via 
ultrasound9 
X 
 
 
X 
 
 
 
 
 
 
Uterine contractions10 
X 
 
 
 
 
 
 
 
 
 
Schedule face-to-face 
post-infusion 
assessment visit 
 
 
X 
 
 
 
 
 
 
 
Investigational Products11 
Investigational product 
(retosiban or atosiban) 
 
X 
X 
X 
 
 
 
 
 
 
Efficacy Assessments 
Date and time of 
delivery  
 
 
 
 
 
 
X12 
 
 
 
Mode of delivery 
 
 
 
 
 
 
X12 
 
 
 
Indication for delivery 
 
 
 
 
 
 
X12 
 
 
 
Neonatal composite 
outcomes 
 
 
 
 
 
 
 
 
X 
 
Neonatal hospital stay 
 
 
 
 
 
 
 
 
X 
 


 
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Procedures 
Screening  
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Maternal Safety Assessments 
Concomitant 
medications 
 
 
X
X 
 
X 
ECG 12-lead13 
X 
 
 
 
 
 
 
 
 
 
Vital sign 
measurements (BP, 
pulse rate, respiratory 
rate, and 
temperature)14 
X 
X 
X 
X 
X 
 
 
 
 
 
AEs, SAEs, and DREs: 
maternal 
 
 
X
X 
 
X 
Breastfeeding status 
 
 
 
 
 
 
 
X 
 
 
Edinburgh Postnatal 
Depression Scale15 
(maternal) 
 
 
 
 
 
 
 
X 
 
 
Local laboratory 
assessments (LFTs 
only)16 
X 
 
 
X 
 
 
 
 
 
 
Central laboratory 
assessments 
(including hematology, 
chemistry, and LFTs)17 
X 
 
X 
X 
X17 
 
 
 
 
 
Physical examination 
(brief) 
 
 
 
 
X 
 
 
 
 
 
Status of postpartum 
bleeding 
 
 
 
 
 
 
 
X 
 
 


 
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Procedures 
Screening  
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Fetal Safety Assessments 
Electronic fetal 
monitoring 
X18 
X19 
X19 
X19 
X20 
 
X21 
 
 
 
AEs/SAEs: fetal 
 
 
X
X 
 
 
 
Neonatal Safety Assessments 
AEs, SAEs, and DREs: 
neonatal 
 
 
 
 
 
 
X
X 
 
Neonatal Apgar Scores 
(1 and 5 minutes) 
 
 
 
 
 
 
X12 
 
 
 
Neonatal growth 
parameters 
 
 
 
 
 
 
X12 
 
 
 
Neonatal blood gases 
 
 
 
 
 
 
X12 
 
 
 
Health Outcome Assessments 
Maternal and neonatal 
health care resource 
use22 
 
 
 
 
 
 
X 
 
X 
 
EQ-5D-5L (maternal) 
 
X 
 
 
 
 
 
X3 
 
 
Pharmacokinetic Assessments 
Maternal PK blood 
sample23 
 
X23 
X23 
 
 
 
 
 
 
 
Cord blood sample24 
 
 
 
 
 
 
X 
 
 
 
Breast milk/colostrum 
sample25 
 
 
 
 
 
 
X 
 
 
 
Histopathology 
Placental tissue 
sample26 
 
 
 
 
 
 
X 
 
 
 


 
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Procedures 
Screening  
Phase 
Inpatient 
Randomized 
Treatment 
Phase 
Retreatment1 
Post-Infusion Assessment 
Phase2 
Delivery 
Phase 
Maternal 
Post-Delivery 
Assessment 
Phase 
(via Telephone) 
Neonatal 
Medical 
Review 
Phase 
Withdrawal
From 
Study 
Day 0 
Day 1 
Day 2 
(Optional – 
1 time only) 
Face-to-face 
post-infusion 
visit 
Weekly 
post-infusion 
telephone 
call 
Information 
collected via 
medical 
records 
review 
6 weeks 
after delivery3 
Delivery 
to 
28 days 
post EDD 
Biomarker Assessments 
Genetic blood sample 
for maternal DNA27 
X 
 
 
 
 
 
 
 
 
 
