Immunogenicity and Safety of the Diphtheria, Tetanus, Pertussis and Inactivated Poliovirus (DPT-IPV) Vaccine Squarekids Co-administered With GSK Biologicals' Human Rotavirus (HRV) Vaccine Rotarix (GSK444563) in Healthy Infants
Phase: PHASE4
Conditions: Rotavirus
Sponsor: GlaxoSmithKline

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Primary Study vaccine and 
number 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’Institut, 89 
1330 Rixensart, Belgium 
• 
Liquid formulation of GlaxoSmithKline (GSK) 
Biologicals’ oral live attenuated human rotavirus 
(HRV) vaccine Rotarix™ (444563) 
Other Study vaccine 
• 
Kitasato Daiichi Sankyo Vaccine Company Ltd’s 
diphtheria, tetanus, pertussis and inactivated 
poliovirus (DPT-IPV) vaccine (Squarekids™). 
eTrack study number and 
Abbreviated Title 
114720 (ROTA-079) 
 
EudraCT number 
2014-005282-78 
 
Date of protocol 
Final Version 03: 03 June 2016 
 
Title 
Immunogenicity and safety of the diphtheria, tetanus, 
pertussis and inactivated poliovirus (DPT-IPV) 
vaccine Squarekids™ co-administered with GSK 
Biologicals’ human rotavirus (HRV) vaccine 
Rotarix™ (444563) in healthy infants. 
 
Detailed Title 
A phase IV, randomised, open-label, controlled study 
to assess the immunogenicity and safety of the 
diphtheria, tetanus, pertussis and inactivated poliovirus 
(DPT-IPV) vaccine Squarekids™ when co- 
administered with GSK Biologicals' oral live 
attenuated HRV liquid vaccine Rotarix™ in healthy 
Japanese infants aged 6 - 12 weeks at the time of the 
first dose of HRV vaccination. 
Co-ordinating author 
, Scientific Writer 
 
Contributing authors 
• 
 
, Clinical Research and 
Development Lead (CRDL) 
• 
, Director, Project Level CRDL 
• 
, Director, Clinical & Epidemiology Project 
Lead, MMRV and Rota 
• 
, Lead Statistician 
• 
PPD 
, Project Statistician 
• 
, Study Delivery Lead, 
SynteractHCR US, for GSK Biologicals 
• 
, Study Delivery Lead, 
Novellas Healthcare Consultant, for GSK 
Biologicals 

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eTrack study number and 
Abbreviated Title 
114720 (ROTA-079) 
 
EudraCT number 
2014-005282-78 
 
Detailed Title 
A phase IV, randomised, open-label, controlled study 
to assess the immunogenicity and safety of the 
diphtheria, tetanus, pertussis and inactivated poliovirus 
(DPT-IPV) vaccine Squarekids™ when co- 
administered with GSK Biologicals' oral live 
attenuated HRV liquid vaccine Rotarix™ in healthy 
Japanese infants aged 6 - 12 weeks at the time of the 
first dose of HRV vaccination. 
 
Contributing authors 
• 
, Study Delivery Manager, 
SynteractHCR US, for GSK Biologicals 
• 
, Clinical Immunology 
representative 
• 
, Clinical Immunology representative 
• 
, Clinical Safety representative 
• 
, Project Data Manager 
• 
, Global Regulatory Affairs representative 
• 
, Global Patents representative 
• 
, Vaccine Supply Coordinator 
• 
, Japan Study Leader 
GSK Biologicals’ Protocol DS v 14.1.1 
 
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or 
use of this information is prohibited. 

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Protocol Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
114720 (ROTA-079) 
 
EudraCT number 
2014-005282-78 
 
Date of protocol 
Final Version 03: 03 June 2016 
 
Detailed Title 
A phase IV, randomised, open-label, controlled study 
to assess the immunogenicity and safety of the 
diphtheria, tetanus, pertussis and inactivated 
poliovirus (DPT-IPV) vaccine Squarekids™ when 
co-administered with GSK Biologicals' oral live 
attenuated HRV liquid vaccine Rotarix™ in healthy 
Japanese infants aged 6 - 12 weeks at the time of the 
first dose of HRV vaccination. 
 
Sponsor signatory 
Paul Gillard, Director, 
Clinical & Epidemiology Project Lead, MMRV and 
Rota 
GlaxoSmithKline Biologicals, SA. 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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I agree: 
Protocol Investigator Agreement 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine 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 
114720 (ROTA-079) 
 
EudraCT number 
2014-005282-78 
 
Date of protocol 
Final Version 03: 03 June 2016 
 
Detailed Title 
A phase IV, randomised, open-label, controlled study 
to assess the immunogenicity and safety of the 
diphtheria, tetanus, pertussis and inactivated 
poliovirus (DPT-IPV) vaccine Squarekids™ when 
co-administered with GSK Biologicals' oral live 
attenuated HRV liquid vaccine Rotarix™ in healthy 
Japanese infants aged 6 - 12 weeks at the time of the 
first dose of HRV vaccination. 
 
Investigator name 
 
 
 
Investigator Address: 
 
 
 
Investigator Phone Number 
 
 
 
Investigator Signature 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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Medical Monitor/Sponsor Information Page 
 
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. Medical Monitor / Sponsor Study Contact for Reporting of a Causally Related 
Adverse Event and Serious Adverse Event 
 
Role 
Name 
Day Time Phone 
Number and email 
address 
After-hours 
Phone/Cell/ 
Pager Number 
Fax 
Number 
Site Address 
Primary 
Medical 
Monitor 
 
Secondary 
 
 
 
 
PPD 
+PPD 
(day time) and 
PPD 
 
hours) 
GSK 
 
(after 
GSK / 
avenue 
Fleming / 
1300 Wavre 
6-15, 
Medical 
Monitor 
 
 
 
 
 
 
 
Causally 
Related 
Adverse 
Event/ SAE 
contact 
information 
 
 
 
 
 
 
 
 
 
Study 
Monitor 
Biologicals 
Central Back- 
up Study 
Contact for 
Reporting 
Causally 
Related 
Adverse Events 
and SAEs: refer 
to protocol 
Section 8.4.2 
GSK 
Biologicals 
Central Back- 
up Study 
Contact for 
Reporting 
Causally 
Related 
Adverse Events 
and SAEs: refer 
to protocol 
Section 8.4.2 
Sendagaya 
4-chome, 
Shibuya-ku, 
Tokyo, 151- 
8566, Japan 
 
 
 
 
 
2-26, 
Shimomiyabi- 
cho, 
Shinjuku-ku, 
Tokyo, 162- 
0822, Japan 
PPD 
PPD 
PPD 
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PPD 

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SYNOPSIS 
Detailed Title 
A phase IV, randomised, open-label, controlled study to 
assess the immunogenicity and safety of the diphtheria, 
tetanus, pertussis and inactivated poliovirus (DPT-IPV) 
vaccine Squarekids™ when co-administered with GSK 
Biologicals' oral live attenuated HRV liquid vaccine 
Rotarix™ in healthy Japanese infants aged 6 - 12 weeks at the 
time of the first dose of HRV vaccination. 
 
Indication 
Active immunisation of infants against gastroenteritis (GE) 
due to rotavirus (RV). 
 
Rationale for the 
study and study 
design 
• 
Rationale for the study 
The burden of severe RV disease among Japanese children is 
substantial. An active surveillance of RV hospitalisation in 
three cities in central Japan showed that RV infection 
accounted for approximately 40% to 50% of hospitalised 
acute GE cases in each city. A further extrapolation of the 
mean incidence of RV hospitalisation in the three cities to the 
national population data for children less than 5 years of age 
estimated that approximately 30,000 hospitalisations occurred 
among Japanese children less than 5 years of age annually, for 
RV acute GE [Kamiya, 2011]. 
 
GlaxoSmithKline (GSK) Biologicals’ rotavirus vaccine 
(Rotarix™) is a vaccine for oral use, containing the live 
attenuated human rotavirus RIX4414 strain. Infants aged 
younger than 3 months who received the vaccine did not 
develop diarrhoea, vomiting or fever [Vesikari, 2004(a)].In a 
study that evaluated the HRV vaccine in Japan, the vaccine 
efficacy against any and severe RV GE which led to medical 
intervention caused by circulating wild-type RV was 79.3% 
and 91.6% respectively. Additionally, the serum anti-RV 
antibody seroconversion rate one-month after the second dose 
of the vaccine was 85.3%. The vaccine was found to be well- 
tolerated, immunogenic and efficacious against RV disease in 
Japanese infants [Kawamura, 2011]. 
 
