Conditions: Obstetric Labour, Premature
Keywords: infants retosiban Preterm Labor long-term safety follow-up
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the safety and outcomes of infants and children who were exposed to retosiban or comparator in utero in the Phase III spontaneous preterm labor (SPTL) treatment studies, to provide assurance that treatment is not associated with significant adverse outcomes in early childhood. The enrolled infants and children will be followed at pre-specified intervals until they reach 24 months chronological age. This study does not require medical interventions or study visits to an investigational site, instead, parents or legal guardians will be prompted at certain time points to complete developmental questionnaires and other data on their children's health status via an electronic device. Data collected during the infant and child follow up study will be managed by a centralized research coordinating center (RCC). Regionally based pediatricians will serve as study principal investigators (referred to as RCC-PIs) for this study. All communications the RCC-PI has with the parent/legal guardian or the child's health care provider (HCP) will occur remotely; there will be no clinic visits.

Detailed description:

Arms:
arm 1: All infants and children born to women who received the placebo (0.9 percent sodium chloride infusion matched for retosiban volume, intravenous \[IV\] loading dose over 5 minutes and continuous infusion rate including dose increase in participants with an inadequate response any time after first hour of treatment) in 200719 study. Current study will not require any medical interventions or study visits to an investigational site. arm 2: All infants and children born to women who received retosiban (6 milligram \[mg\] IV loading dose of retosiban over 5 minutes followed by a 6 mg per hour continuous infusion of retosiban over 48 hours. Participants with an inadequate response any time after first hour of treatment were administered another 6 mg retosiban loading dose followed by 12 mg per hour continuous infusion for remainder of 48-hour treatment period) in 200719 study or 200721 study. Current study will not require any medical interventions or study visits to an investigational site. arm 3: All infants and children born to women who received atosiban (in 3 successive stages; an initial bolus dose of 6.75 mg using atosiban 6.75 mg per 0.9 milliliter \[mL\] solution for injection, followed by continuous high dose infusion at 18 mg per hour for 3 hours, then a lower 6 mg per hour infusion for the remainder of the 48-hour using the atosiban 37.5 mg per 5 mL concentrate for solution) in 200721 study. Current study will not require any medical interventions or study visits to an investigational site.

Interventions: intervention 1: Retosiban intervention 2: Atosiban intervention 3: Placebo
Intervention descriptions: intervention 1: This is a safety follow-up study of infants and children exposed to retosiban during their mother's participation in a Phase III treatment study for SPTL. Infants enrolled in this study will not be administered any investigational product. intervention 2: This is a safety follow-up study of infants and children exposed to atosiban comparator during their mother's participation in a Phase III treatment study for SPTL. Infants enrolled in this study will not be administered any investigational product. intervention 3: This is a safety follow-up study of infants and children exposed to matching placebo for retosiban/ atosiban during their mother's participation in a Phase III treatment study for SPTL. Infants enrolled in this study will not be administered any investigational product

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Follow-Up Study to Assess Long-Term Safety and Outcomes in 
Infants and Children Born to Mothers Participating in Retosiban 
Treatment Studies
Compound Number:
GSK221149
Development Phase:
III
Study Name:
ARIOS
Effective Date:
01-NOV-2018
Protocol Amendment Number:  02
Authors (GSK):  
 
Authors (PPD):  
 
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N194466_00
2014-MAY-14
Original
2014N194466_01
2015-AUG-17
Amendment No. 1
The following changes are reflected in Protocol Amendment No. 1:

Extend the study duration from 24 months to 5 years to identify any potential 
neurodevelopmental and behavioral disorders through annual assessments at 
years 3, 4, and 5, specifically autism and attention deficit hyperactivity disorder.

Add an assessment using a modified version of the CHI questionnaire at 3, 4, 
and 5 years of the child’s chronological age to collect data to identify any 
potential neurodevelopmental and behavioral disorders.

Add an additional assessment of the M-CHAT-R/F at 18 months (corrected age) 
per American Academy of Pediatrics guidelines

Revise to indicate that the M-CHAT-R/F (assessed at 18 and 24 months) and the 
CBCL/1.5-5 (assessed at 24 months) are mandatory for all infants, regardless of 
ASQ-3 results, per American Academy of Pediatrics guidelines

Remove as a neurodevelopment endpoint the proportion of infants referred for 
an additional behavior assessment using the M-CHAT-R/F and CBCL/1.5-5

Clarify that any infant serious adverse events (SAEs) and/or AEs of special 
interest that were unresolved at the end of the Phase III treatment studies and 
any new SAEs reported during this study should be followed to stabilization or 
resolution in those children participating in the follow-up study.

Revise the subgroups that may be included in the safety analyses to reflect study 
design of Phase III SPTL Study 200719 (NEWBORN-1)

Clarify unblinding text to indicate that there is no requirement for the 
investigator to discuss unblinding with the PPD medical monitor in order to 
rapidly unblind a child’s treatment assignment, if needed

Incorporate other administrative changes
2014N194466_02
2018-NOV-01
Amendment No. 2
The following changes are reflected in Protocol Amendment No. 2:

Reduction of study duration from 5 years to 24 months due to:
‒
Termination of the retosiban development program, such that there will be no 
further in utero exposure to retosiban, and hence safety data from this ongoing 
study will not inform the potential risk for future use of retosiban. 
‒
Low recruitment for interventional studies 200719 (NEWBORN-1) and 
 
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GlaxoSmithKline
Document Number
Date
Version
200721 (ZINN). Hence, the number of infants exposed to retosiban in utero 
and included in the current (200722) study is small.
‒
The independent data monitoring committee (IDMC) recommendation that the 
neonatal follow-up be limited to 24 months of age given no safety issues
detected in their unblinded review of available 200722 data and also that 
statistical analysis at a 5-year timepoint would not provide any meaningful 
results due to the small number of enrolled subjects.

Reclassification of all resource utilization endpoints as exploratory endpoints 
due to the reduced sample size

Correction of an error in the mean BSID-III score for the cognitive impairment, 
fine motor and gross motor scales to <4 to reflect that these are not composite 
scores

Incorporation of other administrative changes
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier: 200722 (ARIOS)
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: 
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 Monitors and Serious Adverse Events (SAEs) Contact Information
Issue
North America 
Contract
Latin America Contact
Europe/Asia Contact
Safety Questions
 MD, 
MPH
Associate Medical Director, 
Medical Affairs and 
Pharmacovigilance
PPD
Denver, CO, USA
 MD
Medical Director, Medical 
Affairs and 
Pharmacovigilance
PPD
Buenos Aires, Brazil
Europe:
, MD
Associate Medical Director, 
Medical Affairs and 
Pharmacovigilance
PPD
Sofia, Bulgaria
Asia: 
 MD
Associate Medical Director, 
Medical Affairs and 
Pharmacovigilance
PPD
Kuala Lumpur, Malaysia
SAE Reporting
24-Hour Safety Hotline:
Safety Fax:
24-Hour Safety Hotline:
Safety Fax: 
 
24-Hour Safety Hotline:
Safety Fax:
 
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Regulatory Agency Identifying Number(s):
IND Number: 73287
EudraCT Number: 2014-000499-24
 
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RCC-PI PROTOCOL AGREEMENT PAGE
For protocol 200722 (ARIOS)
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 
RCC staff receives the appropriate information throughout the study. 
RCC-PI Name:
RCC-PI Address:
RCC-PI Phone Number:
RCC-PI Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS AND DEFINITIONS ...........................................................11
PROTOCOL SUMMARY...............................................................................................13
1.
INTRODUCTION....................................................................................................19
1.1.
Background ................................................................................................19
1.1.1.
Previous Human Experience........................................................20
1.2.
Rationale ....................................................................................................21
1.3.
Benefit:Risk Assessment ............................................................................21
1.3.1.
Risk Assessment .........................................................................22
1.3.2.
Benefit Assessment.....................................................................24
1.3.3.
Overall Benefit:Risk Conclusion...................................................25
2.
OBJECTIVES.........................................................................................................26
3.
INVESTIGATIONAL PLAN.....................................................................................28
3.1.
Study Design ..............................................................................................28
3.2.
Discussion of Design ..................................................................................32
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................32
4.1.
Number of Subjects ....................................................................................32
4.2.
Inclusion Criteria.........................................................................................33
4.3.
Exclusion Criteria........................................................................................33
4.4.
Withdrawal Criteria .....................................................................................33
5.
STUDY TREATMENTS..........................................................................................33
5.1.
Investigational Product and Other Study Treatment....................................33
5.2.
Treatment Assignment................................................................................34
5.3.
Blinding.......................................................................................................34
5.4.
Product Accountability ................................................................................35
5.5.
Treatment Compliance................................................................................35
5.6.
Concomitant Medications and Nondrug Therapies......................................35
5.7.
Treatment After the End of the Study..........................................................35
5.8.
Treatment of Study Treatment Overdose....................................................35
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
6.1.
Critical Baseline Assessments....................................................................39
6.2.
Safety .........................................................................................................39
6.2.1.
Morbidity and Mortality Endpoints ................................................39
6.2.1.1.
Parent/Legal Guardian-Completed Child Health 
Inventory ....................................................................39
6.2.1.1.1.
Confirmation of Parent-Reported 
Data........................................................40
6.2.2.
Chronic Medical Conditions .........................................................42
6.2.2.1.
Respiratory Conditions ...............................................42
6.2.2.2.
Neurological Conditions..............................................42
6.2.2.3.
Sensory Conditions ....................................................43
6.2.2.4.
Gastrointestinal Conditions.........................................43
 
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6.2.2.5.
Cardiovascular Conditions..........................................43
6.2.2.6.
Renal Conditions ........................................................44
6.2.2.7.
Growth Parameters ....................................................44
6.2.3.
Congenital Anomalies..................................................................44
6.2.4.
Infant and Child Deaths ...............................................................45
6.2.5.
Parent/Legal Guardian-Completed ASQ-3, M-CHAT-R/F, 
and CBCL/1.5–5 and Possible Referral to a Specialist.................45
6.2.5.1.
The ASQ-3 Score Interpretation and Possible 
Specialist Referral Recommendations........................46
6.2.5.2.
Neurodevelopment .....................................................49
6.2.6.
Overall Measure of Neurodevelopmental Impairment ..................49
6.2.7.
Adverse Events............................................................................50
6.2.7.1.
Definition of an AE......................................................50
6.2.7.2.
Definition of an SAE ...................................................51
6.2.8.
Laboratory and Other Safety Assessment Abnormalities 
Reported as SAEs .......................................................................52
6.2.9.
Cardiovascular Events.................................................................52
6.2.10.
Death Events...............................................................................52
6.2.11.
Time Period and Frequency of Detecting SAEs ...........................53
6.2.12.
Method of Detecting SAEs...........................................................53
6.2.13.
Follow-up of SAEs .......................................................................53
6.2.14.
Prompt Reporting of SAEs and Other Events to GSK/PPD..........53
6.2.14.1.
Regulatory Reporting Requirements for SAEs............54
6.2.15.
Other Safety Outcomes ...............................................................55
6.2.15.1.
Laboratory Assessments ............................................55
6.2.15.2.
Ad Hoc Maternal Reports ...........................................55
6.3.
Health Outcomes........................................................................................55
6.3.1.
Parent/Legal Guardian-Completed Productivity 
Questionnaire ..............................................................................56
7.
DATA MANAGEMENT ...........................................................................................56
7.1.
Data Handling Conventions ........................................................................56
7.1.1.
Attempts to Obtain the Follow-Up Information..............................56
7.1.2.
Loss to Follow-Up........................................................................57
7.2.
Validation Procedures.................................................................................57
7.2.1.
Follow-Up Process for Clarification of Information........................57
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................57
8.1.
Hypotheses.................................................................................................57
8.2.
Study Design Considerations......................................................................58
8.2.1.
Sample Size Assumptions ...........................................................58
8.2.2.
Sample Size Sensitivity................................................................58
8.2.3.
Sample Size Re-Estimation .........................................................58
8.3.
Data Analysis Considerations .....................................................................58
8.3.1.
Analysis Populations....................................................................58
8.3.2.
Analysis Data Sets.......................................................................58
8.3.3.
Treatment Comparisons ..............................................................58
8.3.3.1.
Primary Comparisons of Interest ................................58
8.3.3.2.
Other Comparisons of Interest....................................59
8.3.4.
Interim Analysis ...........................................................................59
8.3.5.
Key Elements of Analysis Plan ....................................................59
8.3.5.1.
Safety Analyses..........................................................59
 
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8.3.5.1.1.
Outcomes...............................................59
8.3.5.1.2.
Serious Adverse Events .........................60
8.3.5.2.
Health Outcomes Analyses ........................................60
8.3.5.3.
Genetic Analyses .......................................................60
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................60
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
9.2.1.
Release of Participant Medical Information..................................61
9.2.2.
Subject Confidentiality .................................................................61
9.3.
Quality Control (Study Monitoring) ..............................................................61
9.4.
Quality Assurance.......................................................................................62
9.5.
Study and RCC Site Closure.......................................................................62
9.6.
Records Retention......................................................................................62
9.7.
Provision of Study Results to RCC-PIs, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication.........................63
9.8.
Independent Data Monitoring Committee....................................................63
10. REFERENCES.......................................................................................................64
11. APPENDICES........................................................................................................67
11.1.
Appendix 1: Protocol Changes....................................................................67
 
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LIST OF ABBREVIATIONS AND DEFINITIONS
AE
adverse event
ADD
attention deficit disorder
ADHD
attention deficit hyperactivity disorder
ASEBA
Achenbach System of Empirically Based Assessment
ASD
autism spectrum disorder
ASQ-3
Ages and Stages Questionnaire-3
BSID-III
Bayley Scale for Infant Development, third edition
CBCL/1.5–5
Child Behavior Checklist for Ages 1.5 to 5
CDC
Centers for Disease Control and Prevention
CHI
Child Health Inventory
CI
confidence interval
CV
cardiovascular
DSM
Diagnostic and Statistical Manual
eCRF
electronic case report form
eDC
electronic data capture
EDD
estimated date of delivery
EPDS
Edinburgh Postnatal Depression Scale
ER/UC
emergency room/urgent care 
EUROCAT
European Surveillance of Congenital Anomalies
FSFV
first subject first visit
GCP
Good Clinical Practice
GMFCS
Gross Motor Functional Classification System
HCP
health care provider
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICU
intensive care unit
IDMC
independent data monitoring committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
kg
kilogram
MACDP
Metropolitan Atlanta Congenital Defects Program 
M-CHAT-R/F
Modified Checklist for Autism in Toddlers-Revised with 
Follow-Up
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
NICU
neonatal intensive care unit
PI
principal investigator
PICU
pediatric intensive care unit
RAP
reporting and analysis plan
RCC
research coordinating center
RCC-PI
research coordinating center-principal investigator
SAE
serious adverse event
SPM
Study Procedures Manual
SPTL
spontaneous preterm labor
 
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DEFINITIONS
Child
Aged from 2 years to up to 12 years, per definition of the 
US Food and Drug Administration
Chronological age
Defined as the time elapsed after birth; it is usually 
described in days, weeks, months, and years
Corrected age
Calculated by subtracting the number of weeks an infant is 
born before 400/7 weeks’ gestation from the chronological 
age. This term is used to describe children up to 3 years of 
age who were born preterm.
End of the Phase III SPTL 
treatment studies
The cut-off date for final review of the neonatal record, 
signifying the end of Phase III spontaneous preterm labor
(SPTL) treatment studies, is the estimated date of delivery 
(EDD) plus 28 days; this is referred to as 28 days post EDD
Estimated date of delivery
Defined as 400/7 weeks’ gestation for all subjects in the 
Phase III SPTL treatment studies
Gestational age 
Determined by (1) known fertilization date, either in vitro 
fertilization or intrauterine insemination, (2) last menstrual 
period confirmed 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 the Phase III 
SPTL treatment studies
Infant
Aged from 1 month to up to 2 years, per definition of the 
US Food and Drug Administration
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
MedDRA
 
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PROTOCOL SUMMARY
Rationale
Advances in perinatal intensive care have resulted in increased survival rates for high risk 
newborns but limited improvement in morbidity. The immaturity of organs, such as the 
brain, lungs, and gastrointestinal tract, render these newborns susceptible to injury and 
abnormal development and function, which often leads to long-term health problems and 
disability. The risk for medical disability is inversely related to the gestational age at 
birth; the most common disabilities include cerebral palsy, cognitive dysfunction, 
blindness and impaired vision, hearing loss, and disorders of psychological development 
(i.e., behavior and emotion).
Over the past decades, few medical interventions have been designed to prevent preterm 
birth and/or reduce the severity of prematurity complications. Such treatments may also 
improve long-term outcomes. One of the major advances in perinatal medicine has been 
the finding that antenatal corticosteroids given to women at risk of imminent preterm 
birth reduces the risks for neonatal mortality and morbidity. Corticosteroids now 
represent the standard of care for an acute antenatal intervention to improve neonatal 
outcomes in the developed world [RCOG, 2011; ACOG, 2012].
However, there is an increasing awareness that the intended beneficial effects of perinatal 
interventions do not necessarily correlate with long-term outcomes. Dexamethasone in 
high daily doses appears to reduce mortality and the incidence of bronchopulmonary 
dysplasia but treatment is associated with numerous short- and long-term adverse 
outcomes, including neurodevelopmental impairment. As a result, treatment with high 
dose dexamethasone is not recommended [Watterberg, 2010]. The ORACLE II Study is 
an example of a perinatal treatment that was associated with adverse long-term outcomes 
and no neonatal benefit. ORACLE II studied the effect of antibiotics to improve neonatal 
outcomes in women with spontaneous preterm labor (SPTL) with intact membranes and 
no evidence of clinical infection. No reduction in neonatal complications was observed. 
However, the long-term follow-up revealed an increase in functional impairment and a 
higher risk for cerebral palsy in children whose mothers had received antibiotics 
[Kenyon, 2001; Kenyon, 2008]. These observations have led to an appreciation that 
perinatal interventions may affect growth and development and have highlighted the 
importance of long-term safety and outcome studies after randomized, controlled studies 
of perinatal interventions. 
The goal of this study (ARIOS), therefore, is to assess the safety and outcomes of infants 
and children who were exposed to retosiban (GSK221149) or comparator in utero in the 
Phase III SPTL treatment studies and provide assurance that treatment is not associated 
with significant adverse outcomes in early childhood.
In May 2017, the corresponding treatment trials 200719 (NEWBORN-1, placebo 
comparison) and 200721 (ZINN, atosiban comparison) were terminated early due to poor 
recruitment and the length of time needed to complete the studies. The placebo-controlled 
trial enrolled only 23 of the target 900 participants over 17 months, and the atosiban 
comparator trial enrolled 97 of the target 330 participants over 29 months. Maternal, 
 
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fetal, and neonatal adverse events were no more common with retosiban than placebo or 
atosiban. The development program was subsequently terminated with no further in utero 
exposure of retosiban planned.
Objectives
The study objective is to assess the safety and outcomes in infants and children who were 
exposed to retosiban or comparator in the Phase III SPTL treatment studies.
Specific objectives include the following:
Primary

To characterize the clinical safety in terms of infant and child morbidity and 
mortality in infants and children exposed to retosiban or comparator in utero

To characterize the clinical safety in terms of neurodevelopment in infants and 
children exposed to retosiban or comparator in utero
Exploratory

To characterize parental productivity loss related to a sick child and infant resource 
utilization in terms of hospital admissions, length of stay, emergency room/urgent 
care (ER/UC) visits, surgical procedures, and referral to specialty care or therapy 
visits for infants (up to age 2 years) exposed to retosiban or comparator in utero
Study Design
ARIOS is a long-term infant and child follow-up study that will prospectively assess 
safety and outcomes of all infants and children born to women who received at least 
1 dose of retosiban or comparator in any of the Phase III SPTL treatment studies. The 
final assessment of the Phase III SPTL treatment studies is a collection of neonatal 
morbidity data and will occur at 28 days after the estimated date of delivery (EDD), 
where EDD is defined as 400/7 weeks’ gestation. After this time, infants become eligible 
for this follow-up study. Ideally, the Phase III SPTL study investigators will obtain 
consent and medical release for this study when the women’s acute episode of preterm 
labor has resolved and prior to discharge from the hospital for the treatment of preterm 
labor. The infant will be able to be consented into the study until the later date of either 
the date of discharge from the birth hospitalization or up to 9 months corrected age. 
Infants and children will be followed at prespecified intervals until they have reached 
24 months chronological age. This study does not require medical interventions or study 
visits to an investigational site. Instead, parents or legal guardians will be prompted at 
certain time points to complete developmental questionnaires and other data regarding 
their child’s health status via an electronic device. Data collected during this follow-up 
study will be managed by a centralized research coordinating center (RCC). Regionally
based pediatricians will serve as the study principal investigators (referred to as RCC-PIs) 
for the follow-up study. All communications the RCC-PI has with the parent/legal 
guardian or the child’s health care provider (HCP) will occur remotely; there will be no 
clinic visits.
 
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The child’s parent/legal guardian will be asked to complete a Child Health Inventory 
(CHI) at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age. The CHI 
questionnaire completed up to the 24-month time point will screen for infant mortality 
and morbidity and will capture data on resource utilization. If the parent/legal guardian 
indicates that the child has been newly diagnosed (after 28 days post EDD) with chronic 
conditions or congenital anomalies, follow-up by the RCC-PI will be undertaken with the 
applicable HCP to confirm the parent report. Persistence or resolution of conditions will 
be determined in subsequent questionnaires after the initial report. 
If the parent/legal guardian indicates that the child has had a hospital visit or surgery or 
that the child has died, the RCC-PI will confirm by obtaining medical and other records 
from HCPs or medical facilities, including a death certificate, if applicable. If the 
parent/legal guardian indicates that the child has had an ER/UC visit, the RCC-PI will use 
discretion and obtain medical records when the reported indication suggests a true 
emergency. Additional details regarding ER/UC visits will be provided in the Study 
Procedures Manual. After review of all records, the RCC-PI may request additional 
targeted follow-up data from the relevant HCP or medical facility if clarification is 
needed on any reported study endpoints or serious adverse events.
During the 24 months of participation in the study, if the parent/legal guardian indicates 
that the infant has been treated by specialists or has had ER/UC visits or hospitalizations, 
he/she will be asked to complete a productivity questionnaire to evaluate loss of parental 
productivity.
When a congenital anomaly is reported, it will be reviewed by an expert in teratology 
who is engaged by the RCC-PI to serve 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.
To screen for a delay in the areas of communication, gross motor, fine motor, 
problem-solving, and personal-social skills, the parent/legal guardian will be asked to 
complete the 9-, 18-, and 24-month Ages and Stages Questionnaire-3 (ASQ-3) when the 
infant’s corrected age corresponds to 9, 18, and 24 months; for example, parents/legal 
guardians of an infant born 3 months premature will complete the 9-month ASQ-3 at 
12 months chronological age. Any child with a score in the black zone (2 SD below the 
mean) in any of the 5 domains of the ASQ-3 will be referred to a qualified assessor for a 
developmental evaluation (e.g., using the Bayley Scale for Infant Development, third 
edition [BSID-III]), unless the child is already under the care of a specialist who has 
recently conducted a BSID-III evaluation. Based on results from the ASQ-3 administered 
at 24 months corrected age and if no cerebral palsy diagnosis has been made to date, the 
infant may be referred to a qualified examiner for a formal assessment of cerebral palsy.
The Modified Checklist for Autism in Toddlers–Revised with Follow-Up 
(M-CHAT-R/F) will be completed for all infants at 18 and 24 months (corrected age) and 
the Child Behavior Checklist for Ages 1.5 to 5 (CBCL/1.5–5) will be completed for all 
infants at 24 months (corrected age) to assess the risk for other behavioral problems or 
autism spectrum disorder (ASD). If at any of these time points a child has an 
M-CHAT-R/F score that indicates further evaluation is required and/or a CBCL/1.5–5 
 
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score above the 97th percentile for a subset of prespecified questions, the child will be 
referred to a specialist for a formal assessment. 
Study Endpoints/Assessments
Study primary endpoints include the following and are further defined in Section 6.2.2:
Morbidity and mortality endpoints:

Proportion of infants and children with newly diagnosed (after 28 days post EDD) 
chronic medical conditions by type of condition will be recorded and include the 
following:

Respiratory conditions

Neurological conditions

Sensory conditions

Gastrointestinal conditions

Cardiovascular conditions

Renal conditions

Growth parameters

Proportion of infants and children with newly diagnosed (after 28 days post EDD) 
congenital anomalies

Proportion of infant and child deaths after 28 days post EDD and until 24 months 
chronological age
Neurodevelopment endpoints:

Neurodevelopment endpoints assessed at ages 9, 18, and 24 months, corrected for 
prematurity:

Proportion of infants with an ASQ-3 score in the black zone in any domain

Proportion of infants with an ASQ-3 score in the black zone for gross motor 
skills

Proportion of infants with an ASQ-3 score in the black zone for fine motor skills

Proportion of infants with an ASQ-3 score in the black zone for communication

Proportion of infants with an ASQ-3 score in the black zone for problem-solving

Proportion of infants with an ASQ-3 score in the black zone for personal-social 
skills

Proportion of infants referred for developmental evaluation (using BSID-III)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
cognitive impairment (<4)
 
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
Proportion of infants with BSID-III score >2 SDs below the mean score for the 
gross motor scale (<4)

Proportion of infants with BSID-III score >2 SDs below the mean score for the 
fine motor scale (<4)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
language scale (<70)

Proportion of infants with a CBCL/1.5–5 score above the 97th percentile for a 
subset of prespecified questions that relate to attention and hyperactivity 
problems 

Proportion of infants indicated as needing further evaluation after completion of 
the M-CHAT-R/F

Proportion of infants referred for neurological evaluation to determine diagnosis 
of cerebral palsy

Proportion of infants with at least 1 of the following indicators of 
neurodevelopmental impairment:

Hearing impaired, uncorrected even with aids (at 24 months chronological age)

Blindness in 1 or both eyes, or sees light only (at 24 months chronological age)

Cerebral palsy (moderate and severe) (at 24 months corrected age)

Cognitive impairment: BSID-III Cognitive Scale Score of >2 SDs below mean 
score (<4) (at 24 months corrected age)

Motor impairment: BSID-III Motor Composite Scale Score of >2 SDs below 
mean score (<70) (at 24 months corrected age)

Diagnosis of ASD, attention deficit disorder (ADD), or attention deficit 
hyperactivity disorder (ADHD)
Exploratory resource utilization endpoints include:

Number of hospital admissions, proportion of infants and children with any hospital 
admission, post-birth hospitalization discharge, by principal and secondary discharge 
diagnosis, type of hospital unit admitted to (e.g., neonatal intensive care unit [NICU], 
Pediatric, pediatric intensive care unit [PICU], Nursery level 3, intensive care unit 
[ICU]), and length of hospital stay per unit after 28 days post EDD and until 24 
months chronological age.
 
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
Combined length of hospital stay in days for all hospital admissions (for infants 
discharged from the delivery hospitalization and for babies who were never 
discharged home post-delivery) after 28 days post EDD and until 24 months 
chronological age.Number of surgical procedures (details of type and whether 
performed on an inpatient basis or at an outpatient/surgical center will be collected 
up to 24 months chronological age only) after 28 days post EDD and until 24 months 
chronological age.

Number of ER/UC visits and proportion of infants with any ER/UC visit after 
28 days post EDD and up to 24 months chronological age.

Number of specialty care or therapy visits and proportion of infants referred for 
specialty care or therapy by type of care/therapy after 28 days post EDD and up to 
24 months chronological age.

Parental productivity loss related to infant hospital admissions, ER/UC visits, or 
specialist care after 28 days post EDD and up to 24 months chronological age.
 
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1.
INTRODUCTION
1.1.
Background
Gestational age at birth is considered the most important predictor of a newborn’s 
subsequent health and survival. Infants born too early and too small have a much greater 
risk of death and both short- and long-term disability than those born at term [Saigal, 
2008]. Early morbidity due to prematurity includes respiratory distress syndrome, 
intraventricular hemorrhage, necrotizing enterocolitis, and sepsis. Late consequences of 
prematurity include chronic lung disease, cerebral palsy, sensory impairment, and 
cognitive deficits. 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 approximately 5% in several European countries to 18% in some African 
countries. In 2013, nearly 450 000 preterm births, defined as childbirth occurring before 
37 completed weeks’ gestation, occurred in the United States [Martin, 2015]. These 
preterm infants had an infant mortality rate approximately 15 times the rate for full-term 
infants; the highest infant mortality rate occurs in infants born prior to 32 weeks’ 
gestation [Matthews, 2010]. Although the risk for complications decreases with 
increasing gestational age, infants born just a few weeks before term carry an increased 
risk for developing medical complications, resulting in excessive mortality and morbidity 
rates during the birth hospitalization, as compared with the rates in full-term infants 
[Engle, 2007].  
Prematurity directly influences the level of medical care, length of hospitalization, and 
associated costs; prematurity sequelae extend the need for continued medical care into 
childhood. Estimates for 2005 placed the annual economic cost in the United States at a 
minimum of 26.2 billion dollars or 51 600 dollars per infant born preterm; roughly 
two-thirds of this cost was for medical care [Behrman, 2007]. 
Oxytocin plays a key role in term and preterm labor. It 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, in all likelihood, represents a common 
step in activation of the myometrium. Paracrine rather than endocrine mechanisms are 
thought to 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 potent, competitive, and highly selective oxytocin receptor 
antagonist. Retosiban inhibits spontaneous and oxytocin-induced contractions in human 
myometrial tissue. Retosiban was being developed for the treatment of spontaneous 
preterm labor (SPTL) in women with intact membranes.
Phase III SPTL treatment studies were conducted to demonstrate the ability of retosiban 
to prolong pregnancy and improve neonatal health, as well as to describe the maternal, 
fetal, and neonatal safety profiles. The treatment studies were terminated due to limited 
 
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recruitment and the development program was subsequently terminated with no further in
utero exposure planned.
1.1.1.
Previous Human Experience
Retosiban has been administered to 219 healthy subjects. A review of the safety data in 
these healthy subjects showed no effects on vital signs, electrocardiogram parameters, or 
laboratory values that were attributable to study drug.
No clinically significant adverse events (AEs) or serious AEs (SAEs) have been reported 
in the completed Phase I studies of healthy volunteers.
Study OTA105256 was the first Phase II clinical study of retosiban in preterm labor 
(n=93) [Thornton, 2015; GlaxoSmithKline Document Number CM2006/00201/06]. The 
study was designed to investigate the safety and dose response of retosiban given 
intravenously to women with intact membranes in preterm labor between 300/7 and 356/7 
weeks of gestation. Final results showed that intravenous retosiban treatment was 
associated with a significant difference in days to delivery and significant reduction in 
preterm births. The mean difference in days to delivery was 8.2 days relative to placebo 
(95% credible interval: 2.7, 13.74). Median prolongation of pregnancy was 35 days in 
women treated with retosiban, compared with 25 days in women assigned to the placebo 
group. The treatment difference was consistent across gestational ages. The proportion of 
preterm births was 18.7% in the retosiban group and 47.2% in the placebo group. The 
relative risk for preterm birth in the retosiban group was 0.38 (95% credible interval: 
0.15, 0.81).
The Phase 3 program included 2 global blinded, randomized, controlled trials (200721 
[ZINN] and 200719 [NEWBORN-1]) and a single infant follow-up trial (200722 
[ARIOS]). Eligible subjects were aged 12 to 45 years with an uncomplicated singleton 
pregnancy and intact membranes in spontaneous preterm labor at 240/7 to 336/7 weeks’ 
gestation. ZINN (N=330) aimed to show superiority of retosiban (IV) over atosiban on 
time to delivery (first subject first visit [FSFV] was March 2015). NEWBORN-1 
(N=900) was designed to demonstrate neonatal benefit (based on a composite endpoint) 
as well as time to delivery or time to treatment failure over placebo (FSFV 
February 2016). The intervention trials were terminated early on 11 May 2017 because of 
slow recruitment and the retosiban project was discontinued permanently. Last subject 
last visit (LSLV) was 24 July 2017 for NEWBORN-1 and 25 August 2017 for ZINN. 
Meaningful analyses of these well-controlled trials could not be performed due to small 
numbers of completing participants. Mean time to delivery or treatment failure in the 
placebo-controlled trial was 18.9 days with retosiban (n=10) versus 11.1 days with 
placebo (n=13). Two neonates in the retosiban and 4 in the placebo group had 
≥1 component of the neonatal composite endpoint. The adjusted mean time to delivery in 
the atosiban comparator trial was 32.51 days with retosiban (n=50) compared with 
33.71 days with atosiban (n=47; P>0.05). Maternal, fetal, and neonatal AEs were no 
more common with retosiban than placebo or atosiban. 
In NEWBORN-1, 1 participant in the retosiban group provided cord blood and breast 
milk samples; retosiban was found in both (cord blood, 1.9 µg/L; breast milk, 3.6 µg/L). 
 
