Immunogenicity and Safety Study of Two Formulations of GlaxoSmithKline (GSK) Biologicals' Human Rotavirus (HRV) Vaccine (444563), in Healthy Infants Starting at Age 6-12 Weeks
Phase: PHASE3
Conditions: Infections, Rotavirus, Rotavirus Vaccines
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l'Institut 89
1330 Rixensart, Belgium
Primary Study vaccine and 
number
Porcine circovirus (PCV)-free liquid formulation of 
GlaxoSmithKline (GSK) Biologicals’ oral live 
attenuated human rotavirus (HRV) vaccine (444563)
Other Study vaccine
Lyophilised formulation of GSK Biologicals’ oral live 
attenuated HRV vaccine (444563)
eTrack study number and 
Abbreviated Title
115461 (ROTA-081)
Investigational New Drug 
(IND) number
BB-IND-16992
EudraCT number
2016-000598-19
Date of protocol
Final Version 1: 03 June 2016
Date of protocol 
amendment/administrative 
change
Administrative change 1 Final: 22 June 2016
Administrative change 2 Final: 06 September 2016
Amendment 1 Final: 09 March 2017
Title
Immunogenicity and safety study of two formulations 
of GlaxoSmithKline (GSK) Biologicals’ human 
rotavirus (HRV) vaccine (444563), in healthy infants 
starting at age 6-12 weeks.
Detailed Title
A phase IIIA, randomised, observer-blind, multi-centre
study to evaluate the clinical consistency of three 
production lots of the Porcine circovirus (PCV)-free 
liquid formulation of GlaxoSmithKline (GSK) 
Biologicals’ oral live attenuated human rotavirus 
(HRV) vaccine and to evaluate the PCV-free liquid 
formulation of GSK Biologicals’ HRV vaccine as 
compared to the currently licensed lyophilised 
formulation of the HRV vaccine in terms of 
immunogenicity, reactogenicity and safety when 
administered as a two-dose vaccination in healthy 
infants starting at age 6-12 weeks.
Co-ordinating author
Contributing authors
(Amended: 09 March 2017)
!
, Clinical & Epidemiology Project 
Lead
!
 Clinical Research and Epidemiology 
Lead
!
, Statistician
!
, Lead Statistician
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eTrack study number and 
Abbreviated Title
115461 (ROTA-081)
Investigational New Drug 
(IND) number
BB-IND-16992
EudraCT number
2016-000598-19
Detailed Title
A phase IIIA, randomised, observer-blind, multi-centre 
study to evaluate the clinical consistency of three 
production lots of the Porcine circovirus (PCV)-free 
liquid formulation of GlaxoSmithKline (GSK) 
Biologicals’ oral live attenuated human rotavirus 
(HRV) vaccine and to evaluate the PCV-free liquid 
formulation of GSK Biologicals’ HRV vaccine as 
compared to the currently licensed lyophilised 
formulation of the HRV vaccine in terms of 
immunogenicity, reactogenicity and safety when 
administered as a two-dose vaccination in healthy 
infants starting at age 6-12 weeks.
Contributing authors
(Amended: 09 March 2017)
!
, Study Delivery Lead
!
, Project Delivery Lead
!
, Clinical Read-Out Team Leader
!
, Laboratory Study Manager
!
, Clinical Safety representative
!
, Oversight Data Manager
!
, Global Regulatory Affairs 
representative
!
, Global Patents representative
!
, Clinical Trial Supply Manager
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2016-2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.

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Protocol Amendment 1 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
115461 (ROTA-081)
IND number
BB-IND-16992
EudraCT number
2016-000598-19
Date of protocol amendment
Amendment 1 Final: 09 March 2017
Detailed Title
A phase IIIA, randomised, observer-blind, multi-
centre study to evaluate the clinical consistency of 
three production lots of the Porcine circovirus (PCV)-
free liquid formulation of GlaxoSmithKline (GSK) 
Biologicals’ oral live attenuated human rotavirus 
(HRV) vaccine and to evaluate the PCV-free liquid 
formulation of GSK Biologicals’ HRV vaccine as 
compared to the currently licensed lyophilised 
formulation of the HRV vaccine in terms of 
immunogenicity, reactogenicity and safety when 
administered as a two-dose vaccination in healthy 
infants starting at age 6-12 weeks.
Sponsor signatory
Paul Gillard,
Clinical & Epidemiology Project Lead (CEPL),
GlaxoSmithKline Biologicals, SA.
Signature
Date
 
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Protocol Amendment 1 Rationale
Amendment number:
Amendment 1
Rationale/background for changes: 
The protocol is being amended to include the text related to the unapproved medical 
devices and incidents associated with it as per Japan specific requirements.
 
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Protocol Amendment 1 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccines and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccines, and more generally about his/her 
financial ties with the sponsor. GSK Biologicals will use and disclose the 
information solely for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
115461 (ROTA-081)
IND number
BB-IND-16992
EudraCT number
2016-000598-19
Date of protocol amendment
Amendment 1 Final: 09 March 2017
Detailed Title
A phase IIIA, randomised, observer-blind, multi-
centre study to evaluate the clinical consistency of 
three production lots of the Porcine circovirus (PCV)-
free liquid formulation of GlaxoSmithKline (GSK) 
Biologicals’ oral live attenuated human rotavirus 
(HRV) vaccine and to evaluate the PCV-free liquid 
formulation of GSK Biologicals’ HRV vaccine as 
compared to the currently licensed lyophilised 
formulation of the HRV vaccine in terms of 
immunogenicity, reactogenicity and safety when 
administered as a two-dose vaccination in healthy 
infants starting at age 6-12 weeks.
Investigator name
Signature
Date
 
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l'Institut 89
1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.4.2.
5.
GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding.
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to
protocol Section 8.8.
 
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SYNOPSIS
Detailed Title
A phase IIIA, randomised, observer-blind, multi-centre study 
to evaluate the clinical consistency of three production lots of 
the Porcine circovirus (PCV)-free liquid formulation of 
GlaxoSmithKline (GSK) Biologicals’ oral live attenuated 
human rotavirus (HRV) vaccine and to evaluate the PCV-free 
liquid formulation of GSK Biologicals’ HRV vaccine as 
compared to the currently licensed lyophilised formulation of 
the HRV vaccine in terms of immunogenicity, reactogenicity 
and safety when administered as a two-dose vaccination in 
healthy infants starting at age 6-12 weeks.
Indication
Active immunisation of infants against gastroenteritis (GE) 
due to rotavirus (RV).
Rationale for the 
study and study 
design

Rationale for the study
Using advanced technology in 2010, researchers from the 
University of California, San Francisco identified 
Deoxyribonucleic acid (DNA) fragments of Porcine 
circovirus type 1 (PCV-1) in Rotarix. Further investigations 
conducted by GlaxoSmithKline (GSK) and the United States 
(US) Food and Drug Administration (FDA) confirmed the 
presence of PCV-1 DNA fragments in Rotarix and its starting 
materials as well as low levels of PCV-1 viral particles during 
production process and in the final container. The evidence 
from retrospective laboratory investigations conducted by 
GSK on 40 HRV vaccine recipients showed that none of the 
subjects who received the HRV vaccine demonstrated 
seroconversion to PCV-1 while the PCV-1 from the vaccine 
was identified in the stool samples of 4 infants from the HRV 
group (at Day 3 and Day 7 post Dose 1). The detection of 
PCV-1 DNA only at the earliest time points post-vaccination 
was consistent with transient passage of DNA through the 
infants’ digestive tracts without replication. Lack of PCV-1 
infection is further supported by the absence of anti-PCV-1 
antibody in the HRV vaccine recipients, including the infants 
who had PCV-1 DNA detected in their stool samples. 
Therefore, currently available data do not suggest occurrence 
of PCV-1 infection in infants who received Rotarix in clinical 
trials [Dubin, 2013]. These results are consistent with 
published literature which indicates that PCV-1 is not capable 
of causing infection in humans [Hattermann, 2004a; 
Hattermann, 2004b].
GSK is in the process of replacing the cell bank and virus 
seeds used as base production material for its HRV vaccine. In 
the meantime, and in accordance with the regulators, the 
 
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company continues to manufacture Rotarix to the existing 
approved production and quality standards to meet public 
health needs worldwide.

Rationale for the study design
In order to support licensure of the PCV-free liquid HRV 
vaccine, GSK Biologicals proposes to conduct a clinical study 
to demonstrate the lot-to-lot consistency of the PCV-free 
liquid HRV vaccine in terms of anti-RV Immunoglobulin A 
(IgA) antibody geometric mean antibody concentrations 
(GMCs), 1-2 months after Dose 2 and the non-inferiority of 
the PCV-free liquid HRV vaccine to GSK Biologicals’ 
currently licensed lyophilised HRV vaccine in terms of anti-
rotavirus IgA seroconversion rates and GMCs 1-2 months 
after Dose 2.
This study is planned to be conducted in 1600 children aged 
6-12 weeks, randomised (1:1:1:1) between groups receiving 
GSK Biologicals’ currently licensed lyophilised HRV vaccine 
and three different lots of PCV-free liquid HRV vaccine.
The current lyophilised PCV-containing vaccine will be used 
as control, since the study is planned to be conducted in US 
and non-US sites and the liquid formulation of Rotarix is not 
licensed in the US.
Two oral doses of the study vaccines will be administered at 
an approximate 1-month or 2-months interval to subjects, 
according to the immunisation schedule for RV vaccine 
administration in participating countries. Blood samples for 
immunogenicity assessment will be collected from all subjects 
before the first dose and at 1-2 months post Dose 2.
An Independent Data Monitoring Committee (IDMC) will 
review the safety data of the first 5%, 10% and 50% of the 
subjects enrolled to evaluate if there is any safety concern 
with the PCV-free liquid HRV vaccine. Enrolment will be 
paused when first 10% of study sets are enrolled, for the 
purpose of the IDMC review of the safety data up to 8 days 
post dose 2 (Day 0-Day 7) and will only resume if the 
outcome of the IDMC review is positive.
Objectives
Co-Primary

To demonstrate the lot-to-lot consistency of the PCV-free 
liquid HRV vaccine in terms of immunogenicity as 
measured by serum anti-RV IgA antibody concentrations 
1-2 months after Dose 2.
 
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Consistency will be demonstrated if, for all pairs of lots, the 
two-sided 95% confidence intervals (CIs) for the ratio of 
anti-RV IgA antibody GMCs 1-2 months after Dose 2 are 
within the [0.5; 2] clinical limit interval.

To demonstrate the immunological non-inferiority of 
PCV-free liquid HRV vaccine as compared to the 
currently licensed lyophilised HRV vaccine in terms of 
seroconversion rates 1-2 months after Dose 2.
Non-inferiority will be demonstrated if the lower limit of the 
two-sided asymptotic standardized 95% CI for the difference 
in seroconversion rate between the PCV-free liquid HRV 
vaccine (pooled HRV liquid groups) and licensed lyophilised 
HRV vaccine is greater than or equal to -10%.

To demonstrate the non-inferiority of the PCV-free liquid 
HRV vaccine to that of the currently licensed lyophilised 
HRV vaccine in terms of serum anti-RV IgA antibody 
concentrations 1-2 months after Dose 2.
Non-inferiority will be demonstrated if the lower limit of the 
two-sided 95% CI for the ratio of anti-RV IgA antibody GMCs 
1-2 months after Dose 2 between the PCV-free liquid HRV 
vaccine (pooled HRV liquid groups) and the lyophilised HRV 
vaccine is greater than or equal to 0.67.
Secondary
Reactogenicity and safety

To evaluate the reactogenicity of the liquid HRV vaccine 
and currently licensed lyophilised HRV vaccine in terms 
of solicited AEs during the 8 days (Day 0-Day 7) follow-
up period after each vaccination.

To assess the safety of the study vaccines in terms of 
unsolicited AEs during the 31 days (Day 0-Day 30) 
follow-up period after each vaccination and Serious 
Adverse Events (SAEs) during the entire study period.
Immunogenicity

To assess the immunogenicity of the PCV-free liquid 
HRV vaccine and the currently licensed lyophilised HRV 
vaccine, in terms of percentage of subjects with anti-RV 
IgA antibody concentrations ≥ 90 U/mL 1-2 months after 
Dose 2.
 
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Study design

Experimental design: Phase IIIA, observer-blind, 
randomised (1:1:1:1), controlled, multi-centric, with four 
parallel groups and a staggered enrolment (Part A and Part 
B).

Duration of the study: The intended duration of the study, 
per subject, will be approximately 7-8 months including 
the 6 months of extended safety follow-up period after 
the last dose of HRV vaccine.

Epoch 001: Primary starting at Visit 1 (Day 0) and 
ending at the safety follow-up contact (Month 7-8).

Primary completion Date (PCD): Visit 3 (Month 2-4).

End of Study (EoS): Last testing results released of 
samples collected at Visit 3 or Last Subject Last Visit
(LSLV) (Follow up contact at month 7-8).

Study groups: The study groups and epoch foreseen in the 
study are provided in Synopsis Table 1.
The study groups and treatments foreseen in the study are 
provided in Synopsis Table 2.
Synopsis Table 1
Study groups and epoch foreseen in the study
Study Groups
Number of 
subjects
Age at Dose 1 (Min-Max)
Epoch
Epoch 001 
Liq_A
400
6 weeks-12 weeks
●
Liq_B
400
6 weeks-12 weeks
●
Liq_C
400
6 weeks-12 weeks
●
Lyo
400
6 weeks-12 weeks
●
Synopsis Table 2
Study groups and treatments foreseen in the study
Treatment name
Vaccine name
Study Groups
Liq_A 
Liq_B
Liq_C
Lyo
HRV Liquid
HRV PCV-free ‡
x
x
x
HRV Lyophilised
HRV *
x
‡ PCV-free HRV liquid vaccine
* Licensed formulation of HRV lyophilised vaccine

PCV-free HRV liquid formulation lot A (also 
referred to as Liq_A group)

PCV-free HRV liquid formulation lot B (also 
referred to as Liq_B group)

PCV-free HRV liquid formulation lot C (also 
referred to as Liq_C group)

GSK Biologicals’ currently licensed lyophilised 
HRV formulation (also referred to as Lyo group)
 
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
Control: active control-GSK Biologicals’ currently 
licensed lyophilised HRV vaccine.

Vaccination schedule: Two doses of HRV vaccine to be 
administered according to a 0, 1-2 month schedule 
according to the immunisation schedule for RV vaccine.

Concomitant administration of routine childhood 
vaccines will be allowed according to local 
immunisation practices in each participating country.

Treatment allocation: Randomised 1:1:1:1 using GSK 
Biologicals’ central randomisation system on Internet 
(SBIR).

Blinding: observer-blind
The blinding of study epoch is provided in Synopsis Table 3.
Synopsis Table 3
Blinding of study epoch
Study Epoch
Blinding*
Epoch 001
Double-blind
Epoch 001
Observer-blind
*Double blind for the three lots of PCV-free HRV liquid vaccine and observer-blind for the liquid formulation versus 
the lyophilised formulation.

Sampling schedule: Blood samples will be collected from 
all subjects at Visit 1 and Visit 3 to measure serum anti-RV 
IgA antibody concentrations using Enzyme Linked 
Immunosorbent Assay (ELISA). 

Recording of GE episodes: Any GE episodes occurring 
from Dose 1 of HRV vaccine up to Visit 3 will be recorded 
for all subjects in the diary card. Parents/Legally 
Acceptable Representative(s) (LARs) will be instructed to 
collect stool sample(s) if the subject develops GE during 
the period from Dose 1 of HRV vaccine up to Visit 3. A 
stool sample should be collected as soon as possible after 
illness begins and preferably not later than 7 days after the 
start of GE symptoms. Two occurrences of diarrhoea will 
be classified as separate episodes if there will be five or 
more diarrhoea-free days between the episodes. Refer to 
the glossary of terms for definitions of GE and diarrhoea.

Recording of Solicited AEs: Solicited AEs (fever, 
fussiness/irritability, loss of appetite, cough/runny nose, 
diarrhoea and vomiting) occurring between the day of each 
HRV vaccine dose and the following 7 days (Day 0-Day 7) 
will be recorded daily using diary cards for all subjects.

Recording of Unsolicited AEs: Unsolicited AEs occurring 
within 31 days (Day 0-Day 30) after each dose of HRV 
vaccine will be recorded using diary cards for all subjects.
 
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
Recording of SAEs: SAEs will be recorded from Visit 1 
(Day 0) up to 6 months after Dose 2 of HRV vaccine.