This study will evaluate the immunogenicity and safety of the 
diphtheria, tetanus, pertussis and inactivated poliovirus (DPT- 
IPV) vaccine Squarekids administered with or without the 
GSK Biologicals’ liquid HRV vaccine, in healthy Japanese 
infants aged 6 - 12 weeks. 
 
GSK Biologicals' liquid HRV vaccine Rotarix is licensed in 
Japan since 2011. Although the concomitant administration of 
GSK Biologicals’ DTP-IPV vaccine has been evaluated 

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during the clinical development of the HRV vaccine 
[Dennehy, 2008], the vaccine differed in composition and 
route of administration from the DPT-IPV vaccine Squarekids 
manufactured in Japan. Hence, as requested by the Japanese 
regulatory authorities, this post-licensure study will evaluate 
the immunogenicity of the DPT-IPV vaccine manufactured in 
Japan when co-administered with the liquid HRV vaccine. 
 
• 
Rationale for the study design 
The study is designed as a randomised, controlled, open-label 
study with two parallel groups. This study will evaluate the 
immunogenicity and safety of the DPT-IPV vaccine when 
administered with or without the liquid HRV vaccine in 
healthy Japanese infants. 
 
The two groups in the study are as follows: 
 
• 
Co-administration group: Subjects will be administered 
the DPT-IPV vaccine according to a 3, 4, 6 month 
schedule and the liquid HRV vaccine according to a 2, 3 
month schedule. 
• 
Staggered group: Subjects will be administered the DPT- 
IPV vaccine according to a 3, 4.5, 6 month schedule and 
the liquid HRV vaccine according to a 2, 3.5 month 
schedule. 
In the Co-administration group, the co-administration of study 
vaccines will be performed only once, when the infant is 
approximately 3 months old. The majority of Japanese infants 
who are administered both DPT-IPV and RV vaccine are co- 
administered only once in accordance with the recommended 
vaccination schedule in Japan. Additionally, the first dose of 
HRV vaccine administration is strongly recommended for 
infants at 6 - 12 weeks of age in Japan [Nakagomi, 2011]. 
 
The study will be conducted in an open-label manner due to 
the difference in the vaccination schedule between the two 
groups. The study will also include a sub-cohort for 
evaluating immunogenicity of the liquid HRV vaccine in 
terms of serum anti-RV IgA antibody seropositivity and 
geometric mean concentrations (GMCs) one month after the 
second dose of the liquid HRV vaccine. 
 
Objectives 
Primary 
 
• 
To demonstrate that the immunogenicity to the antigens 
contained in DPT-IPV vaccine is not impaired by the co- 
administration with GSK Biologicals' liquid HRV 

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vaccine. 
Criteria for non-inferiority (1 month after the third dose of 
DPT-IPV vaccine at Visit 7): 
 
 
Lower limits of the standardised asymptotic 95% 
confidence intervals (CIs) on the differences (Co- 
administered group minus Staggered group) in the 
percentages of subjects with seroprotective 
concentrations  0.1 IU/mL for anti-diphtheria (anti- 
D) antibodies and concentrations  0.1 IU/mL for 
anti-tetanus (anti-T) antibodies are -10% (clinical 
limit for non-inferiority), 
 
Lower limits of the 95% CIs on the differences (Co- 
administered group minus Staggered group) in the 
percentages of subjects with concentrations  10 
IU/mL for antibodies against the pertussis toxoid 
(PT) and filamentous hemagglutinin (FHA) antigens 
(anti-PT and anti-FHA) are  -10% (clinical limit for 
non-inferiority), 
 
Lower limits of the standardised asymptotic 95% CIs 
on the differences (Co-administered group minus 
Staggered group) in the percentages of subjects with 
seroprotective titres (8 ED50) for each of anti- 
poliovirus serotypes 1, 2 and 3 antibodies are  -10% 
(clinical limit for non-inferiority). 
Secondary 
 
• 
To assess the immunogenicity of the liquid HRV vaccine 
in terms of serum anti-RV IgA antibody seropositivity 
and GMCs in a sub-cohort of subjects, 1 month after the 
second dose of the liquid HRV vaccine. 
• 
To assess the immunogenicity to all the antigens 
contained in the DPT-IPV vaccine in terms of GMCs/ 
geometric mean antibody titres (GMTs), 1 month after 
the third dose of the DPT-IPV vaccine. 
• 
To assess reactogenicity and safety after each dose of 
liquid HRV vaccine and first dose of DPT-IPV vaccine in 
terms of solicited symptoms during the 8-day follow-up 
period and unsolicited symptoms during the 31-day 
follow-up period. 
• 
To assess safety in terms of serious adverse events 
(SAEs) from the first dose of study vaccine up to study 
end. 

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Study design 
• 
Experimental design: Phase IV, open-label, randomised, 
controlled, multi-centric, single-country study with two 
parallel groups. 
• 
Duration of the study: 
 
The intended duration of the study, per subject, is 
5 months. 
 
Epoch 001: Primary starting at Visit 1 (Day 0) and 
ending at Visit 7 (Month 5). 
• 
Primary Completion Date (PCD): Visit 7 (Month 5) 
(Refer to Glossary of terms for the definition of PCD) 
• 
End of Study (EoS): Last testing results released of 
samples collected at Visit 7 (Refer to Glossary of terms 
for the definition of EoS) 
• 
Study groups: The study groups and epoch foreseen in the 
study are provided in Synopsis Table 1. 
 
Synopsis Table 1 
Study groups and epochs foreseen in the study 
 
Study groups 
Number of 
subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Co-administration group 
146 
6 weeks - 12 weeks 
x 
Staggered group 
146 
6 weeks - 12 weeks 
x 
 
The study groups and treatment foreseen in the study are provided in Synopsis Table 2. 
 
Synopsis Table 2 
Study groups and treatment foreseen in the study 
 
Treatment name 
Vaccine name 
Study Groups 
Co-administration group 
Staggered group 
Rotarix 
HRV 
x 
x 
Squarekids 
Squarekids 
x 
x 
 
• 
Control: active control (Staggered group). 
 
• 
Vaccination schedules: The vaccination schedules are as 
follows: 
 
Subjects in the Co-administration group will be 
administered the DPT-IPV vaccine according to a 3, 
4, 6 month schedule and the liquid HRV vaccine 
according to a 2, 3 month schedule. 
 
Subjects in the Staggered group will be administered 
the DPT-IPV vaccine according to a 3, 4.5, 6 month 
schedule and the liquid HRV vaccine according to a 
2, 3.5 month schedule. 

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The childhood vaccines Pneumococcal conjugate vaccine 
(PCV), Haemophilus influenzae type B vaccine (Hib), 
Bacillus Calmette-Guérin (BCG) vaccine, hepatitis B vaccine, 
meningococcal vaccine and inactivated influenza vaccine can 
be administered to subjects as per the clinical practice in 
Japan, outside the scope of this study. 
 
• 
Treatment allocation: 1:1 randomisation using GSK 
Biologicals’ central randomisation system on Internet 
(SBIR). 
• 
Blinding: Open-label. The blinding of study epoch is 
provided in Synopsis Table 3. 
 
Synopsis Table 3 
Blinding of study epochs 
 
Study Epochs 
Blinding 
Epoch 001 
open 
 
• 
Sampling schedule: Details of the samples to be collected 
are as follows: 
 
A blood sample of approximately 2 mL will be 
collected from a sub-cohort of subjects (approximately 
half the number of enrolled subjects from each study 
group), 1 month after the administration of the second 
dose of the liquid HRV vaccine. 
 
A second blood sample of approximately 5 mL will be 
collected at Visit 7, 1 month after administration of the 
last dose of DPT-IPV vaccine from all the subjects. 
• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF). 
Number of subjects In order to have 262 subjects (131 in each study group) 
evaluable for the immunogenicity analyses corresponding to the 
primary confirmatory objective, the target sample size to be 
enrolled is at least 292 subjects (146 subjects in each group), 
accounting for a dropout rate of 10%. 
 