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In ZINN, 12 women in the retosiban group provided cord blood samples, none of which 
had detectable levels of retosiban. One participant also provided a breast milk/colostrum 
sample. The retosiban concentration was 0.3 g/L.
1.2.
Rationale
Advances in perinatal intensive care have resulted in increased survival rates for high risk 
newborns but limited improvement in morbidity. The immaturity of organs, such as the 
brain, lungs, and gastrointestinal tract, render these newborns susceptible to injury and 
abnormal development and function, which often leads to long-term health problems and 
disability. The risk for medical disability is inversely related to the gestational age at 
birth; the most common disabilities include cerebral palsy, cognitive dysfunction, 
blindness and impaired vision, hearing loss, and disorders of psychological development 
(i.e., behavior and emotion).
Over the past decades, few medical interventions have been designed to prevent preterm 
birth and/or reduce the severity of prematurity complications. Such treatments may also 
improve long-term outcomes. One of the major advances in perinatal medicine has been 
the finding that antenatal corticosteroids given to women at risk of imminent preterm 
birth reduces the risks for neonatal mortality and morbidity. Corticosteroids now 
represent the standard of care for an acute antenatal intervention to improve neonatal 
outcomes in the developed world [ACOG, 2012; RCOG, 2011].
However, there is an increasing awareness that the intended beneficial effects of perinatal 
interventions do not necessarily correlate with long-term outcomes. Dexamethasone in 
high daily doses appears to reduce mortality and the incidence of bronchopulmonary 
dysplasia but treatment is associated with numerous short- and long-term adverse 
outcomes, including neurodevelopmental impairment. As a result, treatment with 
high-dose dexamethasone is not recommended [Watterberg, 2010]. The ORACLE II 
Study is an example of a perinatal treatment that was associated with adverse long-term 
outcomes and no neonatal benefit. ORACLE II studied the effect of antibiotics to 
improve neonatal outcomes in women with SPTL with intact membranes and no evidence 
of clinical infection. No reduction in neonatal complications was observed. However, the 
long-term follow-up revealed an increase in functional impairment and a higher risk for 
cerebral palsy in children whose mothers had received antibiotics [Kenyon, 2001; 
Kenyon, 2008]. These observations have led to an appreciation that perinatal 
interventions may affect growth and development and have highlighted the importance of 
long-term outcome studies after randomized, controlled studies of perinatal interventions. 
The goal of this study (ARIOS), therefore, is to assess the safety and outcomes of infants 
and children who were exposed to retosiban or comparator in utero in the Phase III SPTL 
treatment studies and provide assurance that treatment is not associated with significant 
adverse outcomes in early childhood.
1.3.
Benefit:Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with 
GSK221149 can be found in the IB and the Phase III SPTL treatment clinical study 
 
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reports. The following section outlines the risk assessment and mitigation strategy for this 
protocol.
1.3.1.
Risk Assessment
This study is a follow-up safety study of infants and children exposed to treatment while 
in utero during their mother’s participation in a Phase III SPTL treatment study of 
retosiban or comparator for SPTL. Infants and children enrolled in this study will not be 
administered any investigational product; therefore, there are no anticipated or known 
risks to the infants and children who participate in this safety study.
 
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The intent of this study is to ensure there have been no unintended consequences to the 
infants and children from exposure to retosiban or comparator during their mother’s 
participation in the Phase III clinical study of retosiban, specifically with respect to the 
following:
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
Fetal exposure 
through placental 
transfer
For both NEWBORN-1 and ZINN, cord 
blood samples were requested from 
subjects who delivered at the 
investigative center within 12 hours 
after discontinuation of study drug. 
Samples were only analyzed for 
subjects randomized to retosiban. A 
total of 4 cord samples were collected 
within NEWBORN-1 (3 placebo:
1 retosiban) and 27 within ZINN 
(12 retosiban: 15 atosiban). Within both 
studies, only 1 cord blood sample 
tested positive for retosiban at a 
concentration of 1.9 µg/L. The 1.9 µg/L 
is approximately 0.006x to 0.01x the 
cord blood concentrations that were 
observed in the pregnant monkey 
toxicity studies (cord blood 
concentrations = 159 to 313 µg/L). 
There were no adverse effects 
observed in the offspring in monkey 
studies, where growth and development 
included a full assessment of reflexive 
behaviors, infant ECG and blood 
chemistry were analyzed. Furthermore, 
a rat post-natal study starting in juvenile 
rats that were 1 day old did not show 
any adverse effects on growth and 
development, including neurobehavior 
and reproductive assessments at 
exposure levels that were 
approximately 800-fold of what was 
observed in the cord blood (gender 
averaged Cmax = 1535 µg/L). Day 1 
old rats were used in this study as they 
were developmentally similar to late 
third term human fetuses. The overall 
animal data indicate that potential risk 
for a fetus exposed gestationally to 
retosiban is negligible.
Analysis of maternal blood and cord 
blood samples was performed to test for 
levels of retosiban in women who 
delivered at an investigative center 
within 12 hours of the completion of 
study treatment infusion as part of the 
Phase III SPTL treatment studies.
Surveillance for signals indicating 
adverse fetal or neonatal effects with 
in utero exposure to retosiban will be 
performed throughout this study.
Infants exposed to retosiban in utero 
will be followed for up to 24 months in 
this study to assess safety and 
neurodevelopmental outcomes.
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
Neonatal exposure 
via breast milk
Positive breast milk samples were 
detected within 1 maternal subject in 
NEWBORN-1 and 1 subject in ZINN, 
with the highest concentration being 
0.36 µg/L. Assuming a standardized 
milk consumption of 0.150 L/kg/day (the 
mean milk intake of a fully breast-fed 
2-month old infant [Begg, 1999; 
Bennett, 1988; Hagg, 2000; Kristensen,
1999]), the worst-case dose of 
retosiban that a breast-fed child would 
be exposed to is 0.54 µg/kg/day 
(3.6 µg/L x 0.15 L/kg/day). This is 
approximately 0.5% of the human dose. 
This is the worst-case scenario because 
the mother is not being administered 
retosiban post-partum during the 
lactation period, and retosiban is 
cleared rapidly, which would rapidly 
diminish the amount retosiban present 
circulation and in the milk. Furthermore, 
based on body surface area, this 
potential infant dose is greater than 
8000-fold, the dose where no adverse 
effects were seen in growth and 
development in the rat post-natal 
development study (rat post-natal 
development study NOAEL = 
30 mg/kg/day; human equivalent dose = 
4800 µg/kg/day). The potential 
lactational dose of retosiban that would 
therefore pose any significant risk to a 
newborn is negligible.
Breast milk/colostrum samples were
collected for measurement of retosiban 
when delivery occurred and lactation 
had started within 12 hours of receiving 
study treatment infusion as part of the 
Phase III SPTL treatment studies.
Infants exposed to retosiban via breast 
milk will be followed for up to 24 months
in this study to assess safety and 
neurodevelopmental outcomes.
ECG = electrocardiogram; NOAEL = no-observed-adverse-effect-level; SPTL = spontaneous preterm labor.
1.3.2.
Benefit Assessment
Babies born prematurely are at risk for death, short-term medical complications, 
long-term disabilities, and developmental problems; these risks are inversely related to 
gestational age. Although babies born before 32 weeks have the greatest risk for death 
and poor health outcomes [Saigal, 2008; Lundqvist, 2009; Matthews, 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 SPTL; the remainder is associated with preterm premature rupture 
of membranes and clinical indications for delivery [Romero, 2000; Goldenberg, 2008].
 
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Treatment of SPTL 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 
gestational age at birth, the development of a treatment that significantly prolongs 
pregnancy in women with SPTL 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 [Thornton, 2015]. However, the results from the Phase III interventional studies
did not provide compelling evidence that retosiban could prolong time to delivery of 
retosiban relative to placebo or atosiban, but because of the low enrollment numbers and 
inadequate statistical power, results should be interpreted with caution.
The benefit to infants and children participating in this study is the focus on following 
morbidity and neurodevelopment for up to 24 months following exposure to retosiban or 
comparator medication. Participating infants and children will have the benefit of access 
to developmental screening (Ages and Stages Questionnaire-3 [ASQ-3], Child Behavior 
Checklist for Ages 1.5 to 5 [CBCL/1.5–5], and the Modified Checklist for Autism in 
Toddlers–Revised with Follow-Up [M-CHAT-R/F]), which may not be routinely 
provided and will allow parents/legal guardians to monitor and track the child’s 
developmental milestones in a formalized manner. In addition, screening results may be 
shared with the child’s physician (HCP or other) as requested by the parent/legal 
guardian. In the event a potential issue is identified and further follow-up is warranted, 
the child will be referred to developmental specialists/qualified assessors for further 
evaluations as part of this study. In this manner, neurodevelopmental issues may be 
identified earlier than would have been normally.
1.3.3.
Overall Benefit:Risk Conclusion
For detailed information on the identified risks and benefit:risk assessment of retosiban, 
refer to the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
CM2006/00201/06]. The overall benefit:risk assessment of retosiban appears favorable 
for the mother and fetus/infant.
 
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2.
OBJECTIVES
The study objective is to assess the safety and outcomes in infants and children who were 
exposed to retosiban or comparator in the Phase III SPTL treatment studies. Table 1
summarizes the specific study objectives and the corresponding endpoints, which are 
described in detail in Section 6.2 (Safety) and Section 6.3 (Health Outcomes).
Table 1
Summary of Study Objectives and Corresponding Endpoints
Objective
Endpoints
Primary
To characterize the clinical safety in terms of infant 
and child morbidity and mortality in infants and 
children exposed to retosiban or comparator in 
utero

Proportion of infants and children with newly diagnosed 
(after 28 days post EDD) chronic medical conditions by type 
of condition will be recorded and include the following:

Respiratory conditions
o
Chronic lung disease
o
Reactive airway disease
o
Vocal cord paralysis
o
Airway obstruction 

Neurological conditions
o
Cerebral palsy
o
Seizure disorder
o
Hydrocephalus requiring shunt

Sensory conditions
o
Vision
o
Vision impairment
o
Blindness in 1 or both eyes, or sees light 
only
o
Hearing 
o
Hearing impairment
o
Deafness in 1 or both ears
o
Hearing impaired, uncorrected even with 
aids

Gastrointestinal conditions
o
GERD (moderate to severe)
o
Tube/parenteral feeding 
o
Short bowel syndrome

Cardiovascular conditions
o
Pulmonary hypertension
o
Hypertension

Renal conditions
o
Renal impairment requiring dialysis

Growth parameters
o
Poor weight gain
o
Reduced length
o
Reduced head circumference
o
Failure to thrive

Proportion of infants and children with newly diagnosed 
(after 28 days post EDD) congenital anomalies

Proportion of infant and child deaths that occur after 
28 days post EDD and until 24 months chronological age
 
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Objective
Endpoints

Neurodevelopment endpoints assessed at ages 9, 18, and 
24 months, corrected for prematurity:

Proportion of infants with an ASQ-3 score in the black 
zone in any domain

Proportion of infants with an ASQ-3 score in the black 
zone for gross motor skills

Proportion of infants with an ASQ-3 score in the black 
zone for fine motor skills

Proportion of infants with an ASQ-3 score in the black 
zone for communication

Proportion of infants with an ASQ-3 score in the black 
zone for problem-solving

Proportion of infants with an ASQ-3 score in the black 
zone for personal-social skills

Proportion of infants referred for developmental 
evaluation (using BSID-III)

Proportion of infants with a BSID-III score >2 SDs 
below the mean score for the cognitive scale (<4)

Proportion of infants with BSID-III score >2 SDs below 
the mean score for the gross motor scale (<4)

Proportion of infants with BSID-III score >2 SDs below 
the mean score for the fine motor scale (<4)

Proportion of infants with a BSID-III score >2 SDs 
below the mean score for the language scale (<70)

Proportion of infants with a CBCL/1.5-5 score above 
the 97th percentile for a subset of prespecified 
questions that relate to attention and hyperactivity 
problems

Proportion of infants indicated as needing further 
evaluation after completion of the M-CHAT-R/F

Proportion of infants referred for neurological 
evaluation to determine diagnosis of cerebral palsy

Proportion of infants with at least 1 of the following 
indicators of neurodevelopmental impairment:

Hearing impaired, uncorrected even with aids (at 
24 months chronological age)

Blindness in 1 or both eyes, or sees light only (at 
24 months chronological age)

Cerebral palsy (moderate and severe) (at 24 months 
corrected age)

Cognitive impairment: BSID-III Cognitive Scale Score 
of >2 SDs below mean score (<4) (at 24 months 
corrected age)

Motor impairment: BSID-III Motor Composite Scale 
Score of >2 SDs below mean score (<70) (at 
24 months corrected age)

Diagnosis of ASD, ADD, or ADHD
 
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Objective
Endpoints
Exploratory
To characterize parental productivity loss related 
to a sick child and infant resource utilization in 
terms of hospital admissions, length of stay, 
ER/UC visits, surgical procedures, and referral to 
specialty care or therapy visits for infants (up to 
age 2 years) exposed to retosiban or comparator 
in utero

Number of hospital admissions, proportion of infants and 
children with any hospital admission, post-birth 
hospitalization discharge, by principal and secondary 
discharge diagnosis, type of hospital unit admitted to (e.g., 
NICU, Pediatric, PICU, Nursery level 3, ICU), and length of 
hospital stay per unit after 28 days post EDD and until 
24 months chronological age

Combined length of hospital stay in days for all hospital 
admissions (for infants discharged from the delivery 
hospitalization and for babies who were never discharged 
home post-delivery) after 28 days post EDD and until 
24 months chronological age

Number of surgical procedures (details of type and whether 
performed on an inpatient basis or at an outpatient/surgical 
center will be collected up to 24 months chronological age 
only) after 28 days post EDD and until 24 months 
chronological age

Number of ER/UC visits and proportion of infants with any 
ER/UC visit after 28 days post EDD and up to 24 months
chronological age

Number of specialty care or therapy visits and proportion of 
infants referred for specialty care or therapy by type of 
care/therapy after 28 days post EDD and up to 24 months
chronological age

Parental productivity loss related to infant hospital 
admissions, ER/UC visits, or specialist care after 28 days 
post EDD and up to 24 months chronological age
ADD = attention deficit disorder; ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder;
ASQ-3 = Ages and Stages Questionnaire-3; BSID-III = Bayley Scales of Infant Development, third edition; 
CBCL/1.5-5 = Child Behavior Checklist for Ages 1.5 to 5; EDD = estimated date of delivery; ER/UC = emergency 
room/urgent care; GERD = gastroesophageal reflux disease; ICU = intensive care unit; M-CHAT-R/F = Modified 
Checklist for Autism in Toddlers-Revised with Follow-Up; NICU = neonatal intensive care unit; PICU = pediatric 
intensive care unit.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
ARIOS is a long-term infant and child follow-up study that will prospectively assess 
safety and outcomes of all infants and children born to women who received at least 
1 dose of retosiban or comparator in any of the Phase III SPTL treatment studies. The 
final assessment of the Phase III SPTL treatment studies is a collection of neonatal 
morbidity data and will occur at 28 days after the EDD, where EDD is defined as 400/7
weeks’ gestation. The end date of the Phase III SPTL treatment studies is referred to as 
28 days post EDD. Either the obstetrician investigators or neonatologist subinvestigators 
from the Phase III SPTL studies or their delegate will be responsible for obtaining 
consent for the infant to participate in the follow-up study; they also will be responsible 
for obtaining the signed medical release forms from all hospitals and HCPs providing 
follow-up care to the infant. Ideally, the Phase III SPTL study investigators will obtain 
 
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consent and medical release when the woman’s acute episode of preterm labor has 
resolved and prior to discharge from the hospital for the treatment of preterm labor. The 
infant will be allowed to be consented into the study until the later date of either the date 
of discharge from the birth hospitalization or up to 9 months corrected age (to allow for 
the infant’s 9-month Child Health Inventory [CHI] and ASQ-3 data collection) via 
follow-up contact from the research coordinating center-principal investigator (RCC-PI) 
to the parent/legal guardian. This follow-up contact and informed consent discussion may 
occur via telephone with signed consent and medical releases transmitted via mail or 
courier. Infants and children will be followed at prespecified intervals until they reach 
24 months chronological age (see Table 2). This study does not require medical 
interventions or study visits to an investigational site. Instead, parents or legal guardians 
will be prompted at certain time points to complete developmental questionnaires and 
other data on their children’s health status via an electronic device. Data collected during 
this follow-up study will be managed by a centralized RCC. Regionally based 
pediatricians will serve as study principal investigators (referred to as RCC-PIs) for this
study. All communications the RCC-PI has with the parent/legal guardian or the child’s 
HCP will occur remotely; there will be no clinic visits. An overview of the study design 
is shown in Figure 1.
Figure 1
Study Design
EDD = estimated date of delivery; HCP = health care provider; RCC = research coordinating center; 
RCC-PI = research coordinating center-principal investigator; SPTL = spontaneous preterm labor.
Electronic data capture (eDC) tools and processes including electronic case report forms 
(eCRF) and electronic patient-reported outcome devices will allow entry of data, 
regardless of when it is obtained. If at any time the data suggest any developmental delay, 
the RCC-PI will refer the child to a specialist (if not already under the care of a specialist) 
for formal evaluation and additional assessments. The child’s local primary care pediatric 
 
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provider will be asked to provide routinely available data on the child to the RCC. 
Additional contacts may occur at the discretion of the RCC personnel to complete the 
data collection. 
The child’s parent/legal guardian will be asked to complete the CHI at 2, 6, 9, 12, 15, 18, 
21, and 24 months of the child’s chronological age. The CHI questionnaire completed up 
to the 24-month time point will screen for infant mortality and morbidity and will capture 
data on resource utilization. If the parent/legal guardian indicates that the child has been 
newly diagnosed (after 28 days post EDD) with chronic conditions or congenital 
anomalies, follow-up will be undertaken with the applicable HCP to confirm the 
parent/legal guardian report. Persistence or resolution of conditions will be determined in 
subsequent questionnaires after the initial report. If protocol-specific evaluations are in 
progress at the end of the child’s protocol-defined participation in this study (24 months
chronological age) and results have not yet been received or reported, the time period 
may be extended to collect those reports.
If the parent/legal guardian indicates that the child has had any emergency room/urgent 
care (ER/UC) visits, he/she will be asked to record the number of visits and to indicate if 
the visit resulted in hospitalization. If the parent/legal guardian indicates that the child has 
been hospitalized or has had any surgeries, medical records from the applicable medical 
facility will be obtained and abstracted for pertinent details, including principal and 
secondary discharge diagnoses, type of hospital unit admitted to (e.g., neonatal intensive 
care unit [NICU], Pediatrics, pediatric intensive care unit [PICU], Nursery level 3, ICU), 
and length of stay. If the parent/legal guardian indicates that the child died after 28 days 
post EDD, details of the death will be obtained from the death certificate or appropriate 
HCP or medical records if the death certificate is not available. Note that all infant deaths 
that occur before 28 days post EDD will be captured and reported as part of the Phase III 
SPTL treatment studies.
During the 24 months of participation in the study, if the parent/legal guardian indicates 
that the infant has been treated by specialists or has had ER/UC visits or hospitalizations, 
he/she will be asked to complete a productivity questionnaire to evaluate loss of parental 
productivity.
The RCC-PI will review all data including medical records, death certificates, data 
provided by the parent/legal guardian, and any follow-up confirmatory data provided by 
HCPs. The RCC-PI may request targeted follow-up data from the relevant HCP or 
medical facility if clarification is needed on any reported study endpoints or SAEs. 
When a congenital anomaly is reported, it will be reviewed by an expert in teratology 
who is engaged by the RCC-PI to serve 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.
To screen for developmental issues, the parent/legal guardian will be asked to complete 
the 9-, 18-, and 24-month ASQ-3 when the infant’s corrected age corresponds to 9, 18, 
and 24 months, for example, parents/legal guardians of an infant born 3 months 
premature will complete the 9-month ASQ-3 at 12 months chronological age. Any child 
 
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who scores in the black zone (2 SD below the mean) (see Section 6.2.5.1) in any of the 
5 domains of the ASQ-3 will be referred to a qualified assessor for a developmental 
evaluation (e.g., using the Bayley Scales of Infant Development, third edition 
[BSID-III]), and a neurologic examination will be conducted, if indicated. An overall 
assessment of delay in the areas of communication, gross and fine motor, 
problem-solving, and personal-social development will be rendered. As part of normal 
management, some infants may already have undergone a formal developmental 
evaluation using the BSID-III; in these cases, if testing was recent (3 months), the 
BSID-III will not be repeated and RCC-PI will request results from the relevant HCP. 
BSID-III retesting will be requested if the child’s ASQ-3 scores are in the black zone on a 
subsequent ASQ-3 test following the first BSID III referral. Based on results from the 
ASQ-3 administered at 24 months corrected age and if no cerebral palsy diagnosis has 
been made to date (see Section 6.2.5.1), the infant may be referred to a qualified 
examiner for a formal assessment of cerebral palsy.
The M-CHAT-R/F will be completed for all infants at 18 and 24 months (corrected age) 
and the CBCL/1.5–5 will be completed for all infants at 24 months (corrected age) to 
assess the risk for other behavioral problems or autism spectrum disorder (ASD). If at 
any of these time points a child has an M-CHAT-R/F score that indicates further 
evaluation is required and/or a CBCL/1.5–5 score above the 97th percentile for a subset 
of prespecified questions, the child will be referred to a specialist for a formal 
assessment.
Protocol Amendment 2 has updated the total study duration to 24 months. Babies or 
infants that have passed the 24-month assessments after the amendment implementation
are not required to continue further within the study, nor do they need to complete any 
subsequent study-related assessments. Following completion of the study, the neonates
will continue their normal pediatric standard of care with their primary care pediatrician 
or health care provider.
The 24-month data will form the final study endpoint assessment timing; however, if data 
have been collected from a baby/infant after they have passed the 24-month endpoint, 
then this data will be included as a data listing within the clinical study report.
Data and genetic samples from the Phase III SPTL treatment studies may be used as part 
of a genetic analysis using data collected in this study, if relevant. No additional genetic 
samples are required. 
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 2), are essential and required for study 
conduct. All specified completion windows for applicable questionnaires (CHI, ASQ-3, 
CBCL/1.5–5, M-CHAT-R/F, and productivity) are provided to help standardize the data 
and avoid overlap. Information captured outside of these windows will be collected and 
analyzed separately, and questionnaires completed outside the completion window will 
not be considered protocol deviations.
 
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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Discussion of Design
Longitudinal infant outcome studies are often fraught with a high rate of loss to follow-up 
that can introduce ascertainment bias [Callanan, 2001; Tin, 1998]. The design of this 
study takes into account the operational and practical challenges involved in retaining 
infants, especially those who may have a diverse set of outcomes due to varying 
gestational age at birth. Rather than requiring visits for formal outcome interviews and 
assessments of the infants and children, parent/legal guardian-reported outcomes will be 
the first-line source of health and developmental information, and parents will record data 
using an eDC system to allow entry of data regardless of where it is obtained. The child’s 
primary HCP will be asked to provide data when the parent/legal guardian reports a 
chronic condition, birth defect, genetic condition or syndrome; or a change in a 
previously reported condition. If the child’s primary HCP is unable to provide the 
information, another relevant HCP involved with the care of the child will also be asked 
to provide data. All congenital anomalies will be reviewed by an expert in teratology who 
is engaged by the RCC-PI to serve as the birth defect evaluator.
Studies have affirmed that parents are a reliable source of information regarding their 
child’s health and development. The validity of parental reports of infant and child 
hospital admissions and chronic health conditions has been shown to be high [Spencer, 
2000]. Likewise, it has been demonstrated with validated tools such as the ASQ-3 that 
parents’ observations are useful in performing developmental screening [Squires, 1998; 
Rydz, 2005]. Using the parents/legal guardians as first-line reporters will ensure the 
quality of data and enhance long-term retention in the safety follow-up. Furthermore, 
because parents tend to spend more time with their child than anyone else, their 
assessments are likely to be reliable. To guard against reporting bias, the parent/legal 
guardian, child’s HCPs, and all study staff will be masked until completion of the 
follow-up study with respect to the mother/child’s Phase III SPTL treatment assignment 
(see Section 5.3).
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
Enrollment of infants into this follow-up study will depend upon enrollment of mothers 
into the Phase III SPTL treatment studies. Efforts will be taken in those studies to 
maximize enrollment of all infants.
4.1.
Number of Subjects
The sample size for this study will depend on the total number of subjects enrolled in the 
Phase III SPTL treatment studies. 
 
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4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB [GlaxoSmithKline Document Number
CM2006/00201/06].
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. 
Infants eligible for enrollment in the study must meet all of the following criteria:
1.
Mother is randomly assigned and dosed (retosiban or comparator) in 1 of the 
Phase III SPTL retosiban clinical studies.
2.
Infant is alive at 28 days post EDD.
3.
Written informed consent is obtained from the parent(s) or legal guardian(s) of the 
infant. The parent/legal guardian of participants aged 12 to 17 years must also 
provide written agreement for the infant to participate in the study where required by 
applicable regulatory and country or state requirements.
4.3.
Exclusion Criteria
Because this study is focused on safety and infant outcomes, all infants who meet the 
inclusion criteria will be eligible to enroll in the study. There are no formal exclusion 
criteria for participation.
4.4.
Withdrawal Criteria
A child may be withdrawn from the study due to loss to follow-up or if the child’s 
parent/legal guardian voluntarily withdraws consent. All data collected up to the time of 
withdrawal will be included in the analysis. If a parent/legal guardian fails to complete an 
assessment, but wishes to remain in the study, they will be allowed to continue by 
completing future assessments.
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
This is a safety follow-up study of infants and children exposed to treatment during their 
mother’s participation in a Phase III SPTL treatment study of retosiban or comparator for 
SPTL. Infants and children enrolled in this study will not be administered any 
investigational product.
 
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5.2.
Treatment Assignment
The Phase III SPTL treatment study treatment group and strata to which mothers were 
assigned will be maintained during analysis of data from the child follow-up study.
5.3.
Blinding
The parent/legal guardian, child, the child’s HCPs, and all study personnel (from this 
study) will remain blinded to the treatment the mother received in the Phase III SPTL 
study and will remain blinded throughout the duration of this child follow-up study.
The child will be given a new subject identification number at the start of this follow-up 
study. The child’s subject identification number from the Phase III SPTL treatment 
studies will be masked to maintain the blind of the follow-up study as treatment 
assignment will be unblinded at the conclusion of the Phase III SPTL treatment studies. 
The details of maintaining study blinding will be provided in the SPM.
There is no formal interim analysis planned for this study. The independent data 
monitoring committee (IDMC) will review unblinded data from this study along with 
data from any ongoing Phase III SPTL treatment study periodically in accordance with 
the IDMC charter. Unblinded data will be provided by an independent statistical data 
analysis committee.
The RCC-PI 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 RCC-PI. 
RCC-PIs have direct access to the subject’s individual study treatment by contacting a 
designated PPD unblinded safety specialist via the SAE 24-Hour Safety Hotline; the 
designated unblinded safety specialist will perform the emergency unblinding and inform 
the RCC-PI of the mother’s treatment assignment (refer to the SPM for details). 
It is preferred (but not required) that the RCC-PI first contact the PPD medical monitor to 
discuss options before unblinding the subject’s treatment assignment. 
After the subject has been unblinded, the investigator should not reveal the treatment 
assignment to the PPD medical monitor unless that information is important for the safety 
of subjects currently enrolled in the study (refer to the SPM for details). 
The date and reason for the unblinding must be fully documented in the eCRF.
This protocol will be filed to the Investigational New Drug Application of the United 
States. Serious AEs requiring an expedited investigational new drug safety report 
(blinded for investigational drug treatment) will be sent to all participating RCC-PIs. 
Further reporting to RCC-PIs or regulatory authorities will be performed in accordance 
with local regulations. 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 
 
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assignment, may be sent to RCC-PIs in accordance with local regulations and/or GSK 
policy. 
5.4.
Product Accountability
Not applicable
5.5.
Treatment Compliance
Not applicable
5.6.
Concomitant Medications and Nondrug Therapies
There are no restrictions regarding permitted medications or nondrug therapies. Infants 
will be followed and treated according to HCP standard of care.
5.7.
Treatment After the End of the Study
Not applicable
5.8.
Treatment of Study Treatment Overdose
Not applicable
6.
STUDY ASSESSMENTS AND PROCEDURES
The child’s parent/legal guardian will be the primary data reporter to the study. 
Confirmation of key study endpoints will be obtained from applicable HCPs or health 
care facilities. The infants and children will be followed beginning from after 28 days 
post EDD and until 24 months chronological age. Baseline characteristics and 
demographic data will be captured from the Phase III SPTL treatment studies and 
combined with child follow-up data for analyses. Refer to Table 2 for a summary of data 
points to be collected and the time frame for assessment.
The time points for parent-completed questionnaires are scheduled to maintain the 
participant’s interest in study continuation and minimize losses to follow-up. 
Questionnaires will be associated with the child’s age; in some cases, the age will be 
chronological and in other cases, it will be corrected for prematurity. The timing of the 
first questionnaire is scheduled to begin at 2 months chronological age and end at 
24 months chronological age. Contingent on the infant’s chronological age at the time of 
entry into the follow-up study, all of the questionnaires may not be completed for each 
participant. The SPM will provide explicit details on study procedures to ensure proper 
timing of questionnaires.
It is noted that as part of the Phase III SPTL treatment studies, the infant’s mother will be 
asked to complete the Edinburgh Postnatal Depression Scale (EPDS) using the same eDC 
 
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system as will be utilized for this study. The EPDS should ideally be completed at 
6 weeks (-2 weeks/+6 weeks) post-delivery but may be completed as early as 4 weeks
post-delivery or as late as 12 weeks post-delivery. While the timing for EPDS may fall 
into the time period for this study, data will be captured as part of the Phase III SPTL 
treatment study, and the SPTL treatment study investigator will be responsible for
reviewing information and any action required. As such, the EPDS is not reflected in
Table 2. The SPM will provide details on the EPDS completion and process.
 
