Immunogenicity, Reactogenicity and Safety Study of Pediarix®, Hiberix® and Prevenar 13® Co-administered With Two Different Formulations of GSK Biologicals' HRV Vaccine (444563) in Healthy Infants 6-12 Weeks of Age
Phase: PHASE3
Conditions: Rotavirus Infection, Rotavirus Vaccines
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l'Institut 89
1330 Rixensart, Belgium
Primary Study vaccine
Porcine circovirus (PCV)-free liquid formulation of 
GlaxoSmithKline (GSK) Biologicals’ oral live 
attenuated human rotavirus (HRV) vaccine (444563)
Other Study vaccines
!
Lyophilized formulation of the oral live attenuated 
HRV vaccine (Rotarix®, GSK Biologicals)
!
Diphtheria and tetanus toxoids and acellular 
pertussis adsorbed, hepatitis B (recombinant) and 
inactivated poliovirus vaccine (Pediarix®, GSK 
Biologicals)
!
Haemophilus b conjugate vaccine (tetanus toxoid 
conjugate) (Hiberix®, GSK Biologicals)
!
Pneumoccocal 13-valent conjugate vaccine 
(diphtheria CRM197 Protein) (Prevenar 13®, 
Manufactured by Wyeth Pharmaceuticals Inc. 
Marketed by Pfizer Inc.)
eTrack study number and 
Abbreviated Title
201663 (ROTA-090)
Investigational New Drug 
(IND) number
BB-IND-16992
EudraCT number
2016-003210-27
Date of protocol
Final Version 1: 27 October 2016
Title
Immunogenicity, reactogenicity and safety study of 
Pediarix®, Hiberix® and Prevenar 13® co-administered 
with two different formulations of GSK Biologicals’
HRV vaccine (444563) in healthy infants 6-12 weeks 
of age.
Detailed Title
A phase IIIA, randomized, single-blind, multi-centric 
study to evaluate the immunogenicity, reactogenicity
and safety of three doses of Pediarix®, Hiberix® and 
Prevenar 13® when co-administered with two doses of 
the PCV-free liquid formulation of GSK Biologicals’ 
oral live attenuated HRV vaccine as compared to the 
currently licensed lyophilized formulation of the HRV 
vaccine in healthy infants 6-12 weeks of age.
Co-ordinating author
, Scientific writer
Contributing authors
!
, Clinical & Epidemiology Project 
Lead (CEPL),
!
, Clinical Research and Development 
Lead (CRDL)
!
and 
, Statisticians

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eTrack study number and 
Abbreviated Title
201663 (ROTA-090)
IND number
BB-IND-16992
EudraCT number
2016-003210-27
Date of protocol
Final Version 1: 27 October 2016
Title
Immunogenicity, reactogenicity and safety study of 
Pediarix®, Hiberix® and Prevenar 13® co-administered 
with two different formulations of GSK Biologicals’ 
HRV vaccine (444563) in healthy infants 6-12 weeks 
of age.
Detailed Title
A phase IIIA, randomized, single-blind, multi-centric
study to evaluate the immunogenicity, reactogenicity
and safety of three doses of Pediarix®, Hiberix® and 
Prevenar 13® when co-administered with two doses of 
the PCV-free liquid formulation of GSK Biologicals’ 
oral live attenuated HRV vaccine as compared to the 
currently licensed lyophilized formulation of the HRV 
vaccine in healthy infants 6-12 weeks of age.
Contributing authors
!
, Lead Statistician
!
and 
, Study 
Delivery Leads
!
, Project Delivery Lead
!
, Clinical Read-Out Team Leader
!
, Laboratory Study Manager
!
, Clinical Safety representative
!
and 
, 
Oversight Data Managers
!
, Study Data Manager
!
, Global Regulatory Affairs 
representative
!
, Global Patents representative
!
, Clinical Trial Supply Manager
GSK Biologicals’ Protocol DS v 15.0
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.

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PPD
PPD
PPD
PPD
PPD
PPD
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Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
201663 (ROTA-090)
IND number
BB-IND-16992
EudraCT number
2016-003210-27
Date of protocol
Final Version 1: 27 October 2016
Detailed Title
A phase IIIA, randomized, single-blind, multi-centric
study to evaluate the immunogenicity, reactogenicity
and safety of three doses of Pediarix®, Hiberix® and 
Prevenar 13® when co-administered with two doses of
the PCV-free liquid formulation of GSK Biologicals’ 
oral live attenuated HRV vaccine as compared to the 
currently licensed lyophilized formulation of the HRV 
vaccine in healthy infants 6-12 weeks of age.
Sponsor signatory
Paul Gillard,
Clinical & Epidemiology Project Lead (CEPL),
GlaxoSmithKline Biologicals, SA.
Signature
Date
 
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Protocol 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’ study 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 vaccine, 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
201663 (ROTA-090)
IND number
BB-IND-16992
EudraCT number
2016-003210-27
Date of protocol
Final Version 1: 27 October 2016
Detailed Title
A phase IIIA, randomized, single-blind, multi-centric
study to evaluate the immunogenicity, reactogenicity
and safety of three doses of Pediarix®, Hiberix® and 
Prevenar 13® when co-administered with two doses of 
the PCV-free liquid formulation of GSK Biologicals’ 
oral live attenuated HRV vaccine as compared to the 
currently licensed lyophilized formulation of the HRV 
vaccine in healthy infants 6-12 weeks of age.
Investigator name
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.
 
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SYNOPSIS
Detailed Title
A phase IIIA, randomized, single-blind, multi-centric study to 
evaluate the immunogenicity, reactogenicity and safety of 
three doses of Pediarix®, Hiberix® and Prevenar 13® when 
co-administered with two doses of the PCV-free liquid 
formulation of GSK Biologicals’ oral live attenuated HRV 
vaccine as compared to the currently licensed lyophilized 
formulation of the HRV vaccine in healthy infants 6-12 weeks 
of age.
Indication
Active immunization 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 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. Low levels of 
PCV-1 viral particles were also detected during the production 
process and in the final container. Retrospective laboratory 
investigations conducted by GSK on 40 human rotavirus 
(HRV) vaccine recipients showed that none of the subjects 
who received the HRV vaccine demonstrated seroconversion 
to PCV-1, however, 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 [Dubin, 2013]. In a follow-up 
retrospective laboratory analysis of samples of 596 subjects, a 
post-vaccination anti-PCV-1 antibody seropositivity rate of 
1% [90% Confidence Interval (CI): 0.3-2.6] in recipients of 
the human RV vaccine (3/299 samples) and 0.3% 
[90% CI: 0.0-1.6] in the placebo group (1/296 samples) was 
observed. The difference in the post-vaccination seropositivity 
and the seroconversion rates between the two study groups 
were -0.66 [90% CI: -2.16-0.60] and -0.33 
[90% CI: -1.70–0.89], respectively. The 90% CI for both 
group differences included 0, indicating that there was no 
statistically significant increase as compared to the placebo 
 
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[Han, 2016]. Therefore, currently available data does not 
suggest occurrence of PCV-1 infection in infants who 
received Rotarix in clinical trials. 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 has replaced the cell bank and virus seeds used as base 
production material for its HRV vaccine. In accordance with 
the regulators, the company continues to manufacture Rotarix
to the existing standards of approved production and quality,
to meet public health needs worldwide.
This study will assess if there is any immune interference 
between the PCV-free liquid HRV vaccine and routine infant 
vaccinations currently in use in the US, namely Pediarix, 
Hiberix and Prevenar 13 as compared to the currently 
licensed lyophilized formulation of the HRV vaccine when 
co-administered with the same routine vaccinations.

Rationale for the study design
The study is designed as a randomized, controlled, 
single-blind study with two parallel groups. This study will 
evaluate the immunogenicity, reactogenicity and safety of the 
vaccines Pediarix, Hiberix and Prevenar 13 that are 
recommended for children in the US during the first year of 
life, when co-administered with the PCV-free liquid HRV 
vaccine as compared to the licensed lyophilized vaccine.
The currently licensed lyophilized Rotarix vaccine 
co-administered with routine infant vaccines in the US has 
been shown not to impair the immune response to any of the 
co-administered antigens [Dennehy 2008]. Therefore, the use 
of the currently licensed lyophilized vaccine as the control is 
considered appropriate. Furthermore, this study design will 
avoid logistical constraints related to the inclusion of 
co-administration and separate administration of US routine 
infant vaccines in the same study.
An Independent Data Monitoring Committee (IDMC), 
consisting of clinical experts and a biostatistician will review 
the safety data periodically to monitor the safety aspects of the 
PCV-free liquid HRV vaccine.
This study will have a single-blind design to ensure that the 
subject’s parent(s)/Legally Acceptable Representative(s) 
(LARs) are not influenced by the knowledge of the Rotarix
formulation when reporting safety events and when 
 
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complying with the study procedure.
Objectives
Co-Primary

To demonstrate the non-inferiority of the immune 
responses to three doses of Pediarix, Hiberix and 
Prevenar 13 when co-administered with two doses of the 
PCV-free liquid HRV vaccine, as compared to when co-
administered with the currently licensed lyophilized HRV 
vaccine, 1 month after Dose 3 of routine infant vaccines.
Criteria for non-inferiority: 

Lower limits of the two-sided standardized 
asymptotic 95% confidence intervals (CIs) on the 
differences between groups (HRV Liq group minus 
HRV Lyo group) in the percentages of subjects with 
seroprotective concentrations (0.1 IU/mL) for each 
of anti-diphtheria (anti-D) and anti-tetanus (anti-T) 
antibodies are -10% (clinical limit for non-
inferiority),

The lower limit of the two-sided standardized 
asymptotic 95% CI on the difference between groups 
(HRV Liq group minus HRV Lyo group) in the 
percentages of subjects with seroprotective 
concentration (10 mIU/mL) for antibodies against 
hepatitis B surface antigen (anti-HBs) is -10% 
(clinical limit for non-inferiority),

Lower limits of the two-sided standardized 
asymptotic 95% CIs on the differences between 
groups (HRV Liq group minus HRV Lyo group) in 
the percentages of subjects with seroprotective titers 
(8 ED50) for each of 
anti-poliovirus serotypes 1, 2 and 3 antibodies are
-5% (clinical limit for non-inferiority),

Lower limits of the two-sided 95% CIs on the 
geometric mean antibody concentrations (GMC) 
ratios (HRV Liq group over HRV Lyo group) for 
antibodies against each of the pertussis toxoid (PT), 
filamentous hemagglutinin (FHA) and pertactin 
(PRN) antigens [anti-PT, anti-FHA and anti-PRN] 
are 0.67 (clinical limit for non-inferiority),

Lower limits of the two-sided 95% CIs on the GMC 
ratios (HRV Liq group over HRV Lyo group) for 
each of the 13 Streptococcus pneumoniae (S. 
pneumoniae) serotypes are 0.5 (clinical limit for 
 
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non-inferiority),

The lower limit of the two-sided standardized 
asymptotic 95% CI on the difference between groups 
(HRV Liq group minus HRV Lyo group) in the 
percentages of subjects with concentration of 
antibodies against polyribosyl-ribitol-phosphate 
antigen (anti-PRP) 0.15 g/mL is - 5%,

The lower limit of the two-sided standardized 
asymptotic 95% CI on the difference between groups 
(HRV Liq group minus HRV Lyo group) in the 
percentages of subjects with concentration of 
antibodies against anti-PRP 1.0 g/mL is -10% 
(clinical limit for non-inferiority).

To rule out a 10% decrease in seroresponse to PT, FHA 
and PRN antigen when Pediarix is co-administered with 
PCV-free-liquid HRV vaccine compared to when 
Pediarix is co-administered with the currently licensed 
lyophilized HRV vaccine.

seroresponse is defined as the percentage of subjects 
showing an antibody concentration above a threshold 
that leads to 95% seroresponse in the control group 
(lyophilized HRV vaccine),

p-value on the difference in seroresponse between 
groups is < 2.5% for each PT, FHA and PRN antigen 
(p-value is computed by integrating on the p-value 
for the null hypothesis that the seroresponse rate in 
the liquid group is < 85% and the a-posteriori 
probability of the threshold in the lyophilized group).
Secondary
Immunogenicity:

To assess the immunogenicity of the PCV-free liquid 
HRV vaccine and currently licensed lyophilized HRV 
vaccine in terms of serum anti-rotavirus immunoglobulin 
A (IgA) antibody seropositivity rate at Visit 4, 3 months 
after Dose 2 of the HRV vaccine.

To assess the immunogenicity of routine infant vaccines 
Pediarix, Hiberix and Prevenar 13 when co-administered 
with the PCV-free liquid HRV vaccine and currently 
licensed lyophilized HRV vaccine at Visit 4, 1 month 
after Dose 3 of routine infant vaccines.
 