Endpoints 
Primary 
 
• 
Immunogenicity with respect to components of the DPT- 
IPV vaccine 1 month after administration of the third dose 
of the vaccine (Visit 7): 
 
anti-diphtheria antibody concentrations ≥ 0.1 IU/mL, 
 
anti-tetanus antibody concentrations ≥ 0.1 IU/mL, 

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 
anti-PT and anti-FHA antibody concentrations 
≥10 IU/mL, 
 
anti-poliovirus serotypes 1, 2 and 3 antibody titre 
≥8 ED50. 
Secondary 
 
• 
Serum anti-RV IgA antibody concentration  20 U/mL and 
seropositivity in a sub-cohort of subjects, 1 month after the 
second dose of the liquid HRV vaccine. 
• 
Serum GMCs/GMTs for anti-diphtheria, anti-tetanus, anti- 
poliovirus serotypes 1, 2 and 3, anti-PT and anti-FHA 
antibodies, 1 month after the third dose of the DPT-IPV 
vaccine. 
• 
Occurrence of solicited general symptoms during the 8-day 
(Days 0-7) follow-up period after each dose of liquid HRV 
vaccine. 
• 
Occurrence of solicited local and general symptoms during 
the 8-day (Days 0-7) follow-up period after the first dose of 
DPT-IPV vaccine. 
• 
Occurrence of unsolicited AEs during the 31-day (Days 0- 
30) follow-up period after each dose of the liquid HRV 
vaccine and the first dose of DPT-IPV vaccine, according 
to the Medical Dictionary for Regulatory Activities 
(MedDRA) classification. 
• 
Occurrence of SAEs from the first dose of the study 
vaccine up to study end (Visit 7). 

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TABLE OF CONTENTS 
 
PAGE 
 
MEDICAL MONITOR/SPONSOR INFORMATION PAGE ................................................ 6 
SYNOPSIS ...................................................................................................................... 7 
LIST OF ABBREVIATIONS ........................................................................................... 19 
GLOSSARY OF TERMS ............................................................................................... 21 
TRADEMARKS ............................................................................................................. 24 
1. 
INTRODUCTION .................................................................................................... 25 
1.1. 
Background ................................................................................................ 25 
1.2. 
Rationale for the study and study design ..................................................... 26 
1.2.1. 
Rationale for the study ................................................................. 26 
1.2.2. 
Rationale for the study design ...................................................... 26 
1.3. 
Benefit : Risk Assessment .......................................................................... 27 
1.3.1. 
Risk Assessment ......................................................................... 28 
1.3.2. 
Benefit Assessment ..................................................................... 28 
1.3.3. 
Overall Benefit: Risk Conclusion .................................................. 29 
2. 
OBJECTIVES ......................................................................................................... 29 
2.1. 
Primary objective ........................................................................................ 29 
2.2. 
Secondary objectives .................................................................................. 29 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 30 
4. 
STUDY COHORT ................................................................................................... 32 
4.1. 
Number of subjects/centres ........................................................................ 32 
4.2. 
Inclusion criteria for enrolment .................................................................... 32 
4.3. 
Exclusion criteria for enrolment ................................................................... 33 
5. 
CONDUCT OF THE STUDY .................................................................................. 34 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process .......................................................................................... 34 
5.2. 
Subject identification and randomisation of treatment .................................. 35 
5.2.1. 
Subject identification .................................................................... 35 
5.2.2. 
Randomisation of treatment ......................................................... 36 
5.2.2.1. 
Randomisation of supplies .......................................... 36 
5.2.2.2. 
Treatment allocation to the subject ............................. 36 
5.2.2.2.1. 
Study group and treatment 
number allocation ................................... 36 
5.2.2.2.2. 
Treatment number allocation for 
subsequent doses ................................... 36 
5.3. 
Method of blinding....................................................................................... 36 
5.4. 
General study aspects ................................................................................ 37 
5.5. 
Outline of study procedures ........................................................................ 37 
5.6. 
Detailed description of study procedures ..................................................... 41 
5.6.1. 
Informed consent ......................................................................... 41 

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5.6.2. 
Check inclusion and exclusion criteria .......................................... 42 
5.6.3. 
Collect demographic data ............................................................ 42 
5.6.4. 
Medical history ............................................................................. 42 
5.6.5. 
History directed physical examination .......................................... 42 
5.6.6. 
Check contraindications, warnings  and  precautions  to 
vaccination ................................................................................... 42 
5.6.7. 
Assess pre-vaccination body temperature .................................... 42 
5.6.8. 
Study group and treatment number allocation .............................. 42 
5.6.9. 
Sampling ...................................................................................... 43 
5.6.9.1. 
Blood sampling for immune response 
assessments .............................................................. 43 
5.6.10. 
Study Vaccines administration ..................................................... 43 
5.6.11. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ..................................................... 43 
5.6.12. 
Recording of AEs and SAEs ........................................................ 43 
5.6.13. 
Study conclusion .......................................................................... 44 
5.7. 
Biological sample handling and analysis ..................................................... 44 
5.7.1. 
Use of specified study materials ................................................... 45 
5.7.2. 
Biological samples ....................................................................... 45 
5.7.3. 
Laboratory assays........................................................................ 45 
5.7.4. 
Biological samples evaluation ...................................................... 47 
5.7.4.1. 
Immunological read-outs ............................................ 47 
5.7.5. 
Immunological correlates of protection ......................................... 47 
6. 
STUDY VACCINES AND ADMINISTRATION ........................................................ 48 
6.1. 
Description of study vaccines ...................................................................... 48 
6.2. 
Medical Devices .......................................................................................... 49 
6.3. 
Storage and handling of study vaccines ...................................................... 49 
6.4. 
Dosage and administration of study vaccines .............................................. 50 
6.5. 
Replacement of unusable vaccine doses .................................................... 50 
6.6. 
Contraindications to subsequent vaccination............................................... 51 
6.7. 
Warnings and precautions .......................................................................... 51 
6.8. 
Concomitant medications/products and concomitant vaccinations .............. 52 
6.8.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 52 
6.8.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses ........................ 52 
6.9. 
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses ......................................................................... 53 
7. 
HEALTH ECONOMICS .......................................................................................... 53 
8. 
SAFETY ................................................................................................................. 53 
8.1. 
Safety definitions ........................................................................................ 54 
8.1.1. 
Definition of an adverse event ...................................................... 54 
8.1.2. 
Definition of a serious adverse event ........................................... 55 
8.1.3. 
Solicited adverse events .............................................................. 55 
8.1.3.1. 
Solicited local (injection-site) adverse events .............. 55 
8.1.3.2. 
Solicited general adverse events ................................ 56 
8.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 56 

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8.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events ........................................................................................... 57 
8.3. 
Detecting and recording adverse events and serious adverse events ......... 57 
8.3.1. 
Time period for detecting and recording adverse events 
and serious adverse events ......................................................... 57 
8.3.2. 
Post-Study adverse events and serious adverse events .............. 60 
8.3.3. 
Evaluation of adverse events and serious adverse events ........... 60 
8.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 60 
8.3.3.2. 
Assessment of adverse events ................................... 60 
8.3.3.2.1. 
Assessment of intensity .......................... 60 
8.3.3.2.2. 
Assessment of causality ......................... 62 
8.3.3.3. 
Assessment of outcomes ............................................ 64 
8.3.3.4. 
Medically attended visits ............................................. 64 
8.4. 
Reporting of causally related adverse events and serious adverse 
events and other events .............................................................................. 64 
8.4.1. 
Prompt reporting of related adverse event and serious 
adverse events to GSK Biologicals .............................................. 64 
8.4.2. 
Contact information for reporting causally related adverse 
events and serious adverse events .............................................. 65 
8.4.3. 
Completion and transmission of causally related AE 
reports and SAE reports to GSK Biologicals ................................ 65 
8.4.3.1. 
Back-up system in case the electronic reporting 
system does not work ................................................. 65 
8.4.4. 
Updating of causally related AE and SAE information after 
removal of write access to the subject’s eCRF ............................. 65 
8.4.5. 
Regulatory reporting requirements for causally related 
AEs and SAEs ............................................................................. 66 
8.5. 
Follow-up of adverse events and serious adverse events ........................... 66 
8.5.1. 
Follow-up during the study ........................................................... 66 
8.5.2. 
Follow-up after the subject is discharged from the study .............. 66 
8.6. 
Treatment of adverse events ....................................................................... 67 
8.7. 
Medical Device Incidents (Including Malfunctions) ...................................... 67 
8.7.1. 
Definitions of a Medical Device Incident ....................................... 67 
8.7.2. 
Procedures for Documenting Medical Device Incidents ................ 68 
8.7.2.1. 
Time  Period  for   Detecting   Medical   Device 
Incidents ..................................................................... 68 
8.7.2.2. 
Documenting Medical Device Incidents ...................... 68 
8.7.3. 
Prompt Reporting of Medical Device Incidents to GSK ................. 69 
8.7.3.1. 
Regulatory Reporting Requirements for 
Medical Device Incidents ............................................ 69 
8.7.4. 
Follow-up of Medical Device Incidents ......................................... 69 
8.8. 
Subject card ................................................................................................ 69 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 70 
9.1. 
Subject completion ...................................................................................... 70 
9.2. 
Subject withdrawal ...................................................................................... 70 
9.2.1. 
Subject withdrawal from the study ................................................ 70 
9.2.2. 
Subject withdrawal from investigational vaccines ......................... 71 
10. STATISTICAL METHODS ...................................................................................... 71 
10.1. Primary endpoint ......................................................................................... 71 