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Table 2
Time and Events Table
Event
28 Days Post EDD
Months
2
6
9
12
15
18
21
24
Written informed consent1
Baseline characteristics and demographic data
X2
RCC confirms and updates contact information from the 
parent/legal guardian
X
Parent/legal guardian completes CHI3
X
X
X
X
X
X
X
X
RCC-PI follows up with HCP and reviews medical or other 
records to confirm parent-reported outcomes
RCC-PI reviews CHI results and refers to birth-defect evaluator 
based on results
Parent/legal guardian completes productivity questionnaire4
Parent/legal guardian completes ASQ-36
X5
X5
X5
RCC-PI reviews ASQ-3 results and refers for developmental 
evaluation based on results6
Parent/legal guardian completes M-CHAT-R/F7
X
X
Parent/legal guardian completes CBCL/1.5–57
X
RCC-PI refers child to specialist for cerebral palsy assessment (if 
required)8
X
 
 
 
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ASQ-3 = Ages and Stages Questionnaire-3; CBCL/1.5–5 = Child Behavior Checklist for ages 1.5 to 5; CHI = Child Health Inventory; EDD = estimated date of delivery; HCP = health 
care provider; M-CHAT-R/F = Modified Checklist for Autism in Toddlers-Revised with Follow-Up; RCC = research coordinating center; RCC-PI = research coordinating center-
principal investigator.
Note:  All specified completion windows for applicable questionnaires (CHI, ASQ-3, CBCL/1.5–5, M-CHAT-R/F, and productivity) are provided to help standardize the data and avoid 
overlap. Information captured outside of these windows will be collected and analyzed separately, and questionnaires completed outside the completion window will not be 
considered protocol deviations.
1.
Collected at the start of the Phase III spontaneous preterm labor (SPTL) treatment studies until the later date of either the date of discharge from the birth hospitalization or up to 
9 months corrected age (to allow for the infant’s 9-month CHI and ASQ-3 data collection).
2.
Captured in Phase III SPTL treatment studies and combined with child follow-up data for analyses.
3.
A positive response by the parent/legal guardian may trigger follow-up with the relevant HCP and/or medical record review for confirmation or more details on the condition or 
hospitalization. At each time point, the completion window of the CHI is +6 weeks.
4.
Completed if infant has been treated by a specialist or has had an emergency room/urgent care or hospital visit. The completion window for the productivity questionnaire is 
+2 weeks from the date of completion of the relevant CHI.
5.
Based on infant’s corrected age. The completion window for the ASQ-3 is +30 days at Month 9 and ±30 days at Months 18 and 24.
6.
If the parent/legal guardian receives a referral, then a qualified specialist will complete required assessments.
7.
The CBCL/1.5–5 and M-CHAT-R/F questionnaires will be completed for all infants. The completion window for the CBCL/1.5–5 and M-CHAT-R/F is +6 weeks at 18 months 
(M-CHAT-R/F only) and +12 weeks at 24 months. 
8.
Referral will be made for infants who score in the black zone for the gross motor skills domain on the 24-month corrected age ASQ-3 and do not have an existing diagnosis of 
cerebral palsy.
 
 
 
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6.1.
Critical Baseline Assessments
The final assessment of the Phase III SPTL treatment studies will occur at 28 days post 
EDD when neonatal morbidity assessments are collected. Select data from this 
assessment will serve as baseline data for this study, in addition to data collected from the 
maternal medical record and newborn medical record during the Phase III SPTL 
treatment studies. These data will be transferred in a blinded manner from the Phase III 
SPTL database to the child follow-up study database.
At Baseline, the Phase III SPTL treatment study investigator will obtain updated contact 
information from the parent/legal guardian; contact information will also be collected for 
at least 1 additional person (as described in the SPM) to minimize the number of infants 
and children lost to follow-up.
6.2.
Safety
The focus will be on collecting the safety outcomes as defined in the objectives (e.g., 
hospitalization, death) and SAEs, including congenital anomalies. Nonserious AEs will 
not be tracked. All SAEs and safety outcomes will be followed until resolution, 
stabilization, or loss to follow-up.
6.2.1.
Morbidity and Mortality Endpoints
The main objective of the study is to characterize the clinical safety in terms of infant 
morbidity and mortality in infants and children exposed to retosiban or comparator during 
the Phase III SPTL treatment studies. The morbidity endpoints will be assessed at 2, 6, 9, 
12, 15, 18, 21, and 24 months of the child’s chronological age. Based on the discretion of 
the RCC-PI, medical records may need to be obtained from the applicable medical 
facility for any infants who have not yet been discharged from their birth hospitalization 
(see Section 6.2.1.1.1 and Section 6.3).
6.2.1.1.
Parent/Legal Guardian-Completed Child Health Inventory
The child’s parent/legal guardian will be asked to complete the CHI at 2, 6, 9, 12, 15, 18, 
21, and 24 months of the child’s chronological age. At each time point, the completion 
window is +6 weeks; however, CHI questionnaires completed outside the completion 
window will not be considered a protocol deviation.
The CHI administered at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s 
chronological age will screen for infant mortality and morbidity and capture data on 
resource utilization. To facilitate data collection, parents/legal guardians will be provided 
with an electronic device that will enable them to provide the protocol-required data. 
They will have the option to use alternative ways to access the same system (e.g., their 
own personal devices). Further details will be provided in the SPM.
The CHI will collect information about the child’s overall health after the child has 
reached 28 days post EDD. The child’s parent/legal guardian will be asked to relate 
 
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information from contacts with the health care system including ER/UC visits, 
hospitalizations, surgeries, use of special equipment, nonmedical therapy, and visits to 
medical specialists. Simple questions will be asked to ascertain whether chronic 
conditions or congenital anomalies related to the study endpoints are affecting the child’s 
health. 
At the initial completion of the CHI, the parent/legal guardian will be asked about all 
morbidity and mortality endpoints and, if required based on the child’s age, the resource 
utilization endpoints. At subsequent completions of the CHI, up to 24 months 
chronological age, the parent/legal guardian will be asked the status of previously 
reported conditions (e.g., worse, better, or resolved), as appropriate. They will also be 
asked if any of the other morbidity and mortality endpoints and resource utilization 
endpoints, as required, have occurred since the last assessment.
The parent/legal guardian will be asked to record anthropometric data such as weight, 
length, and head circumference for the child at each well-child visit in a special electronic 
diary. Data from the diary will be extracted to correspond with study data collection time 
points (e.g., 6-month well-child visit anthropometric data will be associated with the 
6-month study data collection).
6.2.1.1.1.
Confirmation of Parent-Reported Data
If the parent/legal guardian indicates that the child has been newly diagnosed (after 
28 days post EDD) with chronic conditions or congenital anomalies via the CHI, 
follow-up will be undertaken via the RCC-PI with the applicable HCP to confirm the 
parent report. At subsequent CHIs, if the parent/legal guardian indicates that a previously 
reported condition has worsened or resolved, the HCP will also be asked to provide 
confirmation. If the condition qualifies as an SAE, additional information will be 
requested to assist the RCC-PI with the process of SAE reporting.
The specific process by which confirmation with HCPs and health care facilities will be 
obtained is presented in the SPM. 
All morbidity and mortality endpoints (defined in Section 6.2) will require medical 
confirmation. All hospitalizations and deaths require medical confirmation by medical 
records or death certificate. All surgeries, except routine, simple outpatient procedures 
(e.g., circumcision), require confirmation by medical records. If the parent/legal guardian 
indicates that the child has had an ER/UC visit, the RCC-PI will use discretion and obtain 
medical records when the reported indication suggests a true emergency. Additional 
details regarding ER/UC visits will be provided in the SPM. If follow-up with the HCP is 
recommended, medical confirmation of the follow-up is required. 
The confirmation process is iterative and may be triggered at multiple times throughout 
the study to provide confirmation of parent-reported conditions and events. Medical input 
will override parent-reported data. An overview for the collection and review of data for 
the CHI is provided in Figure 2.
 
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Figure 2
Child Health Inventory: Flow Chart of Data Collection and Review
CHI = Child Health Inventory; HCP = health care provider; RCC-PI = research coordinating center-principal investigator.
1.
The CHI completed at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age will screen for infant mortality and morbidity and capture data on resource utilization. 
 
 
 
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6.2.2.
Chronic Medical Conditions
The proportion of infants and children with newly diagnosed (after 28 days post EDD) 
chronic medical conditions by type of condition will be recorded.
6.2.2.1.
Respiratory Conditions
Respiratory conditions will include the following:

Chronic lung disease newly diagnosed (after 28 days post EDD) defined as 
increased oxygen requirements (i.e., any increase in previously documented O2
use, and/or a change to how the child receives supplemental O2)

Reactive airway disease, defined as a chronic lung condition associated with 
inflammation of the airways associated with wheezing and requiring episodic 
ongoing treatment with bronchodilators and/or inhaled or systemic steroids

Paralyzed vocal cords, defined as impairment of the vocal cords that result in 
acute or chronic respiratory compromise or abnormalities in the infant’s voice

Airway obstruction
6.2.2.2.
Neurological Conditions
Neurological conditions will include the following:

Cerebral palsy, defined as a chronic, nonprogressive neurologic disorder 
encompassing impaired motor function affecting movement, posture, balance 
muscle control, coordination, tone, or reflexes.  

Seizure disorder, defined as episodic occurrence of seizure activity requiring 
ongoing anticonvulsant therapy

Hydrocephalus requiring shunt, defined as abnormal accumulation of 
cerebrospinal fluid in the ventricles of the brain requiring permanent shunt 
placement to prevent irreversible neurologic sequelae

ASD, defined as a neurodevelopmental disorder that impairs a child’s ability to 
communicate and interact with others

Attention deficit disorder (ADD), defined as a disorder of attention, 
organization, and impulse control, characterized by a persistent pattern of 
impulsiveness and a short attention span.

Attention deficit disorder with hyperactivity (ADHD), defined as ADD with the 
addition of hyperactive behavior

Learning difficulties, defined as a significantly reduced ability to understand 
new or complex information or to learn new skills

Behavior disorders, defined as a general term to denote behavioral dysfunction 
that do not fall under the category of ADD or ADHD
 
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6.2.2.3.
Sensory Conditions
Sensory conditions will include the following:

Vision

Vision impairment, defined as reduced visual capacity requiring corrective 
lenses

Blindness in 1 or both eyes, defined as absence of all or most vision or sees light 
only

Hearing

Hearing impairment, defined as diminished sensitivity to sounds normally heard 
requiring amplification and not explained by middle ear effusion or chronic 
otitis media

Deafness in 1 or both ears, defined as complete inability to hear even with 
amplification

Hearing impaired, defined as uncorrected even with aids
6.2.2.4.
Gastrointestinal Conditions
Gastrointestinal conditions will include the following:

Gastroesophageal reflux disease, defined as reflux of gastric contents into the 
esophagus causing troublesome symptoms or complications and requiring 
ongoing treatment or surgical intervention

Tube feeding, defined as the use of a nasogastric, orogastric, or gastrostomy 
tube to accomplish some or all infant feedings

Short bowel syndrome, defined as inability to absorb enough nutrients and fluids 
from enteral intake to maintain good health, due to prior removal by surgery of a 
large section of the small intestine
6.2.2.5.
Cardiovascular Conditions
Cardiovascular conditions will include the following:

Pulmonary hypertension, defined as a chronic disorder of the pulmonary 
vasculature characterized by elevated pulmonary vascular resistance 

Hypertension requiring pharmacologic treatment
 
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6.2.2.6.
Renal Conditions
Renal conditions will be defined as the following:

Renal impairment requiring dialysis
6.2.2.7.
Growth Parameters
Growth parameters will include the following:

Poor weight gain, defined as less than the third percentile on standard weight 
chart based on the WHO Child Growth Standards 
(http://www.who.int/childgrowth/standards/en/)

Reduced length, defined as less than the third percentile on standard length chart 
based on the WHO Child Growth Standards 
(http://www.who.int/childgrowth/standards/en/)

Reduced head circumference, defined as 2 or more standard deviations below 
the median based on the WHO Child Growth Standards 
(http://www.who.int/childgrowth/standards/en/)

Failure to thrive as diagnosed by an HCP
6.2.3.
Congenital Anomalies
The proportion of infants with newly diagnosed (after 28 days post EDD) congenital 
anomalies will be assessed. Note: A congenital anomaly is a condition present at birth 
that results from malformation, deformation, or disruption in 1 or more parts of the body, 
a chromosomal abnormality, or a known clinical syndrome. Major congenital anomalies 
have a serious adverse effect on health, development, and functional ability or may 
require surgical or medical management. Minor anomalies are physical findings that vary 
from norms in the general population but do not cause increased morbidity.
When a congenital anomaly is reported, it will be reviewed by an expert in teratology 
who is engaged by the RCC-PI to serve 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 from the child’s HCP in 
making the evaluation and issue targeted queries to the HCP when necessary. If medical 
data are deemed insufficient to complete the evaluation, the birth defect evaluator may 
ask that the RCC-PI request additional medical evaluation of the child. 
For the purpose of this study, the 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].
 
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6.2.4.
Infant and Child Deaths
This study will assess the proportion of infant and child deaths that occur after 28 days 
post EDD and up to 24 months chronological age. 
6.2.5.
Parent/Legal Guardian-Completed ASQ-3, M-CHAT-R/F, and 
CBCL/1.5–5 and Possible Referral to a Specialist
The parent/legal guardian will be asked to complete standardized developmental 
screening of the infant through completion of the ASQ-3. The ASQ-3 was developed and 
validated to be used as a developmental screening tool; it has been used globally and 
translated into a number of different languages. The tool has been demonstrated to 
reliably and accurately identify children with delays who should receive further in-depth 
assessment. The ASQ-3 includes a series of questions designed to assess 5 areas of 
development: communication, gross motor, fine motor, problem-solving, and 
personal-social. The questions target behaviors that are appropriate for particular 
developmental milestones; there are individual ASQ-3 questionnaires for age intervals 
ranging from 2 to 66 months. These behaviors are easy for parents to observe, and they 
are asked to indicate whether or not the child can perform the behavior.
The 9-, 18-, and 24-month ASQ-3 questionnaires will be used in this study. These time 
points comply with recommended developmental screening assessment guidelines from 
the American Academy of Pediatrics [Council on Children with Disabilities, 2006]. The 
parent/legal guardian will be asked to complete the 9-, 18-, and 24-month ASQ-3 when 
the infant’s corrected age corresponds to 9, 18, and 24 months, for example, parents/legal 
guardians of an infant born 3 months premature will complete the 9-month ASQ-3 at 
12 months chronological age. To facilitate data collection, the parent/legal guardian will 
be provided with an electronic device that will enable them to provide the 
protocol-required data. They will have the option to use alternative ways to access the 
same system (e.g., their own personal devices). Further details will be provided in the 
SPM. The completion window for the ASQ-3 is +30 days at Month 9 and ±30 days at 
Months 18 and 24; however, questionnaires completed outside the completion window 
will not be considered a protocol deviation. It is essential to make age adjustments for 
prematurity when selecting the appropriate ASQ-3. Based on results from the ASQ-3 
administered at 24 months corrected age and if no cerebral palsy diagnosis has been made 
to date (see Section 6.2.5.1), the infant may be referred to a qualified examiner for a 
formal assessment of cerebral palsy. 
The M-CHAT-R/F will be completed for all infants at 18 and 24 months (corrected age) 
and the CBCL/1.5–5 will be completed for all infants at 24 months (corrected age) to 
assess the risk for other behavioral problems or ASD. If at any of these time points a 
child has an M-CHAT-R/F score that indicates further evaluation is required and/or a 
CBCL/1.5–5 score above the 97th percentile for a subset of prespecified questions, the 
child will be referred to a specialist for a formal assessment. An overview for the 
collection and review of data for the M-CHAT-R/F and CBCL/1.5–5 is provided in 
Figure 3.
 
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The M-CHAT-R/F is a parent-reported autism screening tool designed to identify 
children 16 to 30 months of age who should receive a more thorough assessment for 
possible early signs of ASD or developmental delay [Robins, 2014]. The M-CHAT-R/F 
consists of 20 questions that are answered with either “yes” or “no.” Total scores on the 
M-CHAT-R/F between 0 and 2 indicate a low risk, scores between 3 and 7 indicate a 
medium risk and triggers administration of the follow-up questionnaire, and scores 
between 8 and 20 indicate a high risk. In this study, infants with test scores that indicate 
that further evaluation is required (either after an initial medium-risk score and further 
follow-up or an initial high-risk score) will be considered to have possible signs of ASD
or developmental delay and will be referred to a developmental specialist for a formal 
assessment.
The CBCL/1.5–5 is a widely used parent-completed questionnaire of the Achenbach 
System of Empirically Based Assessment (ASEBA). The ASEBA is based on carefully 
conducted empirical studies and is designed to assess, in a standardized format, 
behavioral problems and social competencies (Achenbach, 2001). The CBCL/1.5-5 
includes approximately 100 items that describe specific kinds of behavioral, emotional, 
and social problems that characterize preschool children between the ages of 1.5 and 
5 years. Scores on the full CBCL/1.5-5 between the 93rd and 97th percentile are in the 
borderline range and scores above the 97th percentile are in the significant range of 
clinical concern. In this study, infants with test scores above the 97th percentile for a 
subset of prespecified questions that relate to attention or hyperactivity problems 
syndrome or the American Psychiatric Association's Diagnostic and Statistical Manual 
(DSM)-oriented attention-deficit/hyperactivity disorder scale will be considered to have a 
behavior problem, which will trigger a referral to a developmental specialist for a formal 
assessment. 
The completion window for the CBCL/1/5-5 and M-CHAT-R/F is +6 weeks at 
18 months (M-CHAT-R/F only) and +12 weeks at 24 months; however, questionnaires 
completed outside the completion window will not be considered a protocol deviation.
For further details regarding the CBCL/1.5–5 and M-CHAT-R/F, refer to the SPM.
6.2.5.1.
The ASQ-3 Score Interpretation and Possible Specialist Referral 
Recommendations
The ASQ-3 scores for this study will be interpreted and recommendations will be offered 
according to the following:

The child’s development will be considered to be on schedule if the child’s 
ASQ-3 scores are in the white zone (higher than 1 SD below the mean), and no 
further action is required.

If the child’s ASQ-3 scores are in the grey zone (1 SD below the mean), the 
parent/legal guardian may share the ASQ-3 test results with the child’s HCP.
 
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
If any of the child’s ASQ-3 scores are in the black zone (2 SD below the 
mean), then the child’s parent/legal guardian will be asked if the child is already 
under the care of a developmental specialist who can or has made a formal 
assessment (e.g., using the BSID-III). If a recent (3 months) BSID-III was 
conducted, the BSID-III will not be repeated and the RCC-PI will request results 
from the relevant HCP. If the child is not currently under the care of a 
developmental specialist, then the parent/legal guardian will be referred to a 
qualified assessor for developmental evaluation (e.g., using the BSID-III), and a 
neurologic examination will be conducted, if indicated. 

BSID-III retesting will be performed if the child’s ASQ-3 scores are in the black 
zone on a subsequent ASQ-3 test following the first BSID-III referral.

If, at 24 months corrected age, the child’s ASQ-3 gross motor domain score is in 
the black range and the child has not already been diagnosed with cerebral palsy, 
the parent/legal guardian will be referred to a qualified examiner for a formal 
assessment to determine if this condition is present.
Reports from all specialists will be included in the subject’s source documents. For 
further details regarding the ASQ-3 refer to the SPM.
An overview for the collection and review of data for the ASQ-3 is provided in Figure 3.
 
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Figure 3
ASQ-3, M-CHAT-R/F, and CBCL/1.5–5: Flow Chart of Data Collection and Review
ASQ-3 = Ages and Stages Questionnaire-3; BSID-III = Bayley Scales of Infant Development, third edition; CBCL/1.5–5 = Child Behavior Checklist for ages 1.5 to 5; HCP = health care 
provider; M-CHAT-R/F = Modified Checklist for Autism in Toddlers-Revised with Follow-Up; RCC-PI = research coordinating center-principal investigator.
1.
A neurologic examination will also be conducted, if indicated.
 
 
 
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6.2.5.2.
Neurodevelopment
Neurodevelopment will be assessed by determining the proportions of infants diagnosed 
with developmental delays listed below at 9, 18, and 24 months of age, corrected for 
prematurity. 

Proportion of infants with an ASQ-3 score in the black zone for any domain

Proportion of infants with an ASQ-3 score in the black zone for gross motor 
skills

Proportion of infants with an ASQ-3 score in the black zone for fine motor skills

Proportion of infants with an ASQ-3 score in the black zone for communication

Proportion of infants with an ASQ-3 score in the black zone for problem-solving

Proportion of infants with an ASQ-3 score in the black zone for personal-social 
skills

Proportion of infants referred for developmental evaluation (using BSID-III)

Proportion of infants with a BSID-III score >2 SDs below the mean score for 
cognitive impairment (<4)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
gross motor scale (<4)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
fine motor scale (<4)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
language scale (<70)

Proportion of infants with a CBCL/1.5–5 above the 97th percentile for a subset 
of prespecified questions that relate to attention and hyperactivity problems

Proportion of infants indicated as needing further evaluation after completion of 
the M-CHAT-R/F

Proportion of infants referred for neurological evaluation to determine diagnosis 
of cerebral palsy
6.2.6.
Overall Measure of Neurodevelopmental Impairment

Proportion of infants with at least 1 of the following indicators of 
neurodevelopmental impairment: 

Hearing impaired, uncorrected even with aids (at 24 months chronological age)

Blindness in 1 or both eyes, or sees light only (at 24 months chronological age)

Cerebral palsy (moderate defined as grade 2 or 3 and severe defined as grade 4 
or 5 using the Gross Motor Functional Classification System [GMFCS]) (at 
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
Cognitive impairment: BSID-III Cognitive Scale Score of >2 SDs below mean 
score (<4) (at 24 months corrected age)

Motor impairment: BSID-III Motor Composite Scale Score of >2 SDs below 
mean score (<70) (at 24 months corrected age)

Diagnosis of ASD, ADD, or ADHD
6.2.7.
Adverse Events
The RCC-PI or RCC site staff will be responsible for detecting, documenting, and 
reporting events that meet the definition of an SAE. Nonserious AEs will not be tracked.
The outcomes for this study may represent a number of potential adverse drug 
experiences or events that include but may not be limited to the following:

Reports of child hospitalizations (see Section 6.3)

Reports of chronic health conditions in the child (see Section 6.2.2)

Reports of congenital anomalies in the child (see Section 6.2.3)

Reports of child death (see Section 6.2.4)

Reports of developmental delays in the child (see Section 6.2.5.2)

Reports of any other SAEs in the child (see Section 6.2.7.2)
6.2.7.1.
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.
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.
 
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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
6.2.7.2.
Definition of an SAE
An SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
NOTE: The term “life threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient 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.
d.
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.
e.
Is a congenital anomaly/birth defect
f.
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 1 of the other 
 
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outcomes listed in the aforementioned 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.
6.2.8.
Laboratory and Other Safety Assessment Abnormalities 
Reported as SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., electrocardiograms, radiological scans, vital sign 
measurements), including those that worsen from Baseline, felt to be clinically significant 
in the medical and scientific judgment of the RCC-PI are to be recorded as SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the RCC-PI to be more severe than expected for the 
subject’s condition, are not to be reported as SAEs.
6.2.9.
Cardiovascular Events
The RCC-PI will be required to fill out event specific data collection tools for the 
following SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
This information should be recorded in the specific cardiovascular eCRF within 1 week 
of when the SAE(s) are first reported.
6.2.10.
Death Events
The proportion of deaths that occur after 28 days post EDD and up to 24 months
chronological age will be collected.
In addition, all deaths 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.
 
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This information should be recorded in the specific death eCRF within 1 week of when 
the death is first reported.
6.2.11.
Time Period and Frequency of Detecting SAEs
The RCC-PI or RCC site staff is responsible for detecting, documenting, and reporting 
events that meet the definition of an SAE.
Child SAEs will be collected from after 28 days post EDD until 24 months chronological 
age. All SAEs will be reported to GSK/PPD within 24 hours, as indicated in 
Section 6.2.12. 
6.2.12.
Method of Detecting SAEs
Serious AEs will be primarily collected through the CHI questionnaire in an electronic 
device. Designated events and/or responses will be followed by the HCP as discussed in 
Section 6.2.7.2. Care must be taken not to introduce bias when detecting SAEs. If phone 
contact needs to be made with a parent/legal guardian by the RCC-PI, open-ended and 
nonleading verbal questioning of the subject is the preferred method to clarify reported 
SAEs.
6.2.13.
Follow-up of SAEs
Any SAEs or AEs of special interest that were ongoing at the end of the Phase III 
treatment studies and any new SAEs reported during this study will be followed until
resolution, until the condition stabilizes, until the event is otherwise explained, or until 
the subject is lost to follow-up.
6.2.14.
Prompt Reporting of SAEs and Other Events to GSK/PPD
Serious AEs meeting predefined criteria will be reported promptly by the RCC-PI to 
GSK, as described in the following table, once the RCC-PI determines that the event 
meets the protocol definition for that event.
 
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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
CV = cardiovascular; SAE = serious adverse event.
The contact information for reporting SAEs is as follows:
Issue
North America 
Contract
Latin America Contact
Europe/Asia Contact
Serious Adverse 
Event Reporting
24-Hour Safety Hotline:
Safety Fax:
24-Hour Safety Hotline:
Safety Fax:
24-Hour Safety Hotline:
Safety Fax:
The method of recording, evaluating, and following up of SAEs including procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM. Procedures 
for poststudy SAEs are provided in the SPM.
6.2.14.1.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the RCC-PI to GSK is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and RCC-PIs.
The RCC-PI safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to other RCC-PIs as necessary.
 
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The RCC-PI who receives a safety report describing an SAE(s) or other specific safety 
information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will 
notify the IRB/IEC, if appropriate according to local requirements.
6.2.15.
Other Safety Outcomes
6.2.15.1.
Laboratory Assessments
Not applicable
6.2.15.2.
Ad Hoc Maternal Reports
It is possible that during contact with the study staff (RCC staff or RCC-PI), the mother
of the child being followed in this study may report her own AEs/SAEs resultant from 
retosiban or comparator treatment from Phase III SPTL treatment studies in an ad hoc
manner to the RCC study staff or the RCC-PI. The RCC-PI will be responsible for 
conveying such events to the Phase III SPTL treatment study investigator where the 
intervention was given to ensure that all safety outcomes are captured.
6.3.
Health Outcomes
Resource utilization exploratory endpoints include the following: 

Number of hospital admissions, proportion of infants and children with any 
hospital admission, post-birth hospitalization discharge, by principal and 
secondary discharge diagnosis, type of hospital unit admitted to (e.g., NICU, 
Pediatric, PICU, Nursery level 3, ICU), and length of hospital stay per unit after 
28 days post EDD and up to 24 months chronological age.

Combined length of hospital stay in days for all hospital admissions (for infants 
discharged from the delivery hospitalization and for babies who were never 
discharged home post-delivery) after 28 days post EDD and up to 24 months 
chronological age.

Number of surgical procedures (details of type and whether performed on an 
inpatient basis or at an outpatient/surgical center will be collected up to 
24 months chronological age only) after 28 days post EDD and up to 24 months 
chronological age.

Number of ER/UC visits and proportion of infants with any ER/UC visit after 
28 days post EDD and up to 24 months chronological age.

Number of specialty care or therapy visits and proportion of infants referred for 
specialty care or therapy by type of care/therapy after 28 days post EDD and up 
to 24 months chronological age.

Parental productivity loss related to infant hospital admissions, ER/UC visits, or 
specialist care after 28 days post EDD and up to 24 months chronological age.
 
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6.3.1.
Parent/Legal Guardian-Completed Productivity Questionnaire
During the 24 months of participation in the study, if the infant's parent/legal guardian 
reports in one of the CHI questionnaires that the child is being treated by a specialist or 
has had emergency department visits or hospitalizations, they will be asked to complete 
the productivity questionnaire. This assessment asks about the impact of the child’s 
health problems on their ability to work and perform regular daily activities. The same 
tool/process as the other parent/legal guardian-reported outcomes will be used for 
collection of this assessment. The completion window for the productivity questionnaire 
is +2 weeks from the date of completion of the relevant CHI; however, questionnaires 
completed outside the completion window will not be considered a protocol deviation.
7.
DATA MANAGEMENT
7.1.
Data Handling Conventions
For this study, child data will be entered into GSK/PPD-defined eCRFs, transmitted 
electronically to GSK/PPD, and combined with data provided from other sources, e.g., 
data obtained directly from the parent/legal guardian via an electronic device provided by 
the sponsor, its designated vendor, or the patient’s own devices using a secure and 
validated data system. The RCC staff will enter data provided on paper into the 
specifically designed eCRF pages. 
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 Medical Dictionary for Regulatory Activities (MedDRA) and an 
internal validated medication dictionary, GSKDrug.
All eCRFs (including queries and audit trails) will be retained by GSK. In all cases, 
subject initials will not be collected or transmitted to GSK according to GSK policy.
7.1.1.
Attempts to Obtain the Follow-Up Information
When follow-up data are due, the applicable reporter will be contacted and asked to 
provide follow-up information. Subsequent attempts, as necessary, will be made through 
various modes of communication. If there is still no response, a final communication will 
be sent indicating the case is lost to follow-up. If this communication prompts a response 
or the requested data are later received before the study closes, the case will be re-opened 
and will no longer be considered lost to follow-up. Once re-opened, any data from 
assessments that had not been entered at the time the participant was lost to follow-up 
may be collected, if appropriate. If at any point in the follow-up process the reporter 
indicates that the participant is lost to follow-up, no further attempts will be made.
 