Type of study: e.g., self-contained

Data collection: Electronic Case Report Form (eCRF)

Safety monitoring: An IDMC comprising of clinical 
experts and a biostatistician, will review the safety data 
accrued during the study and the details of the review will 
be described in an IDMC charter. The IDMC review will 
happen after enrolment of 5%, 10% and 50% of subjects. 
The IDMC review will happen at the following stages:
Review of all safety data for the first 80 enrolled subjects 
(5% of total enrolment) as soon as data until 8 days post 
Dose 2 (Day 0-Day 7) are available for 80 subjects.

any available data beyond 8 days post Dose 2 will also 
be reviewed.

during this IDMC review, enrolment of subjects will 
continue.
Review of all safety data for the first 160 enrolled subjects 
(10% of total enrolment) as soon as data until 8 days post 
Dose 2 (Day 0-Day 7) are available for160 subjects.

any available data beyond 8 days post Dose 2 will also 
be reviewed.

until this IDMC review, enrolment of subjects will 
pause. Enrolment will resume only if no safety 
concerns are raised by IDMC.
Review of all safety data for the first 800 enrolled subjects 
(50% of total enrolment) as soon as data until 8 days post 
Dose 2 (Day 0-Day 7) are available for 800 subjects.

any available data beyond 8 days post Dose 2 will also 
be reviewed.

during this IDMC review, enrolment of subjects will 
continue.
Number of subjects
The target enrolment will be 1600 subjects (400 subjects in each 
of the PCV-free liquid vaccine groups and 400 subjects in the 
lyophilised vaccine group) to obtain at least 1280 evaluable 
subjects (320 subjects in each of the PCV-free liquid vaccine 
groups and 320 subjects in the lyophilised vaccine group).
 
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Endpoints
Primary

Evaluation of immunogenicity in terms of anti-RV 
antibody concentrations

Serum anti-RV IgA antibody concentrations expressed 
as GMCs 1-2 months after Dose 2 in each of the HRV 
liquid formulation groups (Liq_A, Liq_B and Liq_C).

Anti-RV IgA antibody seroconversion rate* 1-2 
months after Dose 2 in the lyophilised and pooled 
liquid groups.

Serum anti-RV IgA antibody concentrations expressed 
as GMCs 1-2 months after Dose 2 in the lyophilised 
and pooled liquid groups.
*Seroconversion rate is defined as the percentage of subjects 
who were initially seronegative (i.e., with anti-RV IgA antibody 
concentration < 20 U/mL prior the first dose of HRV vaccine) 
and developed anti-RV IgA antibody concentration ≥ 20 U/mL 
at Visit 3.
Secondary

Solicited adverse events

Occurrence of each general solicited symptom within 
the 8 days (Day 0-Day 7) follow-up period after each 
dose of the lyophilised and PCV-free HRV liquid 
vaccine

Unsolicited adverse events. 

Occurrence of unsolicited AEs within 31 days (Day 0-
Day 30) after any dose of HRV vaccine, according to 
the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

Serious adverse events

Occurrence of serious adverse events from Dose 1 up 
to study end.

Evaluation of immunogenicity in terms of anti-RV 
antibody concentrations.

Serum anti-RV IgA antibody concentrations ≥ 90 
U/mL 1-2 months after Dose 2 in the lyophilised and 
pooled liquid groups.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................24
GLOSSARY OF TERMS ...............................................................................................27
TRADEMARK................................................................................................................31
1.
INTRODUCTION....................................................................................................32
1.1.
Background ................................................................................................32
1.2.
Rationale for the study and study design ....................................................33
1.2.1.
Rationale for the study.................................................................33
1.2.2.
Rationale for the study design......................................................33
1.3.
Benefit: Risk Assessment ...........................................................................34
1.3.1.
Risk Assessment .........................................................................34
1.3.2.
Benefit Assessment.....................................................................35
1.3.3.
Overall Benefit: Risk Conclusion..................................................35
2.
OBJECTIVES.........................................................................................................35
2.1.
Co-Primary objectives.................................................................................35
2.2.
Secondary objectives..................................................................................36
3.
STUDY DESIGN OVERVIEW ................................................................................37
4.
STUDY SET...........................................................................................................40
4.1.
Number of subjects/centres ........................................................................40
4.2.
Inclusion criteria for enrolment....................................................................40
4.3.
Exclusion criteria for enrolment...................................................................41
5.
CONDUCT OF THE STUDY ..................................................................................42
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................42
5.2.
Subject identification and randomisation of treatment .................................43
5.2.1.
Subject identification....................................................................43
5.2.2.
Randomisation of treatment.........................................................43
5.2.2.1.
Randomisation of supplies..........................................43
5.2.2.2.
Treatment allocation to the subject.............................43
5.2.2.2.1.
Study group and treatment 
number allocation ...................................43
5.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................44
5.3.
Method of blinding ......................................................................................44
5.4.
General study aspects ................................................................................44
5.5.
Outline of study procedures ........................................................................45
5.6.
Detailed description of study procedures ....................................................47
5.6.1.
Informed consent.........................................................................47
 
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5.6.2.
Check inclusion and exclusion criteria .........................................47
5.6.3.
Check contraindications, warnings and precautions to 
vaccination...................................................................................47
5.6.4.
Medical and vaccination history ...................................................47
5.6.5.
Collect demographic data ............................................................47
5.6.6.
History directed physical examination..........................................48
5.6.7.
Physical examination ...................................................................48
5.6.8.
Assess pre-vaccination body temperature ...................................48
5.6.9.
Study group and treatment number allocation..............................48
5.6.10.
Sampling......................................................................................48
5.6.10.1.
Blood sampling for safety and immune 
response assessments...............................................48
5.6.10.2.
Other biological samples ............................................49
5.6.11.
Study Vaccines administration.....................................................49
5.6.12.
Record regurgitation ....................................................................49
5.6.13.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................49
5.6.14.
Recording of AEs and SAEs ........................................................50
5.6.15.
Phone Contact.............................................................................50
5.6.16.
Study conclusion..........................................................................50
5.7.
Biological sample handling and analysis.....................................................51
5.7.1.
Use of specified study materials ..................................................51
5.7.2.
Biological samples.......................................................................52
5.7.3.
Laboratory assays .......................................................................52
5.7.4.
Biological samples evaluation......................................................53
5.7.4.1.
Immunological read-outs ............................................53
5.7.5.
Immunological correlates of protection.........................................53
6.
STUDY VACCINES................................................................................................54
6.1.
Description of study vaccines......................................................................54
6.2.
Storage and handling of study vaccines......................................................54
6.3.
Dosage and administration of study vaccines .............................................55
6.4.
Replacement of unusable vaccine doses....................................................56
6.5.
Contraindications to subsequent vaccination ..............................................56
6.6.
Warnings and precautions ..........................................................................57
6.7.
Concomitant medications/products and concomitant vaccinations..............58
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................58
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from PPS analyses........................58
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from PPS analyses .........................................................................59
7.
HEALTH ECONOMICS ..........................................................................................59
8.
SAFETY.................................................................................................................59
8.1.
Safety definitions ........................................................................................60
8.1.1.
Definition of an adverse event......................................................60
8.1.2.
Definition of a serious adverse event ...........................................61
8.1.3.
Solicited adverse events..............................................................62
8.1.3.1.
Solicited general adverse events................................62
 
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8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................62
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................62
8.3.
Detecting and recording adverse events, serious adverse events...............63
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events................................................................63
8.3.2.
Post-Study adverse events and serious adverse events..............64
8.3.3.
Evaluation of adverse events and serious adverse events...........65
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................65
8.3.3.2.
Assessment of adverse events...................................66
8.3.3.2.1.
Assessment of intensity..........................66
8.3.3.2.2.
Assessment of causality .........................67
8.3.3.3.
Assessment of outcomes............................................68
8.3.3.4.
Medically attended visits.............................................69
8.4.
Reporting of serious adverse events...........................................................69
8.4.1.
Prompt reporting of serious adverse events to GSK 
Biologicals ...................................................................................69
8.4.2.
Contact information for reporting serious adverse events ............69
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................70
8.4.3.1.
Back-up system in case the electronic 
reporting system does not work..................................70
8.4.4.
Updating of SAE information after removal of write access 
to the subject’s eCRF...................................................................70
8.4.5.
Regulatory reporting requirements for serious adverse 
events..........................................................................................70
8.5.
Follow-up of adverse events and serious adverse events...........................71
8.5.1.
Follow-up of adverse events and serious adverse events............71
8.5.1.1.
Follow-up during the study..........................................71
8.5.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................71
8.6.
Treatment of adverse events ......................................................................71
8.7.
Unblinding...................................................................................................72
8.8.
Emergency unblinding (Amended: 06 September 2016).............................72
8.9.
Subject card................................................................................................73
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................74
9.1.
Subject completion .....................................................................................74
9.2.
Subject withdrawal......................................................................................74
9.2.1.
Subject withdrawal from the study ...............................................74
9.2.2.
Subject withdrawal from investigational vaccines.........................75
10. STATISTICAL METHODS......................................................................................75
10.1.
Primary endpoints.......................................................................................75
10.2.
Secondary endpoints ..................................................................................76
10.3.
Determination of sample size......................................................................76
10.3.1.
Control on type I error..................................................................76
10.3.2.
References for sample size .........................................................77
10.3.3.
Power computation......................................................................78
 
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10.4.
Analyses Sets.............................................................................................79
10.4.1.
Exposed Set ................................................................................79
10.4.2.
Per-Protocol analysis Set of immunogenicity ...............................79
10.5.
Derived and transformed data.....................................................................80
10.6.
Analysis of demographics...........................................................................81
10.7.
Analysis of immunogenicity.........................................................................81
10.7.1.
Within groups assessment...........................................................81
10.7.2.
Between groups assessment.......................................................82
10.8.
Analysis of safety........................................................................................82
10.8.1.
Within groups assessment...........................................................82
10.9.
Interpretation of analyses............................................................................83
10.9.1.
Statistical Methods.......................................................................83
10.10. Conduct of analyses ...................................................................................83
10.10.1. Sequence of analyses..................................................................84
10.10.2. Statistical considerations for interim analyses..............................84
11. ADMINISTRATIVE MATTERS ...............................................................................84
11.1.
Electronic Case Report Form instructions...................................................84
11.2.
Study Monitoring by GSK Biologicals..........................................................85
11.3.
Record retention .........................................................................................85
11.4.
Quality assurance.......................................................................................86
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................86
11.6.
Provision of study results to investigators ...................................................87
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................87
12.1.
Requirements for Germany.........................................................................87
12.1.1.
EXPLANATORY STATEMENT CONCERNING GENDER 
DISTRIBUTION (ARTICLE 7, PARAGRAPH 2 (12) OF 
THE GERMAN GCP ORDER) .....................................................87
12.2.
Requirements for Japan (Amended: 09 March 2017)..................................87
12.2.1.
Regulatory and Ethical Considerations, including the 
Informed Consent Process ..........................................................87
12.2.2.
Study and site closure..................................................................88
12.2.3.
Regulatory and Ethical Considerations ........................................88
12.2.4.
Informed Consent ........................................................................88
12.2.5.
Study Period................................................................................89
12.2.6.
Study administrative structure......................................................89
12.2.7.
Concerning the "Biological sample handling and analysis" ..........89
12.2.8.
Unapproved Medical Devices ......................................................89
12.2.8.1.
Definitions of an Unapproved Medical Device 
Incident.......................................................................90
12.2.8.2.
Detecting and recording Unapproved Medical 
Device Incidents.........................................................90
12.2.8.2.1.
Time Period for Detecting 
Unapproved Medical Device 
Incidents.................................................90
12.2.8.2.2.
Unapproved Medical Device 
Incident Documenting.............................91
12.2.8.3.
Prompt Reporting of Unapproved Medical 
Device Incidents to Sponsor.......................................91
 
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12.2.8.3.1.
Regulatory Reporting 
Requirements for Unapproved 
Medical Device Incidents........................91
12.2.8.4.
Follow-up of Unapproved Medical Device 
Incidents.....................................................................92
13. REFERENCES.......................................................................................................93
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epoch foreseen in the study.......................................38
Table 2
Study groups and treatments foreseen in the study................................38
Table 3
Blinding of study epoch ..........................................................................39
Table 4
List of study procedures .........................................................................46
Table 5
Intervals between study visits.................................................................47
Table 6
Biological samples .................................................................................52
Table 7
Humoral Immunity (Antibody determination)...........................................52
Table 8
Immunological read-outs........................................................................53
Table 9
Study vaccines.......................................................................................54
Table 10
Dosage and administration.....................................................................56
Table 11
Solicited general adverse events............................................................62
Table 12
Reporting periods for collecting safety information .................................64
Table 13
Intensity scales be used by the parent(s)/LAR(s) for solicited 
symptoms during the solicited follow-up period ......................................66
Table 14
Intensity scales for diarrhoea, vomiting and fever occurring 
during the solicited period ......................................................................66
Table 15
Timeframes for submitting serious adverse event reports to GSK 
Biologicals..............................................................................................69
Table 16
Seroconversion rates and standard deviation for log10
transformed concentration post vaccination. ..........................................77
Table 17
Power to demonstrate that the two-sided 95% CIs on the anti-RV 
IgA GMC ratio between PCV free liquid vaccine, 1-2 months after 
dose 2 of HRV vaccine lots are within the [0.5; 2.0] interval for all 
the pair wise comparisons......................................................................78
Table 18
Probability that the lower limit of 95% CI for the difference in 
seroconversion rate (the pooled PCV free liquid vaccine group 
minus the lyophilised vaccine group), 1-2 months after dose 2 of 
HRV vaccine is ≥-10%............................................................................78
Table 19
Probability that the lower limit of the 95% CI on anti-rotavirus IgA 
antibody GMC ratio (the pooled PCV free liquid vaccine group 
 
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divided by the lyophilised vaccine group), 1-2 months after dose 
2 of HRV vaccine is ≥ 0.67 .....................................................................79
Table 20
Unapproved Medical Device(s) ..............................................................89
Table 21
GSK Biologicals’ laboratories .................................................................96
Table 22
Outsourced laboratories.........................................................................96
 
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LIST OF FIGURES
PAGE
Figure 1
Sequence for evaluating the study objectives in order to control 
the overall type I error below 2.5% .........................................................77
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .......................................................................95
APPENDIX B CLINICAL LABORATORIES ..................................................................96
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................97
 
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LIST OF ABBREVIATIONS
AE:
Adverse event
ATP:
According-To-Protocol
CCID50:
Median Cell Culture Infective Dose (quantity of virus 
causing infection in 50% of exposed cells)
CDISC:
Clinical Data Interchange Standards Consortium
CI:
Confidence Interval
CLS:
Clinical Laboratory Sciences
CSR:
Clinical Study Report
DNA:
Deoxyribonucleic acid
eCRF:
electronic Case Report Form
ELISA:
Enzyme Linked Immunosorbent Assay
EoS:
End of Study
ES:
Exposed Set
eTDF:
Electronic Temperature excursion Decision Form
EU: 
European Union
FDA:
Food and Drug Administration 
GCP:
Good Clinical Practice
GE:
Gastroenteritis
GMC:
Geometric Mean antibody Concentration
GSK:
GlaxoSmithKline
HRV:
Human Rotavirus
ICF:
Informed Consent Form
ICH:
International Conference on Harmonisation
IDMC:
Independent Data Monitoring Committee
IEC:
Independent Ethics Committee
 
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IgA:
Immunoglobulin A
IMP:
Investigational Medicinal Products
IND:
Investigational New Drug
IRB:
Institutional Review Board
IS:
Intussusception
Kg:
Kilograms
LAR:
Legally Acceptable Representative
Liq_A:
Group receiving PCV-free HRV liquid formulation lot A 
Liq_B:
Group receiving PCV-free HRV liquid formulation lot B 
Liq_C:
Group receiving PCV-free HRV liquid formulation lot C 
LSLV:
Last Subject Last Visit
Lyo:
Group receiving GSK Biologicals’ currently licensed 
lyophilised HRV formulation
MATEX: 
MATerial Excellence
MedDRA:
Medical Dictionary for Regulatory Activities
Mg:
Milligrams
mL:
Millilitre
PASS:
Power Analysis and Sample Size
PCD:
Primary Completion Date
RT-PCR:
Reverse Transcription Polymerase Chain reaction
PCV:
Porcine Circovirus
PPS:
Per-Protocol Set
RCC:
Reverse Cumulative Curve
RV:
Rotavirus
RVGE:
Rotavirus Gastroenteritis
SAS:
Statistical Analysis System
 
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SAE:
Serious Adverse Event
SBIR:
Randomisation System on Internet
SCID:
Severe Combined Immunodeficiency
SDV:
Source Document Verification
SPM:
Study Procedures Manual
TVC:
Total Vaccinated Cohort
U:
Unit
US:
United States
WHO:
World Health Organisation
 
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GLOSSARY OF TERMS
Adverse event:
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. 
An Adverse Event (AE) can therefore be any 
unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a 
medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e.,
lack of efficacy), abuse or misuse.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
observer-blind study, the subject and the site and sponsor 
personnel involved in the clinical evaluation of the 
subjects are blinded while other study personnel may be 
aware of the treatment assignment (see Section 5.3 for 
details on observer-blinded studies). In a double blind 
study, the subject, the investigator and sponsor staff who 
are involved in the treatment or clinical evaluation of the 
subjects and the review or analysis of data are all unaware 
of the treatment assignment.
Child in care:
A child who has been placed under the control or 
protection of an agency, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Diarrhoea:
Passage of three or more looser than normal stools within 
a day.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
 
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End of Study 
(Synonym of End of 
Trial):
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV). 
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV.
Epoch:
An epoch is a self-contained set of consecutive time
points or a single time point from a single protocol. Self-
contained means that data collected for all subjects at all 
time points within that epoch allows to draw a complete 
conclusion to define or precise the targeted label of the 
product. Typical examples of epochs are primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the Per-Protocol Set (PPS) analysis (see 
Sections 6.7.2 and 10.4 for details on criteria for 
evaluability).
Gastroenteritis:
Diarrhoea with or without vomiting.
Immunological correlate 
of protection:
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
Investigational vaccine:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use.
 