Blood sample for 
maternal inflammation 
biomarker  
X 
 
 
 
 
 
 
 
 
 
Biomarker and genetic 
cord blood sample28 
 
 
 
 
 
 
X 
 
 
 
Other Assessments 
Fetal fibronectin 
(optional)29 
X 
 
 
X 
 
 
 
 
 
 
Cervical length via 
transvaginal ultrasound 
(optional)30 
X 
 
 
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; EPDS = Edinburgh Postnatal Depression Scale; EQ-5D-5L = EuroQol 5-dimensional 5-level questionnaire; IP = investigational 
product; LFT = liver function test; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of normal. 
1. 
For undelivered subjects who are subsequently diagnosed with recurrent preterm labor 24 hours or more following completion of the Inpatient Randomized Treatment Phase, 
retreatment with blinded IP is permitted at the discretion of the investigator (see Protocol Section 3.1.3.1). 
2. 
Subjects who remain undelivered after 48 hours will return for a face-to-face post-infusion assessment visit for obstetric assessments 1 week (acceptable range: 3 to 14 days) 
following the Inpatient Randomized Treatment Phase. (Note: study documents may reference this visit as the 1-week face-to-face post-infusion assessment visit). The subject will 
then be contacted every week via telephone to determine 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. 
If the subject delivers the baby prior to the face-to-face post-infusion assessment visit, central laboratory assessments for hematology, chemistry, and LFTs and the assessments 
for the Delivery Phase (see Protocol Section 3.1.4) will be performed. 


 
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3. 
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) and the EQ-5D-5L (-2 weeks/+6 weeks) (see Protocol Section 3.1.5 for 
list of assessments and visit windows). 
4. 
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. 
5. 
The subject or other legal guardian for the infant will be asked to consent to participate in a separate long-term study to follow infants for safety and neurodevelopment outcomes. 
The subject or other legal guardian for the infant (both delivered and undelivered) will be asked to give consent for the infant follow-up study at any time during the study that is 
appropriate and convenient. Withdrawal from the study after beginning randomized treatment or discontinuing IP does not preclude involvement in the infant follow-up study. 
6. 
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. 
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. Additional cervical examinations (Day 1, Day 2, and/or at the 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 Protocol Section 4.2), 2 examinations must be documented (either 2 digital cervical examinations or 2 
cervical length examinations). 
8. 
An ultrasound for estimation of fetal weight and head circumference is needed at Screening or before retreatment 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 or the date of retreatment. 
9. 
The abdominal ultrasound for determination of the AFI will be performed at Screening and before retreatment. The AFI should be measured using the 4-quadrant method. 
10. 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. 
11. Antenatal corticosteroid treatment should be administered in accordance with national, society, or institutional guidelines. Magnesium sulfate for fetal neuroprotection can be given 
at the discretion of the investigator.  
12. Information regarding delivery will be obtained through a review of the hospital and medical records. Growth parameters include neonatal weight, length, and head circumference. 
13. 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. 
14. Vital signs (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, if criteria are met, also during retreatment, and at the post-infusion assessment visit. During the Inpatient Randomized Treatment Phase and during 
retreatment, vital signs will be assessed and recorded within the following windows relative to the start of the infusion:  15 to 30 minutes, 4 to 8 hours, and 20 to 24 hours, at the 
end of the infusion, at the time of any dose changes, and as warranted by a medical condition. It is suggested (but not required) that oxygen saturation also be assessed at 
Screening and recorded in source documents. 
15. Maternal subjects will complete the EPDS, a self-reported questionnaire, at the maternal follow-up assessment 6 weeks (-2 weeks/+6 weeks) after delivery. 
16. 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%. 
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 Protocol Section 
6.3.1 if ALT or bilirubin is abnormal. 