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10.2. Secondary endpoints .................................................................................. 71 
10.3. Determination of sample size ...................................................................... 72 
10.3.1. 
Reference for sample size ........................................................... 72 
10.3.2. 
Power computation ...................................................................... 73 
10.4. Cohorts for Analyses ................................................................................... 74 
10.4.1. 
Total vaccinated cohort ................................................................ 74 
10.4.2. 
According-to-protocol    cohort    for    analysis     of 
immunogenicity ............................................................................ 74 
10.5. Derived and transformed data ..................................................................... 75 
10.6. Analysis of demographics/baseline characteristics ...................................... 75 
10.7. Analysis of immunogenicity ......................................................................... 76 
10.7.1. 
Within groups assessment ........................................................... 76 
10.7.2. 
Between groups assessment ....................................................... 76 
10.8. Analysis of safety ........................................................................................ 76 
10.9. Interpretation of analyses ............................................................................ 77 
10.10. Conduct of analyses ................................................................................... 77 
10.10.1. Sequence of analyses .................................................................. 78 
10.10.2. Statistical considerations for interim analyses .............................. 78 
11. ADMINISTRATIVE MATTERS ............................................................................... 78 
11.1. Electronic Case Report Form instructions ................................................... 78 
11.2. Study Monitoring by GSK Biologicals .......................................................... 78 
11.3. Record retention ......................................................................................... 79 
11.4. Quality assurance ....................................................................................... 80 
11.5. Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................ 80 
11.6. Provision of study results to investigators .................................................... 80 
11.7. Regulatory and Ethical Considerations, including the Informed 
Consent Process ........................................................................................ 81 
11.8. Study and site closure ................................................................................. 81 
12. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 82 
12.1. Japan specific requirements – Study conduct considerations ...................... 82 
12.1.1. 
Regulatory and Ethical Considerations......................................... 82 
12.1.2. 
Informed Consent ........................................................................ 82 
12.1.3. 
Study period................................................................................. 82 
12.1.4. 
Study administrative structure ...................................................... 83 
13. REFERENCES ....................................................................................................... 83 

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LIST OF TABLES 
 
PAGE 
 
Table 1 
Study groups and epochs foreseen in the study ..................................... 31 
Table 2 
Study groups and treatment foreseen in the study .................................. 31 
Table 3 
Blinding of study epochs ........................................................................ 31 
Table 4 
Sub-cohorts ............................................................................................ 32 
Table 5 
List of study procedures (Co-administration group) ................................ 38 
Table 6 
List of Study procedures (Staggered group) ........................................... 40 
Table 7 
Intervals between study visits ................................................................. 41 
Table 8 
Biological samples ................................................................................. 45 
Table 9 
Humoral Immunity (Antibody determination) ........................................... 46 
Table 10 
Immunological read-outs ........................................................................ 47 
Table 11 
Study vaccines ....................................................................................... 49 
Table 12 
Dosage and administration ..................................................................... 50 
Table 13 
Solicited local adverse events ................................................................ 56 
Table 14 
Solicited general adverse events (HRV vaccine) .................................... 56 
Table 15 
Solicited general adverse events (DPT-IPV vaccine) .............................. 56 
Table 16 
Reporting periods for collecting safety information (Co- 
administration group) .............................................................................. 58 
Table 17 
Reporting periods for collecting safety information (Staggered 
group) .................................................................................................... 59 
Table 18 
Intensity scales for solicited symptoms in infants .................................... 61 
Table 19 
Timeframes for submitting related adverse event and serious 
adverse event reports to GSK Biologicals .............................................. 64 
Table 20 
Reference response rates ...................................................................... 73 
Table 21 
Power for non-inferiority ......................................................................... 74 
Table 22 
GSK Biologicals’ laboratories ................................................................. 86 
Table 23 
Outsourced laboratories ......................................................................... 86 

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LIST OF APPENDICES 
 
PAGE 
 
APPENDIX A LABORATORY ASSAYS ........................................................................ 85 
APPENDIX B CLINICAL LABORATORIES .................................................................. 86 

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LIST OF ABBREVIATIONS 
AE: 
Adverse Event 
 
ATP: 
According-To-Protocol 
 
BCG: 
Bacillus Calmette-Guérin 
 
BMI: 
Body Mass Index 
 
CI: 
Confidence Interval 
 
CCID50: 
Median Cell Culture Infective Dose (quantity of virus 
causing infection in 50% of exposed cells) 
 
CDC: 
Centers for Disease Control and Prevention, USA 
 
DTP/DPT: 
Diphtheria, Pertussis and Tetanus toxoids 
 
eCRF: 
electronic Case Report Form 
 
EoS 
End of Study 
 
FHA: 
Filamentous Haemagglutinin 
 
GCP: 
Good Clinical Practice 
 
GE: 
Gastroenteritis 
 
GMC: 
Geometric Mean Concentration 
 
GMT: 
Geometric Mean Titre 
 
GSK: 
GlaxoSmithKline 
 
Hib: 
Haemophilus influenzae type B vaccine 
 
HRV: 
Human Rotavirus 
 
IgA: 
Immunoglobulin A 
 
IPV: 
Inactivated Poliovirus Vaccine 
 
IS: 
Intussusception 
 
IU: 
International Unit(s) 
 
LAR: 
Legally Acceptable Representative 
 
LSLV: 
Last Subject Last Visit 

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MedDRA: 
Medical Dictionary for Regulatory Activities 
 
mL: 
Millilitre 
 
PCD 
Primary Completion Date 
 
PCV: 
Pneumococcal conjugate vaccine 
 
PT: 
Pertussis Toxoid 
 
RDE: 
Remote Data Entry 
 
RV: 
Rotavirus 
 
SAE: 
Serious Adverse Event 
 
SBIR: 
Randomisation System on Internet 
 
SCID: 
Severe Combined Immunodeficiency 
 
TVC: 
Total Vaccinated Cohort 
 
U: 
Unit 
 
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 an 
open-label study, no blind is used. Both the investigator 
and the subject know the identity of the treatment 
assigned. 
 
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 parent(s) 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. 
 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
 
End of Study: 
 
(Synonym of End of 
Trial) 
For studies without collection of human biologicals 
samples or imaging data, end of study (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 

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8 months after LSLV. 
 
Epoch: 
An epoch is a self-contained set of consecutive 
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion to define or precise the targeted 
label of the product. Typical examples of epochs are 
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety. 
 
eTrack: 
GSK’s tracking tool for clinical trials. 
 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 6.8.2 and 10.4 for details on criteria for 
evaluability). 
 
Immunological correlate 
of protection: 
 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
 
 
Legally acceptable 
representative: 
 
(The terms legal 
representative or legally 
authorised 
representative are used 
in some settings.) 
 
Primary completion 
date: 
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. 
 
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
 
An individual or juridical or other body authorised under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial. 
 
 
 
 
 
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. 
 
Randomisation: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 

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Self-contained study: 
Study with objectives not linked to the data of another 
study. 
 
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. 
 
Sub-cohort: 
A group of subjects for whom specific study procedures 
are planned as compared to other subjects. 
 
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 vaccine or as a control. 
 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation. 
 
Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 

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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. 
 
 
 
 
 
 
 
Trademark of the GlaxoSmithKline group 
of companies 
Generic description 
Squarekids® (Kitasato Daiichi Sankyo 
Vaccine Co., Ltd) 
Absorbed diphtheria purified pertussis, 
tetanus and inactivated polio combined 
vaccine (Salk vaccine) 
Generic description 
Trademark not owned by the 
GlaxoSmithKline group of companies 
Human rotavirus vaccine 
Rotarix™ 

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1. 
INTRODUCTION 
 
1.1. 
Background 
Rotavirus (RV) infection is the leading cause of acute gastroenteritis (GE) and severe 
diarrhoea in infants and young children <5 years of age [Atherly, 2009]. It has been 
estimated that in 2008 approximately 453,000 child deaths were caused due to rotavirus- 
associated acute gastroenteritis. Approximately 85% of this burden is in low-income 
countries globally [WHO position paper, 2013]. Although rotavirus disease only rarely 
causes death in Europe, North America and Australia, it has severe effects in countries of 
southeast Asia (India, Pakistan) and sub-Saharan Africa (DR Congo, Ethiopia, Nigeria) 
[Desselberger, 2012]. 
 