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Reactogenicity and safety:

To assess the reactogenicity of the PCV-free liquid HRV 
vaccine and currently licensed lyophilized HRV vaccine 
in terms of general solicited adverse events (AEs) during 
the 8 day (Day 1-Day 8) follow-up period after each dose 
of HRV vaccine.

To assess the safety of the study vaccines in terms of 
unsolicited AEs during the 31 day (Day 1-Day 31) 
follow-up period after each dose of HRV vaccine and 
serious adverse events (SAEs) during the entire study 
period.
Study design

Experimental design: Phase IIIA, single-blind, 
randomized, controlled, multi-centric study with two 
parallel groups.

Duration of the study: The total duration of the study, per 
subject, will be approximately 10 months including the 6 
months of Extended Safety Follow-Up (ESFU) period 
after the last dose of study vaccine administered.

Epoch 001: Primary starting at Visit 1 (Day 1) and 
ending at the ESFU contact (Month 10).

Primary completion Date (PCD): Last subject attending 
Visit 4.

End of Study (EoS): Last testing results released for 
samples collected at Visit 4. If the last testing results are 
available before the Last Subject Last Visit (LSLV), i.e., 
before the ESFU, the EoS will then be the LSLV.

Study groups: 
The study groups and the epoch foreseen in the study are 
provided in Synopsis Table 1.
The study groups and the treatment 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 001
HRV Liq
640
6 weeks-12 weeks
●
HRV Lyo
640
6 weeks-12 weeks
●
 
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Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment 
name
Vaccine name
Study Groups
HRV Liq
HRV Lyo
HRV Liquid
HRV PCV-free
x
HRV Lyophilized
HRV*
x
Pediarix
DTPa-HBV-IPV
x
x
Hiberix
Hib
x
x
Prevenar 13
Prevenar 13
x
x
* Licensed lyophilized HRV vaccine.

Control: active control-GSK Biologicals’ currently 
licensed lyophilized HRV vaccine.

Vaccination schedule: Two doses of HRV vaccine to be 
administered according to a 0, 2 month schedule as per
the immunization schedule for HRV vaccine 
administration in the US.
Co-administration of routine childhood vaccines 
Pediarix, Hiberix and Prevenar 13 will be performed as 
follows:

All the subjects will receive a dose each of Pediarix,
Hiberix and Prevenar 13 at Visit 1 (Day 1), Visit 2 
(Month 2) and Visit 3 (Month 4).

The routine booster dose for the co-administered 
vaccines will not be administered to subjects as a 
part of this study. Subject’s parent(s)/LARs will be 
reminded at Visit 4 to consult their primary health 
care provider regarding the booster dose of the 
vaccines for their child.

Treatment allocation: Randomized 1:1 using GSK 
Biologicals’ Randomization System on Internet (SBIR).

Blinding: single-blind.
The blinding of the study epoch is provided in 
Synopsis Table 3.
Synopsis Table 1
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
single-blind
 
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
Sampling schedule: Details of the samples to be collected 
are as follows:

Blood samples will be collected from all subjects at 
Visit 4 (Month 5) to measure serum anti-RV IgA 
antibody concentrations and antibody 
concentrations/titers against all the antigens in the 
co-administered vaccines.

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: An IDMC consisting of clinical experts 
and a biostatistician will review the safety data by 
treatment group periodically to monitor the safety aspects 
of the PCV-free liquid HRV vaccine. 
Number of subjects
The target will be to enrol 1280 eligible subjects who will be 
randomly assigned to two study groups in a (1:1) ratio 
(approximately 640 subjects in each group).
Endpoints
Primary

Immunogenicity with respect to components of the routine 
infant vaccines, one month after Dose 3 of routine infant 
vaccines (Visit 4):

Anti-D antibody concentration ≥0.1 IU/mL,

Anti-T antibody concentration ≥0.1 IU/mL,

Anti-HBs antibody concentrations ≥10 mIU/mL,

Anti-poliovirus types 1, 2 and 3 antibody titers 
≥8 ED50,

Anti-PT, anti-FHA and anti-PRN antibody 
concentrations expressed as GMCs,

Anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 
9V, 14, 18C, 19A, 19F, 23F) antibody concentrations
expressed as GMCs,

Anti-PRP antibody concentrations ≥0.15 µg/mL,

Anti-PRP antibody concentrations ≥1.0 µg/mL.

Difference in seroresponse with respect to PT, FHA and 
PRN antigen components one month after Dose 3 of 
routine infant vaccines (Visit 4):

Seroresponse to anti-PT, anti-FHA and anti-PRN.
 
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Secondary

Serum anti-rotavirus IgA antibody seropositivity 3 months 
after Dose 2 of HRV vaccine (Visit 4).

Serum anti-RV IgA antibody concentrations ≥20 U/mL
and ≥90 U/mL 1-2 months after Dose 2.

Immunogenicity with respect to components of the routine 
infant vaccines, one month after Dose 3 of routine infant 
vaccines (Visit 4):

PT, anti-FHA and anti-PRN antibody concentrations 
≥2.693 IU/mL, ≥2.046 IU/mL and ≥2.187 IU/mL, 
respectively.

Anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 
9V, 14, 18C, 19A, 19F, 23F) antibody concentrations 
≥0.35 µg/mL for the ELISA,

Anti-D, anti-T, anti-PRP and anti-HBs antibody 
concentrations expressed as GMCs and anti-poliovirus 
types 1, 2 and 3 antibody concentrations expressed as 
Geometric Mean Titers (GMTs).

Occurrence of general solicited AEs during the 8 day
(Day 1-Day 8) follow-up period after each dose of HRV 
vaccine.

Occurrence of unsolicited AEs within 31 days (Day 1-Day 
31) after any dose of HRV vaccine, according to the 
Medical Dictionary for Regulatory Activities (MedDRA) 
classification.

Occurrence of SAEs from Dose 1 of study vaccines up to 
study end.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................6
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................21
GLOSSARY OF TERMS ...............................................................................................25
TRADEMARKS .............................................................................................................29
1.
INTRODUCTION....................................................................................................30
1.1.
Background ................................................................................................30
1.2.
Rationale for the study and study design ....................................................31
1.2.1.
Rationale for the study.................................................................31
1.2.2.
Rationale for the study design......................................................32
1.3.
Benefit: Risk Assessment ...........................................................................32
1.3.1.
Risk Assessment .........................................................................33
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 COHORT...................................................................................................39
4.1.
Number of subjects/centers ........................................................................39
4.2.
Inclusion criteria for enrollment ...................................................................39
4.3.
Exclusion criteria for enrollment ..................................................................40
5.
CONDUCT OF THE STUDY ..................................................................................41
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................41
5.2.
Subject identification and randomization.....................................................43
5.2.1.
Subject identification....................................................................43
5.2.2.
Randomization of treatment.........................................................43
5.2.2.1.
Randomization 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 ........................................................................44
5.6.
Detailed description of study procedures ....................................................46
5.6.1.
Informed consent.........................................................................46
 
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5.6.2.
Check inclusion and exclusion criteria .........................................47
5.6.3.
Collect demographic data ............................................................47
5.6.4.
Medical and vaccination history ...................................................47
5.6.5.
Physical examination ...................................................................47
5.6.6.
Check contraindications, warnings and precautions to 
vaccination...................................................................................47
5.6.7.
Assess pre-vaccination body temperature ...................................47
5.6.8.
Study group and treatment number allocation..............................48
5.6.9.
Sampling......................................................................................48
5.6.9.1.
Blood sampling for immune response 
assessments ..............................................................48
5.6.10.
Study Vaccines administration.....................................................48
5.6.11.
Record regurgitation ....................................................................48
5.6.12.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................48
5.6.13.
Recording of AEs and SAEs ........................................................49
5.6.14.
Phone Contact.............................................................................49
5.6.15.
Study conclusion..........................................................................49
5.7.
Biological sample handling and analysis.....................................................49
5.7.1.
Use of specified study materials ..................................................50
5.7.2.
Biological sample.........................................................................50
5.7.3.
Laboratory assays .......................................................................51
5.7.4.
Biological samples evaluation......................................................52
5.7.4.1.
Immunological read-outs ............................................52
5.7.5.
Immunological correlates of protection.........................................53
6.
STUDY VACCINES AND ADMINISTRATION ........................................................54
6.1.
Description of study vaccines......................................................................54
6.2.
Storage and handling of study vaccines......................................................56
6.3.
Dosage and administration of study vaccines .............................................57
6.4.
Replacement of unusable vaccine doses....................................................58
6.5.
Contraindications to subsequent vaccination ..............................................58
6.6.
Warnings and precautions ..........................................................................59
6.7.
Concomitant medications/products and concomitant vaccinations..............60
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................60
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............60
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses .............................................................61
7.
HEALTH ECONOMICS ..........................................................................................61
8.
SAFETY.................................................................................................................62
8.1.
Safety definitions ........................................................................................62
8.1.1.
Definition of an adverse event......................................................62
8.1.2.
Definition of a serious adverse event ...........................................63
8.1.3.
Solicited adverse events..............................................................64
8.1.3.1.
Solicited general adverse events................................64
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................64
 
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8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................64
8.3.
Detecting and recording adverse events and serious adverse events.........65
8.3.1.
Time period for detecting and recording adverse events 
and serious adverse events .........................................................65
8.3.2.
Post-Study adverse events and serious adverse events..............66
8.3.3.
Evaluation of adverse events and serious adverse events...........66
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................66
8.3.3.2.
Assessment of adverse events...................................67
8.3.3.2.1.
Assessment of intensity..........................67
8.3.3.2.2.
Assessment of causality .........................69
8.3.3.3.
Assessment of outcomes............................................70
8.3.3.4.
Medically attended visits.............................................70
8.4.
Reporting of serious adverse events...........................................................70
8.4.1.
Prompt reporting of serious adverse events to GSK 
Biologicals ...................................................................................70
8.4.2.
Contact information for reporting serious adverse events ............71
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................71
8.4.3.1.
Back-up system in case the electronic reporting 
system does not work.................................................71
8.4.4.
Updating of SAE information after removal of write access 
to the subject’s eCRF...................................................................72
8.4.5.
Regulatory reporting requirements for serious adverse 
events..........................................................................................72
8.5.
Follow-up of adverse events and serious adverse events ...........................72
8.5.1.
Follow-up during the study...........................................................72
8.5.2.
Follow-up after the subject is discharged from the study..............73
8.6.
Treatment of adverse events ......................................................................73
8.7.
Subject card................................................................................................73
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................73
9.1.
Subject completion .....................................................................................73
9.2.
Subject withdrawal......................................................................................74
9.2.1.
Subject withdrawal from the study................................................74
9.2.2.
Subject withdrawal from study 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..................................................................77
10.3.2.
Reference for sample size: ..........................................................77
10.3.3.
Power computation ......................................................................78
10.4.
Sets for Analyses........................................................................................80
10.4.1.
Exposed Set ................................................................................80
10.4.2.
Per-protocol Set for analysis of immunogenicity...........................80
10.5.
Derived and transformed data.....................................................................81
10.6.
Analysis of demographics ...........................................................................82
10.7.
Analysis of immunogenicity.........................................................................82
10.7.1.
Within group analysis...................................................................82
 
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10.7.2.
Between group assessment.........................................................83
10.8.
Analysis of safety........................................................................................83
10.9.
Interpretation of analyses............................................................................84
10.9.1.
Statistical methods.......................................................................84
10.10. Conduct of analyses ...................................................................................85
10.10.1. Sequence of analyses..................................................................85
10.10.2. Statistical considerations for interim analyses..............................85
11. ADMINISTRATIVE MATTERS ...............................................................................85
11.1.
electronic Case Report Form instructions ...................................................85
11.2.
Study Monitoring by GSK Biologicals..........................................................86
11.3.
Record retention .........................................................................................86
11.4.
Quality assurance.......................................................................................87
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................87
11.6.
Provision of study results to investigators ...................................................87
11.7.
Data Sharing...............................................................................................88
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................88
13. REFERENCES.......................................................................................................88
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epoch foreseen in the study.......................................38
Table 2
Study groups and treatment foreseen in the study .................................38
Table 3
Blinding of study epoch ..........................................................................39
Table 4
List of study procedures .........................................................................45
Table 5
Intervals between study visits.................................................................46
Table 6
Biological sample ...................................................................................51
Table 7
Humoral Immunity (Antibody determination)...........................................51
Table 8
Immunological read-outs........................................................................53
Table 9
Study vaccines.......................................................................................55
Table 10
Dosage and administration.....................................................................58
Table 11
Solicited general adverse events............................................................64
Table 12
Reporting periods for collecting safety information .................................66
Table 13
Intensity scales to be used by the parent(s)/LAR(s) for solicited 
symptoms during the solicited follow-up period ......................................67
Table 14
Intensity scales for diarrhea, vomiting and fever occurring during 
the solicited period .................................................................................68
Table 15
Timeframes for submitting serious adverse events reports to 
GSK Biologicals .....................................................................................70
Table 16
Percentage of subjects above the cut-off................................................77
Table 17
Standard deviation for log10 transformed titer/concentration post-
vaccination.............................................................................................78
Table 18
Power for non-inferiority post-dose 3......................................................79
Table 19
Maximum allowed interval between visits...............................................81
Table 20
GSK Biologicals’ laboratories .................................................................95
Table 21
Outsourced laboratories.........................................................................95
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .......................................................................91
APPENDIX B CLINICAL LABORATORIES ..................................................................95
 