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Legally acceptable 
representative:
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial.
Primary completion 
date:
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcomes, whether the clinical trial
concluded according to the pre-specified protocol or was 
terminated.
Randomisation:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccines or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation.
Treatment number:
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation.
 
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Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
Vomiting:
One or more episodes of forceful emptying of partially 
digested stomach contents ≥ 1 hour after feeding within a 
day.
 
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TRADEMARK
The following trademark is used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the vaccine will 
be written without the superscript symbol ™ or ® and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
Rotarix®/™
Human rotavirus vaccine
 
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1.
INTRODUCTION
1.1.
Background
Rotavirus (RV) infection is the leading cause of acute gastroenteritis (GE) and severe 
diarrhoea in infants and young children <5 years of age [Atherly, 2009]. It has been 
estimated that in 2008, approximately 453,000 (420,000-494,000) deaths were caused 
due to RV. Approximately 85% of this burden was in low-income countries globally 
[WHO position paper, 2013].
Although RV disease only rarely causes death in Europe, North America and Australia, it 
has severe effects in countries of southeast Asia (India, Pakistan) and sub-Saharan Africa 
(DR Congo, Ethiopia, Nigeria) [Desselberger, 2012]. In developed countries, RV 
infection remains the most common cause of hospitalisation for GE in children and leads 
to major medical and societal costs. During the past years, vaccines have been developed 
that could prevent the enormous morbidity and mortality from RV. Two live oral RV
vaccines have been licensed in many countries; one is derived from an attenuated human 
strain of RV and the other combines five bovine-human reassortant strains [Glass, 2006]. 
Each of these vaccines has proven highly effective in preventing severe RV diarrhoea by
substantially reducing number and associated costs of child hospitalisations and clinical 
visits for acute diarrhoea in children. Moreover, these vaccines could reduce deaths from 
diarrhoea and improve child survival through programmes such as childhood 
immunisations and diarrhoeal disease control in developing countries. The World Health 
Organisation (WHO) recognises RV vaccination as an effective measure to prevent RV 
infection and to reduce disease burden, and recommends its inclusion into all national 
infant immunisation programs [WHO position paper, 2013].
GlaxoSmithKline (GSK) Biologicals’ RV vaccine (Rotarix™) is a vaccine for oral use, 
containing the live attenuated human rotavirus (HRV) RIX4414 strain. Infants aged 
younger than 3 months who received the vaccine did not develop diarrhoea, vomiting or 
fever [Vesikari, 2004(a)]. The initial trials that GSK conducted in Finland showed safety, 
immunogenicity and efficacy of the Rotarix vaccine [Vesikari, 2004(b)]. In Latin 
American and European studies, vaccine efficacy of oral live attenuated HRV vaccine 
Rotarix (RIX4414) was high, ranging from 80.5% to 90.4% against severe Rotavirus 
Gastroenteritis (RVGE), and 83.0% to 96.0% against hospitalisation due to RVGE during 
the first two years of life [Vesikari, 2007; Linhares, 2008]. Furthermore, results from a 
phase III clinical study undertaken in Singapore, Hong Kong, and Taiwan showed that 
during the first two years of life, two doses of RIX4414 vaccine provided a high level of 
protection against severe RVGE (vaccine efficacy: 96.1%), and had a safety profile 
similar to placebo [Phua, 2012]. Such safety and efficacy studies in Europe, Latin 
America and Asia have confirmed that the vaccine is safe, well-tolerated and efficacious 
(range: 80-96%) in preventing severe RVGE in the first two years of life [Cunliffe, 
2014].
Rotarix is registered in at least 130 countries and about 280 million doses of the vaccine 
(lyophilised and liquid formulations) are estimated to have been distributed worldwide 
since its launch until July 2015.
 
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Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the epidemiological information of Rotarix vaccine.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
Using advanced technology in 2010, researchers from the University of California, San 
Francisco identified Deoxyribonucleic acid (DNA) fragments of Porcine circovirus type 
1 (PCV-1) in Rotarix. Further investigations conducted by GSK and the United States 
(US) Food and Drug Administration (FDA) confirmed the presence of PCV-1 DNA 
fragments in Rotarix and its starting materials as well as low levels of PCV-1 viral 
particles during production process and in the final container. The evidence from 
retrospective laboratory investigations conducted by GSK on 40 HRV vaccine recipients 
showed that none of the subjects who received the HRV vaccine demonstrated 
seroconversion to PCV-1 while the PCV-1 from the vaccine was identified in the stool 
samples of 4 infants from the HRV group (at Day 3 and Day 7 post Dose 1). The 
detection of PCV-1 DNA only at the earliest time points post-vaccination was consistent 
with transient passage of DNA through the infants’ digestive tracts without replication. 
Lack of PCV-1 infection is further supported by the absence of anti-PCV-1 antibody in 
the HRV vaccine recipients, including the infants who had PCV-1 DNA detected in their 
stool samples. Therefore, currently available data do not suggest occurrence of PCV-1 
infection in infants who received Rotarix in clinical trials [Dubin, 2013]. These results 
are consistent with published literature which indicates that PCV-1 is not capable of 
causing infection in humans [Hattermann, 2004a; Hattermann, 2004b].
GSK is in the process of replacing the cell bank and virus seeds used as base production 
material for its HRV vaccine. In the meantime, and in accordance with the regulators, the 
company continues to manufacture Rotarix to the existing approved production and 
quality standards to meet public health needs worldwide.
1.2.2.
Rationale for the study design
In order to support licensure of the PCV-free liquid HRV vaccine, GSK Biologicals 
proposes to conduct a clinical study to demonstrate the lot-to-lot consistency of the PCV-
free liquid HRV vaccine in terms of anti-RV Immunoglobulin A (IgA) antibody 
geometric mean antibody concentrations (GMCs), 1-2 months after Dose 2 and the non-
inferiority of the PCV-free liquid HRV vaccine to GSK Biologicals’ currently licensed 
lyophilised HRV vaccine in terms of anti-rotavirus IgA seroconversion rates and GMCs 
1-2 months after Dose 2. 
This study is planned to be conducted in 1600 children aged 6-12 weeks, randomised 
(1:1:1:1) between groups receiving GSK Biologicals’ currently licensed lyophilised HRV 
vaccine and three different lots of PCV-free liquid HRV vaccine.
 
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The current lyophilised PCV-containing vaccine will be used as control, since the study is 
planned to be conducted in US and non-US sites and the liquid formulation of Rotarix is 
not licensed in the US.
Two oral doses of the study vaccines will be administered at an approximate 1-month or 
2-months interval to subjects, according to the immunisation schedule for RV vaccine 
administration in participating countries. Blood samples for immunogenicity assessment 
will be collected from all subjects before the first dose and at 1-2 months post Dose 2.
An Independent Data Monitoring Committee (IDMC) will review the safety data of the 
first 5%, 10% and 50% of the subjects enrolled to evaluate if there is any safety concern 
with the PCV-free liquid HRV vaccine. Enrolment will be paused when first 10% of 
study sets are enrolled, for the purpose of the IDMC review of the safety data up to 
8 days post Dose 2 (Day 0-Day 7) and will only resume if the outcome of the IDMC 
review is positive.
1.3.
Benefit: Risk Assessment
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of Rotarix vaccine.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
1.3.1.
Risk Assessment
Important 
Potential/Identified Risk
Data/Rationale 
for Risk
Mitigation Strategy
Investigational study vaccine (Rotarix)
Intussusception
Spontaneous data

Subjects will be followed up to 6 months 
after receipt of the vaccine to check for 
any safety signal.

Subjects should report any untoward 
symptoms experienced after receiving the 
vaccine immediately to the investigator.

All SAEs should be reported immediately 
to GSK.

An IDMC will review the safety data of the 
first 160 subjects enrolled in the study to 
provide recommendation on recruitment 
of the remaining study subjects. Please 
refer to Section 3 for more details.
Hematochezia
Spontaneous data
Gastroenteritis with
vaccine viral shedding in 
infants with severe 
combined 
immunodeficiency (SCID)
Spontaneous data
Kawasaki disease
Based on signal 
observed for Rota 
Teq vaccine
Study Procedures
Allergic reaction to the 
vaccine.
Spontaneous data
Subjects will be observed for at least 30 
minutes after vaccine administration, with 
medical attention available in case of 
anaphylaxis reactions.
 
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1.3.2.
Benefit Assessment
By receiving the HRV vaccine the subject may have the benefit of being protected 
against RV disease. In addition the subject’s participation will benefit other children in 
the future since information collected during this study will help in evaluation of the 
HRV vaccine against RV GE.
In addition, the subjects will undergo a history directed physical examination at the first 
study visit. In case the study doctor discovers any medical condition, the subject will be 
referred to the local healthcare system.
The vaccine and study tests will be provided free of cost to the subjects.
1.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential or identified risks identified in association with [444563/Rotavirus 
vaccine] are justified by the potential benefits (prevention/treatment) that may be 
afforded to subjects receiving the vaccine for immunisation against RV.
2.
OBJECTIVES
2.1.
Co-Primary objectives

To demonstrate the lot-to-lot consistency of the PCV-free liquid HRV vaccine in 
terms of immunogenicity as measured by serum anti-RV IgA antibody 
concentrations 1-2 months after Dose 2.
Consistency will be demonstrated if, for all pairs of lots, the two-sided 95% confidence 
intervals (CIs) for the ratio of anti-RV IgA antibody GMCs 1-2 months after Dose 2 are 
within the [0.5; 2] clinical limit interval.

To demonstrate the immunological non-inferiority of PCV-free liquid HRV vaccine 
as compared to the currently licensed lyophilised HRV vaccine in terms of 
seroconversion rates 1-2 months after Dose 2.
Non-inferiority will be demonstrated if the lower limit of the two-sided asymptotic 
standardized 95% CI for the difference in seroconversion rate between the PCV-free 
liquid HRV vaccine (pooled HRV liquid groups) and licensed lyophilised HRV vaccine is 
greater than or equal to -10%.

To demonstrate the non-inferiority of the PCV-free liquid HRV vaccine to that of the 
currently licensed lyophilised HRV vaccine in terms of serum anti-RV IgA antibody 
concentrations 1-2 months after Dose 2.
 
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Non-inferiority will be demonstrated if the lower limit of the two-sided 95% CI for the 
ratio of anti-RV IgA antibody GMCs 1-2 months after Dose 2 between the PCV-free 
liquid HRV vaccine (pooled HRV liquid groups) and the lyophilised HRV vaccine is 
greater than or equal to 0.67.
Refer to Section 10.1 for the definition of the primary endpoints.
2.2.
Secondary objectives
Reactogenicity and safety

To evaluate the reactogenicity of the liquid HRV vaccine and currently licensed 
lyophilised HRV vaccine in terms of solicited AEs during the 8 days (Day 0-Day 7) 
follow-up period after each vaccination.

To assess the safety of the study vaccines in terms of unsolicited AEs during the 
31 days (Day 0-Day 30) follow-up period after each vaccination and Serious 
Adverse Events (SAEs) during the entire study period.
Immunogenicity

To assess the immunogenicity of the PCV-free liquid HRV vaccine and the currently 
licensed lyophilised HRV vaccine, in terms of percentage of subjects with anti-RV 
IgA antibody concentrations ≥ 90 U/mL 1-2 months after Dose 2.
Refer to Section 10.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
N: Number of subjects planned to be enrolled, n = number of subjects in each group
* Contact (by telephone call or any other convenient procedure) for the safety follow-up will take place 6 months after 
the last dose of HRV vaccine.
** Two oral doses of the study vaccines will be administered at an approximate 1-month or 2-months interval to 
subjects, according to the immunisation schedule for RV vaccine administration in participating countries.
#Blood samples will be taken before the first dose and 1 to 2 months after the second dose.
$An IDMC will review the safety data for the first 80 enrolled subjects (5% of total enrolment) and first 160 enrolled 
subjects (10% of total enrolment) as soon as data until 8 days post Dose 2 (Day 0-Day 7) are available. Enrolment will 
be paused when first 10% of the subjects are enrolled for the purpose of the IDMC review of the safety data and will 
only resume if the outcome of the IDMC review is positive.
Review of the safety data for the first 800 enrolled subjects (50% of total enrolment) will be conducted as soon as data
until 8 days post Dose 2 (Day 0-Day 7) are available for 800 subjects.
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 outline of study procedures (Section 5.5), are essential and required for 
study conduct. 

Experimental design: Phase IIIA, observer-blind, randomised (1:1:1:1), controlled, 
multi-centric, with four parallel groups and a staggered enrolment (Part A and Part 
B).

Duration of the study: The intended duration of the study, per subject, will be 
approximately 7-8 months including the 6 months of extended safety follow-up 
period after the last dose of HRV vaccine.

Epoch 001: Primary starting at Visit 1 (Day 0) and ending at the safety follow-
up contact (Month 7-8).

Primary completion Date (PCD): Visit 3 (Month 2-4).
Refer to glossary of terms for the definition of PCD.
 
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
End of Study (EoS): Last testing results released of samples collected at Visit 3 or 
Last Subject Last Visit (LSLV) (Follow up contact at month 7-8).
Refer to glossary of terms for the definition of EoS.

Study groups: The study groups and epoch foreseen in the study are provided in
Table 1.
Table 1
Study groups and epoch foreseen in the study
Study Groups
Number of 
subjects
Age at Dose 1 (Min-Max)
Epoch
Epoch 001 
Liq_A
400
6 weeks-12 weeks
●
Liq_B
400
6 weeks-12 weeks
●
Liq_C
400
6 weeks-12 weeks
●
Lyo
400
6 weeks-12 weeks
●
The study groups and treatments foreseen in the study are given in Table 2.
Table 2
Study groups and treatments foreseen in the study
Treatment name
Vaccine name
Study Groups
Liq_A 
Liq_B
Liq_C
Lyo
HRV Liquid
HRV PCV-free ‡
x
x
x
HRV Lyophilised
HRV *
x
‡ PCV-free HRV liquid vaccine
* Licensed formulation of HRV lyophilised vaccine

PCV-free HRV liquid formulation lot A (also referred to as Liq_A group)

PCV-free HRV liquid formulation lot B (also referred to as Liq_B group)

PCV-free HRV liquid formulation lot C (also referred to as Liq_C group)

GSK Biologicals’ currently licensed lyophilised HRV formulation (also referred 
to as Lyo group)

Control: active control-GSK Biologicals’ currently licensed lyophilised HRV 
vaccine.

Vaccination schedule: Two doses of HRV vaccine to be administered according to a 
0, 1-2 month schedule according to the immunisation schedule for RV vaccine 
administration in participating countries.

Concomitant administration of routine childhood vaccines will be allowed 
according to local immunisation practices in each participating country.

Treatment allocation: Randomised 1:1:1:1 using GSK Biologicals’ central 
randomisation system on Internet (SBIR).

Blinding: observer-blind
The blinding in the study is given in Table 3.
 
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Table 3
Blinding of study epoch
Study Epoch
Blinding*
Epoch 001
Double-blind
Epoch 001
Observer-blind
*Double blind for the three lots of PCV-free HRV liquid vaccine and observer-blind for the liquid formulation versus the 
lyophilised formulation.