During the past years, vaccines have been developed that could prevent the enormous 
morbidity and mortality from rotavirus. Two live oral rotavirus vaccines have been 
licensed in many countries; one is derived from an attenuated human strain of rotavirus 
and the other combines five bovine-human reassortant strains [Glass, 2006]. Each of 
these vaccines has proven highly effective in preventing severe rotavirus diarrhoea by 
substantially reducing number and associated costs of child hospitalisations and clinical 
visits for acute diarrhoea in children. Moreover, these vaccines could reduce deaths from 
diarrhoea and improve child survival through programmes such as childhood 
immunisations and diarrhoeal disease control in developing countries. The World Health 
Organization (WHO) recognises RV vaccination as an effective measure to prevent RV 
infection and reduce disease burden, and recommends its inclusion into all national infant 
immunisation programs [WHO position paper, 2013]. 
 
GlaxoSmithKline (GSK) Biologicals’ rotavirus vaccine (Rotarix™) is a vaccine for oral 
use, containing the live attenuated human rotavirus RIX4414 strain. Infants aged younger 
than 3 months who received the vaccine did not develop diarrhoea, vomiting or fever 
[Vesikari, 2004(a)]. The initial trials that GSK conducted in Finland showed safety, 
immunogenicity and efficacy of the Rotarix vaccine [Vesikari, 2004(b)]. In Latin 
American and European studies, vaccine efficacy of oral live attenuated human rotavirus 
vaccine Rotarix (RIX4414)was high, ranging from 80.5% to 90.4% against severe 
rotavirus gastroenteritis (RVGE), and 83.0% to 96.0% against hospitalization due to 
RVGE during the first two years of life.[Vesikari, 2007; Linhares, 2008]. Furthermore, 
results from a phase III clinical study undertaken in Singapore, Hong Kong, and Taiwan 
showed that during the first two years of life, two doses of RIX4414 vaccine provided a 
high level of protection against severe RVGE (vaccine efficacy: 96.1%), and had a safety 
profile similar to placebo [Phua, 2012]. Such safety and efficacy studies in Europe, Latin 
America and Asia have confirmed that the vaccine is safe, well-tolerated and efficacious 
(range: 80-96%) in preventing severe rotavirus gastroenteritis in the first two years of life 
[Cunliffe, 2014]. 
 
Please refer to the Prescribing Information for information regarding the pre-clinical and 
clinical studies and the epidemiological information of Rotarix. 

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1.2. 
Rationale for the study and study design 
 
1.2.1. 
Rationale for the study 
 
The burden of severe RV disease among Japanese children is substantial. An active 
surveillance of RV hospitalisation in three cities in central Japan showed that RV 
infection accounted for approximately 40% to 50% of hospitalised acute GE cases in each 
city. A further extrapolation of the mean incidence of rotavirus hospitalisation in the three 
cities to the national population data for children less than 5 years of age estimated that 
approximately 30,000 hospitalisations occurred among Japanese children less than 5 
years of age annually, for RV acute GE [Kamiya, 2011]. 
 
In a study that evaluated the HRV vaccine in Japan, the vaccine efficacy against any and 
severe RV GE which led to medical intervention caused by circulating wild-type RV, was 
79.3% and 91.6% respectively. Additionally, the serum anti-RV antibody seroconversion 
rate one-month after the second dose of the vaccine was 85.3%. The vaccine was found to 
be well-tolerated, immunogenic and efficacious against RV disease in Japanese infants 
[Kawamura, 2011]. 
 
This study will evaluate the immunogenicity and safety of the diphtheria, tetanus, 
pertussis and inactivated poliovirus (DPT-IPV) vaccine Squarekids administered with or 
without the GSK Biologicals’ liquid HRV vaccine, in healthy Japanese infants aged 6 - 
12 weeks. 
 
GSK Biologicals' liquid HRV vaccine Rotarix is licensed in Japan since 2011. Although 
the concomitant administration of GSK Biologicals’ DTP-IPV vaccine has been 
evaluated during the clinical development of the HRV vaccine [Dennehy, 2008], the 
vaccine differed in composition and route of administration from the DPT-IPV vaccine 
Squarekids manufactured in Japan. Hence, as requested by the Japanese regulatory 
authorities, this post-licensure study will evaluate the immunogenicity of the DPT-IPV 
vaccine manufactured in Japan when co-administered with the liquid HRV vaccine. 
 
1.2.2. 
Rationale for the study design 
 
The study is designed as a randomised, controlled, open-label study with two parallel 
groups. This study will evaluate the immunogenicity and safety of the DPT-IPV vaccine 
when administered with or without the liquid HRV vaccine in healthy Japanese infants. 
 
The two groups in the study are as follows: 
 
• 
Co-administration group: Subjects will be administered the DPT-IPV vaccine 
according to a 3, 4, 6 month schedule and the liquid HRV vaccine according to a 2, 3 
month schedule. 
• 
Staggered group: Subjects will be administered the DPT-IPV vaccine according to a 
3, 4.5, 6 month schedule and the liquid HRV vaccine according to a 2, 3.5 month 
schedule. 

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In the Co-administration group, the co-administration of study vaccines will be 
performed only once, when the infant is approximately 3 months old. The majority of 
Japanese infants who are administered both DPT-IPV and RV vaccine are co- 
administered only once in accordance with the recommended vaccination schedule in 
Japan. Additionally, the first dose of HRV vaccine administration is strongly 
recommended for infants at 6 - 12 weeks of age in Japan [Nakagomi, 2011]. 
 
The study will be conducted in an open-label manner due to the difference in the 
vaccination schedule between the two groups. The study will also include a sub-cohort 
for evaluating immunogenicity of the liquid HRV vaccine in terms of serum anti-RV IgA 
antibody seropositivity and geometric mean concentrations (GMCs) one month after the 
second dose of the liquid HRV vaccine. 
 
1.3. 
Benefit : Risk Assessment 
Please refer to the Prescribing Information for the summary of potential risks and benefits 
of the Rotarix vaccine and the Squarekids vaccine. 

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The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
 
1.3.1. 
Risk Assessment 
 
Important Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Investigational study vaccine (Rotarix) 
Intussusception 
Spontaneous data 
• 
Subjects should report any 
untoward symptoms experienced 
after receiving the vaccine 
immediately to the investigator. 
• 
All adverse events (AEs)/serious 
adverse events (SAEs) should be 
reported by the investigator 
immediately to GSK. 
• 
Daily monitoring of SAEs by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team. 
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 
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. 
Investigational study vaccine (DPT-IPV) 
Shock, Anaphylaxis 
Frequency is unknown. 
Subjects will be observed for at least 30 
minutes after vaccine administration, 
with medical attention available in case 
of anaphylaxis reactions. 
Thrombocytopenic purpura 
Frequency is unknown. 
• 
Subjects should report any 
untoward symptoms experienced 
after receiving the vaccine 
immediately to the investigator. 
• 
All AEs/SAEs should be reported 
by the investigator immediately to 
GSK. 
• 
Daily monitoring of SAEs by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team. 
Encephalopathy 
Frequency is unknown. 
Convulsion 
Frequency is unknown. 
 
1.3.2. 
Benefit Assessment 
 
By receiving the liquid HRV vaccine, the subject may become protected against RV 
disease. The information collected during this study will help in evaluation of the HRV 
vaccine co-administration with a DPT-IPV vaccine (Squarekids) manufactured in Japan 
and recommended for routine administration during childhood. Therefore, the subject’s 
participation will benefit other children in the future. 
 
The study vaccines will be administered to subjects according to their prescribed 
vaccination schedule free of cost, as part of the study. 

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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 healthcare system in Japan. 
 
1.3.3. 
Overall Benefit: Risk Conclusion 
 
Considering the measures taken to minimise risk to subjects participating in this study, 
the potential or identified risks in association with Rotarix and Squarekids are justified by 
the potential benefits (prevention) that may be afforded to subjects receiving the vaccines 
for immunisation against RV, diphtheria, tetanus, pertussis and polio. 
 
2. 
OBJECTIVES 
 
2.1. 
Primary objective 
• 
To demonstrate that the immunogenicity to the antigens contained in DPT-IPV 
vaccine is not impaired by the co-administration with GSK Biologicals' liquid HRV 
vaccine. 
Criteria for non-inferiority (1 month after the third dose of DPT-IPV vaccine at Visit 7): 
 
 
Lower limits of the standardised asymptotic 95% confidence intervals (CIs) on 
the differences (Co-administered group minus Staggered group) in the 
percentages of subjects with seroprotective concentrations  0.1 IU/mL for anti- 
diphtheria (anti-D) antibodies and concentrations  0.1 IU/mL for anti-tetanus 
(anti-T) antibodies are -10% (clinical limit for non-inferiority), 
 
Lower limits of the 95% CIs on the differences (Co-administered group minus 
Staggered group) in the percentages of subjects with concentrations  10 IU/mL 
for antibodies against the pertussis toxoid (PT) and filamentous hemagglutinin 
(FHA) antigens (anti-PT and anti-FHA) are  -10% (clinical limit for non- 
inferiority), 
 
Lower limits of the standardised asymptotic 95% CIs on the differences (Co- 
administered group minus Staggered group) in the percentages of subjects with 
seroprotective titres (8 ED50) for each of anti-poliovirus serotypes 1, 2 and 3 
antibodies are  -10% (clinical limit for non-inferiority). 
Refer to Section 10.1 for the definition of the primary endpoint. 
 