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7.1.2.
Loss to Follow-Up
Children for whom follow-up information is never obtained will be considered lost to 
follow-up. These cases will be tallied in the applicable sections of the study reports. All 
other cases with some follow-up data will be analyzed up to the length of child follow-up.
7.2.
Validation Procedures
The ongoing data collection from parents/legal guardians will follow a specific script to 
elicit information from contacts with the health care system. The child’s HCP will also be 
contacted to provide data on the child’s health and resource utilization when triggered by 
information from the parent/legal guardian. As indicated in the previous sections, for 
conditions or events that may meet SAE criteria, medical confirmation and/or medical 
records will be obtained to provide details of the conditions. All study data will be 
captured in carefully designed eCRFs specific to the study objectives.
The ASQ-3, CBCL/1.5-5, and M-CHAT-R/F questionnaires that parents/legal guardians 
will administer at the specific ages or time points have been validated in English and 
selected languages.
Ensuring that the data obtained and delivered to GSK are of high quality will be an 
ongoing, multistep process involving programming of edit checks for critical data 
variables in the data management system and visual review for completeness, logic, 
consistency, and accuracy. As is recommended in regulatory guidance documents, eCRFs 
will be carefully designed to ensure data quality and integrity.
7.2.1.
Follow-Up Process for Clarification of Information
If there are discrepancies in the data, the RCC-PI will contact the appropriate HCP for 
clarification. Subsequent attempts will be made, if necessary. If no further information is 
obtained on an otherwise evaluable case, the discrepant information in the data fields may 
be left blank, identified as “unspecified.” On a case-by-case basis, qualified study staff or 
the RCC-PI may make a determination regarding discrepant information (e.g., 
determination of partially illegible word or illogical year).
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The objective of the study is to describe the safety and morbidity and mortality outcomes 
of children exposed to treatment during Phase III SPTL studies investigating retosiban or 
comparator for the treatment of SPTL. These mortality and morbidity endpoints (as 
described in Section 6.2) will be descriptively summarized.
No type I error adjustments are planned.
 
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8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
The sample size for this study will depend on the total number of subjects enrolled in the 
Phase III SPTL treatment studies. In May 2017, the 2 Phase III SPTL treatment studies 
were terminated early due to the feasibility of recruiting the studies in a timely manner,
meaning that the size of these studies was lower than originally planned. This has 
resulted in a greatly reduced sample size for this study. 
8.2.2.
Sample Size Sensitivity
Not applicable
8.2.3.
Sample Size Re-Estimation
Not applicable
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The primary population for safety assessment will be all infants whose mothers have 
been randomized and received retosiban or comparator in any of the Phase III treatment 
trials. Of these mothers, the infant safety population includes the mother/infant pairs who 
enrolled into the study, the mother/infant pairs who decline to consent to the study, and 
the mother/infant pairs whose fetus/neonates/infants died prior to the enrollment of the 
study. Subjects will be analyzed according to their actual treatment in case this differs 
from their randomized treatment.
8.3.2.
Analysis Data Sets
In this study, the analysis data set is the primary population.
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
The primary treatment groups are retosiban, placebo, and atosiban.
The primary comparisons between these treatment groups will be:

Retosiban versus placebo 

Retosiban versus atosiban
 
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8.3.3.2.
Other Comparisons of Interest
A secondary treatment group will include the pooling of placebo and atosiban into a 
group called “all comparators.” The secondary comparison will be the following:

Retosiban versus all comparators
8.3.4.
Interim Analysis
There is no formal interim analysis planned for this study. The IDMC will review 
unblinded data from this study along with data from any ongoing Phase III SPTL 
treatment study periodically in accordance with the IDMC charter. The unblinded 
periodic safety updates will be performed and delivered to the IDMC by an independent 
statistical data analysis committee. 
In the event of early stopping of the Phase III SPTL development program due to safety 
and/or lack of efficacy, children will continue to be followed until they have reached 
24 months chronological age. 
For any subject for which the CHI questionnaire at 3, 4, and 5 years of the child’s 
chronological age was completed prior to Amendment 2, data will be reported.
Further analysis details will be provided in the reporting and analysis plan (RAP) and/or 
IDMC charter.
8.3.5.
Key Elements of Analysis Plan
8.3.5.1.
Safety Analyses
8.3.5.1.1.
Outcomes
The primary objective of the planned analysis will be to use descriptive statistics to 
describe the safety and morbidity and mortality outcomes of children exposed to 
treatment during the Phase III SPTL studies investigating retosiban or comparator for the 
treatment of SPTL. The endpoints to be descriptively summarized are those described in 
Section 6.2. Descriptive statistics will be calculated by treatment group and by treatment 
group and time, where appropriate.
For binary outcomes, all summary tables will include the number and percentage of 
subjects with the response/event. For continuous variables, all summary tables will 
include: n, mean, median, standard deviation, minimum and maximum. All summary 
tables will include N for each group (i.e., the total number of subjects randomized to each 
group within the appropriate population).
Full details of all planned analyses will be provided in the RAP.
 
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8.3.5.1.2.
Serious Adverse Events
Serious AEs as described in Section 6.2.7.2 will be coded using MedDRA and grouped 
by body system. Serious AEs will be summarized by treatment group as described in 
Section 8.3.3. Within each group, SAEs 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 SAEs, drug-related SAEs, and SAEs leading to withdrawal. Where 
appropriate, SAEs by month will be tabulated separately.
Full details of all safety analyses will be provided in either the final protocol and/or RAP.
8.3.5.2.
Health Outcomes Analyses
The objective of the exploratory planned analysis is to characterize resource utilization in 
infants exposed to retosiban or comparator in the Phase III SPTL treatment studies. 
Exploratory endpoints are those described in Section 6.3. Descriptive statistics may be 
calculated by treatment group and by treatment group and time, where appropriate. Full 
details of the planned exploratory analyses will be provided in the RAP.
8.3.5.3.
Genetic Analyses
Data and genetic samples from the Phase III SPTL treatment studies may be used as part 
of a genetic analysis using data collected in this study, if relevant. No additional genetic 
samples are required.
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 the study, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with the International 
Council for 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 ethical principles that are outlined in the current version of the 
Declaration of Helsinki, including, but not limited to:
 
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
IRB/IEC review and favorable opinion/approval of study protocol and any 
subsequent amendments

Subject informed consent

RCC-PI reporting requirements
GSK/PPD will provide full details of the above procedures, either verbally, in writing, or 
both.
Written informed consent must be obtained for each infant prior to participation in the 
study.
9.2.1.
Release of Participant Medical Information
In order to collect data from the participant’s HCPs, medical release forms for each 
clinician who will report data to the study must be completed and signed by the child’s 
parent/legal guardian.
9.2.2.
Subject Confidentiality
Each participant’s identity will be known only to the third-party contractor, RCC-PIs, and 
relevant HCPs (e.g., pediatrician or specialist). Child identification numbers will be 
assigned and used to identify study participants. The dataset used in the analysis of data 
will contain coded participant identifiers only.
Regulatory authorities or GSK-approved auditors may inspect the study data files, which 
may include personal identifier information of participants.
9.3.
Quality Control (Study Monitoring)
This study will be outsourced to a contract research organization (PPD), which will 
perform study management, clinical operations, data collection, data management, data 
analysis, and report authoring under the guidance of GSK.
In accordance with applicable regulations, GCP, and GSK/PPD procedures, PPD 
monitors will contact the RCC site prior to the start of the study to review with the RCC 
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
 
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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 RCC 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 RCC-PI 
(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.
9.5.
Study and RCC Site Closure
Recruitment in participating countries will begin with initiation of the Phase III SPTL 
treatment studies. Recruitment will continue until the Phase III SPTL treatment studies 
end recruitment. Follow-up will continue until each child enrolled completes the 
24-month questionnaire at 24 months chronological age. For any subject that was 
enrolled prior to Amendment 2, those subjects who have completed the 24 months 
assessments will not be required to complete the CHI questionnaire at 3, 4, and 5 years of 
the child’s chronological age. Study close-out and final reporting activities will be 
initiated on completion of the follow-up on the last study participant.
Upon completion or termination of the study, the PPD monitor will conduct RCC site 
closure activities with the RCC-PI or RCC 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 RCC-PI. When feasible, GSK will provide 
advance notice to the RCC-PI of the impending action. 
If any study with retosiban is suspended or terminated, GSK/PPD will promptly inform 
all RCC-PIs. 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 RCC-PI 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 RCC-PI must maintain all RCC 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 RCC 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, 
 
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electronic); however, caution must be exercised before such action is taken. The RCC-PI 
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 RCC-PI 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 RCC-PI of the time period for retaining the RCC site records 
in order to comply with all applicable regulatory requirements. The minimum retention 
time will meet the strictest standard applicable to a particular RCC site, as dictated by 
local laws/regulations and GSK/PPD standard operating procedures.
The RCC-PI 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 RCC-PI is no longer associated with the 
RCC site.
9.7.
Provision of Study Results to RCC-PIs, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an RCC-PI signatory will be 
identified for the approval of the clinical study report. The RCC-PI 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 RCC-PI with the full summary of the study results. The 
RCC-PI is encouraged to share the summary results with the parent/legal guardian of the 
participating child, as appropriate.
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.
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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10.
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American College of Obstetricians and Gynecologists; Committee on Practice Bulletins–
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Begg EJ, Duffull SB, Saunders DA, et al. Paroxetine in human milk. Br J Clin 
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Behrman RE, Stith BA, eds; Committee on Understanding Premature Birth and Assuring 
Healthy Outcomes. Preterm birth: causes, consequences, and prevention. Washington 
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Benedetto MT, De Cicco F, Rossiello F, et al. Oxytocin receptor in human fetal 
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Callanan C, Doyle L, Rickards A, et al. Children followed with difficulty: how do they 
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Centers for Disease Control and Prevention (CDC). Metropolitan Atlanta Congenital 
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Council on Children with Disabilities; Section on Developmental Behavioral Pediatrics; 
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Engle WA, Tomashek KM, Wallman C; Committee on Fetus and Newborn, American 
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Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Age 
terminology during the perinatal period. Pediatrics. 2004;114(5):1362-4.
 
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European Surveillance of Congenital Anomalies (EUROCAT). Guide 1.3: instructions 
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1.3.pdf (Accessed 30 Apr 2014).
Fuchs AR, Fuchs F, Husslein P, et al. Oxytocin receptors and human parturition: a dual 
role for oxytocin in the initiation of labor. Science. 1982;215(4538):1396-8.
GlaxoSmithKline Document Number CM2006/00201/06. Retosiban Investigator's 
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Goldenberg RL, Culhane JF, Iams JD, et al. Epidemiology and causes of preterm birth. 
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Hagg S, Spigset O. Anticonvulsant use during lactation, Drug Saf. 2000;22(6):425-40.
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Kenyon SL, Taylor DJ, Tarnow-Mordi W; ORACLE Collaborative Group. Broad-
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norfluoxetine in human milk. Br J Clin Pharmacol. 1999;48(4):521-7.
Lundqvist P, Källen K, Hallström I, et al. Trends in outcomes for very preterm infants in 
the southern region of Sweden over a 10-year period. Acta Paediatr. 2009;98(4):648-53.
Marlow N. Is survival and neurodevelopmental impairment at 2 years of age the gold 
standard outcome for neonatal studies? Arch Dis Child Fetal Neonatal Ed.
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Matthews TJ, MacDorman MF. Infant mortality statistics from the 2006 period linked 
birth/infant death data set. Natl Vital Stat Rep. 2010;58(17):1-31.
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Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist 
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Roos C, Spaanderman ME, Schuit E, et al; APOSTELL-II Study Group. Effect of 
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Tocolysis for women in preterm labour. February 2011. 13 p.
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Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from 
infancy to adulthood. Lancet. 2008;371(9608):261-9.
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Thornton S, Miller H, Valenzuela G, et al. Treatment of spontaneous preterm labour with 
retosiban: a phase 2 proof-of-concept study. Br J Clin Pharmacol. Br J Clin Pharmacol. 
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Tin W, Fritz S, Wariyar U, et al. Outcome of very preterm birth: children reviewed with 
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11.
APPENDICES
11.1.
Appendix 1: Protocol Changes
Protocol Amendment Number 01
Protocol Amendment Number 01 is applicable to all RCC sites participating in this study. 
Protocol changes specified in Amendment Number 01 are summarized as follows: 

Extended the study duration from 24 months to 5 years. The rationale for this change 
was to identify any potential neurodevelopmental and behavioral disorders through 
annual assessments at years 3, 4, and 5, specifically autism and attention deficit 
hyperactivity disorder.

Added an assessment using a modified version of the CHI questionnaire at 3, 4, and 
5 years of the child’s chronological age. The rationale for this change is to address 
US Food and Drug Administration recommendations to extend the duration of the 
follow-up period to 5 years. A modified CHI questionnaire will be used to collect 
data to identify any potential neurodevelopmental and behavioral disorders at 3, 4, 
and 5 years of the child’s chronological age.

Added an additional time point for the assessment of the M-CHAT-R/F at 18 months 
(in addition to the assessment at 24 months). The rationale for this change was to 
follow current recommendations from the American Academy of Pediatrics for the 
assessment of the M-CHAT-R/F [Council on Children with Disabilities, 2006].

Revised criteria for assessment using the M-CHAT-R/F, which is assessed at 18 and 
24 months, and CBCL/1.5-5, which is assessed at 24 months, to make these 
assessments mandatory for all infants, regardless of ASQ-3 results. Previous 
requirement for CBCL/1.5–5 and M-CHAT-R/F was limited to children with ASQ-3 
nonmotor (communication, problem-solving, and/or personal-social) domain scores 
in the black zone at 24 months corrected age. The rationale for this change was to 
follow current recommendations from the American Academy of Pediatrics [Council 
on Children with Disabilities, 2006].

Removed as a neurodevelopment endpoint the proportion of infants referred for an 
additional behavior assessment using the M-CHAT-R/F and CBCL/1.5-5. Because 
the CBCL/1.5-5 and M-CHAT-R/F will be assessed for all infants at specified time 
points, regardless of ASQ-3 results, this endpoint is no longer applicable to this 
study.

Clarified that any infant SAEs and/or AEs of special interest that were unresolved at 
the end of the Phase III treatment studies and any new SAEs reported during this 
study should be followed to stabilization or resolution in those children participating 
in the follow-up study.  
 
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
Removed standard care tocolytic therapy as a subgroup that may be explored as part 
of the safety analysis. This subgroup is no longer relevant because the Phase III 
SPTL Study 200719 (NEWBORN-1) prohibits concomitant tocolytic treatment 
during study drug administration.

Added the following subgroups that may be explored as part of the safety analysis: 
established progesterone use, magnesium sulphate use, and tocolytic use following 
study drug discontinuation. The rationale for this change was to align endpoints with 
those in Phase III SPTL Study 200719 (NEWBORN-1).

Incorporated administrative changes as detailed in a Protocol Clarification Letter 
dated 19-Jan-2015, clarifying that there is no requirement for the investigator to 
discuss unblinding with the PPD medical monitor in order to rapidly unblind a 
child's treatment assignment if needed.

Incorporated other administrative changes. The rationale for these changes is to 
ensure a clear and complete protocol for use at the RCC sites.
Specific Changes in the Text
Title Page:
Title:
Follow-Up Study to Assess Long-Term Safety and Outcomes in Infants 
and Children Born to Mothers Participating in Retosiban Treatment 
Studies
Study Name: ARIOS
Authors (GSK): 
 
 
Authors (PPD):
 
Sponsor Information Page:
Clinical Study Identifier: 200722 (ARIOS)
List of Abbreviations and Definitions
ADD
attention deficit disorder
ADHD
attention deficit hyperactivity disorder
ASEBA
Achenbach System of Empirically Based Assessment
ASD
autism spectrum disorder
. . .
GSK
GlaxoSmithKline
 
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Definitions
Child
Aged from 2 years to up to 12 years, per definition of the US Food and 
Drug Administration
Infant
Aged from 1 month to up to 2 years, per definition of the US Food and 
Drug Administration
Summary, Rationale:
One of the major advances in perinatal medicine has been the finding that antenatal 
corticosteroids given to women at risk of imminent preterm birth reduces the risks for 
neonatal mortality and morbidity. Corticosteroids now represent the standard of care for 
an acute antenatal intervention to improve neonatal outcomes in the developed world
[RCOG, 2011; ACOG, 2012].
The goal of this study (ARIOS), therefore, is to assess the safety and outcomes of infants 
and children who were exposed to retosiban (GSK221149) or comparator in the planned 
Phase III SPTL treatment studies and provide assurance that treatment is not associated 
with significant adverse outcomes in early childhood.
Summary, Objectives
The study objective is to assess the safety and outcomes in infants and children who 
were exposed to retosiban or comparator in the Phase III SPTL treatment studies.
Specific objectives include the following:

To characterize the clinical safety in terms of infant morbidity and mortality in 
infants and children exposed to retosiban or comparator in utero

To characterize the clinical safety in terms of neurodevelopment in infants and 
children exposed to retosiban or comparator in utero

To characterize parental productivity loss related to a sick child and infant resource 
utilization in terms of hospital admissions, length of stay, emergency room/urgent 
care (ER/UC) visits, surgical procedures, and referral to specialty care or therapy 
visits for infants (up to age 2 years) exposed to retosiban or comparator in utero
Summary, Study Design:
This ARIOS is a long-term infant and child follow-up study that will prospectively 
assess safety and outcomes of all infants and children born to women who received at 
least 1 dose of retosiban or comparator in any of the Phase III SPTL treatment studies. . . 
. The infant will be able to be consented into the study until the later date of either the 
date of discharge from the birth hospitalization or up to 9 months corrected age. Infants 
and children will be followed at prespecified intervals until they have reached 5 years 
 
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chronological age 24 months corrected age for preterm infants (i.e., an infant born 3 
months preterm will complete the final 24 month study questionnaire at 27 months 
chronological age) and 24 months chronological age for term infants. This study does not 
require medical interventions or study visits to an investigational site. Instead, parents or 
legal guardians will be prompted at certain time points to complete developmental 
questionnaires and other data regarding their child’s health status via an electronic 
device. Data collected during the infant this follow-up study will be managed by a 
centralized research coordinating center (RCC). Regionally based pediatricians will serve 
as the study principal investigators (referred to as RCC-PIs) for the follow-up study. All 
communications the RCC-PI has with the parent/legal guardian or the infant’s child’s 
health care provider (HCP) will occur remotely; there will be no clinic visits.
The infant's child’s parent/legal guardian will be asked to complete a Child Health 
Inventory (CHI) at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age 
and a modified CHI at 3, 4, and 5 years of the child’s chronological age. This The 
CHI questionnaire completed up to the 24-month time point will screen for infant 
mortality and morbidity and will capture data on resource utilization. At the 3-, 4-, and 
5-year time points, the CHI will screen for child mortality and morbidity, including 
any indicators of neurodevelopmental impairment. If the parent/legal guardian 
indicates that the child has been newly diagnosed (after 28 days post EDD) with chronic 
conditions or congenital anomalies, follow-up by the RCC-PI will be undertaken with the 
applicable HCP to confirm the parent report. Persistence or resolution of conditions will 
be determined in subsequent questionnaires after the initial report. 
If the parent/legal guardian indicates that the child has had a hospital visit or surgery or 
that the infant child has died, the RCC-PI will confirm by obtaining medical and other 
records from HCPs or medical facilities, including a death certificate, if applicable. If the 
parent/legal guardian indicates that the child has had an ER/UC visit, the RCC-PI will use 
discretion and obtain medical records when the reported indication suggests a true 
emergency. Additional details regarding ER/UC visits will be provided in the SPM. After 
review of all records, the RCC-PI may request additional targeted follow-up data from 
the relevant HCP or medical facility if clarification is needed on any reported study 
endpoints or serious adverse events (SAEs).
During the first 24 months of participation in the study, Iif the parent/legal guardian 
indicates that the infant has been treated by specialists or has had ER/UC visits or 
hospitalizations, he/she will be asked to complete a productivity questionnaire to evaluate 
loss of parental productivity.
To screen for a delay in the areas of communication, gross motor, fine motor, 
problem-solving, and personal-social skills, the parent/legal guardian will be asked to 
complete the 9-, 18-, and 24-month Ages and Stages Questionnaire-3 (ASQ-3) when the 
infant’s corrected age corresponds to 9, 18, and 24 months, for example, parents/legal 
guardians of an infant born 3 months premature will complete the 9-month ASQ-3 at 
12 months chronological age. Any child with a score in the black zone (2 SD below 
the mean) in any of the 5 domains of the ASQ-3 will be referred to a qualified assessor 
 
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for a developmental evaluation (e.g., using the Bayley Scale for Infant Development, 
third edition [BSID-III]), unless the child is already under the care of a specialist who has 
recently conducted a BSID-III evaluation. Based on results from the ASQ-3 administered 
at 24 months corrected age, parents/legal guardians may be asked to complete the Child 
Behavior Checklist for Ages 1.5 to 5 (CBCL/1.5–5) and the Modified Checklist for 
Autism in Toddlers–Revised with Follow-Up (M-CHAT-R/F) to assess the risk for other 
behavioral problems or autism spectrum disorder or, alternatively, and if no cerebral 
palsy diagnosis has been made to date, the infant may be referred to a qualified 
examiner for a formal assessment of cerebral palsy.
The Modified Checklist for Autism in Toddlers–Revised with Follow-Up 
(M-CHAT-R/F) will be completed for all infants at 18 and 24 months (corrected 
age) and the Child Behavior Checklist for Ages 1.5 to 5 (CBCL/1.5–5) will be 
completed for all infants at 24 months (corrected age) to assess the risk for other 
behavioral problems or autism spectrum disorder (ASD). If at any of these time 
points a child has an M-CHAT-R/F score that indicates further evaluation is 
required and/or a CBCL/1.5–5 score at or above the 97th percentile for a subset of 
prespecified questions, the child will be referred to a specialist for a formal 
assessment.
Summary, Study Endpoints/Assessments
Morbidity and mortality endpoints:

Proportion of infants and children with newly diagnosed (after 28 days post EDD) 
chronic medical conditions by type of condition will be recorded and include the 
following:

Respiratory conditions

Neurological conditions

Sensory conditions

Gastrointestinal conditions

Cardiovascular conditions

Renal conditions

Growth parameters (only up to 24 months chronological age)

Proportion of infants and children with newly diagnosed (after 28 days post EDD) 
congenital anomalies

Proportion of infant and child deaths after 28 days post EDD and until the end of the 
study
 
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Neurodevelopment endpoints:

Neurodevelopment endpoints assessed at ages 9, 18, and 24 months, corrected for 
prematurity:

Proportion of infants referred for developmental evaluation (using BSID-III)

Proportion of infants with a BSID-III score <>2 SDs below the mean score for 
the cognitive impairment (<70)

Proportion of infants with BSID-III score <>2 SDs below the mean score for the 
gross motor scale (<70)

Proportion of infants with BSID-III score <>2 SDs below the mean score for the 
fine motor scale (<70)

Proportion of infants with a BSID-III score <>2 SDs below the mean score for 
the language scale (<70)

Proportion of infants referred for an additional behavioral assessment using the 
CBCL/1.5-5 and M-CHAT-R/F

Proportion of infants with a CBCL/1.5–5 score at or above the 97th percentile 
for a subset of prespecified questions that relate to attention and hyperactivity 
problems 

Proportion of infants indicated as needing further evaluation after completion of 
the M-CHAT-R/F

Proportion of infants referred for neurological evaluation to determine diagnosis 
of cerebral palsy

Proportion of infants with at least 1 of the following indicators of 
neurodevelopmental impairment at the end of the study:

Hearing impaired, uncorrected even with aids (at 24 months chronological 
age)

Blindness in 1 or both eyes, or sees light only (at 24 months chronological age)

Cerebral palsy (moderate and severe) (at 24 months corrected age)

Cognitive impairment: BSID-III Cognitive Scale Score of <>2 SDs below mean 
score (<70) (at 24 months corrected age)

Motor impairment: BSID-III Motor Composite Scale Score of <>2 SDs below 
mean score (<70) (at 24 months corrected age)

Proportion of infants and children with at least 1 of the following indicators of 
neurodevelopmental impairment at the end of the study:

Hearing impaired, uncorrected even with aids 

Blindness in 1 or both eyes or sees light only

Cerebral palsy (moderate and severe)
 
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
Diagnosis of ASD, attention deficit disorder (ADD), or attention deficit 
hyperactivity disorder (ADHD)
Resource utilization endpoints:

Number of hospital admissions, proportion of infants and children with any hospital 
admission, post-birth hospitalization discharge, by principal and secondary discharge 
diagnosis, type of hospital unit admitted to (e.g., NICU, Pediatric, PICU, Nursery 
level 3, ICU), and length of hospital stay per unit after 28 days post EDD and until 
the end of the study.

Combined length of hospital stay in days for all hospital admissions (for infants 
discharged from the delivery hospitalization and for babies who were never 
discharged home post-delivery) after 28 days post EDD and until the end of the 
study.

Number of surgical procedures (by details of type and whether performed on an 
inpatient basis or at an outpatient/surgical center will be collected up to 24 months 
chronological age only) after 28 days post EDD and until the end of the study.

Number of ER/UC visits and proportion of infants with any ER/UC visit after 
28 days post EDD and up to 24 months chronological age.

Number of specialty care or therapy visits and proportion of infants referred for 
specialty care or therapy by type of care/therapy after 28 days post EDD and up to 
24 months chronological age.

Parental productivity loss related to infant hospital admissions, ER/UC visits, or 
specialist care after 28 days post EDD and up to 24 months chronological age.
Section 1.1, Background
Preterm birth rates ranged from approximately 5% in several European countries to 18% 
in some African countries. In 20123, over nearly 450 000 preterm births, defined as 
childbirth occurring before 37 completed weeks’ gestation, occurred in the United States 
[Martin, 201315].
Section 1.1.1, Previous Human Experience
Study OTA105256 was the first Phase II clinical study of retosiban in preterm labor 
(n=93) [Thornton, 2015; GlaxoSmithKline Document Number CM2006/00201/03]. 
The study was designed to investigate the safety and dose response of retosiban given 
intravenously to women with intact membranes in preterm labor between 300/7 and 356/7
weeks of gestation. Final results showed that intravenous retosiban treatment was 
associated with a significant difference in days to delivery and significant reduction in 
preterm births. The mean difference in days to delivery was 8.2 days relative to placebo 
(95% confidence credible interval [CI]: 2.7, 13.74). Median prolongation of pregnancy 
was 35 days in women treated with retosiban, compared with 25 days in women assigned 
to the placebo group. The treatment difference was consistent across gestational ages. 
The proportion of preterm births was 18.7% in the retosiban group and 47.2% in the 
 
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placebo group. The relative risk for preterm birth in the retosiban group was 0.38 (95% 
CI credible interval: 0.15, 0.81).
The emerging safety profile for retosiban appears favorable. Results from protocol 
specified maternal-fetal and neonatal safety assessments were absent of any concerns and 
were similar between the retosiban and placebo groups. Furthermore, no clinically 
significant disparities in AEs were noted between groups [Thornton, 2015]. All reported 
AEs, whether maternal, fetal, or neonatal, were generally consistent with those reported 
either in the Investigator’s Brochure (IB) [GlaxoSmithKline (GSK) Document Number 
CM2006/00201/03], IB Supplement 1 [GlaxoSmithKline Document Number 
2015N228508_00], or in the study population.
Section 1.2, Rationale:
One of the major advances in perinatal medicine has been the finding that antenatal 
corticosteroids given to women at risk of imminent preterm birth reduces the risks for 
neonatal mortality and morbidity. Corticosteroids now represent the standard of care for 
an acute antenatal intervention to improve neonatal outcomes in the developed world
[RCOG, 2011; ACOG, 2012].
The goal of this study (ARIOS), therefore, is to assess the safety and outcomes of infants 
and children who were exposed to retosiban (GSK221149) or comparator in utero in the 
planned Phase III SPTL treatment studies and provide assurance that treatment is not 
associated with significant adverse outcomes in early childhood.
Section 1.3.1., Risk Assessment
This study is a follow-up safety study of infants and children exposed to treatment while 
in utero during their mother’s participation in a Phase III SPTL treatment study of 
retosiban or comparator for SPTL. Infants and children enrolled in this study will not be 
administered any investigational product; therefore, there are no anticipated or known 
risks to the infants and children who participate in this safety study.
The intent of this study is to ensure there have been no unintended consequences to the 
infants and children from exposure to retosiban or comparator during their mother’s 
participation in the Phase III clinical study of retosiban, specifically with respect to the 
following:
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
Fetal exposure 
through placental 
transfer
Preclinical data indicate very minimal, if 
any, maternal central nervous system 
(CNS) penetration or placental transfer 
of retosiban as supported by the 
following: 

In pregnant monkeys there was no 
Analysis of maternal blood and cord 
blood samples will be performed to test 
for levels of retosiban in women who 
deliver at an investigative center within 
12 hours of the completion of study 
treatment infusion as part of the 
 
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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
detectable retosiban in the cord 
blood when mothers were dosed up 
to 100 mg/kg (approximately 
7 times the human exposure). 
However, approximately 4% of 
circulating drug was detected in the 
cord blood when mothers were 
dosed at 300 mg/kg (approximately 
24-fold the human exposure).

Retosiban is a substrate of 
P-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, there were no 
adverse mother and infant 
behavioral or locomotor effects 
observed that were suggestive of 
CNS toxicity. 

In rodent neurobehavioral safety 
studies, there were no adverse 
clinical signs observed at doses up 
to 1000 mg/kg.
Phase III SPTL treatment studies.
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 miniumum of 24 
months up to 5 years in this study to 
assess safety and neurodevelopmental 
outcomes.
Neonatal exposure 
via breast milk
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 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 as part of the 
Phase III SPTL treatment studies.
Infants exposed to retosiban via breast 
milk will be followed for a miniumum of 
24 months up to 5 years in this study to 
assess safety and neurodevelopmental 
outcomes.
SPTL = spontaneous preterm labor.
 
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Section 1.3.2., Benefit Assessment
Given the inverse relationship between the risks for prematurity complications and 
gestational age at birth, the development of a treatment that significantly prolongs 
pregnancy in women with SPTL 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 [Thornton, 2015]. There are currently no safety findings that would preclude 
further development of retosiban for an indication for the treatment of SPTL in 
conjunction with standard of care treatments in women with an uncomplicated, singleton 
pregnancy.
The benefit to infants and children participating in this study is the focus on following 
morbidity and neurodevelopment for a miniumum of 24 months up to 5 years following 
exposure to retosiban or comparator medication. Participating infants and children will 
have the benefit of access to developmental screening (Ages and Stages Questionnaire-3 
[ASQ-3], Child Behavior Checklist for Ages 1.5 to 5 [CBCL/1.5–5], and the Modified 
Checklist for Autism in Toddlers–Revised with Follow-Up [M-CHAT-R/F]), which may 
not be routinely provided and will allow parents/legal guardians to monitor and track the 
infant’s child’s developmental milestones in a formalized manner. In addition, screening 
results may be shared with the infant’s child’s physician (health care providers [HCPs] or 
other) as requested by the parent/legal guardian. In the event a potential issue is identified 
and further follow-up is warranted, the infant child will be referred to developmental 
specialists/qualified assessors for further evaluations as part of this study. In this manner, 
neurodevelopmental issues may be identified earlier than would have been normally.
Section 1.3.3., Overall Benefit:Risk Conclusion
For detailed information on the identified risks and benefit:risk assessment of retosiban, 
refer to the IB and IB Supplement 1 [GlaxoSmithKline Document Number 
CM2006/00201/03; GlaxoSmithKline Document Number 2015N228508_00]. The 
overall benefit:risk assessment of retosiban appears favorable for the mother and 
fetus/infant. Although, experience in pregnant women is limited, no clinical or preclinical 
safety issues have been identified that preclude further development.
Section 2, Objectives
The study objective is to assess the safety and outcomes in infants and children who 
were exposed to retosiban or comparator in the Phase III SPTL treatment studies. Table 1
summarizes the specific study objectives and the corresponding endpoints, which are 
described in detail in Section 6.2 (Safety) and Section 6.3 (Health Outcomes).
 