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LIST OF ABBREVIATIONS
ACIP
Advisory Committee on Immunization Practices
AE
Adverse Event
BMI
Body Mass Index
CCID50
Median Cell Culture Infective Dose (quantity of virus 
causing infection in 50% of exposed cells)
CDC
Centers for Disease Control
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CLIA
ChemiLuminescence ImmunoAssay
CLS
Clinical Laboratory Sciences
CSR
Clinical Study Report
D
Diphtheria
DNA
Deoxyribonucleic acid
DT
Diphtheria toxoid
ECL
ElectroChemiLuminescence
eCRF
electronic Case Report Form
ELISA
Enzyme Linked Immunosorbent Assay
EoS
End of Study
ES
Exposed Set
ESFU
Extended Safety Follow-Up
eTDF
Electronic Temperature excursion Decision Form
FDA
Food and Drug Administration, United States of America
FHA
Filamentous Hemagglutinin
GCP
Good Clinical Practice
GE
Gastroenteritis
 
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GMC
Geometric Mean Concentration
GMT
Geometric Mean Titer
GSK
GlaxoSmithKline
HBs
Hepatitis B surface antigen
HHE
Hypotonic Hyporesponsive Episodes
Hib
Haemophilus type b
HRV
Human Rotavirus
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin G
IM
Intramuscular
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
IS
Intussusception
Kg
Kilograms
LAR
Legally Acceptable Representative
LLOQ
Lower Limit Of Quantification
LSLV
Last Subject Last Visit
MATEX
MATerial Excellence
 
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MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL/ml
Milliliter
NEU
Neutralization Assay
PASS
Power Analysis and Sample Size
PCD
Primary Completion Date
PCV
Porcine circovirus
PPS
Per-Protocol Set
PRN
Pertactin
PRP
Polyribosyl-Ribitol-Phosphate: polysaccharide 
component of the Hib bacterium capsule
PT
Pertussis Toxoid
RT-PCR
Reverse Transcriptase Polymerase Chain Reaction
RV
Rotavirus
SAS
Statistical Analysis System
SAE
Serious Adverse Event
SBIR
Randomization System on Internet
SCID
Severe Combined Immunodeficiency
SDV
Source Document Verification
SmPC
Summary of Product Characteristics
SPM
Study Procedures Manual
S. pneumoniae
Streptococcus pneumoniae
T
Tetanus
TT
Tetanus toxoid
 
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TVC
Total vaccinated cohort
U
Unit
US
United States
WHO
World Health Organization
 
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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 a 
single-blind study, the investigator and/or his staff are 
aware of the treatment assignment but the subject is not.
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.
Diarrhea:
Passage of three or more looser than normal stools within 
a day.
Eligible:
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria.
 
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End of Study (EoS):
(Synonym of End of 
Trial)
For studies without collection of human biological
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 set of consecutive time-points or a single 
time-point from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data collected 
at the time-points included in an epoch must be sufficient 
to fulfil the purpose of the epoch.
Typical examples of epochs are screening, 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 analysis (see Sections 6.7.2
and 10.4 for details on criteria for evaluability).
Gastroenteritis:
Diarrhea 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 [IMP])
A pharmaceutical form of an active ingredient being 
tested 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. 
Legally acceptable 
representative (LAR):
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
 
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(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
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 all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated.
Randomization:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
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.
Study vaccine/product:
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/product/placebo as a 
reference or administered concomitantly, in a clinical trial 
that evaluates the use of an investigational 
vaccine/product.
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.
Treatment number:
A number identifying a treatment to a subject, according 
to 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 AE.
Vomiting:
One or more episodes of forceful emptying of partially 
digested stomach contents ≥1 hour after feeding within a 
day.
 
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TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the vaccines will 
be written without the superscript symbol ™ or ® and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
Rotarix®
Human rotavirus vaccine
Pediarix®
Diphtheria and tetanus toxoids and acellular 
pertussis adsorbed, hepatitis B 
(recombinant) and inactivated poliovirus 
vaccine
Hiberix®
Haemophilus b Conjugate Vaccine (Tetanus 
Toxoid Conjugate)
Trademarks not owned by the 
GlaxoSmithKline group of companies
Generic description
Prevenar 13® (Wyeth Pharmaceuticals Inc.; 
Marketed by Pfizer Inc.)
Pneumoccocal 13-valent conjugate vaccine 
(diphtheria CRM197 protein)
 
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1.
INTRODUCTION
1.1.
Background
Rotavirus (RV) infection is the leading cause of acute gastroenteritis (GE) and severe
diarrhea in infants and young children <5 years of age [Atherly, 2009]. It has been 
estimated that in 2013, approximately 215,000 deaths were caused due to RV. India, 
Nigeria, Pakistan, and Democratic Republic of Congo, accounted for approximately half 
(49%) of all the estimated RV deaths in 2013 [Tate, 2016].
Although RV infection rarely causes death in Europe, North America and Australia, it 
remains the most common cause of hospitalization for GE in children
[Desselberger, 2012]. In developed countries, RV infection remains the most common 
cause of hospitalization for GE in children and leads to major medical and societal costs. 
Over the last many years, the development of vaccines has been beneficial in the 
prevention of considerable morbidity and mortality due to RV. Two live oral HRV
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 have been proven highly effective in preventing severe RV
diarrhea by substantially reducing the number and the associated costs of child 
hospitalizations and clinical visits for acute diarrhea in children. Moreover, these 
vaccines could reduce deaths from diarrhea and improve child survival through programs
such as childhood immunizations and diarrheal disease control in developing countries. 
The World Health Organisation (WHO) recognises HRV vaccination as an effective 
measure to prevent RV infection and to reduce disease burden, and recommends its 
inclusion into all national infant immunization programs, particularly in countries where 
RV GE associated fatality rates are high among children aged <5 years (e.g., south and 
south-eastern Asia and sub-Saharan Africa) [WHO position paper, 2013].
GlaxoSmithKline (GSK) Biologicals’ HRV vaccine (Rotarix™) is a vaccine for oral use, 
containing the live attenuated human rotavirus (HRV) RIX4414 strain. It has previously 
been observed that infants aged younger than three months who received the vaccine did 
not develop diarrhea, vomiting or fever during the trial [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 was high, ranging from 80.5% to 
90.4% against severe RV GE, and 83.0% to 96.0% against hospitalization due to RV GE 
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 Rotarix vaccine provided a high level 
of protection against severe RV GE (vaccine efficacy: 96.1%), and had a safety profile 
similar to the 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 RV GE in the first two years of life 
[Cunliffe, 2014].
 
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Rotarix is registered in at least 130 countries and more than 300 million doses of the 
vaccine (lyophilized and liquid formulations) are estimated to have been distributed 
worldwide since its launch until July 2016.
Please refer to the current Investigator Brochure (IB) 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. Low levels of PCV-1 viral particles were also 
detected during the production process and in the final container. 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, however, 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 [Dubin, 2013]. 
In a follow-up retrospective laboratory analysis of samples of 596 subjects, a 
post-vaccination anti-PCV-1 antibody seropositivity rate of 1% [90% Confidence Interval 
(CI): 0.3-2.6] in recipients of the human RV vaccine (3/299 samples) and 0.3% 
[90% CI: 0.0-1.6] in the placebo group (1/296 samples) was observed. The difference in
the post-vaccination seropositivity and the seroconversion rates between the two study 
groups were -0.66 [90% CI: -2.16-0.60] and -0.33 [90% CI: -1.70–0.89], respectively. 
The 90% CI for both group differences included 0, indicating that there was no 
statistically significant increase as compared to the placebo [Han, 2016]. Therefore, 
currently available data does not suggest occurrence of PCV-1 infection in infants who 
received Rotarix in clinical trials. 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 has replaced the cell bank and virus seeds used as base production material for its 
HRV vaccine. In accordance with the regulators, the company continues to manufacture 
Rotarix to the existing standards of approved production and quality, to meet public 
health needs worldwide.
This study will assess if there is any immune interference between the PCV-free liquid 
HRV vaccine and routine infant vaccinations currently in use in the US, namely Pediarix, 
Hiberix and Prevenar 13 as compared to the currently licensed lyophilized formulation of 
the HRV vaccine when co-administered with the same routine vaccinations.
 
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1.2.2.
Rationale for the study design
The study is designed as a randomized, controlled, single-blind study with two parallel 
groups. This study will evaluate the immunogenicity, reactogenicity and safety of the 
vaccines Pediarix, Hiberix and Prevenar 13 that are recommended for children in the US
during the first year of life, when co-administered with the PCV-free liquid HRV vaccine 
as compared to the licensed lyophilized vaccine.
The currently licensed lyophilized Rotarix vaccine co-administered with routine infant 
vaccines in the US has been shown not to impair the immune response to any of the 
co-administered antigens [Dennehy, 2008]. Therefore, the use of the currently licensed 
lyophilized vaccine as the control is considered appropriate. Furthermore, this study 
design will avoid logistical constraints related to the inclusion of co-administration and 
separate administration of US routine infant vaccines in the same study.
An Independent Data Monitoring Committee (IDMC), consisting of clinical experts and a 
biostatistician will review the safety data periodically to monitor the safety aspects of the 
PCV-free liquid HRV vaccine.
This study will have a single-blind design to ensure that the subject’s parent(s)/Legally 
Acceptable Representative(s) (LARs) are not influenced by the knowledge of the Rotarix
formulation when reporting safety events and when complying with the study procedure.
1.3.
Benefit: Risk Assessment
Please refer to the current IB and the Prescribing information for the summary of 
potential risks and benefits of the Rotarix vaccine.
Please refer to the Prescribing information for information regarding the summary 
potential risks and benefits of Pediarix, Hiberix and Prevenar 13 vaccines.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
 
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1.3.1.
Risk Assessment
Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational study vaccine (Rotarix)
Intussusception (IS)
Spontaneous data

Subjects will be followed 
up to 6 months after receipt 
of the vaccine to check for 
any safety signal.

Parent(s)/LAR(s) should 
report any untoward 
symptoms their child
experiences after receiving 
the vaccine immediately to 
the investigator.

All SAEs should be 
reported by the investigator 
immediately to GSK.

Subjects with SCID will be 
excluded from participating 
in this study (Refer to 
Section 4.3 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
GSK comparator (Pediarix)
Apnoea (in premature 
infants)
Spontaneous data
Risk highest in infants born 
≤28 weeks of gestation (Refer 
to Section 4.3 for more details).
Syncope
Spontaneous data
Subjects will be observed for at 
least 30 minutes after vaccine 
administration, with medical 
attention available in case of 
adverse event.
Hypotonic Hyporesponsive 
Episodes (HHE).
Spontaneous data
Convulsion (with or without 
fever)
Spontaneous data

Subjects will be followed 
up to 6 months after receipt 
of the vaccine to check for 
any safety signal.

Parent(s)/LAR(s) should 
report any untoward 
symptoms their child
experiences after receiving 
the vaccine immediately to 
the investigator.

All SAEs should be 
reported by the investigator 
immediately to GSK.
Fever
Clinical trial data
Encephalopathy
Spontaneous data
 
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Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
GSK comparator (Hiberix)
Apnoea (in premature 
infants)
Spontaneous data
Risk highest in infants born 
≤28 weeks of gestation (Refer 
to Section 4.3 for more details).
Syncope
Spontaneous data
Subjects will be observed for at 
least 30 minutes after vaccine 
administration, with medical 
attention available in case of 
adverse event.
HHE
Spontaneous data
Convulsion (with or without 
fever)
Spontaneous data

Subjects will be followed 
up to 6 months after receipt 
of the vaccine to check for 
any safety signal.

Parent(s)/LAR(s) should 
report any untoward 
symptoms their child
experiences after receiving 
the vaccine immediately to 
the investigator.

All SAEs should be 
reported by the investigator 
immediately to GSK.
Comparator (Prevenar 13)
See Package Insert
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.
Redness, swelling, pain at 
injection site
Clinical trial data

Parent(s)/LAR(s) should 
report any untoward 
symptoms their child 
experiences after receiving 
the vaccine to the 
investigator.

All SAEs should be 
reported by the investigator 
immediately to GSK.
 