Sampling schedule: Blood samples will be collected from all subjects at Visit 1 and 
Visit 3 to measure serum anti-RV IgA antibody concentrations using Enzyme Linked 
Immunosorbent Assay (ELISA).

Recording of GE episodes: Any GE episodes occurring from Dose 1 of HRV vaccine 
up to Visit 3 will be recorded for all subjects in the diary card. Parents/Legally 
Acceptable Representative(s) (LARs) will be instructed to collect stool sample(s) if 
the subject develops GE during the period from Dose 1 of HRV vaccine up to Visit 
3. A stool sample should be collected as soon as possible after illness begins and 
preferably not later than 7 days after the start of GE symptoms. Two occurrences of 
diarrhoea will be classified as separate episodes if there will be five or more 
diarrhoea-free days between the episodes. Refer to the glossary of terms for 
definitions of GE and diarrhoea.

Recording of Solicited AEs: Solicited AEs (fever, fussiness/irritability, loss of 
appetite, cough/runny nose, diarrhoea and vomiting) occurring between the day of 
each HRV vaccine dose and the following 7 days (Day 0-Day 7) will be recorded 
daily using diary cards for all subjects.

Recording of Unsolicited AEs: Unsolicited AEs occurring within 31 days 
(Day 0-Day 30) after each dose of HRV vaccine will be recorded using diary cards
for all subjects.

Recording of SAEs: SAEs will be recorded from Visit 1 (Day 0) up to 6 months after 
Dose 2 of HRV vaccine.

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF)

Safety monitoring: An IDMC comprising of clinical experts and a biostatistician, will 
review the safety data accrued during the study and the details of the review will be 
described in an IDMC charter. The IDMC review will happen after enrolment of 5%, 
10% and 50% of subjects. The IDMC review will happen at the following stages:
Review of all safety data for the first 80 enrolled subjects (5% of total enrolment) as 
soon as data until 8 days post Dose 2 (Day 0-Day 7) are available for 80 subjects.

any available data beyond 8 days post Dose 2 will also be reviewed.

during this IDMC review, enrolment of subjects will continue.
Review of all safety data for the first 160 enrolled subjects (10% of total enrolment) 
as soon as data until 8 days post Dose 2 (Day 0-Day 7) are available for160 subjects. 

any available data beyond 8 days post Dose 2 will also be reviewed.
 
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
until this IDMC review, enrolment of subjects will pause. Enrolment will 
resume only if no safety concerns are raised by IDMC.
Review of all safety data for the first 800 enrolled subjects (50% of total enrolment) 
as soon as data until 8 days post Dose 2 (Day 0-Day 7) are available for 800 subjects.

any available data beyond 8 days post Dose 2 will also be reviewed.

during this IDMC review, enrolment of subjects will continue.
4.
STUDY SET
4.1.
Number of subjects/centres
The target enrolment will be 1600 subjects (400 subjects in each of the PCV-free liquid 
vaccine groups and 400 subjects in the lyophilised vaccine group) to obtain at least 1280 
evaluable subjects (320 subjects in each of the PCV-free liquid vaccine groups and 320 
subjects in the lyophilised vaccine group).
Refer to Section 10.3 for a detailed description of the criteria used in the estimation of 
sample size. 
Overview of the recruitment plan

Subjects will be enrolled at multiple sites in the US and other countries. 
Approximately 25% of subjects will be enrolled in the US.

Enrolment will be terminated when 1600 subjects have been enrolled.

The subjects will be enrolled in two parts: the first part (Part A enrolment) will 
include 160 subjects (approximately 40 subjects in each study group) for IDMC 
safety data evaluation and the second part (Part B enrolment) will include the 
remaining subjects.

Recruitment and randomisation will be monitored by SBIR
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects’ parent(s)/LAR(s) who, in the opinion of the investigator can and will 
comply with the requirements of the protocol (e.g., completion of the diary cards, 
return for follow-up visits).

Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to 
performing any study specific procedure.
 
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
A male or female infant between, and including, 6 and 12 weeks (42-90 days) of age 
at the time of the first study vaccination.

Born full-term (i.e., between a gestation period of 37 weeks 0 days and 41 weeks 6 
days).

Healthy subjects as established by medical history and clinical examination before 
entering into the study.
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care
Please refer to the glossary of terms for the definition of child in care. 

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines during the period starting 30 days before the first dose of study 
vaccines (Day-29 to Day 0), or planned use during the study period.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs since birth. For 
corticosteroids, this will mean prednisone (0.5 mg/kg/day, or equivalent). Inhaled 
and topical steroids are allowed.

Administration of immunoglobulins and/or any blood products since birth or planned 
administration during the study period.

Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g., infliximab).

Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose of vaccine administration 
and ending at Visit 3, with the exception of the inactivated influenza vaccine, which 
is allowed at any time during the study and other licensed routine childhood 
vaccinations.

Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).

Uncorrected congenital malformation (such as Meckel’s diverticulum) of the 
gastrointestinal tract that would predispose for Intussusception (IS).

History of IS.

Family history of congenital or hereditary immunodeficiency.
 
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
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Major congenital defects or serious chronic illness.

Previous vaccination against RV.

Previous confirmed occurrence of RVGE.

GE within 7 days preceding the study vaccine administration (warrants deferral of 
the vaccination).

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines.

Hypersensitivity to latex.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 38.0°C/100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity, the axilla and the 
rectum.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.
5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), all applicable subject 
privacy requirements and the guiding principles of the Declaration of Helsinki. 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject’s parent(s)/LAR(s) informed consent as appropriate. 

Investigator reporting requirements as stated in the protocol.
 
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GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/thumb printed informed consent must be obtained 
from each subject’s parent(s)/LAR(s) as appropriate, prior to participation in the study. 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
5.2.
Subject identification and randomisation of treatment
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects whose 
parent(s)/LAR(s) have consented to their participation in the study, according to the 
range of subject identification numbers allocated to each study centre.
5.2.2.
Randomisation of treatment
5.2.2.1.
Randomisation of supplies
The numbering of supplies will be performed at GSK Biologicals, using a block scheme 
randomisation in MATerial EXcellence (MATEX), a program developed for use in 
Statistical Analysis System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks 
will be shipped to the study centres/warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation of supplies will be prepared.
5.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
5.2.2.2.1.
Study group and treatment number allocation
The target will be to enrol 1600 eligible subjects who will be randomly assigned to four 
study groups in a 1: 1: 1: 1 ratio (approximately 400 subjects in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
SBIR. The randomisation algorithm will use a minimisation procedure accounting for 
 
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centre and country. Minimisation factors will have equal weight in the minimisation 
algorithm.
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s) and having 
checked the eligibility of the subject, the site staff in charge of the vaccine administration 
will access SBIR. Upon providing the subject identification number, the randomisation 
system will determine the study group and will provide the treatment number to be used 
for the first dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
5.2.2.2.2.
Treatment number allocation for subsequent doses 
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
5.3.
Method of blinding 
This study is observer-blind (double blind for the three lots of PCV-free HRV liquid 
vaccine and observer-blind for the liquid formulation versus the lyophilised formulation).
Data will be collected in an observer-blind manner. By observer-blind, it is meant that 
during the course of the study, the vaccines recipient and those responsible for the 
evaluation of any study endpoint (e.g., safety and reactogenicity) will all be unaware of 
which vaccine was administered. To do so, vaccine preparation and administration will 
be done by authorised medical personnel who will not participate in any of the study 
clinical evaluation assays.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects.
 
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The burden of the study for the subject will be minimised as much as possible. For taking 
blood samples, three attempts at most should be performed. If the physician is not 
successful after the third attempt, he/she will make no further attempts. A local numbing 
cream or patch will also be offered at the discretion of the investigator prior to blood 
sampling, in order to minimise pain when blood samples are drawn.
5.5.
Outline of study procedures
The outline of study procedures is detailed in Table 4.
 
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Table 4
List of study procedures
Age
6-12 weeks 3-5 months 4-7 months
9-11 
months
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3
Extended 
Safety 
Follow-up 
Contact
Time points
Day 0
Month 1-2
Month 2-4
Month 7-8
Sampling time points
Pre-Vacc
Post-Vacc 2
Informed consent
●
Check inclusion/exclusion criteria
●
Check contraindications
●
●
Check warnings and precautions
●
●
Medical history
●
Recording of gestational age
●
Recording of demography
●
History directed physical examination
●
History of previous vaccination from birth
●
Pre-vaccination body temperature
●
●
Measure/record height and weight
●
Randomisation
●
Recording of Treatment number
●
●
Blood sampling for anti-RV antibody determination 
(approximately 2 ml)
●
●
Vaccination *
●
●
Record regurgitation
●
●
Distribution of diary cards
O
O
Daily post-vaccination recording of solicited adverse events 
within 8 days (Day 0–Day 7) after each vaccination by subjects’ 
parent(s)/LAR(s) in diary card.
●
●
Recording of non-serious adverse events within 31 days 
(Day 0–Day 30) after each vaccination, by investigator
●
●
●
Recording of GE episodes for all subjects
●
●
●
Collection of stool samples if the child develops GE
●
●
●
Return of diary cards
O
O
Diary card transcription by investigator or designee
●
●
Record any concomitant medication/vaccination in the diary 
card
●
●
●
Record any intercurrent medical conditions
●
●
●
●
Recording of Serious Adverse Events (SAEs) and AEs leading 
to withdrawal
●
●
●
●
Phone Contact
●
Analysis on data collected up to Visit 3
O
Study Conclusion
●
Note: The double-line border indicates the analyses which will be performed on all data obtained up to that visit or 
contact.
● is used to indicate a study procedure that requires documentation in the individual eCRF.
O is used to indicate a study procedure that does not require documentation in the individual eCRF.
* Two oral doses of the study vaccines will be administered at an approximate 1-month or 2-months interval to 
subjects, according to the immunisation schedule for RV vaccine administration in participating countries. Any 
regurgitation or vomiting by the subjects after study vaccine administration should be recorded in the eCRF.
Concomitant administration of routine pediatric vaccines will be allowed according to local immunisation practices in 
each participating country.
LAR = Legally Acceptable Representative
 
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The intervals between study visits are presented in Table 5.
Table 5
Intervals between study visits
Interval
Optimal length of interval 1
Allowed interval
Visit 1Visit 2
1-2 months
28-83 days† after Dose 1
Visit 2Visit 3
1-2 months
28-83 days† after Dose 2
Visit 2Contact‡
6 months
180-210 days after Dose 2 of HRV vaccine
1. Whenever possible the investigator should arrange study visits within this interval.
†. Subjects will not be eligible for inclusion in the Per-Protocol Set (PPS) for immunogenicity if they make the study visit 
outside this interval.
‡A safety follow-up contact (by telephone call or any other convenient procedure) to collect information on SAEs and 
medication taken for treatment of the same.
5.6.
Detailed description of study procedures
5.6.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject’s parent(s)/LAR(s) 
must be obtained before study participation. Refer to Section 5.1 for the requirements on 
how to obtain informed consent, as appropriate.
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment. 
5.6.3.
Check contraindications, warnings and precautions to 
vaccination 
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
5.6.4.
Medical and vaccination history
Obtain the subject’s medical and vaccination history by interview and/or review of the 
subject’s medical records and record any pre-existing conditions or signs and/or 
symptoms present in a subject prior to the first study vaccination in the eCRF. Also 
record any medication and vaccine administration prior to the study vaccination in the 
eCRF.
5.6.5.
Collect demographic data
Record demographic data such as gestational age, gender and geographic ancestry at 
Visit 1 in the subject’s eCRF.
 
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5.6.6.
History directed physical examination
Perform a history directed physical examination. If the investigator determines that the 
subject’s health on the day of vaccination temporarily precludes vaccination, the visit will 
be rescheduled. Collected information needs to be recorded in the eCRF.
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
5.6.7.
Physical examination
Perform a physical examination of the subject, including assessment of 
oral/axillary/rectal, body temperature, height and weight. Collected information needs to 
be recorded in the eCRF. 
Physical examination at each study visit subsequent to the first vaccination visit, will be 
performed only if the subjects’ parent(s)/LAR(s) indicates during questioning that there 
might be some underlying pathology(ies) or if deemed necessary by the Investigator or 
delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
5.6.8.
Assess pre-vaccination body temperature
The oral/axillary/rectal body temperature of each subject needs to be measured prior to 
any study vaccine administration. If the subject has fever [fever is defined as temperature 
38.0°C/100.4°F regardless the location of measurement on the day of vaccination, the 
vaccination visit will be rescheduled within the allowed interval for this visit (see Table 
5).
5.6.9.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in Section
5.2.2. The number of each administered treatment must be recorded in the eCRF.
5.6.10.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
5.6.10.1.
Blood sampling for safety and immune response assessments
Blood samples will be taken during certain study visits as specified in Section 5.5-Outline
of Study Procedures.
 
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
A volume of approximately 2 mL of whole blood (to provide approximately
0.7 mL of serum) should be drawn from all subjects for anti-RV antibody 
determination at Visit 1 (Pre-Vacc) and Visit 3 (Post-Vacc 2). After 
centrifugation, serum samples should be kept at –20°C/–4°F or below until 
shipment. Refer to the SPM for more details on sample storage conditions.
5.6.10.2.
Other biological samples
GE Stool analysis
All GE stool samples collected between Visit 1 and Visit 3 will be tested for the purpose 
of identifying wild type RV exposure during vaccination and to eliminate such cases 
from Per-Protocol Set (PPS) immunogenicity analysis at GSK Biologicals’ laboratory or 
in a validated laboratory designated by GSK Biologicals using standardized and validated 
procedures.
5.6.11.
Study Vaccines administration

After completing all prerequisite procedures prior to vaccination, two oral doses of 
the study vaccines will be administered at an approximate 1-month or 2-months 
interval to subjects, according to the immunisation schedule for RV vaccine 
administration in participating countries (refer to Section 6.3 for detailed description 
of the vaccines administration procedure). If the investigator or delegate determines 
that the subject’s health on the day of administration temporarily precludes vaccines 
administration, the visit will be rescheduled within the allowed interval for this visit 
(refer to Table 5).

The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccines, with appropriate medical treatment readily available 
in case of anaphylaxis.
5.6.12.
Record regurgitation
If regurgitation or vomiting occurs after vaccination, no new study vaccine dose should 
be administered. This information should be recorded in the eCRF. The subject may 
continue to participate in the study but will be excluded from the planned statistical 
analyses on the PPS.
5.6.13.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8.
 
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5.6.14.
Recording of AEs and SAEs

Refer to Section 8.3 for procedures for the investigator to record AEs and SAEs. 
Refer to Section 8.4 for guidelines and how to report SAE reports to GSK 
Biologicals.

The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 
At each vaccination visit, diary cards will be provided to the subject’s parent(s)/LAR(s): 

Recording of GE episodes: Any GE episodes occurring from Dose 1 of HRV vaccine 
up to Visit 3 will be recorded for all subjects in the diary card. Parent(s)/LAR(s) will 
be instructed to collect stool sample(s) if the subject develops GE during the period 
from Dose 1 of HRV vaccine up to Visit 3. A stool sample should be collected as 
soon as possible after illness begins and preferably not later than 7 days after the start 
of GE symptoms. Two occurrences of diarrhoea will be classified as separate 
episodes if there will be five or more diarrhoea-free days between the episodes. 
Refer to the glossary of terms for definitions of GE and diarrhoea.

Recording of Solicited AEs: Solicited AEs (fever, fussiness/irritability, loss of 
appetite, cough/runny nose, diarrhoea and vomiting) occurring between the day of 
each HRV vaccine dose and the following 7 days (Day 0-Day 7) will be recorded 
daily using diary cards for all subjects.

Recording of Unsolicited AEs: Unsolicited AEs occurring within 31 days 
(Day 0-Day 30) after each dose of HRV vaccine will be recorded using diary cards
for all subjects.

Recording of SAEs: SAEs will be recorded from Visit 1 (Day 0) up to 6 months after 
Dose 2 of HRV vaccine.

Collect and verify completed diary cards during discussion with the subject’s 
parent(s)/LAR(s) on Visit 2 and Visit 3.

Any unreturned diary cards will be sought from the subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure. 