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Objective
Endpoints
To characterize the clinical safety in terms of infant 
and child morbidity and mortality in infants and 
children exposed to retosiban or comparator in 
utero

Proportion of infants and children with newly diagnosed 
(after 28 days post EDD) chronic medical conditions by type 
of condition will be recorded and include the following:

Respiratory conditions
o
Chronic lung disease
o
Reactive airway disease
o
Vocal cord paralysis
o
Airway obstruction 

Neurological conditions
o
Cerebral palsy
o
Seizure disorder
o
Hydrocephalus requiring shunt

Sensory conditions
o
Vision
o
Vision impairment
o
Blindness in 1 or both eyes, or sees light 
only
o
Hearing 
o
Hearing impairment
o
Deafness in 1 or both ears
o
Hearing impaired, uncorrected even with 
aids

Gastrointestinal conditions
o
GERD (moderate to severe)
o
Tube/parenteral feeding 
o
Short bowel syndrome

Cardiovascular conditions
o
Pulmonary hypertension
o
Hypertension

Renal conditions
o
Renal impairment requiring dialysis

Growth parameters (only up to 24 months 
chronological age)
o
Poor weight gain
o
Reduced length
o
Reduced head circumference
o
Failure to thrive

Proportion of infants and children with newly diagnosed 
(after 28 days post EDD) congenital anomalies

Proportion of neonatal and infant and child deaths that 
occur after 28 days post EDD and until the end of the study
 
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Objective
Endpoints
To characterize the clinical safety in terms of 
neurodevelopment in infants and children 
exposed to retosiban or comparator in utero

Neurodevelopment endpoints assessed at ages 9, 18, and 
24 months, corrected for prematurity:

Proportion of infants with an ASQ-3 score in the black 
zone in any domain

Proportion of infants with an ASQ-3 score in the black 
zone for gross motor skills

Proportion of infants with an ASQ-3 score in the black 
zone for fine motor skills

Proportion of infants with an ASQ-3 score in the black 
zone for communication

Proportion of infants with an ASQ-3 score in the black 
zone for problem-solving

Proportion of infants with an ASQ-3 score in the black 
zone for personal-social skills

Proportion of infants referred for developmental 
evaluation (using BSID-III)

Proportion of infants with a BSID-III score <>2 SDs 
below the mean score for the cognitive scale (<70)

Proportion of infants with BSID-III score <>2 SDs 
below the mean score for the gross motor scale (<70)

Proportion of infants with BSID-III score <>2 SDs 
below the mean score for the fine motor scale (<70)

Proportion of infants with a BSID-III score <>2 SDs 
below the mean score for the language scale (<70)

Proportion of infants referred for an additional 
behavioral assessment using the CBCL/1.5-5 and 
M-CHAT-R/F

Proportion of infants with a CBCL/1.5-5 score at or
above the 97th percentile for a subset of prespecified 
questions that relate to attention and hyperactivity 
problems

Proportion of infants indicated as needing further 
evaluation after completion of the M-CHAT-R/F

Proportion of infants referred for neurological 
evaluation to determine diagnosis of cerebral palsy

Proportion of infants with at least 1 of the following 
indicators of neurodevelopmental impairment at the end of 
the study:

Hearing impaired, uncorrected even with aids (at 
24 months chronological age)

Blindness in 1 or both eyes, or sees light only (at 
24 months chronological age)

Cerebral palsy (moderate and severe) (at 24 months 
corrected age)

Cognitive impairment: BSID-III Cognitive Scale Score 
of <>2 SDs below mean score (<70) (at 24 months 
corrected age)

Motor impairment: BSID-III Motor Composite Scale 
Score of <>2 SDs below mean score (<70) (at 
24 months corrected age)
 
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Objective
Endpoints

Proportion of infants and children with at least 1 of the 
following indicators of neurodevelopmental impairment 
at the end of the study:

Hearing impaired, uncorrected even with aids 

Blindness in 1 or both eyes, or sees light only

Cerebral palsy (moderate and severe)

Diagnosis of ASD, ADD, or ADHD
To characterize parental productivity loss related 
to a sick child and infant resource utilization in 
terms of hospital admissions, length of stay, 
ER/UC visits, surgical procedures, and referral to 
specialty care or therapy visits for infants (up to 
age 2 years) exposed to retosiban or comparator 
in utero

Number of hospital admissions, proportion of infants and 
children with any hospital admission, post-birth 
hospitalization discharge, by principal and secondary 
discharge diagnosis, type of hospital unit admitted to (e.g., 
NICU, Pediatric, PICU, Nursery level 3, ICU), and length of 
hospital stay per unit after 28 days post EDD and until the 
end of the study.

Combined length of hospital stay in days for all hospital 
admissions (for infants discharged from the delivery 
hospitalization and for babies who were never discharged 
home post-delivery) after 28 days post EDD and until the 
end of the study.

Number of surgical procedures (by details of type and 
whether performed on an inpatient basis or at an 
outpatient/surgical center will be collected up to 
24 months chronological age only) after 28 days post 
EDD and until the end of the study.

Number of ER/UC visits and proportion of infants with any 
ER/UC visit after 28 days post EDD and up to 24 months 
chronological age.

Number of specialty care or therapy visits and proportion of 
infants referred for specialty care or therapy by type of 
care/therapy after 28 days post EDD and up to 24 months
chronological age.

Parental productivity loss related to infant hospital 
admissions, ER/UC visits, or specialist care after 28 days 
post EDD and up to 24 months chronological age.
ADD = attention deficit disorder; ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum 
disorder; ASQ-3 = Ages and Stages Questionnaire-3; BSID-III = Bayley Scales of Infant Development, third 
edition; CBCL/1.5-5 = Child Behavior Checklist for Ages 1.5 to 5; EDD = estimated date of delivery; ER/UC = 
emergency room/urgent care; GERD = gastroesophageal reflux disease; ICU = intensive care unit; M-CHAT-R/F 
= Modified Checklist for Autism in Toddlers-Revised with Follow-Up; NICU = neonatal intensive care unit; PICU = 
pediatric intensive care unit.
Section 3.1., Study Design
This ARIOS is a long-term infant and child follow-up study that will prospectively 
assess safety and outcomes of all infants and children born to women who received at 
least 1 dose of retosiban or comparator in any of the Phase III SPTL treatment studies. . . 
. The infant will be able to be consented into the study until the later date of either the 
date of discharge from the birth hospitalization or up to 9 months corrected age. Infants 
will be followed at prespecified intervals until they have reached 5 years chronological 
age 24 months corrected age for preterm infants (i.e., an infant born 3 months preterm 
will complete the final 24 month study questionnaire at 27 months chronological age) and 
24 months chronological age for term infants. . . . Infants and children will be followed 
 
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at prespecified intervals until they reach 5 years chronological age (see Table 2). This 
study does not require medical interventions or study visits to an investigational site. 
Instead, parents or legal guardians will be prompted at certain time points to complete 
developmental questionnaires and other data on their children’s health status via an 
electronic device. Data collected during the infant this follow up study will be managed 
by a centralized RCC. Regionally based pediatricians will serve as study principal 
investigators (referred to as RCC-PIs) for this study. All communications the RCC-PI has 
with the parent/legal guardian or the infant’s child’s HCP will occur remotely; there will 
be no clinic visits. An overview of the study design is shown in Figure 1.
Figure 1, Study Design
Electronic data capture (eDC) tools and processes including electronic case report forms 
(eCRF) and electronic patient-reported outcome devices will allow entry of data, 
regardless of when it is obtained. If at any time the data suggest any developmental delay 
of an infant, the RCC-PI will refer the infant child to a specialist (if not already under the 
care of a specialist) for formal evaluation and additional assessments. The infant’s child’s 
local primary care pediatric provider will be asked to provide routinely available data on 
the infant child to the RCC. Additional contacts may occur at the discretion of the RCC 
personnel to complete the data collection. 
The infant's child parent/legal guardian will be asked to complete the CHI at 2, 6, 9, 12, 
15, 18, 21, and 24 months of the child’s chronological age and a modified CHI at 3, 4, 
and 5 years of the child’s chronological age. The CHI questionnaire completed up to 
the 24-month time point will screen for infant mortality and morbidity and will capture 
data on resource utilization. At the 3-, 4-, and 5-year time points, the CHI will screen 
for child mortality and morbidity, including any indicators of neurodevelopmental 
impairment. If the parent/legal guardian indicates that the child has been newly 
diagnosed (after 28 days post EDD) with chronic conditions or congenital anomalies 
 
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follow up will be undertaken with the applicable HCP to confirm the parent/legal 
guardian report. Persistence or resolution of conditions will be determined in subsequent 
questionnaires after the initial report. If protocol specific evaluations are in progress at 
the end of the child’s protocol defined participation in this study (24 months corrected 
age for preterm infants or 24 months 5 years chronological age for term infants) and 
results have not yet been received or reported, the time period may be extended to collect 
those reports.
If the parent/legal guardian indicates that the child has had any emergency room/urgent 
care (ER/UC) visits, he/she will be asked to record the number of visits and to indicate if 
the visit resulted in hospitalization. If the parent/legal guardian indicates that the infant
child has been hospitalized or has had any surgeries, medical records from the applicable 
medical facility will be obtained and abstracted for pertinent details, including principal 
and secondary discharge diagnoses, type of hospital unit admitted to (e.g., neonatal 
intensive care unit [NICU], Pediatrics, pediatric intensive care unit [PICU], Nursery 
level 3, ICU), and length of stay. If the parent/legal guardian indicates that the infant
child died after 28 days post EDD, details of the death will be obtained from the death 
certificate or appropriate HCP or medical records if the death certificate is not available. 
Note that all infant deaths that occur before 28 days post EDD will be captured and 
reported as part of the Phase III SPTL treatment studies.
During the first 24 months of participation in the study, Iif the parent/legal guardian 
indicates that the infant has been treated by specialists or has had ER/UC visits or 
hospitalizations, he/she will be asked to complete a productivity questionnaire to evaluate 
loss of parental productivity.
To screen for developmental issues, the parent/legal guardian will be asked to complete 
the 9-, 18-, and 24-month ASQ-3 when the infant’s corrected age corresponds to 9, 18, 
and 24 months, for example, parents/legal guardians of an infant born 3 months 
premature will complete the 9-month ASQ-3 at 12 months chronological age. Any child 
who scores in the black zone (2 SD below the mean) (see Section 6.2.5.1) in any of the 
5 domains of the ASQ-3 will be referred to a qualified assessor for a developmental 
evaluation (e.g., using the Bayley Scales of Infant Development, third edition 
[BSID-III]), and a neurologic examination will be conducted, if indicated. An overall 
assessment of delay in the areas of communication, gross and fine motor, 
problem-solving, and personal-social development will be rendered. As part of normal 
management, some infants may already have undergone a formal developmental 
evaluation using the BSID-III; in these cases, if testing was recent (3 months), the 
BSID-III will not be repeated and RCC-PI will request results from the relevant HCP. 
BSID-III retesting will be requested if the child’s ASQ-3 scores are in the black zone on a 
subsequent ASQ-3 test following the first BSID III referral. Based on results from the 
ASQ-3 administered at 24 months corrected age, parents/legal guardians may be asked to 
complete the Child Behavior Checklist for Ages 1.5 to 5 (CBCL/1.5–5) and the Modified 
Checklist for Autism in Toddlers–Revised with Follow-Up (M-CHAT-R/F) to assess the 
risk for other behavioral problems or autism spectrum disorder or, alternatively, and if no 
cerebral palsy diagnosis has been made to date, the infant may be referred to a 
qualified examiner for a formal assessment of cerebral palsy.
 
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The Modified Checklist for Autism in Toddlers–Revised with Follow-Up 
(M-CHAT-R/F) will be completed for all infants at 18 and 24 months (corrected 
age) and the Child Behavior Checklist for Ages 1.5 to 5 (CBCL/1.5–5) will be 
completed for all infants at 24 months (corrected age) to assess the risk for other 
behavioral problems or autism spectrum disorder (ASD). If at any of these time 
points a child has an M-CHAT-R/F score that indicates further evaluation is 
required and/or a CBCL/1.5–5 score at or above the 97th percentile for a subset of 
prespecified questions, the child will be referred to a specialist for a formal 
assessment.
Section 3.2., Discussion of Design
Longitudinal infant outcome studies are often fraught with a high rate of loss to follow up 
that can introduce ascertainment bias [Callanan, 2001; Tin, 1998]. The design of this 
study takes into account the operational and practical challenges involved in retaining 
infants, especially those who may have a diverse set of outcomes due to varying 
gestational age at birth. Rather than requiring visits for formal outcome interviews and 
assessments of the infants and children, parent/legal guardian-reported outcomes will be 
the first-line source of health and developmental information, and parents will record data 
using an eDC system to allow entry of data regardless of where it is obtained. The child’s 
primary HCP will be asked to provide data when the parent/legal guardian reports a 
chronic condition, birth defect, genetic condition or syndrome; or a change in a 
previously reported condition. If the child’s primary HCP is unable to provide the 
information, another relevant HCP involved with the care of the infant child will also be 
asked to provide data. All congenital anomalies will be reviewed by an expert in 
teratology who is engaged by the RCC-PI to serve as the birth defect evaluator.
Studies have affirmed that parents are a reliable source of information regarding their 
infant’s child’s health and development. The validity of parental reports of infant and 
child hospital admissions and chronic health conditions has been shown to be high 
[Spencer, 2000]. Likewise, it has been demonstrated with validated tools such as the 
ASQ-3 that parents’ observations are useful in performing developmental screening 
[Squires, 1998; Rydz, 2005]. Using the parents/legal guardians as first-line reporters will 
ensure the quality of data and enhance long-term retention in the safety follow-up. 
Furthermore, because parents tend to spend more time with their infants child than 
anyone else, their assessments are likely to be reliable. To guard against reporting bias, 
the parent/legal guardian, infant’s child’s HCPs, and all study staff will be masked until 
completion of the follow-up study with respect to the mother/ infant’s child’s Phase III 
SPTL treatment assignment (see Section 5.3).
Section 4.2, Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB and IB Supplement 1
[GlaxoSmithKline Document Number CM2006/00201/03; GlaxoSmithKline Document 
Number 2015N228508_00].
 
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Section 4.4., Withdrawal Criteria
An infants child may be withdrawn from the study due to loss to follow-up or if the 
infant’s child’s parent/legal guardian voluntarily withdraws consent. All data collected 
up to the time of withdrawal will be included in the analysis. If a parent/legal guardian 
fails to complete an assessment, but wishes to remain in the study, they will be allowed to 
continue by completing future assessments.
Section 5.1., Investigational Product and Other Study Treatment
This is a safety follow-up study of infants and children exposed to treatment during their 
mother’s participation in a Phase III SPTL treatment study of retosiban or comparator for 
SPTL. Infants and children enrolled in this study will not be administered any 
investigational product.
Section 5.2., Treatment Assignment
The Phase III SPTL treatment study treatment group and strata to which mothers were 
assigned will be maintained during analysis of data from the infant child follow-up study.
Section 5.3, Blinding
The parent/legal guardian, infant child, the infant’s child’s HCPs, and all study personnel 
(from this study) will remain blinded to the treatment the mother received in the Phase III 
SPTL study and will remain blinded throughout the duration of this infant child
follow-up study.
The infant child will be given a new subject identification number at the start of this 
follow-up study. The infant’s child’s subject identification number from the Phase III 
SPTL treatment.
The RCC-PI or treating physician may unblind an infant’s 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 RCC-PI. 
The RCC-PI must first discuss options with GSK/PPD medical monitor or appropriate 
GSK/PPD study personnel before unblinding the infant’s treatment assignment. The PPD 
unblinded 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.
GSK’s Global Clinical Safety and Pharmacovigilance department may unblind the 
treatment assignment for any infant with an SAE. The PPD medical monitor may unblind 
the treatment assignment after discussing the rationale for unblinding with the RCC-PI. 
Notification of unblinding will be sent to GSK, PPD, and the RCC site.
 
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This protocol will be filed to the Investigational New Drug Application of the United 
States. Serious AEs requiring an expedited investigational new drug safety report 
(blinded for investigational drug treatment) will be sent to all participating RCC-PIs. 
Further reporting to RCC-PIs or regulatory authorities will be performed in accordance 
with local regulations. 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 RCC-PIs in accordance with local regulations and/or GSK 
policy.
RCC-PIs have direct access to the subject’s individual study treatment by 
contacting a designated PPD unblinded safety specialist via the SAE 24-Hour Safety 
Hotline; the designated unblinded safety specialist will perform the emergency 
unblinding and inform the RCC-PI of the mother’s treatment assignment (refer to 
the SPM for details). 
It is preferred (but not required) that the RCC-PI first contact the PPD medical 
monitor to discuss options before unblinding the subject’s treatment assignment. 
After the subject has been unblinded, the investigator should not reveal the 
treatment assignment to the PPD medical monitor unless that information is 
important for the safety of subjects currently enrolled in the study (refer to the SPM 
for details). 
The date and reason for the unblinding must be fully documented in the eCRF.
Section 6, Study Assessments and Procedures
The infant’s child’s parent/legal guardian will be the primary data reporter to the study. 
Confirmation of key study endpoints will be obtained from applicable HCPs or health 
care facilities. The infants and children will be followed beginning from after 28 days 
post EDD and until 24 months corrected age (for preterm infants) or 24 months 5 years
chronological age (for term infants). Baseline characteristics and demographic data will 
be captured from the Phase III SPTL treatment studies and combined with infant child
follow-up data for analyses. Refer to Table 2 for a summary of data points to be collected 
and the time frame for assessment.
The time points for parent-completed questionnaires are scheduled to maintain the 
participant’s interest in study continuation and minimize losses to follow up. 
Questionnaires will be associated with the infant’s child’s age; in some cases the age will 
be chronological and in other cases, it will be corrected for prematurity. The timing of the 
first questionnaire is scheduled to begin at 2 months chronological age and end at 24 
months corrected age (for preterm infants) or 24 months 5 years chronological age (for 
term infants). Contingent on the infant’s chronological age at the time of entry into the 
follow up study, all of the questionnaires may not be completed for each participant. The 
SPM will provide explicit details on study procedures to ensure proper timing of 
questionnaires.
 
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Table 2
Time and Events Table
Event
28 Days Post 
EDD
Months
Years1
2
6
9
12
15
18
21
24
3
4
5
Written informed consent12
Baseline characteristics and demographic data
X23
RCC confirms and updates contact information from 
the parent/legal guardian
X
Parent/legal guardian completes CHI34
X
X
X
X
X
X
X
X
X34
X34
X34
RCC-PI follows up with HCP and reviews medical or 
other records to confirm parent-reported outcomes
RCC-PI reviews CHI results and refers to birth-defect 
evaluator based on results
Parent/legal guardian completes productivity 
questionnaire45
Parent/legal guardian completes ASQ-356
X56
X56
X56
RCC-PI reviews ASQ-3 results and refers for 
developmental evaluation based on results67
Parent/legal guardian completes M-CHAT-R/F78
X
X
Parent/legal guardian completes CBCL/1.5–578
X
RCC-PI refers child to specialist for cerebral palsy 
assessment (if required) 89
X
ASQ-3 = Ages and Stages Questionnaire-3; CBCL/1.5–5 = Child Behavior Checklist for ages 1.5 to 5; CHI = Child Health Inventory; EDD = estimated date of delivery; HCP = health 
care provider; M-CHAT-R/F = Modified Checklist for Autism in Toddlers-Revised with Follow-Up; RCC = research coordinating center; RCC-PI = research coordinating center-
principal investigator.
Note:  All specified completion windows for applicable questionnaires (CHI, ASQ-3, CBCL/1.5–5, M-CHAT-R/F, and productivity) are provided to help standardize the data and avoid 
overlap. Information captured outside of these windows will be collected and analyzed separately, and questionnaires completed outside the completion window will not be 
considered protocol deviations.
1.
Assessments performed at years 3, 4, and 5 are based on the child’s chronological age.
12. Collected at the start of the Phase III spontaneous preterm labor (SPTL) treatment studies until the later date of either the date of discharge from the birth hospitalization or up to 
9 months corrected age (to allow for the infant’s 9-month CHI and ASQ-3 data collection).
23. Captured in Phase III SPTL treatment studies and combined with infant child follow-up data for analyses.
34. A positive response by the parent/legal guardian may trigger follow-up with the relevant HCP and/or medical record review for confirmation or more details on the condition or 
hospitalization. A modified CHI will be completed at 3, 4, and 5 years of the child’s chronological age. At each time point, the completion window of the CHI is +6 weeks.
 
 
 
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45. Completed if infant has been treated by a specialist or has had an emergency room/urgent care or hospital visit. The completion window for the productivity questionnaire is +2 
weeks from the date of completion of the relevant CHI.
56. Based on infant’s corrected age. The completion window for the ASQ-3 is +30 days at Month 9 and ±30 days at Months 18 and 24.
67. If the parent/legal guardian receives a referral, then a qualified specialist will complete required assessments.
78. The CBCL/1.5–5 and M-CHAT-R/F questionnaires will only be completed for all infants who score in the black zone on the 24 month corrected age ASQ-3 in any of the following 
domains: communication, problem solving, or personal social scale. The completion window for the CBCL/1.5–5 and M-CHAT-R/F is +6 weeks at 18 months (M-CHAT-R/F only)
and +12 weeks at 24 months. 
89. Referral will be made for infants who score in the black zone for the gross motor skills domain on the 24-month corrected age ASQ-3 and do not have an existing diagnosis of 
cerebral palsy.
 
 
 
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Section 6.1., Critical Baseline Assessments
The final assessment of the Phase III SPTL treatment studies will occur at 28 days post 
EDD when neonatal morbidity assessments are collected. Select data from this 
assessment will serve as baseline data for this study, in addition to data collected from the 
maternal medical record and newborn medical record during the Phase III SPTL 
treatment studies. These data will be transferred in a blinded manner from the Phase III 
SPTL database to the infant child follow-up study database.
At Baseline, the Phase III SPTL treatment study investigator will obtain updated contact 
information from the parent/legal guardian; contact information will also be collected for 
at least 1 additional person (as described in the SPM) to minimize the number of infants 
and children lost to follow-up.
Section 6.2.1., Morbidity and Mortality Endpoints
The main objective of the study is to characterize the clinical safety in terms of infant 
morbidity and mortality in infants and children exposed to retosiban or comparator 
during the Phase III SPTL treatment studies. The morbidity endpoints will be assessed at 
2, 6, 9, 12, 15, 18, 21, and 24 months and 3, 4, and 5 years of the child’s chronological 
age. Based on the discretion of the RCC-PI, medical records may need to be obtained 
from the applicable medical facility for any infants who have not yet been discharged 
from their birth hospitalization (see Section 6.2.1.1.1 and Section 6.3).
Section 6.2.1.1., Parent/Legal Guardian-Completed Child Health Inventory
The child’s parent/legal guardian will be asked to complete the CHI at 2, 6, 9, 12, 15, 18, 
21, and 24 months of the child’s chronological age and a modified CHI at 3, 4, and 5 
years of the child’s chronological age. At each time point, the completion window is +6 
weeks; however, CHI questionnaires completed outside the completion window will not 
be considered a protocol deviation.
The CHI will be administered at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s 
chronological age will to screen for infant mortality and morbidity and to capture data on 
resource utilization. At 3, 4, and 5 years of the child’s chronological age, the CHI will 
screen for child mortality and morbidity, including any indicators of 
neurodevelopmental impairment. To facilitate data collection, parents/legal guardians 
will be provided with an electronic device that will enable them to provide the protocol 
required data. They will have the option to use alternative ways to access the same 
system (e.g., their own personal devices). Further details will be provided in the SPM.
. . .
At the initial completion of the CHI, the parent/legal guardian will be asked about all 
morbidity and mortality endpoints and, if required based on the child’s age, the 
resource utilization endpoints. At subsequent completions of the CHI, up to 24 months 
chronological age, the parent/legal guardian will be asked the status of previously 
reported conditions (e.g., worse, better, or resolved), as appropriate. They will also be 
 
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asked if any of the other morbidity and mortality endpoints and resource utilization 
endpoints, as required, have occurred since the last assessment.
 
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Figure 2
Child Health Inventory: Flow Chart of Data Collection and Review
HCP = health care provider; RCC-PI = research coordinating center-principal investigator.
1.
The CHI completed at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age will screen for infant mortality and morbidity and capture data on resource 
utilization. At 3, 4, and 5 years of the child’s chronological age, the CHI will screen for child mortality and morbidity, including any indicators of neurodevelopmental 
impairment.
 
 
 
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Section 6.2.2., Chronic Medical Conditions
The proportion of infants and children with newly diagnosed (after 28 days post EDD) 
chronic medical conditions by type of condition will be recorded.
Section 6.2.2.1., Respiratory Conditions
Respiratory conditions will include the following:

Chronic lung disease newly diagnosed (after 28 days post EDD) defined as 
increased oxygen requirements (i.e., any increase in previously documented O2
use, and/or a change to how the child receives supplemental O2)

Reactive airway disease, defined as a chronic lung condition associated with 
inflammation of the airways associated with wheezing and requiring episodic 
ongoing treatment with bronchodilators and/or inhaled or systemic steroids

Paralyzed vocal cords, defined as impairment of the vocal cords that result in 
acute or chronic respiratory compromise or abnormalities in the infant’s voice

Airway obstruction
Section 6.2.2.2., Neurological Conditions
Neurological conditions will include the following:

Cerebral palsy, defined as a chronic, nonprogressive neurologic disorder 
encompassing impaired motor function affecting movement, posture, balance 
muscle control, coordination, tone, or reflexes.

Seizure disorder, defined as episodic occurrence of seizure activity requiring 
ongoing anticonvulsant therapy

Hydrocephalus requiring shunt, defined as abnormal accumulation of 
cerebrospinal fluid in the ventricles of the brain requiring permanent shunt 
placement to prevent irreversible neurologic sequelae

ASD, defined as a neurodevelopmental disorder that impairs a child’s 
ability to communicate and interact with others

Attention deficit disorder (ADD), defined as a disorder of attention, 
organization, and impulse control, characterized by a persistent pattern of 
impulsiveness and a short attention span.

Attention deficit disorder with hyperactivity (ADHD), defined as ADD with 
the addition of hyperactive behavior

Learning difficulties, defined as a significantly reduced ability to 
understand new or complex information or to learn new skills

Behavior disorders, defined as a general term to denote behavioral 
dysfunction that do not fall under the category of ADD or ADHD
 
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Section 6.2.2.7. Growth Parameters
Growth parameters will be assessed only up to 24 months chronological age and will
include the following:
Section 6.2.3., Congenital Anomalies
When a congenital anomaly is reported, it will be reviewed by an expert in teratology 
who is engaged by the RCC-PI to serve 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 from the infant’s child’s 
HCP in making the evaluation and issue targeted queries to the HCP when necessary. If 
medical data are deemed insufficient to complete the evaluation, the birth defect 
evaluator may ask that the RCC-PI request additional medical evaluation of the infant
child. 
Section 6.2.4., Neonatal and Infant and Child Deaths
This study will assess the proportion of neonatal and infant and child deaths that occur 
after 28 days post EDD and up to 24 months corrected age for preterm infants and 24 
months 5 years chronological age for term infants.
Section 6.2.5., Parent/Legal Guardian-Completed ASQ-3, M-CHAT-R/F, and 
CBCL/1.5–5 and Possible Referral to a Specialist
The 9-, 18-, and 24-month ASQ-3 questionnaires will be used in this study. These time 
points comply with recommended developmental screening assessment guidelines from 
the American Academy of Pediatrics [Council on Children with Disabilities, 2006]. The 
parent/legal guardian will be asked to complete the 9-, 18-, and 24-month ASQ-3 when 
the infant’s corrected age corresponds to 9, 18, and 24 months, for example, parents/legal 
guardians of an infant born 3 months premature will complete the 9-month ASQ-3 at 12 
months chronological age. To facilitate data collection, the parent/legal guardian will be 
provided with an electronic device that will enable them to provide the protocol required 
data. They will have the option to use alternative ways to access the same system (e.g., 
their own personal devices). Further details will be provided in the SPM. The completion 
window for the ASQ-3 is +30 days at Month 9 and ±30 days at Months 18 and 24; 
however, questionnaires completed outside the completion window will not be 
considered a protocol deviation. It is essential to make age adjustments for prematurity 
when selecting the appropriate ASQ-3. Based on results from the ASQ-3 administered at 
24 months corrected age and if no cerebral palsy diagnosis has been made to date (see 
Section 6.2.5.1) parents/legal guardians may be asked to complete the CBCL/1.5–5 and 
the M-CHAT-R/F to assess the risk for other behavioral problems or autism spectrum 
disorder or, alternatively, the infant may be referred to a qualified examiner for a formal 
assessment of cerebral palsy.
The M-CHAT-R/F will be completed for all infants at 18 and 24 months (corrected 
age) and the CBCL/1.5–5 will be completed for all infants at 24 months (corrected 
 
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age) to assess the risk for other behavioral problems or ASD. If at any of these time 
points a child has an M-CHAT-R/F score that indicates further evaluation is 
required and/or a CBCL/1.5–5 score at or above the 97th percentile for a subset of 
prespecified questions, the child will be referred to a specialist for a formal 
assessment. An overview for the collection and review of data for the M-CHAT-R/F 
and CBCL/1.5–5 is provided in Figure 3.
The completion window for the CBCL/1/5-5 and M-CHAT-R/F is +6 week at 
18 months (M-CHAT-R/F) and +12 weeks at 24 months; however, questionnaires 
completed outside the completion window will not be considered a protocol deviation.
For further details regarding the CBCL/1.5–5 and M-CHAT-R/F, refer to the SPM.
Section 6.2.5.1., The ASQ-3 Score Interpretation and Possible Specialist Referral 
Recommendations and Completion of CBCL/1.5-5 and M-CHAT-R/F
The ASQ-3 scores for this study will be interpreted and recommendations will be offered 
according to the following:

The child’s development will be considered to be on schedule if the child’s 
ASQ-3 scores are in the white zone (higher than 1 SD below the mean), and no 
further action is required.

If the child’s ASQ-3 scores are in the grey zone (1 SD below the mean), the 
parent/legal guardian may share the ASQ-3 test results with the child’s HCP.