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1.3.2.
Benefit Assessment
By receiving the HRV vaccine the subject may become 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 the evaluation of PCV-free HRV 
vaccine co-administration with routinely administered childhood vaccines.
Routine childhood vaccinations Pediarix, Hiberix and Prevenar 13 will be administered 
to subjects according to their prescribed vaccination schedule, as part of the study.
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.
1.3.3.
Overall Benefit: Risk Conclusion
Considering the measures taken to minimize the risk to subjects participating in this 
study, the potential or identified risks in association with the HRV vaccine are justified 
by the potential benefits (prevention/treatment) that may be afforded to subjects receiving 
the vaccine for immunization against RV.
2.
OBJECTIVES
2.1.
Co-Primary objectives

To demonstrate the non-inferiority of the immune responses to three doses of 
Pediarix, Hiberix and Prevenar 13 when co-administered with two doses of the
PCV-free liquid HRV vaccine, as compared to when co-administered with the 
currently licensed lyophilized HRV vaccine, 1 month after Dose 3 of routine infant 
vaccines.
Criteria for non-inferiority: 

Lower limits of the two-sided standardized asymptotic 95% confidence intervals 
(CIs) on the differences between groups (HRV Liq group minus HRV Lyo group) 
in the percentages of subjects with seroprotective concentrations (0.1 IU/mL) 
for each of anti-diphtheria (anti-D) and anti-tetanus (anti-T) antibodies are
-10% (clinical limit for non-inferiority),

The lower limit of the two-sided standardized asymptotic 95% CI on the 
difference between groups (HRV Liq group minus HRV Lyo group) in the 
percentages of subjects with seroprotective concentration (10 mIU/mL) for 
antibodies against hepatitis B surface antigen (anti-HBs) is -10% (clinical 
limit for non-inferiority),

Lower limits of the two-sided standardized asymptotic 95% CIs on the 
differences between groups (HRV Liq group minus HRV Lyo group) in the 
 
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percentages of subjects with seroprotective titers (8 ED50) for each of anti-
poliovirus serotypes 1, 2 and 3 antibodies are -5% (clinical limit for non-
inferiority),

Lower limits of the two-sided 95% CIs on the geometric mean antibody 
concentrations (GMC) ratios (HRV Liq group over HRV Lyo group) for 
antibodies against each of the pertussis toxoid (PT), filamentous hemagglutinin 
(FHA) and pertactin (PRN) antigens [anti-PT, anti-FHA and anti-PRN] are 
0.67 (clinical limit for non-inferiority),

Lower limits of the two-sided 95% CIs on the GMC ratios (HRV Liq group over 
HRV Lyo group) for each of the 13 Streptococcus pneumoniae (S. pneumoniae)
serotypes are 0.5 (clinical limit for non-inferiority),

The lower limit of the two-sided standardized asymptotic 95% CI on the 
difference between groups (HRV Liq group minus HRV Lyo group) in the 
percentages of subjects with concentration of antibodies against polyribosyl-
ribitol-phosphate antigen (anti-PRP) 0.15 g/mL is - 5%,

The lower limit of the two-sided standardized asymptotic 95% CI on the 
difference between groups (HRV Liq group minus HRV Lyo group) in the 
percentages of subjects with concentration of antibodies against anti-PRP 1.0 
g/mL is -10% (clinical limit for non-inferiority).

To rule out a 10% decrease in seroresponse to PT, FHA and PRN antigen when 
Pediarix is co-administered with PCV-free-liquid HRV vaccine compared to when 
Pediarix is co-administered with the currently licensed lyophilized HRV vaccine.

seroresponse is defined as the percentage of subjects showing an antibody 
concentration above a threshold that leads to 95% seroresponse in the control 
group (lyophilized HRV vaccine),

p-value on the difference in seroresponse between groups is <2.5% for each PT, 
FHA and PRN antigen (p-value is computed by integrating on the p-value for 
the null hypothesis that the seroresponse rate in the liquid group is <85% and the 
a-posteriori probability of the threshold in the lyophilized group).
Refer to Section 10.1 for the definition of the primary endpoints.
2.2.
Secondary objectives
Immunogenicity:

To assess the immunogenicity of the PCV-free liquid HRV vaccine and currently 
licensed lyophilized HRV vaccine in terms of serum anti-rotavirus immunoglobulin 
A (IgA) antibody seropositivity rate at Visit 4, 3 months after Dose 2 of the HRV 
vaccine.

To assess the immunogenicity of routine infant vaccines Pediarix, Hiberix and
Prevenar 13 when co-administered with the PCV-free liquid HRV vaccine and 
 
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currently licensed lyophilized HRV vaccine at Visit 4, 1 month after Dose 3 of 
routine infant vaccines.
Reactogenicity and safety:

To assess the reactogenicity of the PCV-free liquid HRV vaccine and currently 
licensed lyophilized HRV vaccine in terms of general solicited adverse events (AEs) 
during the 8 day (Day 1-Day 8) follow-up period after each dose of HRV vaccine.

To assess the safety of the study vaccines in terms of unsolicited AEs during the 31
day (Day 1-Day 31) follow-up period after each dose of HRV vaccine and serious 
adverse events (SAEs) during the entire study period.
Refer to Section 10.2 for the definition of the secondary endpoints.
3.
STUDY DESIGN OVERVIEW
N = Number of subjects planned to be enrolled, n = Number of subjects in each study group, BS = blood sample.
Contact (by telephone call or any other convenient procedure) will take place 6 months after Visit 3 for safety follow-up.
An IDMC will review the safety data by treatment group periodically. Details of the review will be described in an IDMC 
charter.
Protocol waivers or exemptions are not allowed unless necessary for the management 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, single-blind, randomized, controlled, multi-centric
study with two parallel groups.
 
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
Duration of the study: The total duration of the study, per subject, will be 
approximately 10 months including the 6 months of Extended Safety Follow-Up 
(ESFU) period after the last dose of study vaccine administered.

Epoch 001: Primary starting at Visit 1 (Day 1) and ending at the ESFU contact 
(Month 10).

Primary completion Date (PCD): Last subject attending Visit 4.
Refer to glossary of terms for the definition of PCD.

End of Study (EoS): Last testing results released for samples collected at Visit 4. If 
the last testing results are available before the Last Subject Last Visit (LSLV), i.e., 
before the ESFU, the EoS will then be the LSLV.
Refer to glossary of terms for the definition of EoS.
The study groups and the 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 001
HRV Liq
640
6 weeks-12 weeks
●
HRV Lyo
640
6 weeks-12 weeks
●
The study groups and the treatment planned for the study are provided in Table 2.
Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine name
Study Groups
HRV Liq
HRV Lyo
HRV Liquid
HRV PCV-free
X
HRV Lyophilized
HRV*
x
Pediarix
DTPa-HBV-IPV
X
x
Hiberix
Hib
X
x
Prevenar 13
Prevenar 13
X
x
* Licensed lyophilized HRV vaccine.

Control: active control-GSK Biologicals’ currently licensed lyophilized HRV 
vaccine.

Vaccination schedule: Two doses of HRV vaccine to be administered according to a 
0, 2 month schedule as per the immunization schedule for HRV vaccine 
administration in the US.
Co-administration of routine childhood vaccines Pediarix, Hiberix and Prevenar 13
will be performed as follows:

All the subjects will receive a dose each of Pediarix, Hiberix and Prevenar 13 at 
Visit 1 (Day 1), Visit 2 (Month 2) and Visit 3 (Month 4).

The routine booster dose for the co-administered vaccines will not be 
administered to subjects as a part of this study. Subject’s parent(s)/LARs will be 
 
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reminded at Visit 4 to consult their primary health care provider regarding the 
booster dose of the vaccines for their child.

Treatment allocation: Randomized 1:1 using GSK Biologicals’ Randomization 
System on Internet (SBIR).

Blinding: single-blind
The blinding of the study epoch is provided in Table 3.
Table 3
Blinding of study epoch
Study Epoch
Blinding
Epoch 001
single-blind

Sampling schedule: Details of the samples to be collected are as follows:

Blood samples will be collected from all subjects at Visit 4 (Month 5) to 
measure serum anti-RV IgA antibody concentrations and antibody 
concentrations/titers against all the antigens in the co-administered vaccines.

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Safety monitoring: An IDMC consisting of clinical experts and a biostatistician will 
review the safety data by treatment group periodically to monitor the safety aspects
of the PCV-free liquid HRV vaccine. 
4.
STUDY COHORT
4.1.
Number of subjects/centers
The target sample size is 832 subjects evaluable for immunogenicity analyses at Visit 4 
(416 subjects in each group). Assuming that approximately 35% of enrolled subjects 
might withdraw or not be evaluable for analyses of immunogenicity, the target sample 
size to be enrolled is 1280 eligible subjects (640 subjects in each group).
Overview of the recruitment plan

The enrollment will be terminated when 1280 eligible subjects have been enrolled.

The recruitment and randomization will be monitored by SBIR.
4.2.
Inclusion criteria for enrollment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
 
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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).

A male or female between, and including, 6 and 12 weeks (42-90 days) of age at the 
time of the first study vaccination.

Written or witnessed/thumb printed informed consent obtained from the 
parent(s)/LAR(s) of the subject prior to performing any study specific procedure.

Healthy subjects as established by medical history and clinical examination before 
entering into the study.
4.3.
Exclusion criteria for enrollment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study 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 1), 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 within the period starting 30 days before the first dose of vaccine 
administration and ending at Visit 4, with the exception of the inactivated influenza 
vaccine, which is allowed at any time during the study, if administered at a site 
which is different from the sites used to administer the co-administered vaccines.

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).
 
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
Uncorrected congenital malformation (such as Meckel’s diverticulum) of the 
gastrointestinal tract that would predispose for Intussusception (IS).

History of IS.

Very prematurely born infants (born ≤28 weeks of gestation).

Family history of congenital or hereditary immunodeficiency.

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 Haemophilus type b (Hib), diphtheria, tetanus, 
pertussis, pneumococcus, RV and/or poliovirus.

Previous confirmed occurrence of RV GE, Hib, diphtheria, tetanus, pertussis,
pneumococcus, hepatitis B and/or polio disease.

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

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.

History of any neurological disorders or seizures.

History of SCID.

Acute disease and/or fever at the time of enrollment. 

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 diarrhea, 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. 
 
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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 
pediatric 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.
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. 
 
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5.2.
Subject identification and randomization
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 center.
5.2.2.
Randomization of treatment
5.2.2.1.
Randomization of supplies
The numbering of HRV vaccine supplies will be performed at GSK Biologicals, using a 
block scheme randomization in MATerial EXcellence (MATEX), a program developed 
for use in Statistical Analysis System (SAS®) (Cary, NC, US) by GSK Biologicals. Entire 
blocks will be shipped to the study centers/warehouse(s).
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centers in this multi-center study and to thus reduce the overall 
study recruitment period, an over-randomization 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 1280 eligible subjects who will be randomly assigned to two
study groups in a (1:1) ratio (approximately 640 subjects in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
SBIR. The randomization algorithm will use a minimization procedure accounting for the
center and the study as minimization factors. Minimization factors will have equal weight 
in the minimization algorithm.
After obtaining the signed and dated ICF from the subject’s parent/LAR 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 randomization 
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.
 
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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 single-blind where the investigator and/or his staff will be aware of the 
treatment assignment and the subject’s parents/LARs will not be aware of the treatment 
assignment.
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.
5.5.
Outline of study procedures
The list of study procedures is detailed in Table 4.
 