2.2. 
Secondary objectives 
• 
To assess the immunogenicity of the liquid HRV vaccine in terms of serum anti-RV 
IgA antibody seropositivity and GMCs in a sub-cohort of subjects, 1 month after the 
second dose of the liquid HRV vaccine. 
• 
To assess the immunogenicity to all the antigens contained in the DPT-IPV vaccine 
in terms of GMCs/ geometric mean antibody titres (GMTs), 1 month after the third 
dose of the DPT-IPV vaccine. 

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• 
To assess reactogenicity and safety after each dose of liquid HRV vaccine and first 
dose of DPT-IPV vaccine in terms of solicited symptoms during the 8-day follow-up 
period and unsolicited symptoms during the 31-day follow-up period. 
• 
To assess safety in terms of serious adverse events (SAEs) from the first dose of 
study vaccine up to study end. 
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 group; BS = Blood Sampling. 
Visit 3 and Visit 5 are applicable only for subjects in the Staggered group. Visit 4 is applicable only for subjects in the 
Co-administration group. 
 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 5.5), are essential and required for 
study conduct. 
 
• 
Experimental design: Phase IV, open-label, randomised, controlled, multi-centric, 
single-country study with two parallel groups. 
• 
Duration of the study: The intended duration of the study, per subject, is 5 months. 
 Epoch 001: Primary starting at Visit 1 (Day 0) and ending at Visit 7 (Month 5). 
• 
Primary Completion Date: Visit 7 (Month 5) (Refer to GLOSSARY OF TERMS for 
the definition of PCD). 
• 
End of Study (EoS): Last testing results released of samples collected at Visit 7 
(Refer to GLOSSARY OF TERMS for the definition of EoS). 

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• 
Study groups: The study groups and epoch foreseen in the study are provided in 
Table 1. 
 
Table 1 
Study groups and epochs foreseen in the study 
 
Study Groups 
Number of subjects 
Age (Min/ - Max) 
Epoch 
Epoch 001 
Co-administration group 
146 
6 weeks - 12 weeks 
x 
Staggered group 
146 
6 weeks - 12 weeks 
x 
 
• 
The study groups and treatment foreseen in the study are provided in Table 2. 
 
Table 2 
Study groups and treatment foreseen in the study 
 
Treatment name 
Vaccine name 
Study Groups 
Co-administration group 
Staggered group 
Rotarix 
HRV 
x 
x 
Squarekids 
Squarekids 
x 
x 
 
• 
Control: active control (Staggered group). 
• 
Vaccination schedules: The vaccination schedules are as follows: 
 
Subjects in the Co-administration group will be administered the DPT-IPV 
vaccine according to a 3, 4, 6 month schedule and the liquid HRV vaccine 
according to a 2, 3 month schedule. 
 
Subjects in the Staggered group will be administered the DPT-IPV vaccine 
according to a 3, 4.5, 6 month schedule and the liquid HRV vaccine according to 
a 2, 3.5 month schedule. 
The childhood vaccines Pneumococcal conjugate vaccine (PCV), Haemophilus 
influenzae type B vaccine (Hib), Bacillus Calmette–Guérin (BCG) vaccine, hepatitis B 
vaccine, meningococcal vaccine and inactivated influenza vaccine can be administered to 
subjects as per the clinical practice in Japan, outside the scope of this study. 
 
• 
Treatment allocation: Randomised 1:1 using GSK Biologicals’ central randomisation 
system on Internet (SBIR). 
• 
Blinding: Open-label. 
The blinding of study epoch is provided in Table 3. 
 
Table 3 
Blinding of study epochs 
 
Study Epoch 
Blinding 
Epoch 001 
open 
 
• 
Sampling schedule: Details of the samples to be collected are as follows: 
 
A blood sample of approximately 2 mL will be collected from a sub-cohort of 
subjects (approximately half the number of enrolled subjects from each study 

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group), 1 month after the administration of the second dose of the liquid HRV 
vaccine. 
 
A blood sample of approximately 5 mL will be collected at Visit 7, 1 month 
after administration of the last dose of DPT-IPV vaccine from all the subjects. 
• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF). 
 
4. 
STUDY COHORT 
 
4.1. 
Number of subjects/centres 
In order to have 262 subjects (131 in each study group) evaluable for the immunogenicity 
analyses corresponding to the primary confirmatory objective, the target sample size to be 
enrolled is at least 292 subjects (146 subjects in each group), accounting for a dropout 
rate of 10%. 
 
Details of the HRV Immunogenicity sub-cohort are provided in Table 4. The sub-cohort 
will consist of 146 subjects (the first 73 subjects enrolled into the study from each study 
group). Since the assessment of immunogenicity in terms of serum anti-RV IgA 
seropositivity and GMCs is not a confirmatory endpoint in this study and no statistical 
testing will be performed, the sample size of this sub-cohort has been chosen to assess the 
immunogenicity of the liquid HRV vaccine in a descriptive manner. 
 
Table 4 
Sub-cohorts 
 
Sub-cohort 
name 
Description 
Estimated number of subjects 
HRV 
Immunogenicity 
sub-cohort 
The serum anti-RV IgA antibody concentration and 
seropositivity 1 month after the second dose of the liquid 
HRV vaccine will be assessed in this sub-cohort of 
subjects. 
146 subjects (approximately half 
the number of subjects (73) from 
each study group)* 
* The first 73 subjects enrolled into each study group will be allocated to the sub-cohort. 
 
Overview of the recruitment plan: 
 
• 
Subjects will be enrolled at multiple sites in Japan. 
• 
Enrolment will be terminated when at least 292 eligible subjects have been enrolled. 
• 
The intended duration of the study, per subject will be approximately 5 months. 
• 
Recruitment will be monitored by SBIR. 
 
4.2. 
Inclusion criteria for enrolment 
Specific information regarding warning, precautions, contraindication, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Prescribing information. 

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Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
 
All subjects must satisfy ALL the following criteria at study entry: 
 
• 
Subjects’ parent(s)/ Legally Acceptable Representative(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 dose of HRV vaccination. 
• 
Written 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. 
• 
Born full-term (i.e. between a gestation period of 37 weeks 0 days and 41 weeks 6 
days) as per the delivery records. 
 
4.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
 
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study: 
 
• 
Child in care. 
Please refer to the glossary of terms for the definition of child in care. 
 
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines within 30 days before the first dose of study vaccine (Day -29 to Day 
0), or planned use during the study period. 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs since birth. For 
corticosteroids, this will mean prednisone ( 0.5 mg/kg/day, or equivalent). Inhaled 
and topical steroids are allowed. 
• 
Administration of immunoglobulins and/or any blood products since birth or planned 
administration during the study period. 
• 
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab). 
• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol within the period starting 30 days before the first dose of HRV vaccine 
administration and ending at Visit 7, with the exception of other routinely 

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administered vaccines like PCV, Hib, BCG, hepatitis B, meningococcal vaccine and 
inactivated influenza vaccines, which are allowed at any time during the study, if 
administered at sites different from the sites used to administer the DPT-IPV 
vaccine. 
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device). 
• 
Uncorrected congenital malformation (such as Meckel’s diverticulum) of the 
gastrointestinal tract that would predispose for Intussusception (IS). 
• 
History of IS. 
• 
Family history of congenital or hereditary immunodeficiency. 
• 
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 rotavirus, diphtheria, tetanus, pertussis and/ or 
poliovirus. 
• 
Previous confirmed occurrence of RV GE, diphtheria, tetanus, pertussis, and/ or 
polio disease. 
• 
GE within 7 days preceding the HRV vaccine administration (warrants deferral of 
the vaccination). 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the HRV or DPT-IPV 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 ≥ 37.5°C on oral, axillary or tympanic setting, or 
≥ 38.0°C on rectal setting. 
 
Subjects with a minor illness (such as 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. 

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The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki. 
 
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines. 
 
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
 
Conduct of the study includes, but is not limited to, the following: 
 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject’s parent(s)/LAR(s) informed consent. 
• 
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), 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. 
 
The investigator has the final responsibility for the final presentation of the ICF 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC. 
 