If any of the child’s ASQ-3 scores are in the black zone (2 SD below the 
mean), then the child’s parent/legal guardian will be asked if the child is already 
under the care of a developmental specialist who can or has made a formal 
assessment (e.g., using the BSID-III). If a recent (3 months) BSID-III was 
conducted, the BSID-III will not be repeated and the RCC-PI will request results 
from the relevant HCP. If the child is not currently under the care of a 
developmental specialist, then the parent/legal guardian will be referred to a 
qualified assessor for developmental evaluation (e.g., using the BSID-III), and a 
neurologic examination will be conducted, if indicated. 

BSID-III retesting will be performed if the child’s ASQ-3 scores are in the black 
zone on a subsequent ASQ 3 test following the first BSID-III referral.

If, at 24 months corrected age, the child’s ASQ-3 nonmotor (communication, 
problem solving, and/or personal-social) domain scores are in the black zone, 
the parent/legal guardian will be asked to fill out the CBCL/1.5–5 and 
M-CHAT-R/F questionnaires. If the results of either assessment indicate an 
increased risk for other behavioral problems or autism spectrum disorder, the 
parent/legal guardian will be referred to a developmental specialist for a more 
formal behavioral assessment.

If, at 24 months corrected age, the child’s ASQ-3 gross motor domain score is in 
the black range and the child has not already been diagnosed with cerebral palsy, 
 
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the parent/legal guardian will be referred to a qualified examiner for a formal 
assessment to determine if this condition is present.
Reports from all specialists will be included in the subject’s source documents. For 
further details regarding the ASQ-3, CBCL/1.5–5, and M-CHAT-R/F, refer to the SPM.
An overview for the collection and review of data for the ASQ-3 is provided in Figure 3.
 
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Figure 3
Ages and Stages Questionnaire-3 ASQ-3, M-CHAT-R/F, and CBCL/1.5–5: Flow Chart of Data Collection and Review
NOTE:  Because of the number of changes to Figure 3 and in order to provide a clear representation of the changes to this figure, the 
figure in original protocol (2014-MAY-14) and revised figure in Amendment 1 are shown below.
Original Figure:
ASQ-3 = Ages and Stages Questionnaire-3; BSID-III = Bayley Scales of Infant Development, third edition; CBCL/1.5–5 = Child Behavior Checklist for ages 1.5 to 5; HCP = health care 
provider; M-CHAT-R/F = Modified Checklist for Autism in Toddlers-Revised with Follow-Up; RCC-PI = research coordinating center-principal investigator.
1.
A neurologic examination will also be conducted, if indicated.
 
 
 
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New Figure:
ASQ-3 = Ages and Stages Questionnaire-3; BSID-III = Bayley Scales of Infant Development, third edition; CBCL/1.5–5 = Child Behavior Checklist for ages 1.5 to 5; HCP = health care 
provider; M-CHAT-R/F = Modified Checklist for Autism in Toddlers-Revised with Follow-Up; RCC-PI = research coordinating center-principal investigator.
1.
A neurologic examination will also be conducted, if indicated.
 
 
 
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Section 6.2.5.2., Neurodevelopment
Neurodevelopment will be assessed by determining the proportions of infants diagnosed 
with developmental delays listed below at 9, 18, and 24 months of age, corrected for 
prematurity.

Proportion of infants with a BSID-III score <>2 SDs below the mean score for 
cognitive impairment (<70)

Proportion of infants with a BSID-III score <>2 SDs below the mean score for 
the gross motor scale (<70)

Proportion of infants with a BSID-III score <>2 SDs below the mean score for 
the fine motor scale (<70)

Proportion of infants with a BSID-III score <>2 SDs below the mean score for 
the language scale (<70)

Proportion of infants referred for an additional behavioral assessment using the 
CBCL/1.5-5 and M-CHAT-R/F

Proportion of infants with a CBCL/1.5–5 at or above the 97th percentile for a 
subset of prespecified questions that relate to attention and hyperactivity 
problems

Proportion of infants indicated as needing further evaluation after completion of 
the M-CHAT-R/F

Proportion of infants referred for neurological evaluation to determine diagnosis 
of cerebral palsy
Section 6.2.6., Overall Measure of Neurodevelopmental Impairment

Proportion of infants with at least 1 of the following indicators of 
neurodevelopmental impairment at the end of the:

Hearing impaired, uncorrected even with aids (at 24 months chronological 
age)

Blindness in 1 or both eyes, or sees light only (at 24 months chronological age)

Cerebral palsy (moderate defined as grade 2 or 3 and severe defined as grade 4 
or 5 using the Gross Motor Functional Classification System [GMFCS]) (at 
24 months corrected age)

Cognitive impairment: BSID-III Cognitive Scale Score of >2 SDs below mean 
score (<70) (at 24 months corrected age)

Motor impairment: BSID-III Motor Composite Scale Score of >2 SDs below 
mean score (<70) (at 24 months corrected age)
 
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
Proportion of infants and children with at least 1 of the following indicators of 
neurodevelopmental impairment at the end of the study:

Hearing impaired, uncorrected even with aids

Blindness in 1 or both eyes, or sees light only

Cerebral palsy (moderate and severe)

Diagnosis of ASD, ADD, or ADHD
Section 6.2.7., Adverse Events
The RCC-PI or RCC site staff will be responsible for detecting, documenting, and 
reporting events that meet the definition of an SAE. Nonserious AEs will not be tracked.
The outcomes for this study may represent a number of potential adverse drug 
experiences or events that include but may not be limited to the following:

Reports of infant child hospitalizations (see Section 6.3)

Reports of chronic health conditions in the infant child (see Section 6.2.2)

Reports of congenital anomalies in the infant child (see Section 6.2.3)

Reports of infant child death (see Section 6.2.4)

Reports of developmental delays in the infant child (see Section 6.2.5.2)

Reports of any other SAEs in the infant child for which there is a definite or a 
reasonable possibility of attribution to retosiban or comparator exposure (see Section 
6.2.7.2)
Section 6.2.8., Laboratory and Other Safety Assessment Abnormalities Reported as 
SAEs
Any nonprotocol-specified abnormal laboratory test results (hematology, clinical 
chemistry, or urinalysis) or other safety assessments (e.g., electrocardiograms, 
radiological scans, vital sign measurements), including those that worsen from Baseline, 
felt to be clinically significant in the medical and scientific judgment of the RCC-PI are 
to be recorded as SAEs. However, any clinically significant safety assessments that are 
associated with the underlying disease, unless judged by the RCC-PI to be more severe 
than expected for the subject’s condition, are not to be reported as SAEs.
Section 6.2.10., Death Events
The proportion of infant deaths that occurred after 28 days post EDD and up to 24 
months corrected age (for preterm infants) or 24 months 5 years chronological age (for 
term infants) will be collected.
 
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Section 6.2.11., Time Period and Frequency of Detecting SAEs
The RCC-PI or RCC site staff is responsible for detecting, documenting, and reporting 
events that meet the definition of an SAE.
Infant Child SAEs will be collected from after 28 days post EDD until 24 months 
corrected age for preterm infants and 24 months 5 years chronological age for term 
infants. However, 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 
concomitant medication, will be recorded from the time a subject consents to participate 
in the study up to the end of the study, i.e., month 24. All SAEs will be reported to 
GSK/PPD within 24 hours, as indicated in Section 6.2.12.
Section 6.2.13., Follow-up of SAEs
Any SAEs or AEs of special interest that were ongoing at the end of the Phase III 
treatment studies and any new SAEs reported during this study will be followed 
until resolution, until the condition stabilizes, until the event is otherwise explained, 
or until the subject is lost to follow-up.
Section 6.2.15.2., Ad Hoc Maternal Reports
It is possible that during contact with the study staff (RCC staff or RCC-PI), the mother 
of the infant child being followed in this study may report her own AEs/SAEs resultant 
from retosiban or comparator treatment from Phase III SPTL treatment studies in an ad 
hoc manner to the RCC study staff or the RCC-PI. The RCC-PI will be responsible for 
conveying such events to the Phase III SPTL treatment study investigator where the 
intervention was given to ensure that all safety outcomes are captured.
Section 6.3., Health Outcomes
Resource utilization endpoints include the following:

Number of hospital admissions, proportion of infants and children with any 
hospital admission, post-birth hospitalization discharge, by principal and 
secondary discharge diagnosis, type of hospital unit admitted to (e.g., NICU, 
Pediatric, PICU, Nursery level 3, ICU), and length of hospital stay per unit after 
28 days post EDD and until the end of the study.

Combined length of hospital stay in days for all hospital admissions (for infants 
discharged from the delivery hospitalization and for babies who were never 
discharged home post-delivery) after 28 days post EDD and until the end of 
the study.

Number of surgical procedures (by details of type and whether performed on an 
inpatient basis or at an outpatient/surgical center will be collected up to 24 
months chronological age only) after 28 days post EDD and until the end of 
the study.
 
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
Number of ER/UC visits and proportion of infants with any ER/UC visit after 
28 days post EDD and up to 24 months chronological age.

Number of specialty care or therapy visits and proportion of infants referred for 
specialty care or therapy by type of care/therapy after 28 days post EDD and up 
to 24 months chronological age.

Parental productivity loss related to infant hospital admissions, ER/UC visits, or 
specialist care after 28 days post EDD and up to 24 months chronological age.
Section 6.3.1., Parent/Legal Guardian-Completed Productivity Questionnaire
During the first 24 months of participation in the study, Iif the infant's parent/legal 
guardian reports in one of the CHI questionnaires that the child is being treated by a 
specialist or has had emergency department visits or hospitalizations, they will be asked 
to complete the productivity questionnaire.
Section 7.1., Data Handling Conventions
For this study, infant child data will be entered into GSK/PPD defined eCRFs, 
transmitted electronically to GSK/PPD, and combined with data provided from other 
sources e.g., data obtained directly from the parent/legal guardian via an electronic device 
provided by the sponsor, its designated vendor, or the patient’s own devices using a 
secure and validated data system. The RCC staff will enter data provided on paper into 
the specifically designed eCRF pages.
Section 7.1.2., Loss to Follow-Up
Infants Children for whom follow-up information is never obtained will be considered 
lost to follow-up. These cases will be tallied in the applicable sections of the study 
reports. All other cases with some follow-up data will be analyzed up to the length of 
infant child follow up.
Section 7.2., Validation Procedures
The ongoing data collection from parents/legal guardians will follow a specific script to 
elicit information from contacts with the health care system. The infant’s child’s HCP 
will also be contacted to provide data on the infant’s child’s health and resource 
utilization when triggered by information from the parent/legal guardian. As indicated in 
the previous sections, for conditions or events that may meet SAE criteria, medical 
confirmation and/or medical records will be obtained to provide details of the conditions. 
All study data will be captured in carefully designed eCRFs specific to the study 
objectives.
 
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Section 8.1., Hypotheses
The objective of the study is to describe the safety and morbidity and mortality outcomes 
of infants children exposed to treatment during Phase III SPTL studies investigating 
retosiban or comparator for the treatment of SPTL. These mortality and morbidity 
endpoints (as described in Section 6.2) will be descriptively summarized.
Section 8.3.4., Interim Analysis
In the event of early stopping of the Phase III SPTL development program due to safety 
and/or lack of efficacy, infants children will continue to be followed until they have 
reached 24 months corrected age for preterm infants and 24 months 5 years
chronological age for term infants.
Section 8.3.5.1.1., Outcomes
The primary objective of the planned analysis will be to use descriptive statistics to 
describe the safety and morbidity and mortality outcomes of infants children exposed to 
treatment during the Phase III SPTL studies investigating retosiban or comparator for the 
treatment of SPTL. The endpoints to be descriptively summarized are those described in 
Section 6.2. Descriptive statistics will be calculated by treatment group and by treatment 
group and time, where appropriate.
For binary outcomes, all summary tables will include the number and percentage of 
subjects with the response/event. The associated 95% CI will also be reported. For those 
endpoints that occur in more than 5 infants children or 1% of the infants children in any 
treatment group, odds ratios and associated 95% CIs will be calculated to compare 
retosiban to placebo, atosiban, and pooled comparator treatment groups. For continuous 
variables, all summary tables will include: n, mean, median, standard deviation, 
minimum and maximum. All summary tables will include N for each group (i.e., the total 
number of subjects randomized to each group within the appropriate population).
To characterize the clinical safety in terms of neurodevelopment in infants children 
exposed to retosiban or comparator, the proportion of infants children with at least 1 of 
the indicators of neurodevelopmental impairment (see Section 6.2.6) at the end of the 
study will be analyzed using a logistic regression model. The model will use a logit link 
function to estimate the log odds of percentage of infants children with indicators of 
neurodevelopmental impairment. The model will include terms for treatment group. The 
number and percentage of subjects in each treatment group, the odds ratios of response 
rates (retosiban versus placebo, retosiban versus atosiban, and retosiban versus all
comparators) and the 95% CIs for the odds ratio of response rates and p values will be 
presented. The analysis may be repeated for each of the individual indicators of 
neurodevelopmental impairment.
 
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To further describe the infant safety profile of retosiban, the following subgroups may be 
explored:

Gestational age of pregnancy at randomization

Established progesterone use (yes or no)

Magnesium sulfate use

Tocolytic use following study drug discontinuation

Maternal age

Region
For each subgroup, infant child safety data will be summarized by treatment and 
subgroup, as previously described. Full details of all planned analyses will be provided in 
the RAP.
Section 9.2.1., Release of Participant Medical Information
In order to collect data from the participant’s HCPs, medical release forms for each 
clinician who will report data to the study must be completed and signed by the infant’s 
child’s parent/legal guardian.
Section 9.2.2., Subject Confidentiality
Each participant’s identity will be known only to the third-party contractor, RCC-PIs, and 
relevant HCPs (e.g., pediatrician or specialist). Infant Child identification numbers will 
be assigned and used to identify study participants. The dataset used in the analysis of 
data will contain coded participant identifiers only.
Section 9.5., Study and RCC Site Closure
Recruitment in participating countries will begin with initiation of the Phase III SPTL 
treatment studies. Recruitment will continue until the Phase III SPTL treatment studies 
end recruitment. Follow-up will continue until each child enrolled completes the 5-year
24 month questionnaire at either 24 months corrected age (for preterm infants) or 
24 months 5 years chronological age (for term infants). Study close-out and final 
reporting activities will be initiated on completion of the follow-up on the last study 
participant.
Section 9.7., Provision of Study Results to RCC-PIs, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication
GSK will also provide the RCC-PI with the full summary of the study results. The 
RCC-PI is encouraged to share the summary results with the parent/legal guardian of the 
participating infant child, as appropriate.
 
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Section 10., References
GlaxoSmithKline Document Number 2015N228508_00. Investigator’s brochure 
supplement 1. FEB-2015.
Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Mathews TJ. Births: final data for 
2013. Natl Vital Stat Rep. 20135;624(91):1-8765.
Thornton S, Miller H, Valenzuela G, et al. Treatment of spontaneous preterm 
labour with retosiban: a phase 2 proof-of-concept study. Br J Clin Pharmacol. 
2015 Mar 27. DOI: 10.1111/bcp.12646. [Epub ahead of print].
 
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Protocol Amendment Number 02
Protocol Amendment Number 02 is applicable to all RCC sites participating in this study. 
Protocol changes specified in Amendment Number 02 are summarized as follows:

Reduction of study duration from 5 years to 24 months due to:
‒
Termination of the retosiban development program, such that there will be no 
further in utero exposure to retosiban, and hence safety data from this ongoing 
study will not inform the potential risk for future use of retosiban.
‒
Low recruitment for interventional studies 200719 (NEWBORN-1) and 
200721 (ZINN). Hence, the number of infants exposed to retosiban in utero 
and included in the current (200722) study is small.
‒
The independent data monitoring committee (IDMC) recommendation that the 
neonatal follow-up be limited to 24 months of age given no safety issues 
detected in their unblinded review of available 200722 data and also that 
statistical analysis at a 5-year timepoint would not provide any meaningful 
results due to the small number of enrolled subjects.

Reclassification of all resource utilization endpoints as exploratory endpoints 
due to the reduced sample size

Correction of an error in the mean BSID-III score for the cognitive impairment, 
fine motor and gross motor scales to <4 to reflect that these are not composite 
scores

Incorporation of other administrative changes
Justification for the Reduction of the ARIOS Study Duration from 5 Years to 
24 Months
The objective of the ARIOS long-term follow-up study was to enable the collection of 
safety data from infants exposed to retosiban in utero for preterm labor to support the 
Phase 3 data package. The design and duration of 5 years was agreed with the regulators, 
including the FDA, PMDA and the EMEA. The collection of data in a clinical trial 
setting would have helped to better inform potential safety concerns prior to approval and 
treatment of an expanded population in the post-marketing setting. In May 2017, the 
corresponding treatment trials 200719 (placebo comparison) and 200721 (atosiban 
comparison) were terminated early due to poor recruitment that made completion of the 
trials unfeasible in a reasonable timeframe. The placebo-controlled trial enrolled only 
23 of the target 900 participants over 17 months, and the atosiban comparator trial 
enrolled 97 of the target 330 participants over 29 months. Maternal, fetal, and neonatal 
AEs were no more common with retosiban than placebo or atosiban in this small dataset. 
GSK also terminated the overall development of retosiban in May 2017, with no further 
development for this asset either in women in spontaneous pre-term labor or any other 
indication. Thus, there will be no further in utero exposure in a clinical trial or a 
post-marketing setting for which there would be a need to inform potential risks.
 
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Due to the early termination of 200719 and 200721, the sample size of ARIOS is small 
with a total of 98 babies enrolled (6 placebo treated subjects from NB-1, 43 atosiban 
treated subjects from ZINN and 49 retosiban treated subjects from NEWBORN-1 and 
ZINN). This represents just 8% of the planned 1230 infants that were to be enrolled in the 
study. The intent of the design of ARIOS was to compare data from the retosiban 
exposed group in each of the treatment trials to the placebo exposed group. In order to 
accomplish this, data from both 200719 and 200721 were to be pooled from all the babies 
exposed to retosiban and compared against placebo-exposed babies. As there were only 
6 babies exposed to placebo with the drop-out rate expected to increase as the study 
progresses, the sample size will not be sufficient to permit a meaningful comparison of 
long-term safety between active treatment and placebo subjects if the follow-up study 
was continued for 5 years of follow-up.
On 28 August 2018, the retosiban IDMC, composed of 1 pediatrician, 2 neonatologists, 
2 maternal-fetal medicine specialists and a statistician, confirmed that there were no 
safety concerns identified following review of ZINN and NEWBORN-1 clinical study 
reports as well as ARIOS adverse events (including congenital anomalies), 
neurodevelopment screening assessments (ASQ-3, CBCL/1.5-5, and MCHAT-R/F), and 
neurodevelopment referrals, from an ARIOS data cut on 15 June 2018, with 34 out of a 
total of 98 babies having already completed 24 months of safety follow-up. The IDMC 
also recommended that the neonatal follow-up be limited to 24 months of age given that 
the small number of enrolled subjects, in particular placebo subjects for comparison, 
would not yield meaningful results. Twenty-four months, in the IDMC collective opinion, 
would allow for detection of major neonatal adverse outcomes and safety signals and as 
such would be sufficient, especially considering that there will be no future development 
of retosiban.
Furthermore, 24-month outcomes are considered by the experts in the field to be 
appropriate for safety assessment (Marlow, 2014). Dr. Neil Marlow, who is an IDMC 
member, in collaboration with regulatory agencies, has developed a manuscript (in press) 
that recommends that 24-month follow-up is appropriate for safety follow-up in this 
population.
Reduction of the study duration from 5 years to 24 months will not impact the care of the 
infant as they will still follow neonatal and pediatric developmental screening standard of 
care as prescribed by their pediatrician or health care provider following completion of 
the study. Therefore, there is no safety risk to the neonate by reducing the study 
follow-up period from 5 years to 24 months.
Administrative changes
Other administrative changes were incorporated into this amendment. The rationale for 
these changes is to ensure a clear and complete protocol for use at the RCC sites.
Specific Changes in the Text
Title Page:
 
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Authors (GSK): 
 
Authors (PPD):
 
Copyright 2015 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited.
SPONSOR SIGNATORY
Kathleen J Beach, MD, MPH
Medicine Development Leader,
Maternal and Neonatal Health Unit
Alternative Discovery and Development
Rajnish Saini, MD
Clinical Director,
Future Pipeline Discovery
Global Health R&D
SPONSOR INFORMATION PAGE
Sponsor Medical Monitors and Serious Adverse Events (SAEs) Contact Information
Issue
North America 
Contract
Latin America Contact
Europe/Asia Contact
Safety Questions
, MD
Medical Director, Medical 
Affairs and 
Pharmacovigilance
PPD
Wilmington, NC, USA
, MD, 
MPH
Associate Medical 
Director, Medical Affairs 
and Pharmacovigilance
PPD
Denver, CO, USA
, MD
Medical Director, Medical 
Affairs and 
Pharmacovigilance
PPD
Buenos Aires, Brazil
Europe: 
, MD
Associate Medical 
Director, Medical Affairs 
and Pharmacovigilance
PPD
Sofia, Bulgaria
Asia:
, MD
Associate Medical 
Director, Medical Affairs 
and Pharmacovigilance
PPD
Kuala Lumpur, Malaysia
SAE Reporting
24-Hour Safety Hotline:
Safety Fax:
24-Hour Safety Hotline:
 
Safety Fax: 
24-Hour Safety Hotline:
Safety Fax:
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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PROTOCOL SUMMARY, Rationale
The goal of this study (ARIOS), therefore, is to assess the safety and outcomes of infants 
and children who were exposed to retosiban (GSK221149) or comparator in utero in the 
planned Phase III SPTL treatment studies and provide assurance that treatment is not 
associated with significant adverse outcomes in early childhood.
In May 2017, the corresponding treatment trials 200719 (NEWBORN-1, placebo 
comparison) and 200721 (ZINN, atosiban comparison) were terminated early due to 
poor recruitment and the length of time needed to complete the studies. The 
placebo-controlled trial enrolled only 23 of the target 900 participants over 
17 months, and the atosiban comparator trial enrolled 97 of the target 
330 participants over 29 months. Maternal, fetal, and neonatal adverse events were 
no more common with retosiban than placebo or atosiban. The development 
program was subsequently terminated with no further in utero exposure of 
retosiban planned.
PROTOCOL SUMMARY, Objectives
Primary

To characterize the clinical safety in terms of infant and child morbidity and 
mortality in infants and children exposed to retosiban or comparator in utero

To characterize the clinical safety in terms of neurodevelopment in infants and 
children exposed to retosiban or comparator in utero
Exploratory

To characterize parental productivity loss related to a sick child and infant resource 
utilization in terms of hospital admissions, length of stay, emergency room/urgent 
care (ER/UC) visits, surgical procedures, and referral to specialty care or therapy 
visits for infants (up to age 2 years) exposed to retosiban or comparator in utero
PROTOCOL SUMMARY, Study Design
Infants and children will be followed at prespecified intervals until they have reached 
5 years 24 months chronological age.
The child’s parent/legal guardian will be asked to complete a Child Health Inventory 
(CHI) at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age and a 
modified CHI at 3, 4, and 5 years of the child’s chronological age. The CHI questionnaire 
completed up to the 24-month time point will screen for infant mortality and morbidity 
and will capture data on resource utilization. At the 3-, 4-, and 5-year time points, the 
CHI will screen for child mortality and morbidity, including any indicators of 
neurodevelopmental impairment.
 
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During the first 24 months of participation in the study, if the parent/legal guardian 
indicates that the infant has been treated by specialists or has had ER/UC visits or 
hospitalizations, he/she will be asked to complete a productivity questionnaire to evaluate 
loss of parental productivity.
If at any of these time points a child has an M-CHAT-R/F score that indicates further 
evaluation is required and/or a CBCL/1.5–5 score at or above the 97th percentile for a 
subset of prespecified questions, the child will be referred to a specialist for a formal 
assessment.
PROTOCOL SUMMARY, Study Endpoints/Assessments
Study primary endpoints include the following and are further defined in Section 6.2.2:
Morbidity and mortality endpoints:

Proportion of infants and children with newly diagnosed (after 28 days post EDD) 
chronic medical conditions by type of condition will be recorded and include the 
following:

Respiratory conditions

Neurological conditions

Sensory conditions

Gastrointestinal conditions

Cardiovascular conditions

Renal conditions

Growth parameters (only up to 24 months chronological age)

Proportion of infants and children with newly diagnosed (after 28 days post EDD) 
congenital anomalies

Proportion of infant and child deaths after 28 days post EDD and until the end of the 
study 24 months chronological age
Neurodevelopment endpoints:

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
cognitive impairment (<70 4)

Proportion of infants with BSID-III score >2 SDs below the mean score for the 
gross motor scale (<70 4)

Proportion of infants with BSID-III score >2 SDs below the mean score for the 
fine motor scale (<70 4)
 
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
Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
language scale (<70 70)

Proportion of infants with a CBCL/1.5–5 score at or above the 97th percentile 
for a subset of prespecified questions that relate to attention and hyperactivity 
problems 

Cognitive impairment: BSID-III Cognitive Scale Score of >2 SDs below mean 
score (<70 4) (at 24 months corrected age)

Motor impairment: BSID-III Motor Composite Scale Score of >2 SDs below 
mean score (<70 70) (at 24 months corrected age)

Proportion of infants and children with at least 1 of the following indicators of 
neurodevelopmental impairment at the end of the study:

Hearing impaired, uncorrected even with aids 

Blindness in 1 or both eyes or sees light only

Cerebral palsy (moderate and severe)

Diagnosis of ASD, attention deficit disorder (ADD), or attention deficit 
hyperactivity disorder (ADHD)
Resource Exploratory resource utilization endpoints include:

Number of hospital admissions, proportion of infants and children with any hospital 
admission, post-birth hospitalization discharge, by principal and secondary discharge 
diagnosis, type of hospital unit admitted to (e.g., neonatal intensive care unit
[NICU], Pediatric, pediatric intensive care unit [PICU], Nursery level 3, intensive 
care unit [ICU)]), and length of hospital stay per unit after 28 days post EDD and 
until the end of the study 24 months chronological age.

Combined length of hospital stay in days for all hospital admissions (for infants 
discharged from the delivery hospitalization and for babies who were never 
discharged home post-delivery) after 28 days post EDD and until the end of the 
study 24 months chronological age.

Number of surgical procedures (details of type and whether performed on an 
inpatient basis or at an outpatient/surgical center will be collected up to 24 months 
chronological age only) after 28 days post EDD and until the end of the study
24 months chronological age.
Section 1.1, Background
Retosiban is was being developed for the treatment of spontaneous preterm labor (SPTL) 
in women with intact membranes.
 
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Phase III SPTL treatment studies will be were conducted to demonstrate the ability of 
retosiban to prolong pregnancy and improve neonatal health, as well as to describe the 
maternal, fetal, and neonatal safety profiles. The treatment studies were subsequently 
terminated due to limited recruitment and the development program was 
subsequently terminated with no further in-utero exposure planned.
Section 1.1.1, Previous Human Experience
Study OTA105256 was the first Phase II clinical study of retosiban in preterm labor 
(n=93) [Thornton, 2015; GlaxoSmithKline Document Number CM2006/00201/0306].
The emerging safety profile for retosiban appears favorable. Results from 
protocol-specified maternal-fetal and neonatal safety assessments were absent of any 
concerns and were similar between the retosiban and placebo groups. Furthermore, no 
clinically significant disparities in AEs were noted between groups [Thornton, 2015]. All 
reported AEs, whether maternal, fetal, or neonatal, were generally consistent with those 
reported in the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
CM2006/00201/03], IB Supplement 1 [GlaxoSmithKline Document Number 
2015N228508_00], or in the study population.
The Phase 3 program included 2 global blinded, randomized, controlled trials 
(200721 [ZINN] and 200719 [NEWBORN-1]) and a single infant follow-up trial 
(200722 [ARIOS]). Eligible subjects were aged 12 to 45 years with an uncomplicated 
singleton pregnancy and intact membranes in spontaneous preterm labor at 240/7 to 
336/7 weeks’ gestation. ZINN (N=330) aimed to show superiority of retosiban (IV) 
over atosiban on time to delivery (first subject first visit [FSFV] was March 2015). 
NEWBORN-1 (N=900) was designed to demonstrate neonatal benefit (based on a 
composite endpoint) as well as time to delivery or time to treatment failure over 
placebo (FSFV February 2016). The intervention trials were terminated early on 
11 May 2017 because of slow recruitment and the retosiban project was 
discontinued permanently. Last subject last visit (LSLV) was 24 July 2017 for 
NEWBORN-1 and 25 August 2017 for ZINN. Meaningful analyses of these 
well-controlled trials could not be performed due to small numbers of completing 
participants. Mean time to delivery or treatment failure in the placebo-controlled 
trial was 18.9 days with retosiban (n=10) versus 11.1 days with placebo (n=13). Two 
neonates in the retosiban and 4 in the placebo group had ≥1 component of the 
neonatal composite endpoint. The adjusted mean time to delivery in the atosiban 
comparator trial was 32.51 days with retosiban (n=50) compared with 33.71 days 
with atosiban (n=47; P>0.05). Maternal, fetal, and neonatal AEs were no more 
common with retosiban than placebo or atosiban. 
In NEWBORN-1, 1 participant in the retosiban group provided cord blood and 
breast milk samples; retosiban was found in both (cord blood, 1.9 µg/L; breast milk, 
3.6 µg/L). In ZINN, 12 women in the retosiban group provided cord blood samples, 
none of which had detectable levels of retosiban. One participant also provided a 
breast milk/colostrum sample. The retosiban concentration was 0.3 g/L.
 
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Section 1.2, Rationale
The goal of this study (ARIOS), therefore, is to assess the safety and outcomes of infants 
and children who were exposed to retosiban or comparator in utero in the planned
Phase III SPTL treatment studies and provide assurance that treatment is not associated 
with significant adverse outcomes in early childhood.
Section 1.3, Benefit:Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with 
GSK221149 can be found in the IB and the Phase III SPTL treatment clinical study 
protocols reports.
 
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Section 1.3.1, Risk Assessment
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
Fetal exposure 
through placental 
transfer
Preclinical data indicate very minimal, if 
any, maternal central nervous system 
(CNS) penetration or placental transfer 
of retosiban as supported by the 
following: 

In pregnant monkeys there was no 
detectable retosiban in the cord 
blood when mothers were dosed up 
to 100 mg/kg (approximately 
7 times the human exposure). 
However, approximately 4% of 
circulating drug was detected in the 
cord blood when mothers were 
dosed at 300 mg/kg (approximately 
24-fold the human exposure).

Retosiban is a substrate of 
P-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, there were no 
adverse mother and infant 
behavioral or locomotor effects 
observed that were suggestive of 
CNS toxicity. 