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Table 4
List of study procedures
Age
6-12 
weeks
4 
months
6 
months
7 
months
12 months
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3
Visit 4
ESFU
(Phone 
contact)
Time-points
Day 1
Month 2
Month 4
Month 5
Month 10
Sampling time-points
Pre-
Vacc
Post-
Vacc
Informed consent
●
Check inclusion/exclusion criteria
●
Collect demographic data
●
Record gestational age
●
Medical history
●
Hepatitis B vaccination history
●
History of previous vaccination from birth other 
than Hepatitis B vaccination
●
Physical examination including length and weight 
measurement
●
Check contraindications and warnings and 
precautions to vaccination
●
●
●
Pre-vaccination body temperature
●
●
●
Vaccines
Randomization and treatment number allocation
●
Treatment number allocation for subsequent 
doses
●
●
Recording of administered treatment number
●
●
●
HRV vaccine administration
●
●
Record regurgitation
●
●
HRV vaccine replacement dose administration in 
case of regurgitation*
●
●
Co-administration of Pediarix, Hiberix and 
Prevenar 13
●
●
●
Lab Assays
Blood sampling for antibody determination (5 
mL)
●
Safety Assessments
Distribution of diary cards
O
O
Record any concomitant 
medications/vaccinations
●
●
●
●
Record any intercurrent medical conditions
●
●
●
●
Recording of solicited adverse events within 8 
days after each dose of HRV vaccination 
(Days 1-Day 8)
●
●
Recording of non-serious adverse events within 
31 days after each dose of HRV vaccination 
(Days 1-31)
●
●
Recording of AEs/SAEs leading to withdrawal 
from study
●
●
●
●
●
Recording of SAEs
●
●
●
●
●
Recording of SAEs related to study participation, 
or to a concurrent GSK medication/vaccine
●
●
●
●
●
Return of diary cards
O
O
 
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Age
6-12 
weeks
4 
months
6 
months
7 
months
12 months
Epoch
Epoch 001
Type of contact
Visit 1
Visit 2
Visit 3
Visit 4
ESFU
(Phone 
contact)
Time-points
Day 1
Month 2
Month 4
Month 5
Month 10
Sampling time-points
Pre-
Vacc
Post-
Vacc
Diary card transcription by investigator or 
designee
●
●
Phone Contact
●
Study Conclusion
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
Post-Vacc = blood sample collected from subjects, one month after the third dose of the co-administered vaccines
(Visit 4); ESFU: Extended Safety Follow-up; AE = Adverse Event; SAE = Serious Adverse Events; LAR = Legally 
Acceptable Representative.
*If regurgitation or vomiting occurs after vaccination, a single replacement dose may be given at the same vaccination 
visit at the discretion of the Investigator.
Advisory Committee on Immunization Practices (ACIP) recommends administering
monovalent Hepatitis B vaccine to all newborns before hospital discharge. Infants who 
did not receive a birth dose should receive three doses of a Hepatitis-B-containing 
vaccine on a schedule of 0, 1 to 2 months, and 6 months starting as soon as feasible. 
Administer the second dose, 1 to 2 months after the first dose (minimum interval of four
weeks), administer the third dose at least eight weeks after the second dose AND at least 
16 weeks after the first dose. The final (third or fourth) dose in the Hepatitis B vaccine 
series should be administered no earlier than age 24 weeks.
Whenever possible, the investigator should arrange study visits within the interval 
described in Table 5.
Table 5
Intervals between study visits
Interval
Optimal length of interval
Visit 1Visit 2
60 days
Visit 2Visit 3
60 days
Visit 3Visit 4
30 days
Visit 3ESFU ‡
6 months
‡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.
Refer to Table 19 for intervals between study visits that determine subjects’ eligibility for 
inclusion in the per-protocol analysis.
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.
 
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5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrollment. 
5.6.3.
Collect demographic data
Record demographic data such as gestational age, sex and race in the subject’s eCRF.
5.6.4.
Medical and vaccination history
Obtain the subject’s medical and vaccination history (including Hepatitis B 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.
5.6.5.
Physical examination
Perform a physical examination of the subject, including assessment of length 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.
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled within the allowed 
interval for this visit (see Table 19).
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. 
5.6.6.
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.
5.6.7.
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 19).
 
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5.6.8.
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.
5.6.9.
Sampling
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
5.6.9.1.
Blood sampling for immune response assessments 
Blood samples will be taken during Visit 4 as specified in Section 5.5, outline of study 
procedures:

A volume of approximately 5 mL of whole blood (to provide approximately
1.75 mL of serum) should be drawn from all subjects for antibody 
determination at Visit 4 (Post-Vacc). 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.
Study Vaccines administration

After completing all prerequisite procedures prior to vaccination, two oral doses of 
the HRV vaccine will be administered at an approximate 2-months interval and three 
doses of co-administered vaccines will be given intramuscularly (IM) at 2, 4 and 6 
months (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 19).

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.
5.6.11.
Record regurgitation
If regurgitation or vomiting occurs after vaccination, a single replacement dose may be 
given at the same vaccination visit at the discretion of the Investigator. This information 
should be recorded in the eCRF. The subject may continue to participate in the study.
5.6.12.
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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5.6.13.
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 HRV vaccination visit, diary cards will be provided to the subject’s 
parent(s)/LAR(s). The subject’s parent(s)/LAR(s) will be instructed to measure and 
record the oral, axillary or rectal body temperature, and any solicited general AEs 
(i.e., on the day of HRV vaccination and during the next 7 days) or any unsolicited 
AEs (i.e., on the day of HRV vaccination and during the next 30 days occurring after 
vaccination). The subject’s parent(s)/LAR(s) will be instructed to return the 
completed diary card to the investigator at the next study visit.

Collect and verify completed diary cards during discussion with the subject’s 
parent(s)/LAR(s).

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.
5.6.14.
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.
5.6.15.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness

complete the Study Conclusion screen eCRF.
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 
 
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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 in countries where this is allowed will be asked to give a 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 US and will only be 
performed once an IEC 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’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). 
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
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 per-protocol analysis (See Section 10.4 for the 
definition of cohorts to be analyzed). 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.
5.7.2.
Biological sample
The biological sample to be collected from subjects is described in Table 6.
 
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Table 6
Biological sample
Sample Type
Quantity
Unit
Sampling time-point
No of subjects
Blood
Approximately 5
ml
Visit 4 (Post-Vacc)
All
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.
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 1
SER
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG
ELI
NA
IU/ml
2.046
GSK 
Biologicals 1
SER
Bordetella 
pertussis.Pertussis Toxin 
Ab.IgG
ELI
NA
IU/ml
2.693
GSK 
Biologicals 1
SER
Bordetella 
pertussis.Pertactin Ab.IgG
ELI
NA
IU/ml
2.187
GSK 
Biologicals 1
SER
Hepatitis B Virus.Surface 
Ab
CLIA
ADVIA Centaur 
anti-HBs2 
(Siemens 
Healthcare)
mIU/ml
6.2
GSK 
Biologicals 1
SER
Haemophilus influenzae 
type b.Polyribosyl Ribitol 
Phosphate Ab
ELI
NA
µg/ml
.153
GSK 
Biologicals 1
SER
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG
ELI
NA
IU/ml
.1
GSK 
Biologicals 1
SER
Clostridium tetani.Tetanus 
Toxoid Ab.IgG
ELI
NA
IU/ml
.1
GSK 
Biologicals 1
SER
Poliovirus Sabin Type 1 Ab
NEU
NA
ED50
8
GSK 
Biologicals 1
SER
Poliovirus Sabin Type 2 Ab
NEU
NA
ED50
8
GSK 
Biologicals 1
SER
Poliovirus Sabin Type 3 Ab
NEU
NA
ED50
8
GSK 
Biologicals 1
SER
S pneu.PS01 IgG
ECL
in-house
µg/ml
.08
GSK 
Biologicals 1
SER
S pneu.PS03 IgG
ECL
in-house
µg/ml
.075
GSK 
Biologicals 1
SER
S pneu.PS04 IgG
ECL
in-house
µg/ml
.061
GSK 
Biologicals 1
 
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System
Component
Method
Kit/Manufacturer
Unit
Cut-off
Laboratory
SER
S pneu.PS05 IgG
ECL
in-house
µg/mll
.198
GSK 
Biologicals 1
SER
S pneu.PS06A IgG
ECL
in-house
µg/ml
.111
GSK 
Biologicals 1
SER
S pneu.PS06B IgG
ECL
in-house
µg/mll
.102
GSK 
Biologicals 1
SER
S pneu.PS07F IgG
ECL
in-house
µg/ml
.063
GSK 
Biologicals 1
SER
S pneu.PS09V IgG
ECL
in-house
µg/ml
.066
GSK 
Biologicals 1
SER
S pneu.PS14 IgG
ECL
in-house
µg/ml
.16
GSK 
Biologicals 1
SER
S pneu.PS18C IgG
ECL
in-house
µg/ml
.111
GSK 
Biologicals 1
SER
S pneu.PS19A IgG
ECL
in-house
µg/ml
.199
GSK 
Biologicals 1
SER
S pneu.PS19F IgG
ECL
in-house
µg/ml
.163
GSK 
Biologicals 1
SER
S pneu.PS23F IgG
ECL
in-house
µg/ml
.073
GSK 
Biologicals 1
1GSK Biologicals laboratory refers to the Clinical Laboratories Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium 
or a validated laboratory designated by GSK Biologicals.
SER = Serum
S pneu = Streptococcus pneumoniae
IgA = Immunoglobulin A
IgG = Immunoglobulin G
ELI = Enzyme-Linked Immunosorbent Assay
NEU = Neutralization Assay
CLIA = ChemiLuminescence ImmunoAssay
NA = Not applicable
mIU = milli International Units; U = Units; IU = International Units
ED 50 = Estimated dose 50%
ECL: ElectroChemiLuminescence
3 The assay cut-off for Hib may be subject to change.
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 priority rank and immunological read-outs are given in Table 8.
 
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Table 8
Immunological read-outs
Blood sampling time-point
No. subjects
Component
Components priority rank
Type of contact and 
time-point
Sampling 
time-point
Visit 4 (Month 5)
Post-Vacc
All
PRP
1
D
2
T
3
Poliovirus serotypes 1, 2 
and 3
4
HBs
5
PT
6
FHA
7
PRN
8
13 S pneumoniae serotypes
9
HRV
10
PRP: polyribosyl-ribitol-phosphate, PT: pertussis toxoid, FHA: filamentous hemagglutinin, PRN: pertactin, HBs: 
hepatitis B surface antigen, D: diphtheria, T: tetanus, HRV: human rotavirus.
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analyzed according to priority ranking provided in Table 8. 
5.7.5.
Immunological correlates of protection
The following cut-offs are accepted as immunological correlates of protection:

Specific antibodies against diphtheria toxoid and tetanus toxoid will be measured by 
Enzyme Linked Immunosorbent Assay (ELISA). The assay cut-offs for anti-D and 
anti-T is currently set at 0.1 IU/mL (ELISA), which provides a conservative estimate 
of the percentage of subjects deemed to be protected [Camargo, 1984; Melville-
Smith, 1983]. 

Antibodies to the anti-HBs will be measured using CLIA. The cut-off of the test is 
set at 6.2 mIU/mL. An antibody concentration 10 mIU/mL defines seroprotection 
[CDC, 1991; WHO, 1988].

Antibodies against poliovirus types 1, 2 and 3 will be determined by a virus micro-
neutralization test adapted from the World Health Organization Guidelines for 
WHO/EPI Collaborative Studies on Poliomyelitis [WHO, 1993]. The lowest dilution 
at which serum samples will be tested is 1:8, from which a test will be considered 
positive. Titers will be expressed in terms of the reciprocal of the dilution resulting in 
50% inhibition. Antibody titers greater than or equal to this value are considered as 
protective.

Data from subjects given unconjugated Hib vaccine suggest that, in the absence of 
induction of immunological memory, a concentration of 0.15 g/mL is indicative of 
short-term protection, with 1 g/mL considered indicative of long-term protection 
[Käyhty, 1983; Anderson, 1984].

No correlate of protection is defined for the immune response to pertussis antigens. 
Antibodies against the pertussis components PT, FHA and PRN will be measured by 
ELISA technique. The current cut-offs for all three pertussis antibodies are the 
 
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Lower Limit Of Quantification (LLOQ) of the assays which are respectively 
2.693 IU/mL for PT, 2.046 IU/mL for FHA and 2.187 IU/mL for PRN. Subjects with 
antibody concentration below this cut-off will be considered seronegative.

Pneumococcal serotype specific total IgG antibodies (antibodies against 1, 3, 4, 5, 
6A, 6B, 7F, 9V, 14, 18C, 19 A, 19F and 23F) will each be measured by multiplex 
ElectroChemiLuminescence (ECL) assays. The LLOQ (in µg/mL) determined for 
each of these strains are shown in Table 7. No correlate of protection is defined for 
the immune response to pneumococcal antigens.

No immunological correlate of protection has been demonstrated so far for the 
antigen used as part of the HRV vaccine.
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.
6.
STUDY VACCINES AND ADMINISTRATION
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 (SmPC).
The study vaccines to be utilized in the study are detailed in Table 9.
 
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Table 9
Study vaccines
Treatment 
name
Vaccine/product 
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 
Lyophilized
HRV
HRV RIX4144 live 
attenuated 
>=10⁶⋅⁰CCID₅₀
Lyophilized vaccine in 
a monodose glass 
vial.
1 ml
2
HRV Diluent
CaCO₃=60mg
Diluent for lyophilized 
vaccine (calcium 
carbonate liquid 
antacid) supplied 
separately in a 
prefilled oral 
applicator.
Pediarix
DTPa-HBV-IPV
DT>=30IU; 
TT>=40IU; PT=25µg; 
FHA=25µg; 
PRN=8µg; 
HBsAg=10µg; 
Inactivated Poliovirus 
type 1 (Mahoney 
strain)=40DU; 
Inactivated Poliovirus 
type 2 (MEF-1 
strain)=8DU; 
Inactivated Poliovirus 
type 3 (Saukett 
strain); 
Aluminium=700µg 
Al3+
The DTPa-HBV-IPV 
component is 
presented as a turbid 
white suspension in a 
pre-filled syringe.
0.5 ml
3
Hiberix
Hib
PRP=10µg; 
TT~=25µg l.
The lyophilized Hib 
component is 
presented as a white 
pellet in a glass vial; it 
must be reconstituted 
before use.
0.5 ml
3
NaCl
NaCl=150mM
Sterile 0.9% saline 
solution
 
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Treatment 
name
Vaccine/product 
name
Formulation
Presentation
Volume to be 
administered
Number 
of 
doses
Prevenar 13
Prevenar 13
PS1=2.2µg CRM197; 
PS3=2.2µg CRM197; 
PS4=2.2µg CRM197; 
PS5=2.2µg CRM197; 
PS6A=2.2µg 
CRM197; 
PS6B=4.4µg 
CRM197; 
PS7F=2.2µg 
CRM197; 
PS9V=2.2µg 
CRM197; 
PS14=2.2µg 
CRM197; 
PS18C=2.2µg 
CRM197; 
PS19A=2.2µg 
CRM197; 
PS19F=2.2µg 
CRM197; 
PS23F=2.2µg 
CRM197; 
AlPO₄=125µg Al3+
Suspension for 
injection in a pre-filled 
syringe.
0.5 ml
3
DT: Diphtheria toxoid, TT: Tetanus toxoid, PT: Pertussis toxoid, FHA: Filamentous hemagglutinin, PRN: Pertactin
CCID50 = median Cell Culture Infective Dose (quantity of virus causing infection in 50% of exposed cells)
ml = milliliter; 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 
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.
 