 
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17. 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 Protocol Section 6.3.1). 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. 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. 
18. Prior to dosing, if the fetal heart rate pattern is nonreassuring, the subject cannot be dosed. 
19. 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 6.3.12.3Error! Reference source not found.). 
20. If the subject has not delivered at the end of the Inpatient Randomized Treatment Phase, fetal heart rate (fetal Doppler heart rate or cardiotocography are both acceptable) 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 Protocol Section 6.3.12.3). 
21. 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 6.3.12.3). 
22. 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. 
23. PK samples will be taken at the following sampling windows (relative to the start of the infusion): 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. A maternal blood sample should be 
collected at the same time as the cord blood sample (see Protocol Section 6.5.1) if the sample time does not already coincide with one of the PK sampling windows. 
24. In subjects who deliver at an investigative center within 12 hours following completion or discontinuation of the IP, the cord blood sample will also be divided for PK analysis as 
well as genetic (if additional consent is provided; Protocol Appendix 1) and biomarker analyses. 
25. 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. 
26. A placental tissue sample will be collected at delivery in subjects who deliver at an investigative center. 
27. A maternal blood sample for genetic research will only be collected from subjects who provide separate informed consent (see Protocol Appendix 1).  
28. A cord blood sample will be collected in subjects who deliver at an investigative center, if additional consent is provided.  
29. Testing for fetal fibronectin will be performed only at those institutions collecting the information as routine practice. Fetal fibronectin will not be used to determine study eligibility. 
30. Cervical length measured by transvaginal ultrasound will be captured only at those institutions collecting the information as routine practice. Cervical length will not be used to 
determine study eligibility. 
 
 
 
 
 


 
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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.  For retreated subjects, start date/time and stop date/time for both initial 
treatment and retreatment will be derived.  
11.3.1. 
Treatment Phases 
Assessments and events will be classified according to the time of occurrence relative to 
study treatment, unless otherwise specified.  
Non-retreated subjects 
Treatment Phase 
Definition 
Pre-treatment 
Date/Time < Initial Study Treatment Start Date/Time  
On-treatment 
Initial Study Treatment Start Date Time ≤  Date Time ≤ Initial Study 
Treatment Stop Date Time + 12 hours or 
Retreated Study Treatment Start Date Time ≤  Date Time ≤ Retreated 
Study Treatment Stop Date Time + 12 hours 
Post-treatment 
Study Treatment Stop Date/Time + 12 hours < Date Time < Retreated 
Study Treatment Start Date Time or  
Date/Time > Retreated Study Treatment Stop Date/Time + 12 hours 
 
Retreated subjects  
 
Treatment Phase 
Definition 
Pre-treatment 
Date/Time < Initial Study Treatment Start Date/Time  
On-treatment 
Initial Study Treatment Start Date Time ≤  Date Time ≤ Initial Study 
Treatment Stop Date Time + 12 hours or 
Retreated Study Treatment Start Date Time ≤  Date Time ≤ Retreated 
Study Treatment Stop Date Time + 12 hours 
Post-treatment 
Study Treatment Stop Date/Time + 12 hours < Date Time < Retreated 
Study Treatment Start Date Time or  
Date/Time > Retreated 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 
Non-retreated subjects 
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. 
 
Retreated subjects 
Treatment State 
Definition 
AE = Pre-treatment 
AE Start Date < Initial 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. 
Initial Study Treatment Start Date  ≤ AE Start Date ≤ Initial Study Treatment 
Stop Date + 1 or 
Retreated Study Treatment Start Date  ≤ AE Start Date ≤ Retreated Study 
Treatment Stop Date + 1 
AE = Post-
treatment 
If AE onset date is after the treatment stop date. 
Initial Study Treatment Stop Date + 1 < AE Start Date < Retreated Study 
Treatment Start Date or  
AE Start Date > Retreated Study Treatment Stop Date + 1 
AE Onset Time 
Since 1st  Dose 
(Days) 
If Initial Study Treatment Start Date > AE Onset Date :  
= AE Onset Date – Initial Study Treatment Start Date 
If Initial Study Treatment Start Date ≤ AE Onset Date :  
= AE Onset Date – Initial Study Treatment Start Date + 1 
Missing otherwise  


 
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Treatment State 
Definition 
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 
Atosiban 
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. 
For the retreated subjects, a baseline will be the latest pre-dose assessment of the initial 
treatment.  
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 assessments 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 interruptions 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 
 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 retreatment/subsequent preterm labor is defined as the days between start 
time of the infusion of IP and the first occurrence among delivery, retreatment and subsequent 
preterm labor 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 
For the delivery date/time of the primary endpoint, 
 Missing data with respect to time to delivery endpoint 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. 
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). 
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.  