The investigator will transcribe the collected information into the eCRF in English.
5.6.15.
Phone Contact
A safety follow-up contact will be done by a telephone call to collect information on 
SAEs and medication taken for treatment of the same.
5.6.16.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
 
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5.7.
Biological sample handling and analysis
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects/subjects’ parent(s)/LAR(s) in countries where this is allowed will be 
asked to give specific consent to allow GSK or a contracted partner to use the 
samples for future research. Future research will be subject to the laws and 
regulations in the respective countries and will only be performed once an 
independent Ethics Committee or Review Board has approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
Any sample testing will be done in line with the consent of the individual 
subject/subject’s parent(s)/LAR(s).
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the PPS analysis (See Section 10.4 for the definition of sets
to be analysed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
 
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5.7.2.
Biological samples
The biological samples to be collected from subjects are described in Table 6.
Table 6
Biological samples
Sample Type
Quantity
Unit
Sampling time point
Subset/No. subjects
Blood
Approximately 2
ml
Pre-Vacc
All
Approximately 2
ml
Post-Vacc 2
All
GE Stool †
NA
NA
From Visit 1 up to Visit 3
All subjects with GE
† Stool analysis performed for subjects who experience GE episodes.
5.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis and/or sample management.
GE Stool analysis
All GE stool samples collected between Visit 1 and Visit 3 will be tested for the purpose 
of identifying wild type RV exposure during vaccination and to eliminate such cases 
from PPS immunogenicity analysis at GSK Biologicals’ laboratory or in a validated 
laboratory designated by GSK Biologicals using standardized and validated procedures.
All GE stool samples will be analysed by ELISA for detection of RV antigen. If a stool 
sample tests positive for RV antigen, the sample will be tested by Reverse Transcription 
Polymerase Chain reaction (RT-PCR) followed by sequencing to determine the G and P 
genotype.
Serum analysis
All serological assays will be performed at GSK Biologicals’ laboratory or in a validated 
laboratory designated by GSK Biologicals using standardized and validated procedures.
The laboratory assays to be performed are presented in Table 7.
Table 7
Humoral Immunity (Antibody determination)
System
Component
Method
Kit/Manufacturer
Unit
Cut-off†
Laboratory
SER
Rotavirus Ab.IgA
ELI
NA
U/ml
20
GSK Biologicals*
†The assay cut-off is subject to change
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium
*GSK Biologicals’ laboratory or validated laboratory designated by GSK Biologicals.
SER = Serum
IgA = Immunoglobulin A
ELI =ELISA (Enzyme Linked Immunosorbent Assay)
U = Units; ml = millilitres
NA = Not Applicable
 
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The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
The immunological read-outs are given in Table 8.
Table 8
Immunological read-outs
Blood sampling time point
Type of contact and time point
Sampling time point
No. subjects
Component
Components
priority rank
Visit 1 (Day 0)
Pre-Vacc
All
anti-HRV IgA
None
Visit 3 (Month 2-4)
Post-Vacc 2
All
anti-HRV IgA
None
GE stool analysis†
Visit 1 (Day 0) to Visit 3 (Month 2-4) From Visit 1 up to Visit 3 All subjects with GE
RV antigen
None
† Stool analysis performed for subjects who experience GE episodes.
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 8.
5.7.5.
Immunological correlates of protection
No immunological correlate of protection has been demonstrated so far for the antigen 
used as part of the HRV vaccine. However, a study by Cheuvart et al., in 2014 indicated 
that post-vaccination anti-RV IgA seropositivity (antibody concentration 20 U/mL) 
may serve as a useful correlate of vaccine efficacy in clinical trials of Rotarix [Cheuvart, 
2014].
The immunological assay results will be communicated to the investigator as soon as 
they become available.
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects’ parent(s)/LAR(s).
For the subjects identified as non-responders, it remains the responsibility of the 
investigator in charge of the subject’s clinical management to determine the medical need 
for re-vaccination and to re-vaccinate the subjects as per local/regional practices.
 
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6.
STUDY VACCINES
6.1.
Description of study vaccines
All candidate vaccines to be used have been developed and manufactured by GSK 
Biologicals. 
The Quality Control Standards and Requirements for each candidate vaccine are 
described in separate Quality Assurance documents (e.g., release protocols, certificate of 
analysis) and the required approvals have been obtained. 
The vaccines are labelled and packed according to applicable regulatory requirements.
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics.
The study vaccines to be utilized in the study are detailed in Table 9.
Table 9
Study vaccines
Treatment 
name
Vaccine name
Formulation
Presentation
Volume to be 
administered
Number of 
doses
HRV Liquid
HRV PCV-free
PCV-free HRV 
RIX4144 live 
attenuated 
>=10⁶⋅⁰CCID₅₀
Liquid vaccine
in a pre-filled 
oral applicator.
1.5 ml
2
HRV 
Lyophilised
HRV
HRV RIX4144 live 
attenuated 
>=10⁶⋅⁰CCID₅₀
Lyophilised 
vaccine in a 
monodose 
glass vial.
1 ml
2
HRV Diluent
CaCO₃=60mg
Diluent for 
lyophilised 
vaccine 
(calcium 
carbonate liquid 
antacid) 
supplied 
separately in a 
prefilled oral 
applicator.
CCID50 = median Cell Culture Infective Dose (quantity of virus causing infection in 50% of exposed cells)
CaCO₃ = Calcium carbonate
HRV = Human Rotavirus
ml = millilitre; mg = milligrams
6.2.
Storage and handling of study vaccines
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
 
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device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting Investigational Medicinal Products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
6.3.
Dosage and administration of study vaccines
Liquid formulation of HRV vaccine
The pre-filled oral applicator is shaken well before use. The vaccine (approximately 
1.5 mL) should then be administered orally as a single dose. 
Lyophilised formulation of HRV vaccine
To prepare GSK Biologicals' HRV lyophilised vaccine for administration, the entire 
content of the supplied diluent (calcium carbonate buffer) should be transferred from the 
oral applicator into the vial of the lyophilised product via the intermediate device. The 
vial should be shaken well to re-suspend the vaccine. The entire volume of the re-
suspended product (approximately 1 mL) should be withdrawn into the same oral 
applicator and the re-suspended product should then be administered promptly as a single 
oral dose.
Administration of the vaccines
In order to allow the swallowing of the entire volume of the single oral dose (of liquid or 
lyophilised formulation), the administration should occur in a quiet environment. The 
child should be seated in a reclining position. Administer orally (i.e., into the child’s 
mouth towards the inner cheek) the entire content of oral applicator. Sufficient time 
should be allowed for the baby to swallow the vaccine solution, to avoid regurgitation or 
vomiting. Should however the subject regurgitate or vomit after study vaccine 
administration, no new study vaccine dose should be administered. This information 
should be recorded in the eCRF. The subject may continue to participate in the study.
 
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The vaccinees will be observed closely for at least 30 minutes, with appropriate medical 
treatment readily available in case of a rare anaphylactic reaction following the 
administration of vaccines.
The vaccination regimen is summarized in Table 10.
Table 10
Dosage and administration
Type of contact and 
time point
volume to be 
administered
Study 
Group
Treatment name
Route 1
Site
Side
Visit 1, Visit 2
1.5 ml
Liq_A
Liq_B
Liq_C
HRV Liquid
O
Not applicable
Not applicable
Visit 1, Visit 2
1 ml
Lyo
HRV Lyophilised
O
Not applicable
Not applicable
1Oral (O)
6.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 30% additional vaccine doses will be 
supplied to replace those that are unusable. 
The investigator will use SBIR to obtain the replacement treatment number. The 
replacement numbers will be allocated by dose. The system will ensure, in a blinded 
manner, that the replacement applicator matches the formulation the subject was assigned 
to by randomisation.
6.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of 
Rotarix vaccine. If any of these events occur during the study, the subject must not 
receive additional doses of vaccines but may continue other study procedures at the 
discretion of the investigator (see Section 8.5). 

Anaphylaxis following the administration of vaccines

Hypersensitivity reaction following the administration of the HRV vaccine.

Any uncorrected congenital malformation of the gastrointestinal tract (such as 
Meckel’s diverticulum) that would predispose for IS.

Any history of IS.

SCID.
The following events constitute contraindications to administration of Rotarix vaccine at 
that point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 5.5), or withdrawn at the discretion of the investigator (see Section 
8.5). 
 
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
Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 38.0°C/100.4°F. The preferred location for 
measuring temperature in this study will be the oral cavity, the axilla and the 
rectum.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory
infection) without fever may be enrolled at the discretion of the investigator.

GE within 7 days preceding the study vaccine administration.
6.6.
Warnings and precautions
The HRV vaccine should under no circumstances be injected.
There are no data on the safety and efficacy of Rotarix in infants with gastrointestinal 
illnesses. Administration of Rotarix may be considered with caution in such infants when, 
in the opinion of the physician, withholding the vaccine entails a greater risk.
The risk of IS has been evaluated in a large safety trial (including 63,225 infants) 
conducted in Latin America and Finland. No increased risk of IS was observed in this 
clinical trial following administration of Rotarix when compared with placebo.
However, post-marketing safety data indicate a transient increased risk of IS after 
vaccination, mostly within 8 days following the administration of the first dose of Rotarix
and, to a lesser extent, the second dose. The overall incidence of IS remains rare. 
Whether Rotarix affects the overall risk of IS has not been established.
Therefore, parent(s)/LAR(s) should be advised to promptly report any symptoms 
indicative of IS (severe abdominal pain, persistent vomiting, bloody stools, abdominal 
bloating and/or high fever).
Excretion of the vaccine virus in the stools is known to occur after vaccination and lasts 
for 10 days on average with peak excretion around the 7th day. In clinical trials, cases of 
transmission of excreted vaccine virus to seronegative contacts of vaccines have been 
observed without causing any clinical symptoms. Rotarix should be administered with 
caution to individuals with immunodeficient close contacts, such as individuals with 
malignancies, or who are otherwise immunocompromised or receiving 
immunosuppressive therapy. Contacts of recent vaccinees should be advised to observe 
careful hygiene (including washing their hands) when changing children’s diapers.
The tip caps of the prefilled oral applicators of diluent may contain natural rubber latex 
which may cause allergic reactions in individuals who are sensitive to latex.
Refer to the approved product label/package insert for more details.
 
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6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study visit, the investigator or delegate should question the subject’s 
parent(s)/LAR(s) about any medications/products taken and vaccinations received by the 
subject.
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF.

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting 30 days before and following each dose of 
study vaccine.

Any concomitant vaccination administered in the period from first study vaccination 
(Visit 1) and ending at the last study visit (Visit 3).

Prophylactic medication (i.e., medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g., an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 38.0°C/100.4°F. The preferred location for measuring temperature in 
this study will be the oral cavity, the axilla and the rectum].

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 
a SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report.

Any antipyretic administered in the period starting 6 hours before vaccination and 
ending 12 hours after vaccination need to be recorded on the specific page of the 
eCRF.
6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from PPS analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
PPS analysis. See Section 10.4 for sets to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used between Visit 1 and Visit 3 during the study period.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e., more than 14 days) during the study period between Visit 1 to Visit 3. For 
 
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corticosteroids, this will mean prednisone (0.5 mg/kg/day, or equivalent). Inhaled 
and topical steroids are allowed.

Immunoglobulins and/or any blood products administered during the study period 
between Visit 1 to Visit 3.

Long-acting immune-modifying drugs administered at any time during the study 
period (e.g., infliximab).

A vaccine not foreseen by the study protocol administered during the period starting 
from 30 days before the first vaccination and ending at Visit 3*, with the exception 
of the inactivated influenza vaccine, which is allowed at any time during the study, 
and other licensed routine childhood vaccinations.
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its SPC or PI and 
according to the local governmental recommendations and provided a written 
approval of the Sponsor is obtained. A detailed, comprehensive list of reasons for 
elimination from PPS analyses will be established at the time of data cleaning.
6.8.
Intercurrent medical conditions that may lead to elimination
of a subject from PPS analyses
At each study visit subsequent to the first vaccination, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition. If it is the case, the 
condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the PPS for immunogenicity if, during the study, they 
incur a condition that has the capability of altering their immune response or are 
confirmed to have an alteration of their initial immune status.
7.
HEALTH ECONOMICS
Not applicable.
8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an Adverse Event (AE) or SAE 
as provided in this protocol. 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs or symptoms they perceive as serious.
 
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8.1.
Safety definitions
8.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. 
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

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 vaccines administration even 
though they 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 
vaccines or a concurrent medication (overdose per se should not be reported as an 
AE/SAE).

Signs, symptoms temporally associated with study vaccines administration.

Significant failure of expected pharmacological or biological action. 

Pre-or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e., invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
Examples of an AE DO NOT include:

Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, admission for routine examination).

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. 
 
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
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
8.1.2.
Definition of a serious adverse event 
A SAE is any untoward medical occurrence that:
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, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) 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, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
Medical or scientific judgement 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 hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
 
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8.1.3.
Solicited adverse events
8.1.3.1.
Solicited general adverse events
The following general AEs will be solicited (Table 11):
Table 11
Solicited general adverse events
Fever
Irritability/Fussiness
Diarrhoea
Vomiting
Loss of appetite
Cough/runny nose
Note: Temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF. The temperature can be recorded by any age-appropriate route. 
The preferred route for recording temperature in this study will be oral, axillary or rectal.
8.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g., clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g., vital signs etc) that are 
judged by the investigator to be clinically significant will be recorded as AE or SAE if 
they meet the definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. 
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
Not applicable.
 
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8.3.
Detecting and recording adverse events, serious adverse 
events
8.3.1.
Time period for detecting and recording adverse events, serious 
adverse events 
All AEs starting within 31 days following administration of each dose of study vaccine 
(Day 0 to Day 30) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
Any GE episodes occurring from Dose 1 of HRV vaccine up to Visit 3 will be recorded.
The time period for collecting and recording SAEs will begin at the receipt of study 
vaccines until the subject is discharged from the study. See Section 8.4 for instructions on 
reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the receipt of study vaccines.
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e.,
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject’s parent(s)/LAR(s) consents to participate in the study until they are 
discharged from the study.
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 12.
 
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Table 12
Reporting periods for collecting safety information
Study 
activity
Pre-
Vacc*
Visit 1
Dose 1
8 days 
post 
Vacc
31 days 
post 
Vacc
Visit 2
Dose 2
8 days 
post 
Vacc
31 days 
post 
Vacc
Visit 3
Extended 
Safety 
follow-up
Day 0
Month1-2
Month 2-4
Month 7-8
Solicited 
general 
AEs
Unsolicited 
AEs
GE 
episodes**
SAEs and 
AEs 
leading to 
withdrawal
SAEs
SAEs related 
to study 
participation 
or concurrent 
GSK 
medication/va
ccine
* consent obtained. Pre-Vacc: pre-vaccination; Vacc: vaccination; Post-Vacc: post-vaccination
** If GE will appear during the solicited period then it will be recorded on the solicited AEs screen of eCRF as diarrhoea
and if it will appear outside the solicited period up to Visit 3 then it will be recorded as an unsolicited AE.
8.3.2.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 12. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccines, the investigator will promptly 
notify the Study Contact for Reporting SAEs.
 
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8.3.3.
Evaluation of adverse events and serious adverse events
8.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as:
‘Has your child acted differently or felt different in any way since receiving the vaccine 
or since the last visit?’
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
 
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8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described in Table 13 and 
Table 14:
Table 13
Intensity scales be used by the parent(s)/LAR(s) for solicited 
symptoms during the solicited follow-up period
Adverse Event
Intensity grade
Parameter
Fever*
Record temperature in °C/°F using any age-appropriate route
Irritability/Fussiness
0
Behaviour as usual
1
Crying more than usual/no effect on normal activity
2
Crying more than usual/interferes with normal activity
3
Crying that cannot be comforted/prevents normal activity
Diarrhoea $
Record the number of looser than normal stools/day
Vomiting §
Record the number of vomiting episodes/day
Loss of appetite
0
Appetite as usual
1
Eating less than usual/no effect on normal activity
2
Eating less than usual/interferes with normal activity
3
Not eating at all
Cough/runny nose
0
Normal
1
Cough/runny nose which is easily tolerated
2
Cough/runny nose which interferes with daily activity
3
Cough/runny nose which prevents daily activity
* Fever is defined as temperature 38.0°C/100.4°F. The preferred location for measuring temperature in this study 
will be the oral cavity, the axilla and the rectum.
$ Diarrhoea is defined as passage of three or more looser than normal stools within a day.
§ Vomiting is defined as one or more episodes of forceful emptying of partially digested stomach contents ≥ 1 hour 
after feeding within a day.
Table 14
Intensity scales for diarrhoea, vomiting and fever occurring during 
the solicited period
Adverse Event
Intensity 
grade
Parameter
Diarrhoea $
0
Normal (0-2 looser than normal stools/day)
1
3 looser than normal stools/day
2
4-5 looser than normal stools/day
3
6 looser than normal stools/day
Vomiting §
0
Normal (no emesis)
1
1 episode of vomiting/day
2
2 episodes of vomiting/day
3
3 episodes of vomiting/day
Fever
0
temperature < 38.0°C/100.4° F
1
temperature 38.0°C/100.4° F – 38.5°C/101.3 F 
2
temperature > 38.5°C/101.3 F – 39.5°C/103.1 F
3
temperature > 39.5°C/103.1 F
$ Diarrhoea is defined as passage of three or more looser than normal stools within a day.
§ Vomiting is defined as one or more episodes of forceful emptying of partially digested stomach contents ≥ 1 hour 
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The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities 
(in a young child, such an AE would, for example, prevent 
attendance at day-care centre and would cause the 
parent(s)/LAR(s) to seek medical advice.)
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 8.1.2.
8.3.3.2.2.
Assessment of causality
The definitions for ‘NO’ and ‘YES’ have been written in such a way that all events that 
have been attributed a ‘NO’ can be pooled with events which in the primary vaccination 
study were determined to be ‘not related’ or ‘unlikely to be related’ to vaccination. Those 
events that are attributed a ‘YES’ can be pooled with those events that in the past were 
determined to have a ‘suspected’ or ‘probable’ relationship to vaccination in the primary 
vaccination study.
The investigator is obligated to assess the relationship between investigational vaccine 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational vaccine will be considered and 
investigated. The investigator will also consult the IB and/or Prescribing Information for 
marketed products to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
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In case of concomitant administration of multiple vaccines/products, it may not be 
possible to determine the causal relationship of general AEs to the individual vaccine 
administered. The investigator should, therefore, assess whether the AE could be causally 
related to vaccination rather than to the individual vaccines.
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the study vaccine?
YES
:
There is a reasonable possibility that the vaccines contributed to the 
AE. 
NO
:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccines. There are other, more 
likely causes and administration of the study vaccines is not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccines, if applicable.