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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. 
Lyophilized formulation of HRV vaccine
To prepare GSK Biologicals' HRV lyophilized 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 lyophilized product via the intermediate device. The 
vial should be shaken well to resuspend the vaccine. The entire volume of the 
resuspended product (approximately 1 mL) should be withdrawn into the same oral 
applicator and the resuspended product should then be administered promptly as a single 
oral dose.
Administration of the oral vaccines
In order to allow the swallowing of the entire volume of the single oral dose (of liquid or 
lyophilized 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. If regurgitation or vomiting occurs after vaccination, a single replacement dose 
may be given at the same vaccination visit. This information should be recorded in the 
eCRF. The subject may continue to participate in the study. 
Administration of the intramuscular vaccines
In order to ensure proper IM injection of the co-administered vaccines, a needle of at 
least 1 inch (2.54 cm) length, 25 gauge will be used [Diggle, 2006; Zuckerman, 2000].
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.
 
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Table 10
Dosage and administration
Type of 
contact and 
time-point
Study 
group
Treatment 
name
Volume to be 
administered
Route1
Site
Location
Directionality2
Laterality
Visit 1, Visit 2
HRV Liq
HRV Liquid
1.5 ml
O
Not applicable
Not applicable
Not 
applicable
Visit 1 , Visit 2
HRV Lyo
HRV 
Lyophilized
1 ml
O
Not applicable
Not applicable
Not 
applicable
Visit 1, Visit 2, 
Visit 3
HRV Liq, 
HRV Lyo
Pediarix
0.5 ml
IM
Thigh
Upper
Right
Visit 1, Visit 2, 
Visit 3
HRV Liq, 
HRV Lyo
Hiberix
0.5 ml
IM
Thigh
Anterolateral
Right
Visit 1, Visit 2, 
Visit 3
HRV Liq, 
HRV Lyo
Prevenar 
13
0.5 ml
IM
Thigh
Lower
Left
1Oral (O), Intramuscular (IM)
2 Directionality is a qualifier for further detailing the location of the vaccine administration.
6.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 30% additional vaccine doses will be 
supplied to replace those that are unusable.
6.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of the 
study vaccines. 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 vaccine(s).

Hypersensitivity reaction following the administration of the vaccine(s).

Any uncorrected congenital malformation of the gastrointestinal tract (such as 
Meckel’s diverticulum) that would predispose for IS.

Any history of IS.

SCID.

Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe.

Contraindication for pertussis-containing vaccines: 

Encephalopathy of unknown etiology, defined as an acute, severe central 
nervous system disorder, occurring within 7 days following previous vaccination 
with pertussis-containing vaccine and generally consisting of major alterations 
in consciousness, unresponsiveness, generalized or focal seizures that persist 
more than a few hours, with failure to recover within 24 hours.

Individuals with progressive neurologic disorder, including infantile spasms, 
uncontrolled epilepsy, or progressive encephalopathy should not receive a 
 
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pertussis-containing vaccine until a treatment regimen has been established and 
the condition has stabilized.
Refer to the approved product label/package inserts for warnings and precautions for the 
use of Pediarix, Prevenar13, Rotarix (currently licensed lyophilized HRV vaccine) and 
Hiberix vaccines.
The following events constitute contraindications to administration of the study vaccines
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 the subject may be withdrawn at the discretion of the 
investigator (see Section 8.5). 

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 diarrhea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.

GE within 7 days preceding the HRV 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.
Post-marketing safety data indicate a transient increased risk of IS after vaccination, 
mostly within 7 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, parents/LARs 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.
 
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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 of the co-administered vaccines for 
information on the warnings and precautions concerning their administration.
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 following each dose of study 
vaccine.

Any concomitant vaccination administered in the period from first study vaccination 
(Visit 1) and ending at Visit 4.

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.
6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol 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 
 
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per-protocol analysis. See Section 10.4 for per protocol set for analysis of 
immunogenicity.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period between the first vaccination at Visit 1 to the 
blood sampling at Visit 4.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e., more than 14 days) during the study period between Visit 1 to Visit 4. For 
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 the first vaccination at Visit 1 to the blood sampling at Visit 4.

Administration of long-acting immune-modifying drugs 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 dose of vaccine administration and ending at Visit 4* 
blood sampling, with the exception of the inactivated influenza vaccine, which is 
allowed at any time during the study if administered at a site which is different from 
the sites used to administer the co-administered vaccines.
* 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 
immunization program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its SmPC or Prescribing 
Information 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 per-protocol analyses
At each study visit subsequent to the first vaccination/the vaccination visit, 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 if occurring up 
to Visit 4.
Subjects may be eliminated from the PPS for analysis of 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.
 
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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 AE or SAE as provided in 
this protocol. 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should they/the subject manifest any signs or symptoms they perceive as serious.
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.
 
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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.

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 hospitalization or prolongation of existing hospitalization,
Note: In general, hospitalization 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 hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition (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, diarrhea, 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 hospitalization but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
 
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outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization.
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
Diarrhea
Vomiting
Loss of appetite
Cough/runny nose
Note: Parent(s)/LAR(s) will be instructed to measure and record the oral, axillary or
rectal body temperature in the evening. Should additional temperature measurements be 
performed at other times of day, parent(s)/LAR(s) will be instructed to record the highest 
temperature in the diary card.
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, 
hematology, 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 and serious 
adverse events
8.3.1.
Time period for detecting and recording adverse events and
serious adverse events
All AEs starting within 31 days following administration of Dose 1 and Dose 2 of the 
HRV vaccine (Day 1 to Day 31) must be recorded into the appropriate section of the 
eCRF, irrespective of intensity or whether or not they are considered vaccination-related.
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 consents to participate in the study until she/he is 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
Event
Pre-
V1*
Visit 1 7 d 
post 
V1
30 d 
post-
V1
Visit 2 7 d 
post
V2
30 d 
post-
V2
Visit 3
7 d 
post 
V3
30 d
post-
V3
Visit 4
ESFU 
contact
Day 1
Month 2
Month 4
Month 
5
Month 
10
Solicited general 
AEs
Unsolicited AEs
AEs/SAEs 
leading to 
withdrawal from 
the study
SAEs 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine
* i.e., consent obtained. V: vaccination; Post-V: post-vaccination.
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 study vaccines, the investigator will promptly notify the 
Study Contact for Reporting SAEs.
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 vaccines
or since the last visit?’
 
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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.
8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
Intensity of the following solicited AEs will be assessed as described in Table 13 and 
Table 14.
Table 13
Intensity scales to 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
Behavior 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
Diarrhea$
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.
$ Diarrhea 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 
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Table 14
Intensity scales for diarrhea, vomiting and fever occurring during 
the solicited period
Adverse Event
Intensity 
grade
Parameter
Diarrhea $
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
$ Diarrhea 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.
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 a day-care center 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.
 
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8.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccines and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e.,
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products.
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 
study vaccines will be considered and investigated. The investigator will also consult the 
IB and/or and/or SmPC 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 
used when determining regulatory reporting requirements.
Causality of all 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 study 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.
 
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
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).
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
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded 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 events 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.
 
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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: 
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. 
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PPD
PPD
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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.
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 study 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 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 
last visit of the subject.
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 30 
days after the last vaccination.
 
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8.5.2.
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 a paper/electronic 
Expedited Adverse Events Report and/or pregnancy 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 a SAE should 
be recorded in the subject’s eCRF (refer to Section 6.7).
8.7.
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 during the study duration.
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.
 
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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:

SAE

Unsolicited non-serious AE

Solicited AE

Protocol violation (specify)

Consent withdrawal, not due to an AE*

Moved from the study area

Lost to follow-up

Other (specify)
*In case a subject is withdrawn from the study because he/she/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/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 8.5.2).
 
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9.2.2.
Subject withdrawal from study vaccines
A ‘withdrawal’ from the study 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 study 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 study vaccines will be 
documented on the Vaccine Administration page/screen of the eCRF. The investigator 
will document whether the decision to discontinue further vaccination/treatment 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:

SAE

Unsolicited non-serious AE

Solicited AE

Not willing to be vaccinated

Other (specify)
10.
STATISTICAL METHODS
10.1.
Primary endpoints

Immunogenicity with respect to components of the routine infant vaccines, one 
month after Dose 3 of routine infant vaccines (Visit 4):

Anti-D antibody concentration ≥0.1 IU/mL,

Anti-T antibody concentration ≥0.1 IU/mL,

Anti-HBs antibody concentrations ≥10 mIU/mL,

Anti-poliovirus types 1, 2 and 3 antibody titers ≥8 ED50,

Anti-PT, anti-FHA and anti-PRN antibody concentrations expressed as GMCs,

Anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 
23F) antibody concentrations expressed as GMCs,

Anti-PRP antibody concentrations ≥0.15 µg/mL,

Anti-PRP antibody concentrations ≥1.0 µg/mL.

Difference in seroresponse with respect to PT, FHA and PRN antigen components 
one month after Dose 3 of routine infant vaccines (Visit 4):

Seroresponse to anti-PT, anti-FHA and anti-PRN.
 
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10.2.
Secondary endpoints

Serum anti-rotavirus IgA antibody seropositivity 3 months after Dose 2 of HRV 
vaccine (Visit 4).

Serum anti-RV IgA antibody concentrations ≥20 U/mL and ≥90 U/mL 1-2 
months after Dose 2.

Immunogenicity with respect to components of the routine infant vaccines, one 
month after Dose 3 of routine infant vaccines (Visit 4):

PT, anti-FHA and anti-PRN antibody concentrations ≥2.693 IU/mL, ≥2.046
IU/mL and ≥2.187 IU/mL, respectively.

Anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F,
23F) antibody concentrations ≥0.35 µg/mL for the ELISA,

Anti-D, anti-T, anti-PRP and anti-HBs antibody concentrations expressed as 
GMCs and anti-poliovirus types 1, 2 and 3 antibody concentrations expressed as 
Geometric Mean Titers (GMTs).

Occurrence of general solicited AEs during the 8 day 
(Day 1-Day 8) follow-up period after each dose of HRV vaccine.

Occurrence of unsolicited AEs within 31 days (Day 1-Day 31) after any dose of 
HRV vaccine, according to the Medical Dictionary for Regulatory Activities 
(MedDRA) classification.

Occurrence of SAEs from Dose 1 of study vaccines up to study end.
10.3.
Determination of sample size
The target sample size is 832 subjects evaluable for immunogenicity analyses at Visit 4 
(416 subjects in each group). Assuming that approximately 35% of enrolled subjects 
might withdraw or not be evaluable for analyses of immunogenicity, the target sample 
size to be enrolled is 1280 subjects (640 subjects in each group).
The primary objective of this study is to demonstrate the immune response elicited to all 
antigens contained in each of the routine infant vaccines Pediarix, Hiberix and
Prevenar 13 when co-administered with PCV-free liquid HRV vaccine is non-inferior to 
that elicited when co-administered with the lyophilized HRV vaccine.
 