5.2. 
Subject identification and randomisation of treatment 
 
5.2.1. 
Subject identification 
 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre. 

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5.2.2. 
Randomisation of treatment 
 
5.2.2.1. 
Randomisation of supplies 
 
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centres /warehouse(s). 
 
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation (30%) of supplies will be prepared. 
 
5.2.2.2. 
Treatment allocation to the subject 
 
The treatment numbers will be allocated by component. 
 
5.2.2.2.1. 
Study group and treatment number allocation 
 
Allocation of the subject to a study group at the investigator site will be performed using 
a randomisation system on internet (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for centre and HRV immunogenicity sub-cohort. 
 
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s), and having 
checked the eligibility of the subject, the site staff in charge of the vaccine administration 
will access SBIR. Upon providing the subject identification number, the randomisation 
system will determine the study group and will provide the treatment number to be used 
for the first dose. 
 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions. 
 
5.2.2.2.2. 
Treatment number allocation for subsequent doses 
 
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group. 
 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
5.3. 
Method of blinding 
This study is an open label study. 

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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 for subjects in the Co-administration group is provided in 
Table 5. 

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Table 5 
List of study procedures (Co-administration group) 
 
Age 
2 
months 
3 
months 
3.5 
months 
4 
months 
4.5 
months 
6 
months 
7 months 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Time-points 
Day 0 Month 1 Month 
1.5 
Month 2 Month 
2.5 
Month 4 
Month 5 
Sampling time-points 
Post- 
Vacc 1 
Post- 
Vacc 2 
Post Vacc 3 
Informed consent 
● 
Check inclusion/exclusion criteria 
● 
Collect demographic data 
● 
Record gestational age 
● 
Medical history 
● 
History directed physical examination 
● 
Check contraindications and warnings and 
precautions 
O 
O 
O 
O 
Pre-vaccination body temperature 
● 
● 
● 
● 
Measure/record height and weight 
● 
Vaccines 
Study group and treatment number allocation 
O 
Treatment number allocation for subsequent 
doses 
O 
O 
O 
Recording of administered treatment number 
● 
● 
● 
● 
HRV Vaccine administration 
● 
● 
DPT-IPV vaccine administration 
● 
● 
● 
Laboratory Assays 
Blood sampling for antibody determination 
● 
(~2 mL) 
● 
(~5 mL) 
Safety assessments 
Record any concomitant 
medications/vaccinations 
● 
● 
● 
● 
● 
Record any intercurrent medical conditions 
● 
● 
● 
● 
Distribution of diary cards 
O 
O 
O 
O 
Return of diary cards 
O 
O 
O 
O 
Diary card transcription by investigator 
● 
● 
● 
● 
Recording of solicited general adverse events 
during the 8 day (Days 0–7) follow-up period 
after each dose of HRV vaccine, by subjects’ 
parent(s)/LAR(s) in diary card 
● 
● 
Recording of solicited local and general 
adverse events during the 8 day (Days 0– 
7)follow-up period after the first dose of DPT- 
IPV vaccine, by subjects’ parent(s)/LAR(s) in 
diary card 
● 
Recording of unsolicited adverse events 
within 31 days post-vaccination (Days 0-30) 
after each dose of HRV vaccine, by subjects’ 
parent(s)/LAR(s) in diary card 
● 
● 
Recording of unsolicited adverse events 
within 31 days post-vaccination (Days 0-30) 
after the first dose of DPT-IPV vaccine, by 
subjects’ parent(s)/LAR(s) in diary card 
● 

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Age 
2 
months 
3 
months 
3.5 
months 
4 
months 
4.5 
months 
6 
months 
7 months 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Time-points 
Day 0 Month 1 Month 
1.5 
Month 2 Month 
2.5 
Month 4 
Month 5 
Sampling time-points 
Post- 
Vacc 1 
Post- 
Vacc 2 
Post Vacc 3 
Recording of AEs/SAEs leading to withdrawal 
from study 
● 
● 
● 
● 
● 
Recording of SAEs and causally related AEs 
● 
● 
● 
● 
● 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine 
● 
● 
● 
● 
● 
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 1 = blood sample collected from subjects in the HRV immunogenicity sub-cohort in the Co-administration 
group, one month after the second dose of the liquid HRV vaccine; Post-Vacc 3 = blood sample collected from all the 
subjects, one month after the third dose of the DPT-IPV vaccine. 
Visit 3 and Visit 5 are not applicable for subjects in the Co-administered group and hence have been shaded in grey. 
 
The list of study procedures for subjects in the Staggered group is provided in Table 6. 

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Table 6 
List of Study procedures (Staggered group) 
 
Age 
2 months 
3 
months 
3.5 
months 
4 
months 
4.5 
months 
6 
months 
7 
months 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Time-points 
Day 0 
Month 
1 
Month 
1.5 
Month 2 
Month 
2.5 
Month 4 Month 5 
Sampling time-points 
Post- 
Vacc 1 
Post- 
Vacc 2 
Post 
Vacc 3 
Informed consent 
● 
Check inclusion/exclusion criteria 
● 
Collect demographic data 
● 
Record gestational age 
● 
Medical history 
● 
History directed physical examination 
● 
Check contraindications and warnings and 
precautions 
O 
O 
O 
O 
O 
Pre-vaccination body temperature 
● 
● 
● 
● 
● 
Measure/record height and weight 
● 
Vaccines 
Study group and treatment number 
allocation 
O 
Treatment number allocation for subsequent 
doses 
O 
O 
O 
O 
Recording of administered treatment number 
● 
● 
● 
● 
● 
HRV Vaccine administration 
● 
● 
DPT-IPV vaccine administration 
● 
● 
● 
Laboratory Assays 
Blood sampling for antibody determination 
● 
(~2 mL) 
● 
(~5 mL) 
Safety assessments 
Record any concomitant 
medications/vaccinations 
● 
● 
● 
● 
● 
● 
Record any intercurrent medical conditions 
● 
● 
● 
● 
● 
Distribution of diary cards 
O 
O 
O 
O 
O 
Return of diary cards 
O 
O 
O 
O 
O 
Diary card transcription by investigator 
● 
● 
● 
● 
● 
Recording of solicited general adverse 
events during the 8 day (Days 0–7)follow-up 
period after each dose of HRV vaccine, by 
subjects’ parent(s)/LAR(s) in diary card 
● 
● 
Recording of solicited local and general 
adverse events during the 8 day (Days 0– 
7)follow-up period after the first dose of 
DPT-IPV vaccine, by subjects’ 
parent(s)/LAR(s) in diary card 
● 
Recording of unsolicited adverse events 
within 31 days post-vaccination (Days 0-30) 
after each dose of HRV vaccine, by subjects’ 
parent(s)/LAR(s) in diary card 
● 
● 
Recording of unsolicited adverse events 
within 31 days post-vaccination (Days 0-30) 
after the first dose of DPT-IPV vaccine, by 
subjects’ parent(s)/LAR(s) in diary card 
● 

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Age 
2 months 
3 
months 
3.5 
months 
4 
months 
4.5 
months 
6 
months 
7 
months 
Epoch 
Epoch 001 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Time-points 
Day 0 
Month 
1 
Month 
1.5 
Month 2 
Month 
2.5 
Month 4 Month 5 
Sampling time-points 
Post- 
Vacc 1 
Post- 
Vacc 2 
Post 
Vacc 3 
Recording of AEs/SAEs leading to 
withdrawal from study 
● 
● 
● 
● 
● 
● 
Recording of SAEs and causally related AEs 
● 
● 
● 
● 
● 
● 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine 
● 
● 
● 
● 
● 
● 
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 2 = blood sample collected from subjects in the HRV immunogenicity sub-cohort in the Staggered group, 
one month after the second dose of the liquid HRV vaccine; Post-Vacc 3 = blood sample collected from all the 
subjects, one month after the third dose of the DPT-IPV vaccine. 
Visit 4 is not applicable for subjects in the Staggered group and hence has been shaded in grey. 
The intervals to be considered within the study are provided in Table 7. 
Table 7 
Intervals between study visits 
Study Group 
Interval 
Optimal length of interval 1 
Allowed interval2 
Co-administration group 
Visit 1Visit 2* 
30 days 
28 days - 42 days 
Visit 2Visit 4 
30 days 
28 days – 42days 
Visit 4Visit 6 
56 days 
28 days - 56 days 
Visit 6Visit 7 
30 days 
21 days - 48 days 
Staggered group 
Visit 1Visit 2* 
30 days 
28 days - 42 days 
Visit 2Visit 3 
15 days 
7 days - 21 days 
Visit 3Visit 5** 
30 days 
28 days - 42 days 
Visit 5Visit 6 
45 days 
28 days – 56 days 
Visit 6Visit 7 
30 days 
21 days - 48 days 
1. Whenever possible the investigator should arrange study visits within this interval. 
2. Subjects will not be eligible for inclusion in the According To Protocol (ATP) cohort for analysis of immunogenicity if 
they make the study visit outside this interval. 
* Visit 2 should take place when the subject is 3 months of age or older. 
**The period between Visit 2 and Visit 5 should be within 8 weeks. 
There should be a time-period of at least 7 days between the administration of an inactivated vaccine and any other 
vaccine, and 28 days between the administration of a live virus vaccine and any other vaccine, in Japan. Please refer 
to the package inserts of Rotarix and Squarekids for more details. 
 