 
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Element 
Reporting Detail 
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 
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' 


 
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Element 
Reporting Detail 
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 Primary 
and Key Secondary Endpoints with Missing Data 
11.7.1. 
Time to Delivery 
The time to delivery is defined as the days between the delivery and start time of the 
infusion of IP.  If the delivery date is missing or unknown i.e. subjects withdrew from the 
study or lost to follow-up, the time to delivery data will be the missing data, which will 
be handled in below methods. 
This analysis addresses the question “What is the prolongation effect for the mother of an 
initial decision to prescribe treatment, regardless of what subjects received?” This is also 
referred to as a de facto analysis (Carpenter 2013). The treatment effect on the time to 
delivery will be estimated on randomized subjects regardless of adherence. The delivery 
data after treatment discontinuation, treatment switch (i.e. at retreatment), or use of 
rescue medication will be collected and will be included in the primary analysis.  Missing 
data from subjects who withdraw from study participation will be imputed using last 
contact date or last record available in the study database.  The last record are those 
clinical records that the subjects were last contacted but remained undelivered.  For those 
subjects who are lost to follow-up, a date of birth of delivery date will be obtained from 
the search of national database if applicable.   
11.7.2. 
Neonatal Composite Outcome  
Neonatal Composite outcome is proportion of neonates with any diagnosis from the 
neonatal morbidity and mortality composite determined up to 28 days after EDD (of 400/7 
weeks).   
This analysis is also a de facto analysis as defined for time to delivery, and will include 
all mother and neonate pairs regardless of adherence.  The delivery data after treatment 
discontinuation, treatment switch (i.e. at retreatment), or use of rescue medication will be 
collected and will be included in the primary analysis.   
Analysis of the primary endpoint will be performed using multiple imputation methods 
described as below (Carpenter et al 2013). The MI method will be implemented with the 
SAS® MI procedure, using the logistic regression method. The model includes treatment 
(TRT) and GA at birth (GA_birth) as predictors, where GA at birth is considered 
complete with missing values (if any) being imputed with the last contact date or last 
record available. PROC MI will replace each missing neonatal composite score with a set 
of plausible values, assuming data are MAR. The missing data will be filled in 1000 
times to generate 1000 complete data sets. Sample SAS® code of the procedure can be 
found in below: 
proc mi data=dsetin seed=xxx out=dsetmi nimpute=1000; 
       class TRT composite; 
       monotone logistic; 
       var TRT GA_birth composite; 
run; 


 
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Once the 1000 completed datasets are produced, analysis of the neonatal composite 
outcome will be repeated on these imputed datasets, using a logistic regression model to 
estimate the effect of treatment on the outcome adjusting for GA at 
randomization(GA_rand) and progesterone use as covariate:  
proc logistic data=dsetmi; 
       class TRT(desc); 
       model composite(event='1') = TRT GA_rand EPU; 
       ods output PARAMETERESTIMATES=parms ODDSRATIOS=odds; 
       by _Imputation_; 
run;  
PROC MIANALYZE will then be used to combine the results of analyses on the multiply 
imputed datasets based on Rubin’s combination rules (Rubin, 1987).  
As the estimates of odds ratios follow a log-normal distribution, a log transformation can 
be applied to normalize these estimates in order to be able to apply Rubin’s rules. These 
combination rules take as input estimates of a statistic obtained from multiple imputed 
datasets as well as standard errors of these estimates, and produce the overall pooled 
estimate, overall standard error, confidence interval and a p-value from a univariate 
hypothesis test of the statistic being equal to zero. An example of SAS® code is given 
below: 
*** log-transform odds ratio estimates and obtain standard error from CIs; 
data lgodds;  
       set odds(where=(index(effect,"TRT"))); 
       log_or=log(OddsRatioEst); 
       log_or_se=(log(UpperCL)-log(LowerCL))/(2*1.96); 
run; 
*** combine transformed estimates; 
proc mianalyze data=lgodds; 
       modeleffects log_or; 
       stderr log_or_se; 
       ods output PARAMETERESTIMATES=lgsodds_mi; 
run; 
*** back-transform combined values; 
data odds_mi;  
       set lgsodds_mi; 
       OddsRatioEst = exp(estimate); * pooled odds ratio; 
       LowerCL=OddsRatioEst*exp(-1.96*stderr); * pooled lower limit; 
       UpperCL=OddsRatioEst*exp( 1.96*stderr); * pooled upper limit; 
run; 