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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 
type I error below 2.5%, a hierarchical procedure will be used for the multiple study 
objectives. That is, an objective will be reached if its associated criterion is met and the 
previous objectives were reached. The same order in which the study objectives are listed 
in Section 2.1 will be considered for hypothesis testing.
The sample size has been estimated in order to obtain at least 90% 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 Section10.3.3.
10.3.2.
Reference for sample size:
References were chosen based on observed response and standard deviations in studies 
Rota-060 (107531) and Hib-097 (112957).
The percentage of subjects above the cut-off is detailed in Table 16.
Table 16
Percentage of subjects above the cut-off
Study
Timing
Cut-off
N
n
%
LL
UL
Rota-060 (Co-
administered group)
Post dose 3
D 0.1 IU/mL
178
178
100
97.9
100
T 0.1 IU/mL
178
178
100
97.9
100
HBs≥10 mIU/mL#
169
169
100
97.8
100
IPV1 1:8
128
128
100
97.2
100
IPV2 1:8
139
139
100
97.4
100
IPV3 1:8
146
146
100
97.5
100
PRP ≥0.15 µg/mL
180
177
98.3
95.2
99.7
PRP ≥1 µg/mL
180
161
89.4
84.0
93.5
Hib-097 (ActHib group)
Post dose 3
D 0.1 IU/mL
273
273
100
98.7
100
T 0.1 IU/mL
274
274
100
98.7
100
HBs ≥10 mIU/mL#
258
257
99.6
97.9
100
IPV1 1:8
181
181
100
98.0
100
IPV2 1:8
192
188
97.9
94.8
99.5
IPV3 1:8
323
323
100
98.9
100
PRP ≥0.15 µg/mL
1590
1536
96.6
95.6
97.4
PRP≥1 µg/mL
274
246
89.8
85.6
93.1
Hib-097 (Pooled Hiberix 
group)
Post dose 3
D 0.1 IU/mL
393
393
100
99.1
100
T 0.1 IU/mL
393
393
100
99.1
100
HBs ≥10 mIU/mL#
363
362
99.7
98.5
100
IPV1 1:8
248
246
99.2
97.1
99.9
IPV2 1:8
280
275
98.2
95.9
99.4
IPV3 1:8
257
254
98.8
96.6
99.8
PRP ≥0.15 µg/mL
1590
1536
96.6
95.6
97.4
PRP≥1 µg/mL
1590
1291
81.2
79.2
83.1
N= Number of subjects with available results, n (%) = Number (percentage) of subjects with titer/concentration within 
the specified range, D = Diphtheria, T = Tetanus; IPV1 = Polio virus type 1; IPV2 = Polio virus type 2; IPV3 = Polio 
 
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virus type 3; PRP = Polyribosyl-Ribitol-Phosphate; HBs = Hepatitis B; LL/UL = 95% exact CI; # irrespective of whether it 
was given at birth or not.
The standard deviation for log10 transformed concentrations post-vaccination is presented 
in Table 17.
Table 17
Standard deviation for log10 transformed titer/concentration post-
vaccination 
Antigen
Rota-060 
Post dose 3
(Co-administration 
group)
Hib-097
(ActHib group)
Hib-097
(Pooled Hiberix group)
PT
0.257
0.281
0.297
PRN
0.397
0.407
0.409
FHA
0.264
0.255
0.293
Anti-4
0.335
0.295
0.301
Anti-6B
0.549
0.524
0.496
Anti-9V
0.351
0.357
0.381
Anti-14
0.345
0.409
0.405
Anti-18C
0.376
0.336
0.375
Anti-19F
0.332
0.293
0.317
Anti-23F
0.444
0.426
0.447
Anti-1
-
0.337
0.354
Anti-19A
-
0.398
0.358
Anti-3
-
0.281
0.341
Anti-5
-
0.361
0.387
Anti-6A
-
0.350
0.347
Anti-7F
-
0.311
0.326
PT = Pertussis Toxoid, PRN = Pertactin, FHA = Filamentous Hemagglutinin
10.3.3.
Power computation
The sample size has been estimated in order to obtain at least 90% power to demonstrate 
the primary objectives (Bonferroni adjustment of type II error). A hierarchical procedure 
will be used for the multiple study objectives. That is, an objective will be reached if its 
associated criterion is met and the previous objectives were reached. The same order in 
which the study objectives are listed in Section 2.1 will be considered for hypothesis 
testing.
The power computations were based on the following methods:

Non-inferiority on percentage of subjects with titer/concentration above pre-specified 
cut-off: Type II error is obtained using PASS 2005, one-sided non-inferiority test for 
two proportions, under the alternative of equal proportions (Miettinen and Nurminen 
method).

Non-inferiority on GMC: Type II error is obtained using PASS 2005, one-sided 
non-inferiority test for two from normal data with common variance, under the 
alternative of equal means;
 
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To account for the multiplicity of comparison, the global type II errors were 
conservatively estimated as the sum of individual type II errors.
The power associated to the target sample size for the conclusion on each inferential 
objective of this study is detailed below.
Table 18 details the power for non-inferiority post-dose 3.
Table 18
Power for non-inferiority post-dose 3
Margin
Reference
N
HRV Liq Group
N
HRV Lyo Group
Type II error
Anti-D 0.1 IU/mL
10.0%
99.5%
416
416
0.0%
Anti-T 0.1 IU/mL
10.0%
99.5%
416
416
0.0%
Anti-IPV1 1:8
5.0%
99.5%
416
416
0.0%
Anti-IPV2 1:8
5.0%
98.8%
416
416
0.1%
Anti-IPV3 1:8
5.0%
99.5%
416
416
0.0%
Anti-HBs ≥10 mIU/mL
10.0%
98.0%
416
416
0.0%
Anti-PT GMC
0.67
0.297
416
416
0.0%
Anti-FHA GMC
0.67
0.293
416
416
0.0%
Anti-PRN GMC
0.67
0.409
416
416
0.0%
Anti-1 GMC
0.5
0.549
416
416
0.0%
Anti-3 GMC
0.5
0.549
416
416
0.0%
Anti-4 GMC
0.5
0.335
416
416
0.0%
Anti-5 GMC
0.5
0.549
416
416
0.0%
Anti-6A GMC
0.5
0.549
416
416
0.0%
Anti-6B GMC
0.5
0.549
416
416
0.0%
Anti-7F GMC
0.5
0.549
416
416
0.0%
Anti-9V GMC
0.5
0.381
416
416
0.0%
Anti-14 GMC
0.5
0.409
416
416
0.0%
Anti-18C GMC
0.5
0.376
416
416
0.0%
Anti-19A GMC
0.5
0.549
416
416
0.0%
Anti-19F GMC
0.5
0.332
416
416
0.0%
Anti-23F GMC
0.5
0.447
416
416
0.0%
Anti-PRP 0.15 µg/mL
5.0%
96.5%
416
416
4.8%
Anti-PRP 1 µg/mL
10.0%
81.2%
416
416
4.4%
Seroresponse to PT$
10.0%
0.297
416
416
0.1%
Seroresponse to FHA$
10.0%
0.293
416
416
0.1%
Seroresponse to PRN$
10.0%
0.409
416
416
0.1%
Global Power > 90.0%
N = Number of evaluable subjects per group, Anti-D = anti-diphtheria antibody, Anti-T = anti-tetanus antibody, 
Anti-IPV1 = anti-poliovirus type 1, Anti-IPV2 = anti-poliovirus type 2, Anti-IPV3 = anti-poliovirus type 3, Anti-PT = anti-
pertussis toxoid antibody, Anti-FHA = anti-filamentous hemagglutinin, Anti-PRN = anti-pertactin antibody, Anti-PRP 
=antibodies against polyribosyl-ribitol-phosphate; Anti-HBs =antibodies against hepatitis B.
For Anti-PRP, anti-D, anti-T, anti-IPV1, anti-IPV2 and anti-IPV3 antibodies, the reference used for power calculation is 
rate. For the rest of the antibodies, the standard deviation values were considered.
*For rates ~100%, a conservative reference of 99.5% is taken.
$Power results were based on the simulation assuming the distribution of immune response from HRV Liq group and 
HRV Lyo group are the same, and equal sero-response rate between groups under the alternative (seroresponse for 
 
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anti-PT, anti-FHA and anti-PRN in HRV liq group were defined as the percentage of subjects showing an antibody 
concentration above a threshold that led to 95% seroresponse in the HRV lyo), 1-sided, alpha=0.025.
10.4.
Sets for Analyses
10.4.1.
Exposed Set

The Exposed Set (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 is available.
The ES analysis will be performed per treatment actually administered at Dose 1. 
10.4.2.
Per-protocol Set for analysis of immunogenicity
The PPS for immunogenicity will include all eligible subjects from the ES:

who have received the study vaccines according to their random assignment,

who comply with the vaccination schedule of routine infant vaccines and HRV 
vaccines as per Table 19,

for whom the routine infant vaccines were administered according to the protocol as 
per Table 10,

for whom the HRV vaccine liquid or lyophilized formulation was administered 
according to protocol,

who have not received a vaccine not specified or forbidden in the protocol up to 
Visit 4 blood sampling,

who had not received medication forbidden by the protocol up to Visit 4 blood 
sampling,

whose underlying medical condition(s) was (were) not forbidden by the protocol up 
to Visit 4 blood sample,

for whom data concerning immunogenicity endpoint measures are available. This 
will include subjects for whom assay results are available for antibodies against at 
least one routine infant vaccine antigen component,

who comply with the blood sampling schedule after the 3rd dose of Pediarix, Hiberix 
and Prevenar 13 as per Table 19,

who have no concomitant infection up to Visit 4 blood sample, which may influence 
the immune system.
 
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Table 19
Maximum allowed interval between visits
Interval
Allowed length of interval
Visit 1Visit 2
49 days-83 days after Dose 1 of study vaccines 1
Visit 2Visit 3
56 days-83 days after Dose 2 of study vaccines 1
Visit 3 Visit 4
21 days-48 days after Dose 3 of study vaccines 1
Visit 3 ESFU
180 days-210 days after Dose 3 of study vaccines
1 Subjects will not be eligible for inclusion in the Per-Protocol Set (PPS) for analysis of immunogenicity, if they make 
the study visit outside this interval. This is not applicable for the interval between Visit 3 and ESFU.
10.5.
Derived and transformed data

A seronegative subject is a subject whose antibody concentration is below the cut-off 
value.

A seropositive subject is a subject whose antibody concentration is greater than or 
equal to the cut-off value. The applicable thresholds are presented in Table 7.

A seroprotected subject is a subject whose antibody concentration is greater than or 
equal to the level defining clinical protection. The following seroprotection 
thresholds are applicable:

anti-D antibody concentrations 0.1 IU/mL.

anti-T antibody concentrations 0.1 IU/mL.

anti-HBs antibody concentrations 10 mIU/mL.

anti-poliovirus types 1, 2 and 3 antibody titers ≥8 ED50.

anti-PRP antibody concentrations 0.15 µg/mL.

Other cut-offs to be considered:

anti RV IgA antibody concentration 90 U/mL.

anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F,
23F) antibody concentrations ≥0.35 µg/mL for the ELISA.

anti-PRP antibody concentrations 1.0 µg/mL.

The GMC calculation will be performed by taking the anti-log of the mean of the log 
concentration transformations. Note that antibody concentrations below the cut-off of 
the assay will be given an arbitrary value of half the cut-off while antibody 
concentration above the assay cut-off but below the Limit of Quantification will be 
given the assay cut-off as value.
Handling of missing data: 
Immunogenicity:

For a given subject and a given immunogenicity measurement, missing or 
non-evaluable measurements will not be replaced. 
 
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Reactogenicity and Safety:

For analysis of solicited, unsolicited AEs (such as SAEs or AEs by primary 
MedDRA term), and for the analysis of concomitant medications, all vaccinated 
subjects will be considered. Subjects who did not report the event or the concomitant 
medication will be considered as subjects without the event or the concomitant 
medication respectively.
10.6.
Analysis of demographics
The median, mean, range and standard deviation of age (in weeks) at each study vaccine
dose and of the gestational age will be computed by group. The median, mean and 
standard deviation of length (in centimeters) and weight (in kilograms) at Visit 1 will
computed by group. The racial and sex composition of the subjects will be presented.
The distribution of subjects enrolled among the study centers will be tabulated as a whole 
and per group.
The number 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.
10.7.
Analysis of immunogenicity
The primary analysis will be based on the PPS for analysis of immunogenicity. An 
analysis on the ES will be performed only if, in any group, more than 5% of the 
vaccinated subjects with immunological data are excluded from the PPS for 
immunogenicity.
The following section describes the analyses that will be performed.
10.7.1.
Within group analysis
For each treatment group, one month after Dose 3 of routine infant vaccines at Visit 4 
(Month 5) time-point:

Seroprotection rates against HBsAg, diphtheria toxoid, tetanus toxoid, PRP antigen 
and poliovirus types 1, 2 and 3 (with exact 95% CI) will be calculated.

Seropositivity rates and their exact 95% CIs for antibodies against PT, FHA, PRN, 
anti-rotavirus, S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 
19F, 23F and HBsAg will be tabulated.

Percentage of subjects with anti-pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 19F, 23F) antibody concentrations ≥0.35 µg/mL with 95% CI will be 
calculated.
 
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
Percentage of subjects with anti-PRP antibody concentrations 1.0 g/mL will be 
calculated with 95% CI.

Percentage of subjects with anti RV IgA antibody concentration 90 U/mL will be 
calculated with 95% CI.