Erroneous administration.

Other cause (specify).
8.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
 
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8.3.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalisation, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the in the 
eCRF. 
8.4.
Reporting of serious adverse events
8.4.1.
Prompt reporting of serious adverse events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 15, once the investigator determines that 
the event meets the protocol definition of a SAE.
Table 15
Timeframes for submitting serious adverse event reports to GSK 
Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours* ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
* Timeframe allowed after receipt or awareness of the information.
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE.
8.4.2.
Contact information for reporting serious adverse events
Study Contact for Reporting SAEs
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: +
 or +
Email address: 
US sites only:
Fax: 
Canadian sites only:
Fax: 
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PPD
PPD
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PPD

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8.4.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
8.4.4.
Updating of SAE information after removal of write access to the 
subject’s eCRF
When additional SAE information is received after removal of the write access to the 
subject’s eCRF, new or updated information should be recorded on the appropriate paper 
report, with all changes signed and dated by the investigator. The updated report should 
be faxed to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or 
to GSK Biologicals Clinical Safety and Pharmacovigilance department within the 
designated reporting time frames specified in Table 15.
8.4.5.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
 
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Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccines and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation.
8.5.
Follow-up of adverse events and serious adverse events
8.5.1.
Follow-up of adverse events and serious adverse events 
8.5.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 15).
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study.
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 31
days after the last vaccination.
8.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs, or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using an electronic Expedited 
Adverse Events Report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.6.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7).
 
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8.7.
Unblinding
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the investigational vaccines, 
prior to regulatory reporting. The GSK Biologicals’ Central Safety Physician is 
responsible for unblinding the treatment assignment in accordance with the specified 
timeframes for expedited reporting of SAEs (refer to Section 8.4.1).
8.8.
Emergency unblinding (Amended: 06 September 2016)
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the treatment is essential for the clinical management or welfare of the subject, as judged 
by the investigator.
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment.
The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e., he/she cannot access the automated Internet-based system).
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals.
 
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GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician: 
Outside US/Canada:
+
 (GSK Biologicals Central Safety Physician on-call)
For US/Canada only:
+
(GSK Biologicals’ Central Safety Physician on-call) (Amended 06 
September 2016)
GSK Biologicals’ Central Safety Physician Back-up:
Outside US/Canada:
+
US/Canada only:
+
(Amended 06 September 2016)
Emergency Unblinding Documentation Form transmission:
Outside US & Canada:
Fax: +
or +
US/Canada only:
Fax: +
8.9.
Subject card
Study subjects’ parent(s)/LAR(s) must be provided with the address and telephone 
number of the main contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each subject’s 
parent(s)/LAR(s). In an emergency situation this card serves to inform the responsible 
attending physician that the subject is in a clinical study and that relevant information 
may be obtained by contacting the investigator.
Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times.

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PPD
PPD
PPD
PPD
PPD
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PPD

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9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who is available for the concluding contact foreseen in the protocol is 
considered to have completed the study.
9.2.
Subject withdrawal
Withdrawals will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who 
was not available for the concluding contact foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s) 
has withdrawn consent, the investigator will document the reason for withdrawal of 
consent, if specified by the subject’s parent(s)/LAR(s), in the eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.5.1.2).
 
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9.2.2.
Subject withdrawal from investigational vaccines
A ‘withdrawal’ from the investigational vaccines refers to any subject who does not 
receive the complete treatment, i.e., when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccines may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol. 
Information relative to premature discontinuation of the investigational vaccines will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination was made by the 
subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Other (specify).
10.
STATISTICAL METHODS
10.1.
Primary endpoints

Evaluation of immunogenicity in terms of anti-RV antibody concentrations. 

Serum anti-RV IgA antibody concentrations expressed as GMCs 1-2 months 
after Dose 2 in each of the HRV liquid formulation groups (Liq_A, Liq_B and 
Liq_C).

Anti-RV IgA antibody seroconversion rate* 1-2 months after Dose 2 in the 
lyophilised and pooled liquid groups.

Serum anti-RV IgA antibody concentrations expressed as GMCs 1-2 months 
after Dose 2 in the lyophilised and pooled liquid groups.
*Seroconversion rate is defined as the percentage of subjects who were initially 
seronegative (i.e., with anti-RV IgA antibody concentration < 20 U/mL prior the first 
dose of HRV vaccine) and developed anti-RV IgA antibody concentration ≥ 20 U/mL at 
Visit 3.
 
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10.2.
Secondary endpoints

Solicited adverse events

Occurrence of each general solicited symptom within the 8 days (Day 0-Day 7) 
follow-up period after each dose of the lyophilised and PCV-free HRV liquid 
vaccine

Unsolicited adverse events. 

Occurrence of unsolicited AEs within 31 days (Day 0-Day 30) after any dose of 
HRV vaccine, according to the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

Serious adverse events

Occurrence of serious adverse events from Dose 1 up to study end.

Evaluation of immunogenicity in terms of anti-RV antibody concentrations.

Serum anti-RV IgA antibody concentrations ≥ 90 U/mL 1-2 months after Dose 2 
in the lyophilised and pooled liquid groups.
10.3.
Determination of sample size
The target enrolment will be 1600 subjects (400 subjects in each of the PCV-free liquid 
vaccine groups and 400 subjects in the lyophilised vaccine group) to obtain at least 1280 
evaluable subjects (320 subjects in each of the PCV-free liquid vaccine groups and 320 
subjects in the lyophilised vaccine group) for the evaluation of the co-primary objectives 
assuming that approximately 20% of the enrolled subjects will not be evaluable. 
10.3.1.
Control on type I error
A 2.5% nominal type I error will be used for each co-primary evaluation. To control the 
overall type I error below 2.5%, a hierarchical procedure will be used for the multiple 
study objectives as shown in Figure 1.
 
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Figure 1
Sequence for evaluating the study objectives in order to control the 
overall type I error below 2.5%
The sample size has been estimated in order to obtain at least 91% power to demonstrate 
the co-primary objectives. The power associated with the target sample size for the 
conclusion on each inferential objective of this study is detailed in Section 10.3.3.
10.3.2.
References for sample size
Table 16
Seroconversion rates and standard deviation for log10 transformed 
concentration post vaccination.
Antigen
Endpoint
Rota-060
(Sep-ad 
group)
Rota-061
(Pooled Liq 
group)
Rota-061
(Lyo
group)
Rota-036
(HRV 
group)
Rota-054
(HRV 
group)
Rota-023
(HRV 
group)
Rota-068
(HRV 
group)
Rota-
028/029/
030
(HRV 
group)
RV IgA
N
121
746
252
787
147
393
318
115
SCR 
(>=20U/ml)
86.0%[95%
CI: 
78.5;91.6] *
88.6%[95%CI
:86.1;90.8]
90.5% 
[95%CI: 
86.2;93.8]
86.5%[95
%CI: 
83.9;88.8]
85.7%[95%
CI: 
79.0;90.9]
76.8%[95%
CI: 
72.4;80.9]
88.1%[95
%CI: 
84.0;91.4]
93.9%[95
%CI: 
87.9;97.5]
SD
0.728
0.791
0.791
0.735
0.747
0.760
0.710
0.625
SCR = Seroconversion rate
SD = Standard deviation for log10 transformed concentration post vaccination.
*Seropositivity
 
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10.3.3.
Power computation
The power computations were based on the following methods

Consistency on GMC: Type II error was obtained using Power Analysis and Sample 
Size (PASS) 2005, one-sided non-inferiority test for 2 means, under the alternative 
of equal means & alpha=2.5%. The type II error was multiplied by 6 to account for 
the 6 pair wise lot comparisons.

NI on Seroconversion rate: Type II error was obtained using PASS 2005, one-sided 
non-inferiority test for 2 proportions, under the alternative of equal proportions
(Miettinen and Nurminen’s Likelihood Score Test of the Difference).

NI on GMC: Type II error was obtained using PASS 2005, one-sided non-inferiority 
test for 2 means, under the alternative of equal means and variances.
To account for the multiplicity of comparison, the global type II errors were 
conservatively estimated as the sum of individual type II errors.
Table 17
Power to demonstrate that the two-sided 95% CIs on the anti-RV IgA 
GMC ratio between PCV free liquid vaccine, 1-2 months after dose 2 
of HRV vaccine lots are within the [0.5; 2.0] interval for all the pair 
wise comparisons
Endpoint
Standard deviation
[Log10 (titre)]
N evaluable
(each PCV free HRV liquid 
group)
Power
Anti-RV IgA antibody 
concentration
0.750
320
99.4%
0.790*
320
98.2%
0.850
320
96.4%
*=Reference used for the global power computation
Table 18
Probability that the lower limit of 95% CI for the difference in 
seroconversion rate (the pooled PCV free liquid vaccine group 
minus the lyophilised vaccine group), 1-2 months after dose 2 of 
HRV vaccine is ≥-10%
Seroconversion rate
N evaluable
(pooled PCV free HRV 
liquid group)
N evaluable
(lyophilised HRV 
group)
Power
Lyophilised 
formulation of HRV 
vaccine
Liquid formulation 
of PCV free HRV 
vaccine
75%
75%
960
320
96.0%
80%
80%
960
320
98.1%
85%*
85%*
960
320
99.5%
90%
90%
960
320
99.9%
*=Reference used for the global power computation
 
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Table 19
Probability that the lower limit of the 95% CI on anti-rotavirus IgA 
antibody GMC ratio (the pooled PCV free liquid vaccine group 
divided by the lyophilised vaccine group), 1-2 months after dose 2 of 
HRV vaccine is ≥ 0.67
Endpoint
Standard deviation
[Log10 (titre)]
N evaluable
(pooled PCV 
free HRV liquid 
group)
N evaluable
(lyophilised 
HRV group)
Power
Anti-RV IgA antibody 
concentration
0.750
960
320
95.3%
0.790*
960
320
93.2%
0.850
960
320
89.4%
*=Reference used for the global power computation
10.4.
Analyses Sets
Note that in order to align to ICH and Clinical Data Interchange Standards Consortium
(CDISC) terminology the Total vaccinated cohort (TVC) and the According-To-Protocol
(ATP) cohort used in previous Rota studies have been renamed as Exposed Set (ES) and 
PPS, respectively.
10.4.1.
Exposed Set
The ES will include all subjects with at least one study vaccine administration 
documented:

a safety analysis based on the ES will include all vaccinated subjects,

an immunogenicity analysis based on the ES will include all vaccinated subjects for 
whom immunogenicity data are available.
The ES analysis will be performed per treatment actually administered at dose 1.
10.4.2.
Per-Protocol analysis Set of immunogenicity
The PPS for immunogenicity will include all subjects from the ES: 

who have received both the doses of study vaccine,

for whom the HRV vaccine liquid or lyophilised formulation was administered 
according to protocol and subjects did not regurgitate after vaccination,

who have not received a vaccine prohibited by the protocol up to Visit 3,

for whom the randomisation code has not been broken

who were seronegative for serum anti-RV IgA antibodies on the day of Dose 1

who have not received medication prohibited by the protocol up to Visit 3 as listed in 
Section 6.7.2,

whose underlying medical condition was not prohibited by the protocol up to Visit 3 
as listed in Section 6.8,

who comply with the vaccination schedule (Table 5),
 
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
who comply with blood sampling schedule (Table 5),

for whom immunogenicity data are available at the post-vaccination sampling time
point,

who have no RV other than vaccine strain in GE stool samples collected up to 
Visit 3,

who have no concomitant infection unrelated to the vaccine up to Visit 3, which may 
influence the immune response.
10.5.
Derived and transformed data
Demography:

For a given subject and a given demographic variable, missing measurements will
not be replaced.
Immunogenicity:

The cut-off value of anti-rotavirus IgA antibody is defined by the laboratory before 
the analysis and is described in Section 5.7.3.

Seroconversion rate is defined as the percentage of subjects who were initially 
seronegative (i.e., with anti-RV IgA antibody concentration < 20 U/mL prior the first 
dose of HRV vaccine) and developed anti-RV IgA antibody concentration 
≥20 U/mL at Visit 3.

Antibody concentrations below the assay cut-off will be given an arbitrary value of 
half the assay cut-off for the purpose of GMC calculation.

The GMC calculations will be performed by taking the anti-log of the mean of the 
log concentration transformations. Antibody concentrations below the cut-off of the 
assay will be given an arbitrary value of half the cut-off for the purpose of GMC 
calculation.

For a given subject and a given immunogenicity measurement time point, missing or 
non-evaluable measurements will not be replaced.
Reactogenicity and safety:

Subjects who missed reporting symptoms (solicited/unsolicited or concomitant
medications) will be treated as subjects without symptoms (solicited/unsolicited or
concomitant medications, respectively).
 
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10.6.
Analysis of demographics
The following calculations will be performed for each group and for the pooled liquid 
vaccine group:

The distribution of subjects enrolled among the study centres and countries will be
tabulated as a whole and for each group.

The numbers of subjects who withdraw from the study will be tabulated by group 
according to the reason for drop-out.

The deviations from specifications for age and intervals between study visits will be 
tabulated by group.

The median, mean, range and standard deviation of age (in weeks) at each HRV 
vaccine dose and of the gestational age will be computed by group. The median, 
mean and standard deviation of height (in centimetres) and weight (in kilograms) at 
Visit 1 will be computed by group. The racial and sex composition will be presented.
These calculations will also be performed by country.

Summary of co-administered vaccinations (i.e., vaccinations given on the day of 
each HRV vaccine dose) and intercurrent vaccinations (i.e., vaccinations from birth 
up to Visit 3, excluding vaccination given on the day of HRV vaccine doses) will be 
summarized by group for the ES.
10.7.
Analysis of immunogenicity
The primary analysis will be based on the PPS for analysis of immunogenicity. If, in any 
vaccine group, the percentage of vaccinated subjects with serological results excluded 
from the PPS for analysis of immunogenicity is 5% or more, a second analysis based on 
the ES will be performed to complement the PPS analysis.
10.7.1.
Within groups assessment
The following calculations will be performed for each group and for the pooled liquid 
vaccine group.

For each group, at each time point that anti-rotavirus IgA is measured,

Seropositivity/seroconversion rates and their exact 95% CI will be computed,

Percentage of subjects with anti-RV IgA antibody concentrations ≥ 90 U/mL
and their exact 95% CI will be computed.

GMCs and their 95% CIs will be computed.

The above mentioned descriptive analyses will also be performed by country.

The distribution of anti-RV IgA antibody concentrations at Visit 3 will be displayed 
using Reverse Cumulative Curves (RCCs).
 
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10.7.2.
Between groups assessment

The 95% CI for the ratio of anti-RV IgA antibody GMCs at Visit 3 between any pair 
of the three lots of the HRV liquid vaccine will be computed (first co-primary 
objective).