In rodent neurobehavioral safety 
studies, there were no adverse 
clinical signs observed at doses up 
to 1000 mg/kg.
Analysis of maternal blood and cord 
blood samples will be was performed to 
test for levels of retosiban in women 
who deliver delivered at an 
investigative center within 12 hours of 
the completion of study treatment 
infusion as part of the Phase III SPTL 
treatment studies.
Surveillance for signals indicating 
adverse fetal or neonatal effects with 
in utero exposure to retosiban will be 
performed throughout this study.
Infants exposed to retosiban in utero 
will be followed for up to 5 years
24 months in this study to assess 
safety and neurodevelopmental 
outcomes.
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
For both NEWBORN-1 and ZINN, 
cord blood samples were requested 
from subjects who delivered at the 
investigative center within 12 hours 
after discontinuation of study drug. 
Samples were only analyzed for 
subjects randomized to retosiban. A 
total of 4 cord samples were 
collected within NEWBORN -1 
(3 placebo: 1 retosiban) and 27 
within ZINN (12 retosiban: 15 
atosiban). Within both studies, only 
1 cord blood sample tested positive 
for retosiban at a concentration of 
1.9 µg/L. The 1.9 µg/L is 
approximately 0.006x to 0.01x the 
cord blood concentrations that were 
observed in the pregnant monkey 
toxicity studies (cord blood 
concentrations = 159 to 313 µg/L). 
There were no adverse effects 
observed in the offspring in monkey 
studies, where growth and 
development included a full 
assessment of reflexive behaviors, 
infant ECG and blood chemistry were 
analyzed. Furthermore, a rat post-
natal study starting in juvenile rats 
that were 1 day old did not show any 
adverse effects on growth and 
development, including 
neurobehavior and reproductive 
assessments at exposure levels that 
were approximately 800-fold of what 
was observed in the cord blood 
(gender averaged Cmax = 1535 µg/L). 
Day 1 old rats were used in this 
study as they were developmentally 
similar to late third-term human 
fetuses. The overall animal data 
indicate that potential risk for a fetus 
exposed gestationally to retosiban is 
negligible.
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
Neonatal exposure 
via breast milk
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 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
were collected for measurement of 
retosiban when delivery occurs
occurred and lactation has had started 
within 12 hours of receiving study 
treatment infusion as part of the Phase 
III SPTL treatment studies.
Infants exposed to retosiban via breast 
milk will be followed for up to 5 years
24 months in this study to assess 
safety and neurodevelopmental 
outcomes.
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Retosiban [e.g., GSK221149]
Positive breast milk samples were 
detected within 1 maternal subject in 
NEWBORN-1 and 1 subject in ZINN, 
with the highest concentration being 
0.36 µg/L. Assuming a standardized 
milk consumption of 0.150 L/kg/day 
(the mean milk intake of a fully 
breast-fed 2-month old infant [Begg, 
1999; Bennett, 1988; Hagg, 2000; 
Kristensen, 1999]), the worst-case 
dose of retosiban that a breast-fed 
child would be exposed to is 0.54 
µg/kg/day (3.6 µg/L x 0.15 L/kg/day). 
This is approximately 0.5% of the 
human dose. This is the worst-case 
scenario because the mother is not 
being administered retosiban post-
partum during the lactation period, 
and retosiban is cleared rapidly,
which would rapidly diminish the 
amount retosiban present circulation 
and in the milk. Furthermore, based 
on body surface area, this potential 
infant dose is greater than 8000-fold,
the dose where no adverse effects 
were seen in growth and 
development in the rat post-natal 
development study (rat post-natal 
development study NOAEL = 
30 mg/kg/day; human equivalent 
dose = 4800 µg/kg/day). The 
potential lactational dose of 
retosiban that would therefore pose 
any significant risk to a newborn is 
negligible.
ECG = electrocardiogram; NOAEL = no-observed-adverse-effect-level; SPTL = spontaneous preterm labor.
Section 1.3.2, Benefit Assessment
Given the inverse relationship between the risks for prematurity complications and 
gestational age at birth, the development of a treatment that significantly prolongs 
pregnancy in women with SPTL 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 [Thornton, 2015]. There are currently no safety findings that would preclude 
 
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further development of retosiban for an indication for the treatment of SPTL in 
conjunction with standard of care treatments in women with an uncomplicated, singleton 
pregnancy However, the results from the Phase III interventional studies did not 
provide compelling evidence that retosiban could prolong time to delivery of 
retosiban relative to placebo or atosiban, but because of the low enrollment 
numbers and inadequate statistical power, results should be interpreted with 
caution.
The benefit to infants and children participating in this study is the focus on following 
morbidity and neurodevelopment for up to 5 years 24 months following exposure to 
retosiban or comparator medication.
Section 1.3.3, Overall Benefit:Risk Conclusion
For detailed information on the identified risks and benefit:risk assessment of retosiban, 
refer to the Investigator’s Brochure (IB) and IB Supplement 1 [GlaxoSmithKline 
Document Number CM2006/00201/0306; GlaxoSmithKline Document Number 
2015N228508_00]. Although, experience in pregnant women is limited, no clinical or 
preclinical safety issues have been identified that preclude further development.
 
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Table 1, Summary of Study Objectives and Corresponding Endpoints
Objective
Endpoints
Primary

To characterize the clinical safety in terms of infant 
and child morbidity and mortality in infants and 
children exposed to retosiban or comparator in 
utero

Proportion of infants and children with newly diagnosed 
(after 28 days post EDD) chronic medical conditions by type 
of condition will be recorded and include the following:

Respiratory conditions
o
Chronic lung disease
o
Reactive airway disease
o
Vocal cord paralysis
o
Airway obstruction 

Neurological conditions
o
Cerebral palsy
o
Seizure disorder
o
Hydrocephalus requiring shunt

Sensory conditions
o
Vision
o
Vision impairment
o
Blindness in 1 or both eyes, or sees light 
only
o
Hearing 
o
Hearing impairment
o
Deafness in 1 or both ears
o
Hearing impaired, uncorrected even with 
aids

Gastrointestinal conditions
o
GERD (moderate to severe)
o
Tube/parenteral feeding 
o
Short bowel syndrome

Cardiovascular conditions
o
Pulmonary hypertension
o
Hypertension

Renal conditions
o
Renal impairment requiring dialysis

Growth parameters (only up to 24 months 
chronological age)
o
Poor weight gain
o
Reduced length
o
Reduced head circumference
o
Failure to thrive

Proportion of infants and children with newly diagnosed 
(after 28 days post EDD) congenital anomalies

Proportion of infant and child deaths that occur after 
28 days post EDD and until the end of the study 24 months 
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Objective
Endpoints
To characterize the clinical safety in terms of 
neurodevelopment in infants and children exposed 
to retosiban or comparator in utero

Neurodevelopment endpoints assessed at ages 9, 18, and 
24 months, corrected for prematurity:

Proportion of infants with an ASQ-3 score in the black 
zone in any domain

Proportion of infants with an ASQ-3 score in the black 
zone for gross motor skills

Proportion of infants with an ASQ-3 score in the black 
zone for fine motor skills

Proportion of infants with an ASQ-3 score in the black 
zone for communication

Proportion of infants with an ASQ-3 score in the black 
zone for problem-solving

Proportion of infants with an ASQ-3 score in the black 
zone for personal-social skills

Proportion of infants referred for developmental 
evaluation (using BSID-III)

Proportion of infants with a BSID-III score >2 SDs 
below the mean score for the cognitive scale (<70 4)

Proportion of infants with BSID-III score >2 SDs below 
the mean score for the gross motor scale (<70 4)

Proportion of infants with BSID-III score >2 SDs below 
the mean score for the fine motor scale (<70 4)

Proportion of infants with a BSID-III score >2 SDs 
below the mean score for the language scale (<70 70)

Proportion of infants with a CBCL/1.5-5 score at or 
above the 97th percentile for a subset of prespecified 
questions that relate to attention and hyperactivity 
problems

Proportion of infants indicated as needing further 
evaluation after completion of the M-CHAT-R/F

Proportion of infants referred for neurological 
evaluation to determine diagnosis of cerebral palsy

Proportion of infants with at least 1 of the following 
indicators of neurodevelopmental impairment:

Hearing impaired, uncorrected even with aids (at 
24 months chronological age)

Blindness in 1 or both eyes, or sees light only (at 
24 months chronological age)

Cerebral palsy (moderate and severe) (at 24 months 
corrected age)

Cognitive impairment: BSID-III Cognitive Scale Score 
of >2 SDs below mean score (<70 4) (at 24 months 
corrected age)

Motor impairment: BSID-III Motor Composite Scale 
Score of >2 SDs below mean score (<70 70) (at 
24 months corrected age)

Proportion of infants and children with at least 1 of the 
following indicators of neurodevelopmental impairment at 
the end of the study:

Hearing impaired, uncorrected even with aids 

Blindness in 1 or both eyes, or sees light only

Cerebral palsy (moderate and severe)

Diagnosis of ASD, ADD, or ADHD
 
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Objective
Endpoints
Exploratory
To characterize parental productivity loss related 
to a sick child and infant resource utilization in 
terms of hospital admissions, length of stay, 
ER/UC visits, surgical procedures, and referral to 
specialty care or therapy visits for infants (up to 
age 2 years) exposed to retosiban or comparator 
in utero

Number of hospital admissions, proportion of infants and 
children with any hospital admission, post-birth 
hospitalization discharge, by principal and secondary 
discharge diagnosis, type of hospital unit admitted to (e.g., 
NICU, Pediatric, PICU, Nursery level 3, ICU), and length of 
hospital stay per unit after 28 days post EDD and until the 
end of the study 24 months chronological age

Combined length of hospital stay in days for all hospital 
admissions (for infants discharged from the delivery 
hospitalization and for babies who were never discharged 
home post-delivery) after 28 days post EDD and until the 
end of the study 24 months chronological age

Number of surgical procedures (details of type and whether 
performed on an inpatient basis or at an outpatient/surgical 
center will be collected up to 24 months chronological age 
only) after 28 days post EDD and until the end of the study
24 months chronological age

Number of ER/UC visits and proportion of infants with any 
ER/UC visit after 28 days post EDD and up to 24 months 
chronological age

Number of specialty care or therapy visits and proportion of 
infants referred for specialty care or therapy by type of 
care/therapy after 28 days post EDD and up to 24 months 
chronological age

Parental productivity loss related to infant hospital 
admissions, ER/UC visits, or specialist care after 28 days 
post EDD and up to 24 months chronological age
ADD = attention deficit disorder; ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; 
ASQ-3 = Ages and Stages Questionnaire-3; BSID-III = Bayley Scales of Infant Development, third edition; 
CBCL/1.5-5 = Child Behavior Checklist for Ages 1.5 to 5; EDD = estimated date of delivery; ER/UC = emergency 
room/urgent care; GERD = gastroesophageal reflux disease; ICU = intensive care unit; M-CHAT-R/F = Modified 
Checklist for Autism in Toddlers-Revised with Follow-Up; NICU = neonatal intensive care unit; PICU = pediatric 
intensive care unit.
Section 3.1, Study Design
Infants and children will be followed at prespecified intervals until they reach 5 years
24 months chronological age (see Table 2).
 
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Figure 1, Study Design
Original Figure:
Updated Figure:
The child’s parent/legal guardian will be asked to complete the CHI at 2, 6, 9, 12, 15, 18, 
21, and 24 months of the child’s chronological age and a modified CHI at 3, 4, and 
5 years of the child’s chronological age. The CHI questionnaire completed up to the 
24-month time point will screen for infant mortality and morbidity and will capture data 
 
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on resource utilization. At the 3-, 4-, and 5-year time points, the CHI will screen for child 
mortality and morbidity, including any indicators of neurodevelopmental impairment.
If protocol-specific evaluations are in progress at the end of the child’s protocol-defined 
participation in this study (5 years 24 months chronological age) and results have not yet 
been received or reported, the time period may be extended to collect those reports.
During the first 24 months of participation in the study, if the parent/legal guardian 
indicates that the infant has been treated by specialists or has had ER/UC visits or 
hospitalizations, he/she will be asked to complete a productivity questionnaire to evaluate 
loss of parental productivity.
The M-CHAT-R/F will be completed for all infants at 18 and 24 months (corrected age) 
and the CBCL/1.5–5 will be completed for all infants at 24 months (corrected age) to 
assess the risk for other behavioral problems or autism spectrum disorder (ASD). If at 
any of these time points a child has an M-CHAT-R/F score that indicates further 
evaluation is required and/or a CBCL/1.5–5 score at or above the 97th percentile for a 
subset of prespecified questions, the child will be referred to a specialist for a formal 
assessment.
Protocol Amendment 2 has updated the total study duration to 24 months. Babies or 
infants that have passed the 24-month assessments after the amendment 
implementation are not required to continue further within the study, nor do they 
need to complete any subsequent study related assessments. Following completion of 
the study, the neonates will continue their normal pediatric standard of care with 
their primary care pediatrician or health care provider.
The 24-month data will form the final study endpoint assessment timing; however, if 
data has been collected from a baby/infant after they have passed the 24-month
endpoint, then this data will be included as a data listing within the clinical report.
Section 4.2, Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB and IB Supplement 1 
[GlaxoSmithKline Document Number CM2006/00201/0306; GlaxoSmithKline 
Document Number 2015N228508_00].
Section 6, Study Assessments and Procedures
The infants and children will be followed beginning from after 28 days post EDD and 
until 5 years 24 months chronological age.
The timing of the first questionnaire is scheduled to begin at 2 months chronological age 
and end at 5 years 24 months chronological age.
 
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The EPDS should ideally be completed at 6 weeks (± -2 weeks/+6 weeks) post-delivery 
but may be completed as early as 1 4 weeks post-delivery or as late as 12 weeks post-
delivery.
 
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Table 2, Time and Events Table
Event
28 Days Post 
EDD
Months
Years1
2
6
9
12
15
18
21
24
3
4
5
Written informed consent2
Baseline characteristics and demographic data
X3
RCC confirms and updates contact information from 
the parent/legal guardian
X
Parent/legal guardian completes CHI4
X
X
X
X
X
X
X
X
X4
X4
X4
RCC-PI follows up with HCP and reviews medical or 
other records to confirm parent-reported outcomes
RCC-PI reviews CHI results and refers to birth-defect 
evaluator based on results
Parent/legal guardian completes productivity 
questionnaire5
Parent/legal guardian completes ASQ-36
X6
X6
X6
RCC-PI reviews ASQ-3 results and refers for 
developmental evaluation based on results7
Parent/legal guardian completes M-CHAT-R/F8
X
X
Parent/legal guardian completes CBCL/1.5–58
X
RCC-PI refers child to specialist for cerebral palsy 
assessment (if required)9
X
 
 
 
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ASQ-3 = Ages and Stages Questionnaire-3; CBCL/1.5–5 = Child Behavior Checklist for ages 1.5 to 5; CHI = Child Health Inventory; EDD = estimated date of delivery; HCP = health 
care provider; M-CHAT-R/F = Modified Checklist for Autism in Toddlers-Revised with Follow-Up; RCC = research coordinating center; RCC-PI = research coordinating center-
principal investigator.
Note:  All specified completion windows for applicable questionnaires (CHI, ASQ-3, CBCL/1.5–5, M-CHAT-R/F, and productivity) are provided to help standardize the data and avoid 
overlap. Information captured outside of these windows will be collected and analyzed separately, and questionnaires completed outside the completion window will not be 
considered protocol deviations.
1.
Assessments performed at years 3, 4, and 5 are based on the child’s chronological age.
1. 2. Collected at the start of the Phase III spontaneous preterm labor (SPTL) treatment studies until the later date of either the date of discharge from the birth hospitalization or up to 
9 months corrected age (to allow for the infant’s 9-month CHI and ASQ-3 data collection).
2. 3. Captured in Phase III SPTL treatment studies and combined with child follow-up data for analyses.
3. 4. A positive response by the parent/legal guardian may trigger follow-up with the relevant HCP and/or medical record review for confirmation or more details on the condition or 
hospitalization. A modified CHI will be completed at 3, 4, and 5 years of the child’s chronological age. At each time point, the completion window of the CHI is +6 weeks.
4. 5. Completed if infant has been treated by a specialist or has had an emergency room/urgent care or hospital visit. The completion window for the productivity questionnaire is +2 
weeks from the date of completion of the relevant CHI.
5. 6. Based on infant’s corrected age. The completion window for the ASQ-3 is +30 days at Month 9 and ±30 days at Months 18 and 24.
6. 7. If the parent/legal guardian receives a referral, then a qualified specialist will complete required assessments.
7. 8. The CBCL/1.5–5 and M-CHAT-R/F questionnaires will be completed for all infants. The completion window for the CBCL/1.5–5 and M-CHAT-R/F is +6 weeks at 18 months 
(M-CHAT-R/F only) and +12 weeks at 24 months. 
8. 9. Referral will be made for infants who score in the black zone for the gross motor skills domain on the 24-month corrected age ASQ-3 and do not have an existing diagnosis of 
cerebral palsy.
 
 
 
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Section 6.2.1
The morbidity endpoints will be assessed at 2, 6, 9, 12, 15, 18, 21, and 24 months and 3, 
4, and 5 years of the child’s chronological age.
Section 6.2.1.1, Parent/Legal Guardian-Completed Child Health Inventory
The child’s parent/legal guardian will be asked to complete the CHI at 2, 6, 9, 12, 15, 18, 
21, and 24 months of the child’s chronological age and a modified CHI at 3, 4, and 
5 years of the child’s chronological age. At each time point, the completion window is 
+6 weeks; however, CHI questionnaires completed outside the completion window will 
not be considered a protocol deviation.
The CHI administered at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s 
chronological age will screen for infant mortality and morbidity and capture data on 
resource utilization. At 3, 4, and 5 years of the child’s chronological age, the CHI will 
screen for child mortality and morbidity, including any indicators of neurodevelopmental 
impairment.
 
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Figure 2, Child Health Inventory: Flow Chart of Data Collection and Review
Original Figure:
CHI = Child Health Inventory; HCP = health care provider; RCC-PI = research coordinating center-principal investigator.
1.
The CHI completed at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age will screen for infant mortality and morbidity and capture data on resource utilization. 
At 3, 4, and 5 years of the child’s chronological age, the CHI will screen for child mortality and morbidity, including any indicators of neurodevelopmental impairment.
 
 
 
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Updated Figure:
CHI = Child Health Inventory; HCP = health care provider; RCC-PI = research coordinating center-principal investigator.
1.
The CHI completed at 2, 6, 9, 12, 15, 18, 21, and 24 months of the child’s chronological age will screen for infant mortality and morbidity and capture data on resource utilization. 
At 3, 4, and 5 years of the child’s chronological age, the CHI will screen for child mortality and morbidity, including any indicators of neurodevelopmental impairment.
 
 
 
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Section 6.2.2.7, Growth Parameters
Growth parameters will be assessed only up to 24 months chronological age and will
include the following:
Section 6.2.4, Infant and Child Deaths
This study will assess the proportion of infant and child deaths that occur after 28 days 
post EDD and up to 5 years 24 months chronological age.
Section 6.2.5, Parent/Legal Guardian-Completed ASQ-3, M CHAT R/F, and 
CBCL/1.5–5 and Possible Referral to a Specialist
If at any of these time points a child has an M-CHAT-R/F score that indicates further 
evaluation is required and/or a CBCL/1.5–5 score at or above the 97th percentile for a 
subset of prespecified questions, the child will be referred to a specialist for a formal 
assessment.
In this study, infants with test scores at or above the 97th percentile for a subset of 
prespecified questions that relate to attention or hyperactivity problems syndrome or the 
American Psychiatric Association's Diagnostic and Statistical Manual (DSM)-oriented 
attention-deficit/hyperactivity disorder scale will be considered to have a behavior 
problem, which will trigger a referral to a developmental specialist for a formal 
assessment.
The completion window for the CBCL/1/5-5 and M-CHAT-R/F is +6 weeks at 
18 months (M-CHAT-R/F only) and +12 weeks at 24 months; however, questionnaires 
completed outside the completion window will not be considered a protocol deviation.
Section 6.2.5.2, Neurodevelopment

Proportion of infants with a BSID-III score >2 SDs below the mean score for 
cognitive impairment (<70 4)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
gross motor scale (<70 4)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
fine motor scale (<70 4)

Proportion of infants with a BSID-III score >2 SDs below the mean score for the 
language scale (<70 70)

Proportion of infants with a CBCL/1.5–5 at or above the 97th percentile for a 
subset of prespecified questions that relate to attention and hyperactivity 
problems
Section 6.2.6, Overall Measure of Neurodevelopmental Impairment

Cognitive impairment: BSID-III Cognitive Scale Score of >2 SDs below mean 
score (<70 4) (at 24 months corrected age)
 
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
Motor impairment: BSID-III Motor Composite Scale Score of >2 SDs below 
mean score (<70 70) (at 24 months corrected age)

Proportion of infants and children with at least 1 of the following indicators of 
neurodevelopmental impairment at the end of the study:

Hearing impaired, uncorrected even with aids 

Blindness in 1 or both eyes, or sees light only

Cerebral palsy (moderate and severe)

Diagnosis of ASD, ADD, or ADHD
Section 6.2.10, Death Events
The proportion of deaths that occur after 28 days post EDD and up to 5 years 24 months
chronological age will be collected.
Section 6.2.11, Time Period and Frequency of Detecting SAEs
Child SAEs will be collected from after 28 days post EDD until 5 years 24 months
chronological age. All SAEs will be reported to GSK/PPD within 24 hours, as indicated 
in Section 6.2.12.
Section 6.2.14, Prompt Reporting of SAEs and Other Events to GSK/PPD
The contact information for reporting SAEs is as follows:
Issue
North America 
Contract
Latin America Contact
Europe/Asia Contact
Serious Adverse 
Event Reporting
24-Hour Safety Hotline:
Safety Fax:
24-Hour Safety Hotline:
Safety Fax:
24-Hour Safety Hotline:
Safety Fax:
Section 6.3, Health Outcomes
Resource utilization exploratory endpoints include the following: 

Number of hospital admissions, proportion of infants and children with any 
hospital admission, post-birth hospitalization discharge, by principal and 
secondary discharge diagnosis, type of hospital unit admitted to (e.g., NICU, 
Pediatric, PICU, Nursery level 3, ICU), and length of hospital stay per unit after 
28 days post EDD and until the end of the study up to 24 months chronological 
age.
 
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
Combined length of hospital stay in days for all hospital admissions (for infants 
discharged from the delivery hospitalization and for babies who were never 
discharged home post-delivery) after 28 days post EDD and until the end of the 
study up to 24 months chronological age.

Number of surgical procedures (details of type and whether performed on an 
inpatient basis or at an outpatient/surgical center will be collected up to 
24 months chronological age only) after 28 days post EDD and until the end of 
the study up to 24 months chronological age.
Section 6.3.1, Parent/Legal Guardian-Completed Productivity Questionnaire
During the first 24 months of participation in the study, if the infant's parent/legal 
guardian reports in one of the CHI questionnaires that the child is being treated by a 
specialist or has had emergency department visits or hospitalizations, they will be asked 
to complete the productivity questionnaire.
Section 8.1, Hypotheses
If deemed appropriate, point estimates and associated 95% confidence intervals (CIs) 
may be calculated for the comparison of retosiban to placebo and retosiban to atosiban 
for some safety endpoints. No type I error adjustments are planned.
Section 8.2.1, Sample Size Assumptions
The sample size for this study will depend on the total number of subjects enrolled in the 
Phase III SPTL treatment studies. At In May 2017, the time of protocol publishing, 
2 Phase III SPTL treatment studies are planned that will enroll at total of approximately 
1100 mothers. However, were terminated early due to the number feasibility of studies 
and/or size of recruiting the studies may change depending on in a timely manner, 
meaning that the outcome of the first planned Phase III SPTL treatment study, such that 
the total number of mothers enrolled could be size of these studies was lower or higher
than currently planned. originally planned. This has resulted in a greatly reduced 
sample size for this study.
Section 8.3.1, Analysis Populations
The primary population for safety assessment will be all infants whose mothers have 
been randomized and received retosiban or comparator in any of the Phase III 
treatment trials. Of these mothers, the infant safety population includes the 
mother/infant pairs who enrolled into the study with at least 1 observation, the 
mother/infant pairs who decline to consent to the study, and the mother/infant pairs 
whose fetus/neonates/infants died prior to the enrollment of the study. Subjects will 
be analyzed according to their actual treatment in case this differs from their randomized 
treatment. All analyses will be based on the primary population dataset.
 
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Section 8.3.4, Interim Analysis
In the event of early stopping of the Phase III SPTL development program due to safety 
and/or lack of efficacy, children will continue to be followed until they have reached 
5 years 24 months chronological age. 
For any subject for which the CHI questionnaire at 3, 4, and 5 years of the child’s 
chronological age was completed prior to Amendment 2, data will be reported.
Section 8.3.5.1.1, Outcomes
For binary outcomes, all summary tables will include the number and percentage of 
subjects with the response/event. The associated 95% CI will also be reported. For those 
endpoints that occur in more than 5 children or 1% of the children in any treatment 
group, odds ratios and associated 95% CIs will be calculated to compare retosiban to 
placebo, atosiban, and pooled comparator treatment groups. For continuous variables, all 
summary tables will include: n, mean, median, standard deviation, minimum and 
maximum. All summary tables will include N for each group (i.e., the total number of 
subjects randomized to each group within the appropriate population).
To characterize the clinical safety in terms of neurodevelopment in children exposed to 
retosiban or comparator, the proportion of children with at least 1 of the indicators of 
neurodevelopmental impairment (see Section 6.2.6) at the end of the study will be 
analyzed using a logistic regression model. The model will use a logit link function to 
estimate the log odds of percentage of children with indicators of neurodevelopmental 
impairment. The model will include terms for treatment group. The number and 
percentage of subjects in each treatment group, the odds ratios of response rates 
(retosiban versus placebo, retosiban versus atosiban, and retosiban versus all 
comparators) and the 95% CIs for the odds ratio of response rates and p values will be 
presented. The analysis may be repeated for each of the individual indicators of 
neurodevelopmental impairment.
To further describe the infant safety profile of retosiban, the following subgroups may be 
explored:

Gestational age of pregnancy at randomization

Established progesterone use (yes or no)

Magnesium sulfate use

Tocolytic use following study drug discontinuation

Maternal age

Region
For each subgroup, child safety data will be summarized by treatment and subgroup, as 
previously described. Full details of all planned analyses will be provided in the RAP.
 
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Section 8.3.5.2, Health Outcomes Analyses
The primary objective of the exploratory planned analysis will be to use descriptive 
statistics is to characterize resource utilization in infants exposed to retosiban or 
comparator in the Phase III SPTL treatment studies. The Exploratory endpoints to be 
descriptively summarized are those described in Section 6.3. Descriptive statistics will
may be calculated by treatment group and by treatment group and time, where 
appropriate. Additional analyses and modeling may be conducted to further characterize 
the resource utilization of infants exposed to retosiban, placebo, and atosiban. Full details 
of the planned exploratory analyses will be provided 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 principles that are outlined in the current version of the
Declaration of Helsinki 2008, including, but not limited to:
Section 9.5, Study and RCC Site Closure
Follow-up will continue until each child enrolled completes the 5-year questionnaire at 
5 years chronological age. 24-month questionnaire at 24 months chronological age. 
For any subject that was enrolled prior to Amendment 2, those subjects who have 
completed the 24 months assessments will not be required to complete the CHI 
questionnaire at 3, 4, and 5 years of the child’s chronological age.
Section 10, References
Begg EJ, Duffull SB, Saunders DA, et al. Paroxetine in human milk, Br J Clin 
Pharmacol. 1999;48(2):142-7.
Bennett PN (ed), 1988, Drugs and human lactation, Amsterdam: Elsevier.
GlaxoSmithKline Document Number 2015N228508_00. CM2006/00201/06. Retosiban 
Investigator's Brochure Version 3 Supplement 1. FEB-2015 6. JUN_2018.
GlaxoSmithKline Document Number CM2006/00201/03. Retosiban Investigator's 
Brochure Version 3. APR-2014.
Hagg S, Spigset O. Anticonvulsant use during lactation, Drug Saf. 2000;22(6):425-
40.
Kristensen JH, Ilett KF, Hackett LP, et al. Distribution and xxcretion of fluoxetine 
and norfluoxetine in human milk. Br J Clin Pharmacol. 48(4):521-7.
Marlow N. Is survival and neurodevelopmental impairment at 2 years of age the 
gold standard outcome for neonatal studies? Arch Dis Child Fetal Neonatal Ed.
2015;100(1):F82-4.
 
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200722
1
Division
:
Worldwide Development
Information Type     
:
Reporting and Analysis Plan (RAP) Version 2.0
Title
:
Reporting and Analysis Plan for Follow-Up Study to Assess 
Long-Term Safety and Outcomes in Infants and Children 
Born to Mothers Participating in Retosiban Treatment Studies
Compound Number
:
GSK221149
Effective Date 
:
5-DEC-2019
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 200722.  

This RAP is intended to describe the planned 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.

Change in Version 2.0: Change from ‘<70’ to ‘<4’ for cognitive scale score, gross 
motor scale score and fine motor scale score of >2 SDs below mean score in Section 
2.2.
Author’s Name and Functional Area: 
8-MAR-2019
Biostatistician, PPD
5-DEC-2019
Sr. Manager, Biostatistics, PPD
Approved by: 
5-DEC-2019
Director Statistics & Programming, GlaxoSmithKline
Signature: 
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................4
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
5.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS..................................................................................11
5.1.
Primary Comparisons of Interest.................................................................11
5.2.
Other Comparisons of Interest....................................................................11
5.3.
Multiplicity Adjustment ................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Planned Analyses Overview .......................................................................12
6.2.
Disposition of Subjects................................................................................13
6.3.
Demographic and Baseline Characteristics.................................................13
6.4.
Medical Conditions (Current/Past) ..............................................................14
7.
PRIMARY STATISTICAL ANALYSES....................................................................15
7.1.
Efficacy Analyses........................................................................................15
7.2.
Safety Analyses..........................................................................................15
7.2.1.
Overview of Planned Analyses ....................................................15
7.2.2.
Adverse Events............................................................................16
7.2.2.1.
Serious Adverse Events .............................................16
7.2.2.2.
Congenital Anomaly ...................................................17
7.2.2.3.
Death .........................................................................17
7.2.3.
Neurodevelopment Assessment at 9, 18, and 24 months ............17
7.2.4.
Neurodevelopment Assessment at 3, 4, and 5 years ...................17
7.2.5.
Neurodevelopment Impairment at the End of Study.....................18
7.2.6.
Health Outcome...........................................................................18
8.
DEVIATION OF PLANNED ANALYSES FROM PROTOCOL.................................18
9.
REFERENCES.......................................................................................................19
10. APPENDICES........................................................................................................20
10.1.
Appendix 1: Protocol Deviation Definitions..................................................21
10.2.
Appendix 2: Time and Events .....................................................................22
10.3.
Appendix 3: Treatment States and Phases.................................................24
10.4.
Appendix 4: Data Display Standards & Handling Conventions....................25
 
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10.4.1.
Study Treatment & Sub-group Display Descriptors......................25
10.4.2.
Baseline Definition.......................................................................25
10.4.3.
Reporting Process & Standards...................................................25
10.5.
Appendix 5: Derived and Transformed Data ...............................................27
10.5.1.
General........................................................................................27
10.6.
Appendix 6: Premature Withdrawals & Handling of Missing Data ...............28
10.6.1.
Premature Withdrawals................................................................28
10.6.2.
Handling of Missing Data.............................................................28
10.6.2.1.
Handling of Missing/Partial Dates...............................28
10.7.
Appendix 7: Abbreviations & Trade Marks ..................................................29
10.7.1.
Abbreviations...............................................................................29
10.7.2.
Trademarks .................................................................................29
10.8.
Appendix 8: List of Data Displays ...............................................................30
10.8.1.
Data Display Numbering..............................................................30
10.8.2.
Study Population Tables..............................................................31
10.8.3.
Safety Tables...............................................................................32
10.8.4.
ICH Listings .................................................................................33
10.8.5.
Non-ICH Listings..........................................................................34
 
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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 safety analyses and 
outputs required for the final Clinical Study Report (CSR) of study 200722. 
Protocol

This RAP is based on the original protocol (Dated: 14-May-2014), protocol 
amendment 01 (Dated: 17-Aug-2015), protocol amendment 02 (Dated: 01-Nov-
2018) of study GSK200722 [GlaxoSmithKline Document Numbers: 
2014N194466_00, GlaxoSmithKline Document Numbers 2014N194466_01, and 
GlaxoSmithKline Document Numbers 2014N194466_02] and the most recent
version of the electronic Case Report Form (eCRF).
Objective 
To assess the safety and outcomes in infants and children who were 
exposed to retosiban or comparator in the Phase III Spontaneous 
Preterm Labor (SPTL) treatment studies.
Endpoint
Morbidity and mortality endpoints.
Neurodevelopment endpoints.
Exploratory resource utilization endpoint.
Details are further defined in Section 2.2.
Study 
Design
Long-term infant and child follow-up study (with no medical 
interventions or study visits to an investigational site required), during 
which parents or legal guardians will complete developmental 
questionnaires and other data on their children’s health status via an 
electronic device at prespecified intervals until their children reach 24 
months corrected age (or chronological age, if applicable), to
prospectively assess safety and outcomes of all infants and children born 
to women who received at least 1 dose of retosiban or comparator in any 
of the Phase III SPTL treatment studies.
Planned 
Analyses

There is no formal interim analysis planned for this study.