 
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11.7.3. 
Proportional of Preterm Birth <37 weeks or ≥ 37 weeks  
If the delivery date is missing or unknown i.e. subjects withdrew from the study or lost to 
follow-up, the proportion of births data will be the missing data, which will be handled in 
below methods. 
The analysis of proportion of preterm birth uses the de facto analysis.   Missing data from 
subjects who withdraw from study participation will be imputed using last contact date or 
last record available in the study database.    The last record are those clinical records that 
the subjects were last contacted but remained undelivered. 
11.7.4. 
Length of Hospital Stay  
The handling of missing data in neonatal hospital length of stay can be summarized as 
follows. 
Length of hospital stay will be log-transformed (at base 10) and checked for normality 
prior to analysis. If the normality assumption holds, the missing values in the length of 
hospital stay will be multiple imputed and then analyzed using an analysis of covariance 
adjusting for the covariate of GA at entry and established progesterone use (yes or no).  If 
the normality assumption is violated, the missing values will not be imputed and 
Wilcoxon rank sum test will be performed to compare the two treatments with all 
observed data.  
If the length of stay data is log-normally distributed, the missing data (in log scale) will 
be imputed using the SAS® MI procedure with the regression method. The model 
includes treatment (TRT) and GA at birth (GA_birth) as predictors, where GA at birth is 
considered complete with missing values (if any) being imputed with the last contact date 
or last record available in the study database. The missing data will be filled in 1000 
times to generate 1000 complete data sets. Sample SAS® code of the procedure can be 
found in below: 
proc mi data=dsetin seed=xxx out=dsetmi nimpute=1000; 
       class TRT; 
       monotone regression; 
       var TRT GA_birth log_length_stay; 
run; 
Once the 1000 completed datasets are produced, analysis of the log-transformed length of 
hospital stay will be repeated on these imputed datasets, using a regression model to 
estimate the effect of treatment adjusting for GA at randomization (GA_rand) as 
continuous covariate and established progesterone use (EPU) as categorical covariate:  
proc mixed DATA=dsetmi; 
       class TRT EPU ; 
       model log_length_stay = TRT GA_rand EPU / solution cl; 
       lsmeans trtmt / cl diff; 
       by _Imputation_; 


 
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       ods output diffs=lgdiffs SolutionF=params CovB=covb; 
run; 
PROC MIANALYZE will then be used to combine the results of analyses on the multiply 
imputed datasets based on Rubin’s combination rules (Rubin, 1987): 
proc mianalyze data=lgdiffs; 
       modeleffects estimate; 
       stderr stderr; 
       ods otuput PARAMETERESTIMATES=diffs_mi; 
run; 
The combined results will be back transformed to normal scale afterwards. 
 


 
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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)  Time to delivery 
 Length of hospital stay 
Analysis 
 Finite Mixture Models for the Time to Delivery 
 Analysis of Covariance for the Length of hospital stay 
 For the time to delivery, the FMM model assumptions will be examined and appropriate 
adjustments maybe applied based on the data. 
  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 
Amniotic 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 
ICU  
Intensive Care Unit 
IDMC  
Independent Data Monitoring Committee 


 
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Abbreviation 
Description 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
ITT 
Intent-to-treat 
Kg 
Kilogram 
MedDRA  
Medical Dictionary for Regulatory Activities 
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 
Figures 
Study Population 
1.01 to 1.xx 
1.01 
Efficacy 
2.01 to 2.xx 
2.01 
Safety 
3.01 to 3.xx 
N/A 
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 
 
 
1.27 
Maternal ITT 
 
Summary of Maternal Prior Medications  
 
 
1.28 
Maternal ITT 
 
Summary of Maternal Concomitant Medications 
 
 
1.29 
Maternal ITT 
 
Summary of Maternal Obstetrical Medications 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
75 
 