The asymptotic standardized 95% CI for the difference in seroconversion rate at 
Visit 3 between the PCV-free liquid HRV vaccine (pooled HRV liquid groups) and 
lyophilised HRV vaccine will be computed (second co-primary objective).

The 95% CI for the ratio of anti-RV IgA antibody GMCs at Visit 3 between the
PCV-free liquid HRV vaccine (pooled HRV liquid groups) and lyophilised HRV 
vaccine will be computed (third co-primary objective).
Refer to Section 2.1 for the criteria of the respective co-primary objectives.
10.8.
Analysis of safety
The ES will be used for the analysis of safety. 
10.8.1.
Within groups assessment
The following calculations will be performed for each group and for the pooled liquid 
vaccine group:
The percentage of doses and of subjects reporting at least one symptom (solicited or
unsolicited) during the 8 days (Day 0-Day 7) solicited follow-up period post vaccination
will be computed, along with exact 95% CI. The same calculations will be done for 
symptoms (solicited or unsolicited) rated as grade 3 in intensity and for symptoms 
(solicited or unsolicited) assessed as causally related to vaccination.
The percentage of doses and of subjects reporting each individual solicited general
symptom will be computed, over the 8 days (Day 0-Day 7) solicited follow-up period
post vaccination, along with exact 95% CI. The same calculations will be done for each 
individual general solicited symptom rated as grade 3 in intensity, for each individual 
solicited general symptom assessed as causally related to vaccination and those that 
resulted in a medically attended visit.
The verbatim reports of unsolicited AEs will be reviewed by a physician and the signs
and symptoms will be coded according to MedDRA. Every verbatim term will be
matched with the appropriate Preferred Term. The percentage of subjects with unsolicited
AEs occurring within 31 days (Day 0-Day 30) follow-up period after any dose with its 
exact 95% CI will be tabulated by group, and by preferred term. Similar tabulation will 
be done for unsolicited AEs rated as grade 3, for unsolicited AEs with causal relationship 
to vaccination and those that resulted in a medically attended visit.
The percentage of subjects reporting GE episodes from Dose 1 of HRV vaccine up to 
Visit 3 will be tabulated by group.
The percentage of subjects with presence of RV in GE stool samples collected from Dose 
1 of HRV vaccine up to Visit 3 will be tabulated by group.
 
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The percentage of GE episodes with no available stool results from Dose 1 of HRV 
vaccine up to Visit 3 will be tabulated.
The percentage of subjects who started taking at least one concomitant medication from 
HRV vaccination to Day 7 after vaccinations will be tabulated with exact 95% CI. The 
percentages of subjects who started taking at least one concomitant medication during the 
study period will be tabulated with exact 95% CI.
SAEs reported during the study period will be described in detail.
10.9.
Interpretation of analyses
Except for analyses addressing criteria specified in the co-primary objectives referred as 
confirmatory analyses, all the analyses will be descriptive/exploratory in nature. The use 
of these descriptive/exploratory analyses should be limited to support the confirmatory 
analyses or to generate hypothesis.
10.9.1.
Statistical Methods

The exact CIs for a proportion within a group will be calculated using SAS [Clopper, 
1934].

The standardized asymptotic CI for the group difference in proportion will be 
calculated using SAS. The method used within GSK Biologicals is Method 6
[Newcombe, 1998].

The CI for GMCs will be obtained within each group separately. The CI for the 
mean of log-transformed concentration will be first obtained assuming that log-
transformed values were normally distributed with unknown variance. The CI for the 
GMCs will then be obtained by exponential-transformation of the CI for the mean of 
log-transformed concentration.

The GMC group ratio will be obtained using an ANOVA model on the logarithm-
transformed concentrations. The ANOVA model will include the vaccine group and 
the country as fixed effects. The GMC ratio and their 95% CI will be derived by 
exponential-transformation of the corresponding group contrast in the model.
10.10.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
 
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10.10.1.
Sequence of analyses
Safety data that is as clean as possible will be analysed for IDMC review. Details of the 
review will be described in an IDMC charter.
An analysis will be conducted once all the study data up to Visit 3 are available and 
cleaned and Rota-IgA ELISA testing at 1-2 month post-dose 2 has been fully completed.
The Clinical Study Report (CSR) with data up to Visit 3 will be used for the registration 
of PCV-free liquid vaccine in European Union (EU) and ‘rest of world’ countries. This 
CSR will be submitted as soon as it is available.
In addition, an integrated clinical study report containing all data will be written and 
made available to the investigators and submitted to regulatory authorities as appropriate,
e.g., for licensure of PCV-free liquid vaccine in US. This report will include the 
following:

An analysis of the serum anti-RV IgA antibody concentrations, 1-2 months after
Dose 2 in the lyophilised and pooled liquid groups.

The reactogenicity and safety analysis of SAEs and AEs leading to drop out reported 
after Visit 3 up to the safety follow-up contact.

The final analyses of all data conducted after conclusion of the safety follow-up 
phase.
This report will also summarize all the SAEs reported from Visit 1 up to the safety 
follow-up contact to account for the SAEs not reported in the earlier study report due to 
late reporting of SAEs.
10.10.2.
Statistical considerations for interim analyses
All confirmatory analyses will be conducted after all the study data up to Visit 3 are 
available and therefore no statistical adjustment for interim analyses is required.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
11.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
 
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While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
11.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, 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, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form. 
For eCRF, the monitor freezes completed and approved screens at each visit.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
11.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
 
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inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
11.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
11.5.
Posting of information on publicly available clinical trial 
registers and publication policy
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations.
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary PCD and to have secondary 
endpoint disclosed at latest 12 months after the LSLV as described in the protocol.
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors.
 
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11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
12.
COUNTRY SPECIFIC REQUIREMENTS
12.1.
Requirements for Germany
12.1.1.
EXPLANATORY STATEMENT CONCERNING GENDER 
DISTRIBUTION (ARTICLE 7, PARAGRAPH 2 (12) OF THE 
GERMAN GCP ORDER)
There is no intention to conduct specific analyses investigating the relationship between 
the gender of the subjects and the immunogenicity and safety of the GSK Biologicals’ 
oral live attenuated human rotavirus (HRV) vaccine. The ratio of male to female subjects 
recruited into the study (ROTA-081) is expected to be in line with the demographics of 
the population aged 6-12 weeks in the Member State.
12.2.
Requirements for Japan (Amended: 09 March 2017)
12.2.1.
Regulatory and Ethical Considerations, including the Informed
Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favourable opinion/approval of the study protocol and 
amendments as applicable 

Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable) 

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol deviations 
to IRB/IEC) 
GSK will provide full details of the above procedures, either verbally, in writing, or both.
 
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12.2.2.
Study and site closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the investigator 
or the head of the medical institution, where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
12.2.3.
Regulatory and Ethical Considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27th March, 1997)” and the Pharmaceuticals and Medical Devices Act.
The statement “I acknowledge that I am responsible for the overall study conduct.” on the 
Investigator Protocol Agreement Page means the investigator’s responsibility as defined 
by Japanese GCP.
GSK will submit the CTN to the regulatory authorities in accordance with the 
Pharmaceuticals and Medical Devices Act before conclusion of any contract for the 
conduct of the study with study sites.
12.2.4.
Informed Consent
Prior to participation in the study, the investigator (or sub-investigator) should fully 
inform the potential subject and/or the subject’s legally acceptable representative of the 
study including the written information. The investigator (or sub-investigator) should 
provide the subject and/or the subject's legally acceptable representative ample time and 
opportunity to inquire about details of the study. The subject and/or the subject’s legally 
acceptable representative should sign and personally date the consent form. If the subject 
wishes to consider the content of the written information at home, he/she may sign the 
consent form at home. The person who conducted the informed consent discussion and 
the study collaborator giving supplementary explanation, where applicable, should sign 
 
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and personally (signature) date the consent form. If an impartial witness is required, the 
witness should sign and personally date the consent form. The investigator (or sub-
investigator) should retain this signed and dated form (and other written information) 
together with the source medical records, such as clinical charts (in accordance with the 
rules for records retention, if any, at each medical institution) and give a copy to the 
subject and/or the subject’s legally acceptable representative.
12.2.5.
Study Period
Study period is included in Exhibit 1.
12.2.6.
Study administrative structure
Sponsor information and List of Medical Institutions and Investigators are included in 
Exhibit 1.
12.2.7.
Concerning the "Biological sample handling and analysis"
In the Section 5.7 "Biological sample handling and analysis", the content is replaced for 
Japan specific content in Exhibit 1.
12.2.8.
Unapproved Medical Devices
GSK provides a medical device which has not been approved in Japan for the use in 
this study. 
Unapproved medical device incidents, including those resulting from malfunctions of 
the device, must be detected, documented, and reported by the investigator throughout 
the study.
Table 20
Unapproved Medical Device(s)
General Name
Manufacture Name
Brand Name
Pre-filled syringe
SCHOTT Schweiz AG
SYR.1,75ML ROTA FORMAVITRUM 
FM27
Plunger rod of the Pre-filled 
syringe
PLASTICS SYSTEMS PACKAGING 
(PSP)
PLUNGER ROD SHORT PS 
SYRINGE 1.75 ML
Plunger stopper
BD Medical Pharmaceutical Systems
BD HYPAK SCF plunger stopper
Backstop
BD Medical Pharmaceutical Systems
BD HYPAK Backstop
Enteral Transfer Adapter Device*
SCHOTT Schweiz AG
Enteral Transfer Adapter (ETA)
*only used for lyophilised HRV vaccine.
Note: Incidents fulfilling the criteria of an AE/SAE will also follow the processes 
outlined in Section 8.3 to8.8 of the protocol.
 
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12.2.8.1.
Definitions of an Unapproved Medical Device Incident

An unapproved medical device incident is any malfunction or deterioration in the 
characteristics and/or performance of a device as well as any inadequacy in the 
instructions for use, which, directly or indirectly, may lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health. The non-
occurrence of such a result may be due to other fortunate circumstances or due to 
the intervention of health care personnel. 
It is sufficient that:

An incident associated with an unapproved device happens and the incident is 
such that, if it occurs again, may lead to death or a serious deterioration in health.
A serious deterioration in state of health can include any of the following:

life-threatening illness;

permanent impairment of body function or permanent damage to body structure;

condition necessitating medical or surgical intervention to prevent one of the 
above;

foetal distress, foetal death, or any congenital abnormality or birth defects.
Examples of incidents are:

A participant, user, caregiver, or healthcare professional is injured as a result of 
an unapproved medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by an unapproved 
medical device failure. 

A misdiagnosis due to unapproved medical device failure leads to inappropriate 
treatment. 

A participant’s health deteriorates due to unapproved medical device failure.
12.2.8.2.
Detecting and recording Unapproved Medical Device Incidents
The detection and documentation procedures described in this protocol apply to all 
unapproved medical devices provided for use in the study.
12.2.8.2.1. Time Period for Detecting Unapproved Medical Device Incidents
Unapproved medical device incidents or malfunctions of the device that result in an 
incident will be detected, documented, and reported during the entire study period. 
 
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If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to an 
unapproved medical device provided for the study, the investigator will promptly notify 
the sponsor.
12.2.8.2.2. Unapproved Medical Device Incident Documenting
Any unapproved medical device incident occurring during the study will be 
documented in the participant’s medical records, in accordance with the investigator’s 
normal clinical practice, and on the appropriate form. For incidents fulfilling the 
criteria of an AE or an SAE, the appropriate AE/SAE eCRF page will be completed as 
described in Section 8.3 to8.8.
The form will be completed as thoroughly as possible and signed by the unblind (sub-) 
investigator before transmittal to the unblind monitor via Fax or an e-mail. Blinding
needs to be maintained during this process.
It is very important that the investigator provides his/her assessment of causality 
(relationship to the unapproved medical device provided by GSK) at the time of the 
initial report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident.
12.2.8.3.
Prompt Reporting of Unapproved Medical Device Incidents to Sponsor
Unapproved medical device incidents will be reported to the sponsor within 24 hours 
after the investigator determines that the event meets the criteria of an unapproved 
medical device incident, as described in Section 12.2.8.1.
The Medical Device Incident Report Form will be sent to unblind monitor via Fax 
or an e-mail. Refer to the Exhibit 1 for the contact information of unblind monitor.
In the absence of facsimile or e-mail equipment, notification by telephone is acceptable 
for incidents, with a copy of the ‘Medical Device Incident Report Form’ sent by an 
overnight mail.
12.2.8.3.1. Regulatory Reporting Requirements for Unapproved Medical Device 
Incidents
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of incidents to the IRB/IEC. 
 
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12.2.8.4.
Follow-up of Unapproved Medical Device Incidents
All unapproved medical device incidents involving an AE will be followed and reported 
in the same manner as other AEs. This applies to all participants, including those who 
discontinue study treatment or the study.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated, to elucidate the nature and/or causality of the incident.
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the unblind (sub-) investigator.
 
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13.
REFERENCES
Atherly D, Dreibelbis R, Parashar U D, et al. Rotavirus Vaccination: Cost-Effectiveness 
and Impact on Child Mortality in Developing Countries The Journal of Infectious 
Diseases 2009; 200:S28–38.
Clopper C J, Pearson E S. The Use Of Confidence Or Fiducial Limits Illustrated In The 
Case Of The Binomial. Biometrika. 1934; 26(4): 404-13.
Cheuvart B, Neuzil KM, Steele AD, et al. Association of serum anti-rotavirus 
immunoglobulin A antibody seropositivity and protection against severe rotavirus 
gastroenteritis: Analysis of clinical trials of human rotavirus vaccine. Hum Vaccin 
Immunother. 2014; 10: 505-511.
Cunliffe N, Zaman K., Rodrigo C. et al. Early exposure of infants to natural rotavirus 
infection: a review of studies with human rotavirus vaccine RIX441, BMC Pediatrics
2014, 14:295.
Desselberger U. Updating prevaccination rotavirus-associated mortality Lancet Infect Dis 
2012; 12: 94-96.
Dubin G, Toussaint JF, Cassart JP, et al. Investigation of a regulatory agency enquiry into 
potential porcine circovirus type 1 contamination of the human rotavirus vaccine, 
Rotarix™: Approach and outcome. 2013; 9: 2398-2408.
Glass R I, Parashar U D, Bresee J S, et al. Rotavirus vaccines: current prospects and 
future challenges, Lancet 2006; 368: 323–32.
Hattermann K, Roedner C, Schmitt C, et al. Infection studies on human cell lines with 
porcine circovirus type 1 and porcine circovirus type 2. Xenotransplantation. 2004(a); 
11(3): 284-94.
Hattermann K, Maerz A, Slanina H, et al. Assessing the risk potential of porcine 
circoviruses for xenotransplantation: consensus primer-PCR-based search for a human 
circovirus. Xenotransplantation. 2004(b); 11(6): 547-50.
Linhares AC, Velázquez FR, Pérez-Schael I, et al. Efficacy and safety of an oral live 
attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 
years of life in Latin American infants: a randomised, double-blind, placebo-controlled 
phase III study. Lancet. 2008; 371(9619): 1181-9.
Newcombe R, Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Statist. Med. 1998, 17, 873-890.
Phua KB, Lim FS, Lau YL et al. Rotavirus vaccine RIX4414 efficacy sustained during 
the third year of life: A randomised clinical trial in an Asian population, Vaccine 2012; 
30: 4552– 4557.
 
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Vesikari T, Karvonen A, Korhonen T, et al. Safety and immunogenicity of RIX4414 live 
attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants. 
Vaccine 2004(a); 22: 2836–42.
Vesikari T, Karvonen A, Puustinen L, et al. Efficacy of RIX4414 live attenuated human 
rotavirus vaccine in Finnish infants. Pediatr Infect Dis J 2004(b); 23: 937–43.
Vesikari T, Karvonen A, Prymula R. et al. Efficacy of human rotavirus vaccine against 
rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, 
double-blind controlled study. Lancet 2007; 370:1757–63.
WHO position paper. Weekly epidemiological record. Rotavirus vaccines WHO position 
paper - 2013; 88: 49–64.
 