Final 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. 
Analysis 
Population

The primary population for safety assessment will be the Infant Safety population.

The ARIOS Safety population is a subset of the Infant Safety population for which 
the mother/infant pairs who enrolled into the ARIOS study
Hypothesis

The objective of the study is to describe the safety and morbidity and mortality 
outcomes of children exposed to treatment during Phase III SPTL studies 
investigating retosiban or comparator for the treatment of SPTL. 

No type I error adjustments are planned.
 
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Safety
Analyses

Descriptive statistics will be used to describe the safety and morbidity and 
mortality outcomes of children exposed to treatment during the Phase III SPTL 
studies investigating retosiban or comparator for the treatment of SPTL.

Descriptive statistics will be used to describe the clinical safety in terms of 
neurodevelopment in infants and children exposed to retosiban or comparator. 

Serious Adverse Events (AEs) will be summarized by in infants exposed to 
retosiban or comparator in the Phase III SPTL treatment studies.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Due to early termination of the study, not all originally planned data analyses as outlined 
in the protocol will be performed. More details are given in Section 8.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints

To characterize the 
clinical safety in terms 
of infant and child 
morbidity and mortality 
in infants and children 
exposed to retosiban or 
comparator in utero 

Proportion of infants and children with newly diagnosed (after 28 days 
post EDD) chronic medical conditions by type of condition will be 
recorded and include the following:

Respiratory conditions
o
Chronic lung disease
o
Reactive airway disease
o
Vocal cord paralysis
o
Airway obstruction 

Neurological conditions
o
Cerebral palsy
o
Seizure disorder
o
Hydrocephalus requiring shunt

Sensory conditions
o
Vision
o
Vision impairment
o
Blindness in 1 or both eyes, or sees light only
o
Hearing 
o
Hearing impairment
o
Deafness in 1 or both ears
o
Hearing impaired, uncorrected even with aids

Gastrointestinal conditions
o
GERD (moderate to severe)
o
Tube/parenteral feeding 
o
Short bowel syndrome

Cardiovascular conditions
o
Pulmonary hypertension
o
Hypertension

Renal conditions
o
Renal impairment requiring dialysis

Growth parameters 
o
Poor weight gain
o
Reduced length
o
Reduced head circumference
o
Failure to thrive

Proportion of infants and children with newly diagnosed (after 28 days 
post EDD) congenital anomalies

Proportion of infant and child deaths that occur after 28 days post EDD 
and until 24 months chronological age1
 
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Objectives
Endpoints

Neurodevelopment endpoints assessed at ages 9, 18, and 24 months, 
corrected for prematurity:

Proportion of infants with an ASQ-3 score in the black zone in any 
domain

Proportion of infants with an ASQ-3 score in the black zone for gross 
motor skills

Proportion of infants with an ASQ-3 score in the black zone for fine 
motor skills

Proportion of infants with an ASQ-3 score in the black zone for 
communication

Proportion of infants with an ASQ-3 score in the black zone for 
problem-solving

Proportion of infants with an ASQ-3 score in the black zone for 
personal-social skills

Proportion of infants referred for developmental evaluation (using 
BSID-III)

Proportion of infants with a BSID-III score >2 SDs below the mean 
score for the cognitive scale (<4)

Proportion of infants with BSID-III score >2 SDs below the mean 
score for the gross motor scale (<4)

Proportion of infants with BSID-III score >2 SDs below the mean 
score for the fine motor scale (<4)

Proportion of infants with a BSID-III score >2 SDs below the mean 
score for the language scale (<70)

Proportion of infants with a CBCL/1.5-5 score above the 97th 
percentile for a subset of prespecified questions that relate to 
attention and hyperactivity problems

Proportion of infants indicated as needing further evaluation after 
completion of the M-CHAT-R/F

Proportion of infants referred for neurological evaluation to 
determine diagnosis of cerebral palsy

Proportion of infants with at least 1 of the following indicators of 
neurodevelopmental impairment:

Hearing impaired, uncorrected even with aids (at 24 months 
chronological age)

Blindness in 1 or both eyes, or sees light only (at 24 months 
chronological age)

Cerebral palsy (moderate and severe) (at 24 months corrected age2)

Cognitive impairment: BSID-III Cognitive Scale Score of >2 SDs 
below mean score (<4) (at 24 months corrected age)

Motor impairment: BSID-III Motor Composite Scale Score of >2 SDs 
below mean score (<70) (at 24 months corrected age)

Diagnosis of ASD, ADD, or ADHD
 
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Objectives
Endpoints
Exploratory

To characterize 
parental 
productivity loss 
related to a sick 
child and infant 
resource 
utilization in 
terms of hospital 
admissions, 
length of stay, 
ER/UC visits, 
surgical 
procedures, and 
referral to 
specialty care or 
therapy visits for 
infants (up to 
age 2 years) 
exposed to 
retosiban or 
comparator in 
utero

Number of hospital admissions, proportion of infants and children with 
any hospital admission, post-birth hospitalization discharge, by principal 
and secondary discharge diagnosis, type of hospital unit admitted to 
(e.g., NICU, Pediatric, PICU, Nursery level 3, ICU), and length of hospital 
stay per unit after 28 days post EDD and until 24 months chronological 
age

Combined length of hospital stay in days for all hospital admissions (for 
infants discharged from the delivery hospitalization and for babies who 
were never discharged home post-delivery) after 28 days post EDD and 
until 24 months chronological age Number of surgical procedures (details 
of type and whether performed on an inpatient basis or at an 
outpatient/surgical center will be collected up to 24 months chronological 
age only) after 28 days post EDD and until 24 months chronological age
Number of ER/UC visits and proportion of infants with any ER/UC visit 
after 28 days post EDD and up to 24 months chronological age

Number of specialty care or therapy visits and proportion of infants 
referred for specialty care or therapy by type of care/therapy after 28 
days post EDD and up to 24 months chronological age

Parental productivity loss related to infant hospital admissions, 
ER/UC visits, or specialist care after 28 days post EDD and up to 
24 months chronological age
ADD = attention deficit disorder; ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; 
ASQ-3 = Ages and Stages Questionnaire-3; BSID-III = Bayley Scales of Infant Development, third edition; 
CBCL/1.5-5 = Child Behavior Checklist for Ages 1.5 to 5; EDD = estimated date of delivery; ER/UC = emergency 
room/urgent care; GERD = gastroesophageal reflux disease; ICU = intensive care unit; M-CHAT-R/F = Modified 
Checklist for Autism in Toddlers-Revised with Follow-Up; NICU = neonatal intensive care unit; PICU = pediatric 
intensive care unit.
1Chronological age is age [in months] after the infant was born 
2 Corrected age is age [in months] after expected date of full-term delivery (chronological age minus the number of  
months that the infant was born early)
 
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2.3.
Study Design
Overview of Study Design and Key Features
EDD = estimated date of delivery; HCP = health care provider; RCC = research coordinating center; 
RCC-PI = research coordinating center-principal investigator; SPTL = spontaneous preterm labor.
Overview of Key Study Design Features
Design Features:

Long-term infant and child follow-up study (up to 24 months 
corrected age (or chronological age, if applicable))

Subjects are infants and children born to women who received 
at least 1 dose of retosiban or comparator in any of the 
Phase III SPTL treatment studies.

This study does not require medical interventions or study 
visits to an investigational site.

Parents or legal guardians will be prompted at certain time 
points to complete developmental questionnaires and other 
data on their children’s health status via an electronic device 
until infants and children have reached 24 months corrected 
age (or chronological age, if applicable).
Dosing:

Infants and children enrolled in this study will not be 
administered any investigational product.
Treatment Assignment:

The Phase III SPTL treatment study treatment group and 
strata to which mothers were dosed will be maintained during 
analysis of data from the child follow-up study.
Interim Analysis

There is no formal interim analysis planned for this study.
 
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2.4.
Statistical Hypotheses
The objective of the study is to describe the safety and morbidity and mortality outcomes 
of children exposed to treatment during Phase III SPTL studies investigating retosiban or 
comparator for the treatment of SPTL. These mortality and morbidity endpoints (as 
described in protocol Section 6.2) will be descriptively summarized.
Protocol amendment 02 has updated the total study duration to 2 years. Babies or infants 
that have passed the 2-year assessments after the amendment implementation are not 
required to continue further within the study, nor do they need to complete any 
subsequent stud- related assessments.
Descriptive summaries will utilize data collected up to and including the 2-year 
assessments. Data collected beyond the 2 year assessment will be presented, but not 
included in the summaries.
No type I error adjustments are planned.
3.
PLANNED ANALYSES
All planned analyses will be done using SAS version 9.3 or higher. The Analysis Data 
Model (ADaM) will be created per ADaM implementation guide version 1.1. Details on 
derivation of variables will be specified in the specification document of ADaM. All 
analysis tables, listings, and figures will be generated based on ADaM and/or Study Data 
Tabulation Model (SDTM).
3.1.
Interim Analyses
There is no formal interim analysis planned for this study. 
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.
Actual treatment data have been distributed.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Infant Safety 

All the infants whose mothers have been 
randomized and received retosiban or comparator 
in any of the Phase III treatment trials will be 
included in the Infant Safety analysis population.

Of these mothers, the Infant Safety population 
includes the mother/infant pairs who enrolled into 
the ARIOS study, the mother/infant pairs who 
decline to consent to the study, and the 
mother/infant pairs whose fetus/neonates/infants 
has died prior to the enrolment of the study.  

Subjects will be analyzed according to their actual 
treatment in case this differs from their 
randomized treatment.

Disposition

All safety analyses
ARIOS Safety

Subset of the Infant Safety population for which 
the mother/infant pairs enrolled into the ARIOS 
study.

Demographic

All safety analyses 
Data collected up to and including the 2-year assessments will be included in the 
descriptive summaries. Data collected beyond the 2-year assessment will be presented, 
but not included in the summaries.
4.1.
Protocol Deviations
Protocol deviations are tracked by the study team throughout the conduct of the study in 
accordance with the Protocol Deviation Management Plan (Reference).  
5.
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
AND DATA HANDLING CONVENTIONS
5.1.
Primary Comparisons of Interest
The primary treatment groups are retosiban, placebo, and atosiban.
The primary comparisons between these treatment groups will be:

Retosiban versus placebo

Retosiban versus atosiban
5.2.
Other Comparisons of Interest
A secondary treatment group will include the pooling of placebo and atosiban into a
group called “all comparators”. The secondary comparison will be the following:

Retosiban versus all comparators
 
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5.3.
Multiplicity Adjustment
There will be no multiplicity adjustment.
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Definitions 
10.2
Appendix 2: Time and Events
10.3
Appendix 3: Treatment States and Phases
10.4
Appendix 4: Data Display Standards & Handling Conventions
10.5
Appendix 5: Derived and Transformed Data
10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
10.7
Appendix 7: Abbreviations & Trade Marks
10.8
Appendix 8: List of Data Displays
6.
STUDY POPULATION ANALYSES
6.1.
Planned Analyses Overview
All analyses will be based on both populations as defined in Section 4, except where 
specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 8: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Display’s Generated
Table
Figure
Listing
Subject Disposition (Infant Safety population, only)
Subject Disposition
Y
Y
Reasons for Withdrawals
Y
Y
Number of Infants Enrolled at Milestone
Y
Demography (ARIOS Safety population, only)
Demographics and Baseline Characteristics
Y
Y
Race & Racial Combinations
Y
Y
NOTES:
1.
Subject Disposition TLFs will only be created for the Infant Safety population.
2.
Demography TLFs will only be created for the ARIOS Safety population
3.
Y = Yes display generated
 
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6.2.
Disposition of Subjects
Analyses of disposition data will be based only on the Infant Safety population as defined 
in Section 4.
Subject status with respect to study status will be summarized in relation to: 

Enrolled

Not enrolled

Died in treatment studies

Study completion and withdrawal/death
The number and percentage of subjects with the above study status will be reported by 
treatment group. Reasons for withdrawal will be presented. 
Subject status with respect to each study milestone will be summarized in relation to: 

Treated at treatment studies

Infant consented to ARIOS

Infant not consented to ARIOS

Enrolled at ARIOS
The number and percentage of subjects with the above study milestone will be reported 
by treatment group. The number and percentage of subjects reaching each study 
milestone after enrolling in ARIOS (infant death, 9 months, 18 months, and 24 months) 
will be presented. 
A completed subject is defined as one who has completed all phases of the study up to 
and including the 2-year assessment. Note: due to protocol amendment 02 which updated 
the total study duration to 2 years, some infants may have data collected after the 2-year 
assessment.
Subject disposition data will also be listed. All disposition summaries will be performed 
using the Infant Safety population. 
6.3.
Demographic and Baseline Characteristics
Analyses of demographic and baseline characteristics will be based only on the ARIOS 
Safety population as defined in Section 4.
Continuous variables, such as birth weight (kg), APGAR at 5 minutes after birth, and 
other baseline characteristics as needed will be summarized using descriptive statistics
(mean, standard deviation, median, minimum, and maximum) by treatment group. 
 
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The following categorical variables will be summarized by reporting the number and 
percentage of subjects in each category by treatment group:

Age of infant at enrollment

Sex

Birth weight category (<1 kg, 1 - < 2.5 kg, and >= 2.5 kg)

Maternal 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)

Infant GA at birth (4 GA strata: 240/7 to 256/7, 260/7 to 276/7, 280/7 to 306/7 and 310/7
to 336/7 , 340/7 to 366/7, and 370/7 to 416/7) 

APGAR category at 5 minutes after birth (<7 and >= 7)
Demographic and baseline characteristics data will also be listed. Summaries will be 
performed using the ARIOS Safety population. 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.
All demographic and baseline characteristics except age of infant at enrollment stated 
above will be obtained from Phase III SPTL treatment studies.
Age of infant at enrollment is calculated in months between the date of birth and the date 
of enrollment in ARIOS study.
6.4.
Medical Conditions (Current/Past)
Analyses of medical conditions (current/past) will be based on both populations as 
defined in Section 4, except where specified.
The number and percentages of subjects with newly diagnosed chronic medical 
conditions (respiratory, neurological, sensory, gastrointestinal, cardiovascular, renal 
conditions, and growth parameter) will be presented. 
In addition, subject level listings of newly diagnosed chronic medical condition will be 
listed.
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
There is no efficacy analysis planned for this study. 
7.2.
Safety Analyses
All safety summaries will be performed for both populations as defined in Section 4. A 
listing of all safety data will be presented.
The primary objective of the planned analysis will be to use descriptive statistics to
describe the safety and morbidity and mortality outcomes of children exposed to
treatment during the Phase III SPTL studies investigating retosiban or comparator for the
treatment of SPTL up to 24 months chronological age. The endpoints to be descriptively 
summarized are those described in Section 2.2. Descriptive statistics will be calculated by 
treatment group and/or time (up to 24 months chronological age), where appropriate.
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 in each treatment group).
The focus will be on collecting the safety outcomes as defined in the objectives (e.g.,  
death) and serious AEs (SAEs), including congenital anomalies.
Nonserious AEs will not be tracked. All SAEs and safety outcomes will be followed until 
resolution, stabilization, or loss to follow-up.
7.2.1.
Overview of Planned Analyses
The safety analyses will be based on both populations as defined in Section 4.
Table 3 provides an overview of the planned analyses with further details of data displays 
being presented in Appendix 8: List of Data Displays.
Table 3
Overview of Planned Safety Analyses
Endpoints
Observed
Summary
Individual
T
F
F
L
Newly Diagnosed Chronic Medical Condition
Y
Y
Adverse Events (AE)
   Serious Adverse Events
Y
Y
   Death
Y
   Infant Congenital Anomalies 
Y
Infant Neurodevelopment Assessments
Y
Y
 
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Endpoints
Observed
Summary
Individual
T
F
F
L
Infant Neurodevelopment Impairment
Y
Y
Infant Hospital Utilization
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.
7.2.2.
Adverse Events
Nonserious AEs will not be tracked.
7.2.2.1.
Serious Adverse Events
SAEs 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, SAEs 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, 
SAEs will be presented in descending order from the PT with the highest total incidence 
to the PT with the lowest total incidence. If the total incidence for any two or more PTs 
within an SOC is equal, the PTs will be presented in alphabetical order. A PT will not be 
presented if no adverse events occur within the level. At each level of summarization, a 
subject is counted only once if the subject reported one or more events.
The seriousness of an AE should be assessed by the Investigator independently from the 
severity of the AE. An 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, or is a congenital anomaly/birth 
defect.
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.
The number and percentage of subjects with any SAEs occurred before subjects reach 
24 months chronological age will be summarized by treatment group in the tables. Within 
each group, SAEs will be summarized by frequency and proportion of total subjects, by 
event type, and by category of body system. A listing of SAEs will be provided.
 
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7.2.2.2.
Congenital Anomaly
Congenital anomaly reported in Phase III SPTL treatment studies, reported in ARIOS 
study (up to 1 year; after 1 year) will be summarized by treatment group. Congenital 
anomalies will be included in SAE listing. 
7.2.2.3.
Death
A listing of infant deaths will be provided. 
7.2.3.
Neurodevelopment Assessment at 9, 18, and 24 months
Neurodevelopment will be assessed by determining the proportions of infants diagnosed
with developmental delays listed below at 9, 18, and 24 months of age, corrected for
prematurity.
Endpoints related to Ages and Stages Questionnaire version 3 (ASQ-3) score and 
developmental evaluation described in Section 2.2 will be descriptively summarized at 9, 
18, and 24 months by treatment group. For subjects with an ASQ-3 score in the black 
zone (>= 2 standard deviation [SD] below the mean) for any domain and referred for 
development evaluation, number of infants and percentage with Bayley Scales of Infant 
Development 3rd edition (BSID-III) and non-BSID-III results will be summarized. For 
subjects with an ASQ-3 score in the black zone for any domain, referred for development 
evaluation, but no assessment done, reason of no assessment done will be summarized. In 
addition to endpoints described in Section 2.2, number of infants and percentage with 
moderate or severe developmental delay using non BSID-III score will be summarized.
For BSID-III score, scaled scores for cognitive, receptive communication, expressive 
communication, fine motor, and gross motor will be derived from the subtest total raw 
scores and range from 1–19, with a mean of 10 and an SD of 3. Language composite 
scores will be derived from sums of receptive communication and expressive 
communication scaled scores. The composite score will be scaled to a metric with a mean 
of 100 and an SD of 15, and range from 40–160.
Endpoints related to Modified Checklist for Autism in Toddlers Revised with Follow-Up 
(M-CHAT-R/F) described in Section 2.2 will be descriptively summarized at 18, and 24 
months by treatment group.
Endpoints related to Child Behavior Checklist for Ages 1.5 to 5 (CBCL/1.5-5) and
cerebral palsy in Section 2.2 will be descriptively summarized at 24 months by treatment 
group.
Neurodevelopment assessment data will be presented in listings. 
7.2.4.
Neurodevelopment Assessment at 3, 4, and 5 years
New neurodevelopmental impairment from Question 8 in Modified Child Health 
Inventory (CHI) will be listed.
 
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7.2.5.
Neurodevelopment Impairment at the End of Study
Number of infants and percentage of neurodevelopment impairment endpoints and 
individual components will be summarized at the end of study (24 months). Individual 
components at the end of study are listed in in Section 2.2. 
Motor composite score will be derived from fine motor and gross motor scaled scores in 
a similar fashion to language composite score described in Section 7.2.3
7.2.6.
Health Outcome
Due to the early termination of the intervention studies (NEW-BORN 1 and ZINN) and 
the subsequent low enrolment in this study, exploratory health outcome data will only be 
provided in listings.
8.
DEVIATION OF PLANNED ANALYSES FROM
PROTOCOL
No changes will be made to the planned analyses after the breaking of the study blind.
 
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9.
REFERENCES
Bayley Scales of Infant and Toddler Development Third Edition, Copyright © 2006 by 
NCS Pearson, Inc.
 
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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Definitions 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Treatment States and Phases
Section 10.4
Appendix 4: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.5
Appendix 5: Derived and Transformed Data

General, Study Population & Safety

Efficacy
Section 10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Other RAP Appendices
Section 10.7
Appendix 7: Abbreviations & Trade Marks
Section 10.8
Appendix 8: List of Data Displays
 
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10.1.
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.
Summary of protocol deviation will not be presented.
 
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10.2.
Appendix 2: Time and Events
Event
28 Days Post EDD
Months
2
6
9
12
15
18
21
24
Written informed consent1
Baseline characteristics and demographic data
X2
RCC confirms and updates contact information from the 
parent/legal guardian
X
Parent/legal guardian completes CHI3
X
X
X
X
X
X
X
X
RCC-PI follows up with HCP and reviews medical or other 
records to confirm parent-reported outcomes
RCC-PI reviews CHI results and refers to birth-defect evaluator 
based on results
Parent/legal guardian completes productivity questionnaire4
Parent/legal guardian completes ASQ-36
X5
X5
X5
RCC-PI reviews ASQ-3 results and refers for developmental 
evaluation based on results6
Parent/legal guardian completes M-CHAT-R/F7
X
X
Parent/legal guardian completes CBCL/1.5–57
X
RCC-PI refers child to specialist for cerebral palsy assessment (if 
required)8
X
 
 
 
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ASQ-3 = Ages and Stages Questionnaire-3; CBCL/1.5–5 = Child Behavior Checklist for ages 1.5 to 5; CHI = Child Health Inventory; EDD = estimated date of delivery; HCP = health 
care provider; M-CHAT-R/F = Modified Checklist for Autism in Toddlers-Revised with Follow-Up; RCC = research coordinating center; RCC-PI = research coordinating center-
principal investigator.
Note:  All specified completion windows for applicable questionnaires (CHI, ASQ-3, CBCL/1.5–5, M-CHAT-R/F, and productivity) are provided to help standardize the data and avoid 
overlap. Information captured outside of these windows will be collected and analyzed separately, and questionnaires completed outside the completion window will not be 
considered protocol deviations.
1.
Collected at the start of the Phase III spontaneous preterm labor (SPTL) treatment studies until the later date of either the date of discharge from the birth hospitalization or up to 
9 months corrected age (to allow for the infant’s 9-month CHI and ASQ-3 data collection).
2.
Captured in Phase III SPTL treatment studies and combined with child follow-up data for analyses.
3.
A positive response by the parent/legal guardian may trigger follow-up with the relevant HCP and/or medical record review for confirmation or more details on the condition or 
hospitalization. At each time point, the completion window of the CHI is +6 weeks.
4.
Completed if infant has been treated by a specialist or has had an emergency room/urgent care or hospital visit. The completion window for the productivity questionnaire is 
+2 weeks from the date of completion of the relevant CHI.
5.
Based on infant’s corrected age. The completion window for the ASQ-3 is +30 days at Month 9 and ±30 days at Months 18 and 24.
6.
If the parent/legal guardian receives a referral, then a qualified specialist will complete required assessments.
7.
The CBCL/1.5–5 and M-CHAT-R/F questionnaires will be completed for all infants. The completion window for the CBCL/1.5–5 and M-CHAT-R/F is +6 weeks at 18 months 
(M-CHAT-R/F only) and +12 weeks at 24 months. 
8.
Referral will be made for infants who score in the black zone for the gross motor skills domain on the 24-month corrected age ASQ-3 and do not have an existing diagnosis of 
cerebral palsy.
 
 
 
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10.3.
Appendix 3: Treatment States and Phases
Not applicable. 
This is a safety follow-up study of infants and children exposed to treatment during their 
mother’s participation in a Phase III SPTL treatment study of retosiban or comparator for 
SPTL. Infants and children enrolled in this study will not be administered any 
investigational product.
 
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10.4.
Appendix 4: Data Display Standards & Handling 
Conventions
10.4.1.
Study Treatment & Sub-group Display Descriptors
Study Treatment Descriptions
Code
Description
Order of Table Presentation
1
Retosiban (Combined)
4
2
ZINN Atosiban
2
3
NEWBORN-1 Placebo
1
2, 3
Comparators (Combined)
3
10.4.2.
Baseline Definition
Baseline characteristics and demographic data will be captured from the Phase III SPTL 
treatment studies and combined with child follow-up data for analyses. For all endpoints 
in ARIOS study, baseline value is not required for analysis.
10.4.3.
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 1.1.

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
Formats

For safety analyses, all data will be reported according to the actual treatment the mother
received.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
 
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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. 
Planned and Actual Time

Reporting for tables and formal statistical analyses :
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 for mother 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 summaries and statistical analyses.
Unscheduled Visits

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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10.5.
Appendix 5: Derived and Transformed Data
10.5.1.
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.

Unscheduled visit will be included in the listings. 
Study Day

Calculated as the number of days from the first study treatment date for mothers :
[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
Note: All assessments should be done after the first study treatment date for mothers.    
 
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10.6.
Appendix 6: Premature Withdrawals & Handling of Missing 
Data
10.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion status is defined as subjects who are prematurely 
withdrawn.

Subjects who are withdrawn from study participation after enrolment in ARIOS 
study will not be replaced.
10.6.2.
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.

For disposition and demographic data, no imputation will be done.  

For safety and neurodevelopment data, it will be assumed that the events of 
interest did not occur.
10.6.2.1.
Handling of Missing/Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays. No imputation 
will be applied.
 
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10.7.
Appendix 7: Abbreviations & Trade Marks
10.7.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ASQ-3
Ages and Stages Questionnaire version 3
BMI
Body mass index
BSID III
Bayley Scales of Infant Development 3rd Edition
CBCL/1.5-5
Child Behaviour Checklist for Ages 1.5-5
CHI
Child Health Inventory
CSR
Clinical Study Report
eCRF
electronic Case Report Form
EDD
Estimated Date of Delivery
FMM
Finite Mixture Models
GA 
Gestational Age
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IDSL
Integrated Data Standards Library
MedDRA 
Medical Dictionary for Regulatory Activities
M-CHAT-R/F
Modified Checklist for Autism in Toddlers Revised with Follow-Up
RAP
Reporting and Analysis Plan
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
SPTL
Spontaneous Preterm Labor
10.7.2.
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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10.8.
Appendix 8: List of Data Displays
A separate document for shells contains all table, listing and figures’ (TLFs) for the 
planned final analysis. 
10.8.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
10.1 to 10.4
Safety
10.5, 20.5, 10.6, 20.6
Other Analysis
10.7, 20.7, 10.8, 20.8, 
10.10, 20.10, 10.11, 20.11
Section
Listings
ICH Listings
37, 38, 42 to 44
Other Listings
39 to 41, 45, 46
 
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10.8.2.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition 
10.1
Infant Safety
Infant Subject Disposition 
10.2
Infant Safety
Number of Infants Enrolled at Milestone 
Demographics
10.3
ARIOS
Safety
Infant Subject Demographic and Baseline 
Characteristics
10.4
ARIOS
Safety
Summary of Subject Race and Racial Combinations
Medical Condition
10.6
Infant Safety 
Newly Diagnosed Chronic Medical Condition
20.6
ARIOS 
Safety
Newly Diagnosed Chronic Medical Condition
 
 
 
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10.8.3.
Safety Tables
Safety Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Adverse Events
10.5
Infant Safety 
Summary of Infant Serious Adverse Events
20.5
ARIOS Safety
Summary of Infant Serious Adverse Events
Neurodevelopment Assessments
10.7
Infant Safety
Neurodevelopment Assessments (ASQ-3 and BSID-III scores) at 9, 18 and 24 Months
20.7
ARIOS Safety
Neurodevelopment Assessments (ASQ-3 and BSID-III scores) at 9, 18 and 24 Months
10.8
Infant Safety
Neurodevelopment Assessments (CBCL/1.5-5. M-CHAT-R/F, Cerebral Palsy or 
Behavioral Specialist) at 18 and 24 Months
20.8
ARIOS Safety
Neurodevelopment Assessments (CBCL/1.5-5. M-CHAT-R/F, Cerebral Palsy or 
Behavioral Specialist) at 18 and 24 Months
10.9
Infant Safety 
Neurodevelopment Impairment at the End of Study (24 Months)
20.9
ARIOS Safety
Neurodevelopment Impairment at the End of Study (24 Months)
Congenital Anomaly
10.10
Infant Safety 
Summary of Congenital Anomaly
20.10
ARIOS Safety
Summary of Congenital Anomaly
 
 
 
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10.8.4.
ICH Listings
ICH Listings
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
37
ARIOS Safety
Study Disposition
Demographics
38
ARIOS Safety
Demographic and Baseline Characteristics
43
ARIOS Safety
Race and Racial Combinations
Adverse Events
42
ARIOS Safety
Infant Serious Adverse Events
44
ARIOS Safety
Infant Deaths
 
 
 
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10.8.5.
Non-ICH Listings
Non-ICH Listings
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Medical Condition
39
ARIOS Safety
Newly Diagnosed Chronic Medical Conditions
Health Outcome
46
ARIOS Safety
Infant Hospital Utilization
Neurodevelopment
40
ARIOS Safety
Neurodevelopment Assessments at 9, 18 and 24 Months
41
ARIOS Safety
Neurodevelopment Assessments at 3, 4 and 5 Years
45
ARIOS Safety
Developmental Evaluation
 
 
 
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