Study Population Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
1.30 
Maternal ITT 
 
Summary of Maternal Magnesium Sulfate 
 
 
1.31 
Maternal ITT 
 
Summary of Maternal Antenatal Corticosteroids 
 
 
  


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
76 
 
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 
 
Analysis of Time to Delivery 
 
 
2.03 
Maternal ITT 
 
Summary of Time to Delivery, Retreatment or 
Subsequent PTL 
 
 
2.04 
Maternal ITT 
 
Analysis of Time to Delivery Using ANCOVA 
 
 
2.51 
Maternal ITT 
 
Summary Statistics for Time to Delivery by Gestational 
Age Group 
 
 
2.52 
Maternal ITT 
 
Summary Statistics for Time to Delivery by Established 
Progesterone Group 
 
 
2.53 
Maternal ITT 
 
Summary Statistics for Time to Delivery by PTL criteria 
(IC#4) 
 
 
2.54 
Maternal ITT 
 
Summary Statistics for Time to Delivery by Labor Onset 
Status 
 
 
Neonatal Composite Endpoint 
2.101 
Neonatal ITT 
 
Proportion of Neonatal Composite Endpoint 
 
 
2.102 
Neonatal ITT 
 
Proportion of Modified Neonatal Composite Endpoint 
 
 
2.151 
Neonatal ITT 
 
Proportion of Neonatal Composite Endpoint by 
Gestational Age Group 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
77 
 
Efficacy Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
2.152 
Neonatal ITT 
 
Proportion of Neonatal Composite Endpoint by 
Established Progesterone Group 
 
 
Proportion of Births 
2.181 
Maternal ITT 
 
Proportion of Births 
 
 
2.201 
Maternal ITT 
 
Proportion of Births by Gestational Age Group 
 
 
2.202 
Maternal ITT 
 
Proportion of Births by Established Progesterone Group 
 
 
Neonatal Hospital Admission: Length of Neonatal Hospital Stay 
2.301 
Neonatal ITT 
 
Analysis of Neonatal Hospital Stay  
 
 
2.321 
Neonatal ITT 
 
Summary Statistics for Neonatal Hospital Stay by 
Maternal Gestational Age Group 
 
 
2.322 
Neonatal ITT 
 
Summary Statistics for Neonatal Hospital Stay by 
Established Progesterone Group 
 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
78 
 
 
11.11.4. 
Efficacy Figures 
Efficacy Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Time to Delivery 
2.01 
Maternal 
ITT 
 
Kaplan-Meier Plot of Time to Delivery by Treatment 
Group 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
79 
 
11.11.5. 
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 
 
 
3.31 
Maternal 
Safety 
 
Summary of Maternal Adverse Events by Maximum 
Grade or Intensity 
 
 
3.41 
Maternal 
Safety 
 
Summary of Most Common Maternal Adverse Events 
 
 
3.51 
Maternal 
Safety 
 
Summary of Maternal Serious Adverse Events 
 
 
3.71 
Maternal 
Safety 
 
Summary of Maternal Adverse Events of Special 
Interest 
 
 
3.72 
Maternal 
Safety 
 
Summary of Maternal Adverse Events of Special 
Interest by Gestational Age Group 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
80 
 
Safety Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
3.81 
Maternal 
Safety 
 
Summary of Maternal Disease-Related Adverse 
Events 
 
 
Fetal Adverse Events 
3.111 
Maternal 
Safety 
 
Summary of Fetal Adverse Events 
 
 
3.131 
Maternal 
Safety 
 
Summary of Fetal Adverse by Maximum Grade or 
Intensity 
 
 
3.141 
Maternal 
Safety 
 
Summary of Most Common Fetal Adverse Events 
 
 
3.151 
Maternal 
Safety 
 
Summary of Fetal Serious Adverse Events 
 
 
3.171 
Maternal 
Safety 
 
Summary of Fetal Adverse Events of Special Interest 
 
 
3.172 
Maternal 
Safety 
 
Summary of Fetal Adverse Events of Special Interest 
by Gestational Age Group 
 
 
Neonatal Adverse Events 
3.211 
Neonatal 
Safety 
 
Summary of Neonatal Adverse Events 
 
 
3.231 
Neonatal 
Safety 
 
Summary of Neonatal Adverse by Maximum Grade or 
Intensity 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
81 
 