GMC/GMT with 95% CI will be tabulated for antibodies against each antigen.
The above mentioned descriptive analyses will also be performed by race and sex.
The distribution of antibody concentrations/titers for each appropriate serotype/antigen 
will be displayed using tables and/or reverse cumulative distribution curves.
For anti-HBs antibodies, an analysis will be done according to vaccination history to 
Hepatitis B vaccine.
10.7.2.
Between group assessment
For each treatment group, one month after Dose 3 of routine infant vaccines at Visit 4 
(Month 5) time-point:

Two-sided asymptotic standardized 95% CIs for the difference in the percentage of 
subjects with titer/concentration above or equal to pre-specified clinical thresholds 
will be computed (HRV Liq group minus HRV Lyo group).

The two-sided 95% CIs for the group GMC/GMT ratio (HRV Liq group over HRV 
Lyo group) will be computed using an ANOVA model on the logarithm10 
transformation of the concentrations. The ANOVA model will include the vaccine 
group as fixed effects. In addition, for anti-HBs, the model will include the Hepatitis 
B vaccination history as co-variable.

For the group comparison in anti-PT, FHA, PRN seroresponse at one month post 
dose 3, P-value for testing H0: P85% vs. H1: P>85% (P= % of subjects in HRV liq 
group with seroresponse (above a threshold that leads to 95% seroresponse in the 
HRV lyo group) will be computed. P-value will be computed by integrating on the 
p-value for the null hypothesis that the seroresponse rate in the HRV lyo group is 
<85% and the a-posteriori probability of the threshold in the HRV liq group.
10.8.
Analysis of safety
The ES will be used for the analysis of safety. 
The following calculations will be performed for each group:
The percentage of doses and of subjects reporting at least one symptom (solicited or
unsolicited) during the 8 day (Day 1-Day 8) 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, those assessed as 
causally related to vaccination, those rated as grade 3 in intensity with causal relationship 
to vaccination and those that resulted in a medically attended visit.
 
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The percentage of doses and of subjects reporting each individual solicited general
symptom will be computed, over the 8 day (Day 1-Day 8) 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, those assessed as 
causally related to vaccination, those rated as grade 3 in intensity with causal relationship 
to vaccination and those that resulted in a medically attended visit. For fever, additional 
analyses will be performed by 0.5C increments. These calculations will also be 
performed by sex and race.
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 day (Day 1-Day 31) 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, for unsolicited AEs rated as grade 3 with causal relationship to 
vaccination and those that resulted in a medically attended visit.
The percentage of subjects who started taking at least one concomitant medication, 
antipyretic medication and prophylactic antipyretic medication during the 8 day 
(Days 1-8) and 31 day (Days 1-31) follow-up period post-vaccination will be tabulated by 
dose, overall per subject and over all the doses.
Subjects who experienced at least one SAE during the entire study period (from Dose 1 
till ESFU Contact at Month 10) will be reported and the SAEs 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 95% CIs for a proportion within a group will be based on the method by 
Clopper [Clopper, 1934].

The standardized asymptotic CI for the group difference in proportion is the method 
6 described in the Newcombe paper [Newcombe, 1998]

The 95% CIs of the group GMC/GMT ratios will be computed using an ANOVA 
model on the logarithm10 transformation of the concentrations/titers. The ANOVA 
model will include the vaccine group as fixed effects. In addition, for anti-HBs, the 
model will include the Hepatitis B vaccination history as co-variable.

The 95% CI for GMTs/GMCs will be obtained within each group separately. The 
95% CI for the mean of log-transformed titer/concentration will be first obtained 
assuming that log-transformed values were normally distributed with unknown 
variance. The 95% CI for the GMTs/GMCs will then be obtained by exponential-
transformation of the 95% CI for the mean of log-transformed titer/concentration.
 
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
P-value for seroresponse endpoint will be computed by integrating on the p-value for 
the null hypothesis that the seroresponse rate in the HRV lyo group is <85% and the 
a-posteriori probability of the threshold in the HRV liq group.
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.
10.10.1.
Sequence of analyses
Safety data that is as clean as possible will be analyzed for IDMC review. Details of the 
review will be described in an IDMC charter. The final analyses of all data will be 
conducted after conclusion of the ESFU contact and will include the final analyses of 
immunogenicity, reactogenicity and safety.
An integrated clinical study report containing all data will be written and made available 
to the investigators and submitted to regulatory authorities as appropriate.
10.10.2.
Statistical considerations for interim analyses
All analyses will be conducted on final data 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, public disclosure requirements 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.
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 by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data. 
 
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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 other items, 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. 
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 
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 
 
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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. 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, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report.
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 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.
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 
 
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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.
11.7.
Data Sharing
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non-GSK studies, to investigate further about the study product(s) and other 
product(s), and/or the disease/condition under investigation and related diseases and 
conditions.
12.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
13.
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Rotavirus Mortality in Children <5 Years of Age, 2000-2013. Clin Infect Dis. 2016: S96-
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attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants. 
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rotavirus vaccine in Finnish infants. Pediatr Infect Dis J 2004(b); 23: 937–43.
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APPENDIX A
LABORATORY ASSAYS
Rotavirus Ab.IgA Determination
The anti-rotavirus antibody concentrations are determined by a validated anti-rotavirus 
IgA ELISA. Microtiter plates (96-well) are coated with an anti-rotavirus monoclonal 
antibody. The wells are washed and incubated with (positive wells) or without (negative 
wells) RV. 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. Color development proportional to the quantity of 
bound anti-rotavirus IgA occurs in the presence of a chromogen, TetraMethylBenzidine 
(TMB), 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 milliliter are calculated relative to 
the four-parameter logistic function generated from the standard curve.
Poliovirus
Presence of antibodies against poliovirus types 1, 2 and 3 will be determined by a virus 
micro-neutralization test adapted from the World Health Organization Guidelines for 
WHO/EPI Collaborative Studies on Poliomyelitis. The starting dilution at which serum 
samples will be tested is 1/8, from which a test will be considered positive. Titers will be 
expressed in terms of the reciprocal of the dilution resulting in 50% inhibition.
Streptococcus
Pneumococcal serotype-specific immunoglobin G (IgG) antibodies (antibodies against 
serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) will be measured by ECL
multiplex assays. The antibody concentration will be determined by logistic log 
comparison of the assay curves with a standard reference serum sp007 available from the 
US Food and Drug Administration (FDA) for which concentration of IgG to each of the 
13 serotypes is known in µg/mL.
Anti-FHA ELISA (Bordetella pertussis, Filamentous Hemaglutinin Ab.IgG)
Antibody responses against FHA will be quantified by ELISA using purified FHA 
antigen extracted from Bordetella Pertussis culture in virulence Phase I as coating. The 
antigen is coated onto a 96-wells microplate. After a washing and a blocking step, 
dilutions of serum samples, controls and standard are incubated on the coated plate. The 
microplate is washed and mouse HorseRadishPeroxidase (HRP)-conjugated anti-human 
IgG monoclonal antibodies are added. After incubation, unbound antibodies are removed 
by washing and TetraMethylBenzidine (TMB) is incubated to reveal the enzyme activity. 
Color reaction is stopped by addition of sulfuric acid and the resulting yellow color is 
measured spectrophotometrically.
The intensity of the color is directly proportional to the concentration of the anti-FHA 
antibodies present in the sample.
 
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Concentrations are calculated from a reference standard curve using a four parameters 
logistic fitting algorithm and expressed in International units (IU/mL). 
Anti-PT ELISA (Bordetella pertussis, Pertussis Toxin Ab.IgG)
Antibody responses against PT will be quantified by ELISA using purified PT antigen 
extracted from Bordetella Pertussis culture in virulence Phase I as coating. The antigen is 
coated onto a 96-wells microplate. After a washing and a blocking step, dilutions of 
serum samples, controls and standard are incubated on the coated plate. The microplate is 
washed and mouse HorseRadishPeroxidase (HRP)-conjugated anti-human IgG 
monoclonal antibodies are added. After incubation, unbound antibodies are removed by 
washing and is incubated to reveal the enzyme activity. Color reaction is stopped by 
addition of sulfuric acid and the resulting yellow color is measured 
spectrophotometrically.
The intensity of the color is directly proportional to the concentration of the anti-PT 
antibodies present in the sample.
Concentrations are calculated from a reference standard curve using a 4 parameters 
logistic fitting algorithm and expressed in International units (IU/mL). 
Anti-PRN ELISA (Bordetella pertussis, Pertactin Ab.IgG)
Antibody responses against PRN will be quantified by ELISA using purified PRN 
antigen extracted from Bordetella Pertussis culture in virulence Phase I as coating. The 
antigen is coated onto a 96-wells microplate. After a washing and a blocking step, 
dilutions of serum samples, controls and standard are incubated on the coated plate. The 
microplate is washed and mouse HorseRadishPeroxidase (HRP)-conjugated anti-human 
IgG monoclonal antibodies are added. After incubation, unbound antibodies are removed 
by washing and TetraMethylBenzidine (TMB) is incubated to reveal the enzyme activity. 
Color reaction is stopped by addition of sulfuric acid and the resulting yellow color is 
measured spectrophotometrically.
The intensity of the color is directly proportional to the concentration of the anti-PRN 
antibodies present in the sample.
Concentrations are calculated from a reference standard curve using a 4 parameters 
logistic fitting algorithm and expressed in International units (IU/mL). 
Anti-D ELISA (Corynebacterium diphtheria, Diphtheria Toxoid Ab.IgG)
Antibody responses against D will be quantified by ELISA using purified D antigen as 
coating. The antigen is coated onto a 96-wells microplate. After a washing and a blocking 
step, dilutions of serum samples, controls and standard are incubated on the coated plate. 
The microplate is washed and mouse HorseRadishPeroxidase (HRP)-conjugated 
anti-human IgG monoclonal antibodies are added. After incubation, unbound antibodies 
are removed by washing and TetraMethylBenzidine (TMB) is incubated to reveal the 
enzyme activity. Color reaction is stopped by addition of sulfuric acid and the resulting 
yellow color is measured spectrophotometrically.
 
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The intensity of the color is directly proportional to the concentration of the anti-D
antibodies present in the sample.
Concentrations are calculated from a reference standard curve using a 4 parameters 
logistic fitting algorithm and expressed in International units (IU/mL). 
Anti-T ELISA (Clostridium tetani, Tetanus Toxoid Ab.IgG)
Antibody responses against T will be quantified by ELISA using purified T antigen as 
coating. The antigen is coated onto a 96-wells microplate. After a washing and a blocking 
step, dilutions of serum samples, controls and standard are incubated on the coated plate. 
The microplate is washed and mouse HorseRadishPeroxidase (HRP)-conjugated 
anti-human IgG monoclonal antibodies are added. After incubation, unbound antibodies 
are removed by washing and TetraMethylBenzidine (TMB) is incubated to reveal the 
enzyme activity. Color reaction is stopped by addition of sulfuric acid and the resulting 
yellow color is measured spectrophotometrically.
The intensity of the color is directly proportional to the concentration of the anti-T
antibodies present in the sample.
Concentrations are calculated from a reference standard curve using a 4 parameters 
logistic fitting algorithm and expressed in International units (IU/mL). 
Anti-PRP ELISA (Haemophilus influenzae type b, Polyribosyl Ribitol Phosphate Ab)
Antibody responses against PRP will be quantified by ELISA using purified PRP antigen 
extracted from inactivated Haemophilus influenzae type b as coating. The antigen is 
coated onto a 96-wells microplate. After a washing and a blocking step, dilutions of 
serum samples, controls and standard are incubated on the coated plate. The microplate is 
washed and goat HorseRadishPeroxidase (HRP)-conjugated anti-human Ig to polyclonal 
antibodies are added. After incubation, unbound antibodies are removed by washing and 
TetraMethylBenzidine (TMB) is incubated to reveal the enzyme activity. Color reaction 
is stopped by addition of sulfuric acid and the resulting yellow color is measured 
spectrophotometrically.
The intensity of the color is directly proportional to the concentration of the anti-PRP 
antibodies present in the sample.
Concentrations are calculated from a reference standard curve using a 4 parameters 
logistic fitting algorithm and expressed in micrograms (µg/mL). 
Hepatitis B virus
The ADVIA Centaur Anti-HBS2 assay is a sandwich immunoassay using direct, 
chemiluminometric technology. HBsAg (ad and ay)are covalently coupled to magnetic 
latex particules in the Solid Phase. In the Lite Reagent, the HBs Ag (ad and ay) is labelled 
with acridinum ester. Non-magnetic latex particules are added from the ancillary well. 
The sample is incubated simultaneously with Lite Reagent, Solis Phase and Acillary 
Reagent. Antibody-antigen complexes will form if anti-HBs is present in the sample. A 
 
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direct relationship exist between the amount of anti-HBs activity present in the patient 
sample and the amount of relative light units (RLUs) detected by the system.
 
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APPENDIX B
CLINICAL LABORATORIES
Table 20
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biological’s Clinical 
Laboratories 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 21
Outsourced laboratories
Laboratory
Address
Q² Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
US
Q² Solutions Clinical Trials (UK)
1 Simpson Parkway
The Alba Campus
Rosebank
Livingston
EH54 7EG
UK
 
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