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APPENDIX A
LABORATORY ASSAYS
Serum Analysis
The anti-rotavirus antibody concentrations are determined by a validated anti-rotavirus 
IgA ELISA. Microtitre plates (96-well) are coated with an anti-rotavirus monoclonal 
antibody. The wells are washed and incubated with (positive wells) or without (negative 
wells) rotavirus. Following incubation, the plates are washed and serum, standard and 
control dilutions are incubated in both types of wells (positive and negative). Bound 
anti-rotavirus IgA in the well are detected by incubation with peroxidase conjugated 
anti-human IgA polyclonal antibodies. Colour development proportional to the quantity 
of bound anti-rotavirus IgA occurs in the presence of a chromogen, TMB 
(TetraMethylBenzidine), and measured spectrophotometrically. Specific optical densities
are calculated for each sample/control/standard dilution by measuring the difference 
between positive and negative wells, the use of negative wells allowing to assess 
non-specific IgA binding. The concentrations of the samples expressed in units per 
millilitre are calculated relative to the four-parameter logistic function generated from the 
standard curve.
Antigen Detection in Stool Samples
The rotavirus antigen in stool samples collected during GE episodes will be detected by 
ELISA at Central Lab (GSK or designated laboratory).
RV strain genotyping 
The rotavirus RNA will be isolated from Elisa rotavirus positive stool samples. In order 
to determine the rotavirus P and G type, VP4 and VP7 genes will be then amplified by 
Reverse Transcription Polymerase Reactions (RT-PCR) using two separate primer sets. 
VP4 and VP7 amplimers will be further analysed by direct sequencing. The sequences 
will be interpreted using BLAST database searches in Genbank and phylogenetic 
analysis.
 
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APPENDIX B
CLINICAL LABORATORIES
Table 21
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biological’s Clinical Laboratory 
Sciences (CLS), Rixensart 
Biospecimen Reception-B7/44
Rue de l'Institut, 89-B-1330 Rixensart-Belgium 
GSK Biological’s CLS, Wavre-Nord 
Noir Epine
Avenue Fleming, 20-B-1300 Wavre-Belgium
Table 22
Outsourced laboratories
Laboratory
Address
Q² Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Q² Solutions Clinical Trials (UK)
1 Simpson Parkway
The Alba Campus
Rosebank
Livingston
EH54 7EG
UK
DDL Diagnostic Laboratory
Visseringlaan 25
2288 ER Rijswijk
The Netherlands
 
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APPENDIX C
AMENDMENTS AND ADMINISTRATIVE CHANGES 
TO THE PROTOCOL
GlaxoSmithKline Biologicals
Vaccines R &D
Protocol Administrative Change 1
eTrack study number 
and Abbreviated Title
115461 (ROTA-081)
IND number
BB-IND-16992
EudraCT number
2016-000598-19
Administrative change 
number:
Administrative change 1
Administrative change 
date:
22 June 2016
Co-ordinating author:
Rationale/background for changes: 
This protocol administrative change 1 is being done to include mandatory text specific 
for Japan and Germany.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
TITLE PAGE
Contributing authors
!
, Clinical & Epidemiology Project 
Lead
!
, Project Statistician
!
, Lead Statistician
!
and 
, Study 
Delivery Leads
!
and
, Project 
Delivery Leads
!
, Clinical Immunology 
representative Clinical Read-Out Team Leader
!
, Laboratory Study Manager
!
, Clinical Safety representative
!
, Project Data Manager
!
, Global Regulatory Affairs 
representative
!
, Global Patents representative

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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!
, Keyrus BioPharma for GSK 
Biologicals and 
, Vaccine 
Supply Coordinators Clinical Trial Supply 
Managers
Placeholder for name and signature of “Leiter der klinischen Prufung” for Germany, on 
the Protocol Investigator Agreement page has been added as shown below:
Leiter der klinischen Prüfung 
name, function and title
Signature
Date
List of Abbreviations has been updated for IEC, IMP and IRB as shown below:
IEC: Independent Ethics Committee
IMP: Investigational Medicinal Products
IRB: Institutional Review Board
Section 5.4 General study aspects has been updated as shown below:
The burden of the study for the subject will be minimised as much as possible. For 
taking blood samples, three attempts at most should be performed. If the physician is 
not successful after the third attempt, he/she will make no further attempts. A local 
numbing cream or patch will also be offered at the discretion of the investigator 
prior to blood sampling, in order to minimise pain when blood samples are drawn.
Table 4 List of study procedures has been updated as shown below:
Blood sampling for anti-RV antibody determination (at least approximately 2 ml)
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Section 5.6.10.1 Blood sampling for safety and immune response assessments has 
been updated as shown below:
A volume of at least approximately 2 mL of whole blood (to provide at least
approximately 0.7 mL of serum) should be drawn from all subjects for anti-RV 
antibody determination at Visit 1 (Pre-Vacc) and Visit 3 (Post-Vacc 2). After 
centrifugation, serum samples should be kept at –20°C/–4°F or below until shipment. 
Refer to the SPM for more details on sample storage conditions.
Table 6 Biological samples has been updated as shown below:
Sample Type
Quantity
Unit
Sampling time point
Subset/No. subjects
Blood
At least
Approximately 2
mL
Pre-Vacc
All
At least
Approximately 2
mL
Post-Vacc 2
All
GE stool†
NA
NA
From Visit 1 up to Visit 3
All subjects with GE
Section 10.10.1 Sequence of analyses has been modified as shown below:
Safety data that is as clean as possible will be analysed for IDMC review. Details of the 
review will be described in an IDMC charter.
An analysis will be conducted once all the study data up to Visit 3 are available and 
cleaned and Rota-IgA ELISA testing at 1-2 month post-dose 2 has been fully completed.
The Clinical Study Report (CSR) with data up to Visit 3 will be used for the registration 
of PCV-free liquid vaccine in European Union (EU) and ‘rest of world’ countries. This 
CSR will be submitted as soon as it is available (without waiting for the safety follow-
up data) since safety follow-up is not requested in EU and ‘rest of world’ countries, in 
order to accelerate the launch of PCV-free vaccine.
In addition, an integrated clinical study report containing all data will be written and 
made available to the investigators and submitted to regulatory authorities as 
appropriate, e.g., for licensure of PCV-free liquid vaccine in US. This report will 
include the following:

An analysis of the serum anti-RV IgA antibody concentrations, 1-2 months after
Dose 2 in the lyophilised and pooled liquid groups.

The reactogenicity and safety analysis of SAEs and AEs leading to drop out 
reported after Visit 3 up to the safety follow-up contact.

The final analyses of all data conducted after conclusion of the safety follow-up 
phase.
This report will also summarize all the SAEs reported from Visit 1 up to the safety 
follow-up contact to account for the SAEs not reported in the earlier study report due to 
late reporting of SAEs.
The safety follow-up data will be needed for licensure in US and thus the integrated 
clinical study report will be submitted in US.
 
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Section 12 COUNTRY SPECIFIC REQUIREMENTS has been updated for 
Germany and Japan as shown below:
Requirements for Germany
EXPLANATORY STATEMENT CONCERNING GENDER DISTRIBUTION 
(ARTICLE 7, PARAGRAPH 2 (12) OF THE GERMAN GCP ORDER)
There is no intention to conduct specific analyses investigating the relationship 
between the gender of the subjects and the immunogenicity and safety of the GSK 
Biologicals’ oral live attenuated human rotavirus (HRV) vaccine. The ratio of male to 
female subjects recruited into the study (ROTA-081) is expected to be in line with the 
demographics of the population aged 6-12 weeks in the Member State.
Requirements for Japan
Regulatory and Ethical Considerations, including the Informed Consent 
Process
The study will be conducted in accordance with all applicable regulatory 
requirements, and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the 
Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favourable opinion/approval of the study protocol and 
amendments as applicable 

Signed informed consent to be obtained for each subject before participation in 
the study (and for amendments as applicable) 

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC) 
GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
Study and site closure

Upon completion or premature discontinuation of the study, the GSK monitor 
will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK 
Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.
 
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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK 
will promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
Regulatory and Ethical Considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW 
Notification No.28 dated 27th March, 1997)” and Law for Ensuring the Quality, 
Efficacy, and Safety of Drugs and Medical Devices.
The statement “I acknowledge that I am responsible for the overall study conduct.” 
on the Investigator Protocol Agreement Page means the investigator’s responsibility 
as defined by Japanese GCP.
GSK will submit the CTN to the regulatory authorities in accordance with Article 80-2 
of the Law for Ensuring the Quality, Efficacy, and Safety of Drugs and Medical 
Devices before conclusion of any contract for the conduct of the study with study 
sites.
Informed Consent
Prior to participation in the study, the investigator (or sub-investigator) should fully 
inform the potential subject and/or the subject’s legally acceptable representative of 
the study including the written information. The investigator (or sub-investigator) 
should provide the subject and/or the subject's legally acceptable representative ample 
time and opportunity to inquire about details of the study. The subject and/or the 
subject’s legally acceptable representative should sign and personally date the consent 
form. If the subject wishes to consider the content of the written information at home, 
he/she may sign the consent form at home. The person who conducted the informed 
consent discussion and the study collaborator giving supplementary explanation, 
where applicable, should sign and personally (signature) date the consent form. If an 
impartial witness is required, the witness should sign and personally date the consent 
form. The investigator (or sub-investigator) should retain this signed and dated form 
(and other written information) together with the source medical records, such as 
clinical charts (in accordance with the rules for records retention, if any, at each 
medical institution) and give a copy to the subject and/or the subject’s legally 
acceptable representative.
 
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Study Period
Study period is included in Exhibit 1.
Study administrative structure
Sponsor information and List of Medical Institutions and Investigators are included 
in Exhibit 1.
Concerning the "Biological sample handling and analysis"
In the Section 5.7 "Biological sample handling and analysis", the content is replaced 
for Japan specific content in Exhibit 1.
 
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GlaxoSmithKline Biologicals
Vaccines R &D
Protocol Administrative Change 2
eTrack study number 
and Abbreviated Title
115461 (ROTA-081)
IND number
BB-IND-16992
EudraCT number
2016-000598-19
Administrative change 
number:
Administrative change 2
Administrative change 
date:
06 September 2016
Co-ordinating author:
Rationale/background for changes: 
The GSK Biologicals’ Contact information for Emergency Unblinding for United 
States (US) and Canada have changed. This protocol administrative change provides 
the new numbers.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
The list of contributing authors has been updated.
Section 8.8 Emergency unblinding has been updated as shown below.
GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician: 
Outside US/Canada:
+
 (GSK Biologicals Central Safety Physician on-call)
For US/Canada only:
+
 +
  (GSK Biologicals’ Central Safety Physician on-
call) (Amended 06 September 2016)
GSK Biologicals’ Central Safety Physician Back-up:
Outside US/Canada: 
+
US/Canada only:
+
+ 
(Amended 06 September 2016)
Emergency Unblinding Documentation Form transmission:
Outside US & Canada:
Fax: +
 or +
US/Canada only:
Fax: +
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GlaxoSmithKline Biologicals
Vaccines R &D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
115461 (ROTA-081)
IND number
BB-IND-16992
EudraCT number
2016-000598-19
Administrative change 
number:
Amendment 1
Administrative change 
date:
09 March 2017 
Co-ordinating author:
Rationale/background for changes: 
The protocol is being amended to include the text related to the unapproved medical 
devices and incidents associated with it as per Japan specific requirements.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
The list of contributing authors has been updated.
Contributing authors
!
, Clinical & 
Epidemiology Project Lead
!
, Clinical Research and 
Epidemiology Lead
!
, Project 
Statistician
!
, Lead Statistician
!
 and 
,
, Study Delivery 
Leads
!
 and
,
Project Delivery Leads
!
, Clinical Read-Out 
Team Leader
!
, Laboratory Study 
Manager
!
, Clinical Safety 
representative
!
, 
Project Oversight Data Manager
!
, Global Regulatory 
Affairs representative
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!
, 
Global Patents representative
!
, Keyrus BioPharma for 
GSK Biologicals and
 
, Clinical Trial Supply 
Managers
Section 12 COUNTRY SPECIFIC REQUIREMENTS has been updated for Japan
as shown below:
12.2.3 Regulatory and Ethical Considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27th March, 1997)” and Law for Ensuring the Quality, Efficacy, and 
Safety of Drugs and Medical Devices the Pharmaceuticals and Medical Devices Act.
The statement “I acknowledge that I am responsible for the overall study conduct.” on 
the Investigator Protocol Agreement Page means the investigator’s responsibility as 
defined by Japanese GCP.
GSK will submit the CTN to the regulatory authorities in accordance with Article 80-2 
of the Law for Ensuring the Quality, Efficacy, and Safety of Drugs and Medical 
Devices the Pharmaceuticals and Medical Devices Act before conclusion of any 
contract for the conduct of the study with study sites.
12.2.8 Unapproved Medical Devices
GSK provides a medical device which has not been approved in Japan for the use in 
this study. 
Unapproved medical device incidents, including those resulting from malfunctions 
of the device, must be detected, documented, and reported by the investigator 
throughout the study.
Table 20 Unapproved Medical Device(s)
General Name
Manufacture Name
Brand Name
Pre-filled syringe
SCHOTT Schweiz AG
SYR.1,75ML ROTA FORMAVITRUM 
FM27
Plunger rod of the Pre-filled 
syringe
PLASTICS SYSTEMS PACKAGING 
(PSP)
PLUNGER ROD SHORT PS 
SYRINGE 1.75 ML
Plunger stopper
BD Medical Pharmaceutical Systems
BD HYPAK SCF plunger stopper
Backstop
BD Medical Pharmaceutical Systems
BD HYPAK Backstop
Enteral Transfer Adapter Device*
SCHOTT Schweiz AG
Enteral Transfer Adapter (ETA)
*only used for lyophilised HRV vaccine.
Note: Incidents fulfilling the criteria of an AE/SAE will also follow the processes 
outlined in Section 8.3 to8.8 of the protocol.
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12.2.8.1 Definitions of an Unapproved Medical Device Incident

An unapproved medical device incident is any malfunction or deterioration in 
the characteristics and/or performance of a device as well as any inadequacy in 
the instructions for use, which, directly or indirectly, may lead to or might have 
led to the death of a participant/user/other person or to a serious deterioration in 
his/her state of health.

Not all incidents lead to death or serious deterioration in health. The non-
occurrence of such a result may be due to other fortunate circumstances or due 
to the intervention of health care personnel.
It is sufficient that:

An incident associated with an unapproved device happens and the incident is 
such that, if it occurs again, may lead to death or a serious deterioration in 
health.
A serious deterioration in state of health can include any of the following:

life-threatening illness;

permanent impairment of body function or permanent damage to body 
structure;

condition necessitating medical or surgical intervention to prevent one of the 
above;

foetal distress, foetal death, or any congenital abnormality or birth defects.
Examples of incidents are:

A participant, user, caregiver, or healthcare professional is injured as a result of 
an unapproved medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by an unapproved 
medical device failure. 

A misdiagnosis due to unapproved medical device failure leads to inappropriate 
treatment. 

A participant’s health deteriorates due to unapproved medical device failure.
12.2.8.2 Detecting and recording Unapproved Medical Device Incidents
The detection and documentation procedures described in this protocol apply to all 
unapproved medical devices provided for use in the study.
 
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12.2.8.2.1 Time Period for Detecting Unapproved Medical Device Incidents
Unapproved medical device incidents or malfunctions of the device that result in an 
incident will be detected, documented, and reported during the entire study period. 
If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to an 
unapproved medical device provided for the study, the investigator will promptly 
notify the sponsor.
12.2.8.2.2 Unapproved Medical Device Incident Documenting
Any unapproved medical device incident occurring during the study will be 
documented in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the appropriate form. For incidents 
fulfilling the criteria of an AE or an SAE, the appropriate AE/SAE eCRF page will 
be completed as described in Section 8.3 to8.8.
The form will be completed as thoroughly as possible and signed by the unblind 
(sub-) investigator before transmittal to the unblind monitor via Fax or an e-mail. 
Blinding needs to be maintained during this process.
It is very important that the investigator provides his/her assessment of causality 
(relationship to the unapproved medical device provided by GSK) at the time of the 
initial report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident.
12.2.8.3 Prompt Reporting of Unapproved Medical Device Incidents to Sponsor
Unapproved medical device incidents will be reported to the sponsor within 24 hours 
after the investigator determines that the event meets the criteria of an unapproved 
medical device incident, as described in Section 12.2.8.1.
The Medical Device Incident Report Form will be sent to unblind monitor via Fax 
or an e-mail. Refer to the Exhibit 1 for the contact information of unblind monitor.
In the absence of facsimile or e-mail equipment, notification by telephone is 
acceptable for incidents, with a copy of the ‘Medical Device Incident Report Form’ 
sent by an overnight mail.
12.2.8.3.1 Regulatory Reporting Requirements for Unapproved Medical Device 
Incidents
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.
 
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The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC. 
12.2.8.4 Follow-up of Unapproved Medical Device Incidents
All unapproved medical device incidents involving an AE will be followed and 
reported in the same manner as other AEs. This applies to all participants, including 
those who discontinue study treatment or the study.
The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated, to elucidate the nature and/or causality of 
the incident.
New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the unblind (sub-) investigator.
 
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