Safety Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
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 
 
 
3.272 
Neonatal 
Safety 
 
Summary of Neonatal Adverse Events of Special 
Interest by Gestational Age Group 
 
 
3.281 
Neonatal 
Safety 
 
Summary of Neonatal Disease-Related Adverse 
Events 
 
 
Maternal Hospital Admission 
3.301 
Maternal 
Safety 
 
Summary of Maternal Hospital Admission (In-patient) 
 
 
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 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
82 
 
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 
 
 
Neonatal Hospital Admission 
3.463 
Neonatal 
Safety 
 
Summary of Neonatal Hospital Unit Utilization At Birth 
 
 
3.464 
Neonatal 
Safety 
 
Analysis of Length of Neonatal NICU Stays At Birth   
 
 
Maternal Placental Data 
3.501 
Maternal 
Safety 
 
Summary of Placental Findings 
 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
83 
 
11.11.6. 
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 
 
 
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 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
84 
 
ICH Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
12 
Maternal ITT 
 
Maternal Baseline Characteristics I 
 
 
13 
Maternal ITT 
 
Maternal Baseline Characteristics II 
 
 
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 
Safety 
 
Prior and Concomitant Medications 
 
 
24 
Maternal 
Safety 
 
Obstetrical Medications 
 
 
25 
Maternal 
Safety 
 
Magnesium Sulfate 
 
 
26 
Neonatal 
Safety 
 
Antenatal Corticosteroids 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
85 
 
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 
 
 
46 
Maternal 
Safety 
 
Maternal Adverse Events of Special Interest: Pelvic 
Abscess 
 
 
49 
Maternal 
Safety 
 
Maternal Adverse Events of Special Interest: Wound 
Infection 
 
 
52 
Maternal 
Safety 
 
Maternal Adverse Events of Special Interest: 
Postpartum Hemorrhage 
 
 
53 
Maternal 
Safety 
 
Maternal Adverse Events of Special Interest: 
Placental Abruption 
 
 
56 
Maternal 
Safety 
 
Fetal Adverse Events of Special Interest: Category II-
III FHR Event 
 
 
57 
Maternal 
Safety 
 
Maternal Disease-Related Adverse Events 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
86 
 
ICH Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
76 
Maternal 
Safety 
 
All Fetal Adverse Events 
 
 
77 
Maternal 
Safety 
 
Fetal Serious Adverse Events 
 
 
78 
Maternal 
Safety 
 
Fetal Adverse Events of Special Interest 
 
 
82 
Neonatal 
Safety 
 
All Neonatal Adverse Events 
 
 
83 
Neonatal 
Safety 
 
Neonatal Serious Adverse Events 
 
 
84 
Neonatal 
Safety 
 
Neonatal Adverse Events of Special Interest 
 
 
86 
Neonatal 
Safety 
 
Neonatal Adverse Events of Special Interest: 
Respiratory Distress Syndrome 
 
 
89 
Neonatal 
Safety 
 
Neonatal Adverse Events of Special Interest: 
Intraventricular Hemorrhage 
 
 
91 
Neonatal 
Safety 
 
Neonatal Adverse Events of Special Interest: 
Neonatal Acidosis 
 
 
92 
Neonatal 
Safety 
 
Neonatal Adverse Events of Special Interest: 
Hyperbilirubinemia 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
87 
 
ICH Listings 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
96 
Neonatal 
Safety 
 
Neonatal Disease-Related Adverse Events 
 
 
97 
Neonatal 
Safety 
 
Neonatal Deaths 
 
 
111 
Neonatal 
Safety 
 
Neonatal Disease-Related Adverse Events: 
Retinopathy of Prematurity 
 
 
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 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
88 
 
11.11.7. 
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 
 
 
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) 
 
 


 
CONFIDENTIAL 
 
 
 
GSK200721 
 
89 
 
Non-ICH Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
405 
Maternal 
Safety 
 
Cervical Exam 
 
 
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 
 
 
Placental Data 
464 
Maternal 
Safety 
 
Placental Findings