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 
enrolment. 
 
5.6.3. 
Collect demographic data 
 
Record demographic data such as age, gender and ethnicity in the subject’s eCRF. Record 
gestational age of the subject in the eCRF. 
 
5.6.4. 
Medical history 
 
Obtain the subject’s medical 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. 
History directed physical examination 
 
Perform a history directed physical examination. If the investigator determines that the 
subject’s health on the day of vaccination temporarily precludes vaccination, the visit will 
be rescheduled within the allowed interval. Collected information needs to be recorded in 
the eCRF. 
 
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
 
5.6.6. 
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 6.6 and 6.7 for more details. 
 
5.6.7. 
Assess pre-vaccination body temperature 
 
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccine administration. The preferred route for recording 
temperature in this study will be axillary or tympanic. If the subject has fever [fever is 
defined as temperature  37.5°C for oral, axillary or tympanic route, or  38.0°C for 
rectal route] on the day of vaccination, the vaccination visit will be rescheduled within 
the allowed interval for this visit (see Table 7). 
 
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. 

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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 certain study visits as specified in Section 5.5. 
 
• 
A volume of approximately 2 mL of whole blood (to provide at least 0.7 mL of 
serum) should be drawn from all subjects included in the HRV immunogenicity sub- 
cohort for analysis of humoral immune response one month after the second dose of 
the liquid HRV vaccine, i.e., at Visit 4 for the Co-administration group and at Visit 5 
for the Staggered group. A volume of approximately 5 mL of whole blood (to 
provide at least 1.8 mL of serum) should be drawn from all subjects included in the 
study for analysis of humoral immune response at Visit 7. After centrifugation, 
serum samples should be kept at –20°C 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, one dose of HRV 
will be administered orally or/and one dose of DPT-IPV vaccine will be administered 
subcutaneously (refer to Section 6.4 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 7). 
• 
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. 
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 6.8. 
 
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.9. 
 
5.6.12. 
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 AEs related to the study 
vaccines and SAE reports to GSK Biologicals. 

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• 
The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 
• 
At each vaccination visit, diary cards will be provided to the subject’s 
parent(s)/LAR(s). 
 
After each HRV vaccination, the subject’s parent(s)/LAR(s) will record body 
(axillary or tympanic) temperature and any solicited general AEs (i.e. on the day 
of each vaccination and during the next 8 days [Day 0-7]) or any unsolicited 
AEs (i.e. on the day of vaccination and during the next 30 days occurring after 
vaccination). 
 
After the first dose of DPT-IPV vaccine administration, subject’s 
parent(s)/LAR(s) will record solicited local/general AEs during the 8 day (Day 
0-Day 7) follow-up period and any unsolicited AEs during the 31 day (Day 0- 
Day 30) follow-up period only. 
 
In addition other AEs outside the specified duration will also be captured in the 
diary card. 
• 
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) on Visit 7. 
• 
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. 
 
5.6.13. 
Study conclusion 
 
The investigator will: 
 
• 
review data collected to ensure accuracy and completeness. 
• 
complete the Study Conclusion screen in the 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 only be used for protocol mandates described in this protocol. 
 
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s). 

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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 ATP analysis (See Section 10.4 for the definition of 
cohorts to be analysed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM. 
 
5.7.2. 
Biological samples 
 
The biological samples to be collected from subjects are described in Table 8. 
 
Table 8 
Biological samples 
 
Sample type 
Quantity 
Unit 
Time points 
Blood 
Approximately 2 
mL 
Visit 4 in Co-administration group, Visit 5 in Staggered group 
Approximately 5 
mL 
Visit 7 
5.7.3. 
Laboratory assays 
 
Please refer to APPENDIX A for a detailed description of the anti-Rotavirus IgA ELISA 
performed in the study. Please refer to APPENDIX B for the address of the clinical 
laboratories used for sample analysis and/or sample management. 
 
Serological assays for the determination of antibodies will be performed by Enzyme- 
Linked Immunosorbent Assay (ELISA) or neutralisation assay (NEU) at a GSK 
Biologicals’ laboratory or in a laboratory designated by GSK Biologicals using 
standardised and validated procedures (refer to Table 9). 

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Table 9 
Humoral Immunity (Antibody determination) 
 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit 
Assay 
Cut-off** 
Laboratory 
SER 
Corynebacterium 
diphtheriae.Diphtheria Toxoid 
Ab.IgG 
ELI 
NA 
IU/ml 
0.1 
GSK Biologicals* 
SER 
Clostridium tetani.Tetanus 
Toxoid Ab.IgG 
ELI 
NA 
IU/ml 
0.1 
GSK Biologicals* 
SER 
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG 
ELI 
NA 
IU/ml 
2.046 
GSK Biologicals* 
SER 
Bordetella pertussis.Pertussis 
Toxin Ab.IgG 
ELI 
NA 
IU/ml 
2.693 
GSK Biologicals* 
SER 
Poliovirus Sabin Type 1 Ab 
NEU 
NA 
ED50 
8 
GSK Biologicals* 
SER 
Poliovirus Sabin Type 2 Ab 
NEU 
NA 
ED50 
8 
GSK Biologicals* 
SER 
Poliovirus Sabin Type 3 Ab 
NEU 
NA 
ED50 
8 
GSK Biologicals* 
SER 
Rotavirus Ab.IgA 
ELI 
NA 
U/ml 
20 
GSK Biologicals* 
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; or 
a laboratory designated by GSK Biologicals. 
** These cut-offs are subject to change due to assay re-development. 
SER = Serum 
ELI = Enzyme-Linked Immunosorbent Assay 
NEU = Neutralisation Assay 
NA = Not applicable 
U = Units; IU = International Units 
EU = ELISA Units 
ED50 = Effective dose to inhibit 50% of the maximum. 
 
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. 

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5.7.4. 
Biological samples evaluation 
 
5.7.4.1. 
Immunological read-outs 
 
The immunological read-outs are given in Table 10. 
 
Table 10 
Immunological read-outs 
 
Blood sampling time-point 
Sub-cohort Name 
Group 
No. of 
subjects 
Component 
Components 
priority rank 
Type of 
contact and 
time point 
Sampling 
time point 
Visit 4 (Month 
2) 
Post-Vacc 
1 
HRV 
Immunogenicity 
sub-cohort 
Co- 
administration 
Group 
73* 
Anti-RV IgA 
Not Applicable 
Visit 5 (Month 
2.5) 
Post-Vacc 
2 
HRV 
Immunogenicity 
sub-cohort 
Staggered 
Group 
73* 
Anti-RV IgA 
Not Applicable 
Visit 7 (Month 
5) 
Post-Vacc 
3 
All subjects 
292 
D 
1 
T 
2 
PT 
3 
FHA 
4 
Poliovirus types 
1, 2 and 3 
5 
D: diphtheria, T: tetanus, PT: pertussis toxoid, FHA: filamentous haemagglutinin, HRV: human rotavirus. 
Post-Vacc 1 = blood sample collected from subjects in the HRV immunogenicity sub-cohort in the Co-administration 
group, one month after the second dose of the liquid HRV vaccine; Post-Vacc 2 = blood sample collected from subjects 
in the HRV immunogenicity sub-cohort in the Staggered group, one month after the second dose of the liquid HRV 
vaccine; Post-Vacc 3 = blood sample collected from all the subjects, one month after the third dose of the DPT-IPV 
vaccine. 
* The first 73 subjects enrolled into each of the study groups will be allocated to the HRV immunogenicity sub-cohort. 
This is half the total number of subjects to be enrolled in each study group. 
 
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 10. 
 
5.7.5. 
Immunological correlates of protection 
 
Details of the immunological correlates of protection are provided below: 
 
• 
Anti-diphtheria and anti-tetanus antibody concentrations will be measured by ELISA 
and expressed in international units per mL (IU/mL), with respect to a reference 
serum. It is generally accepted that for both diphtheria and tetanus, antibody 
concentrations  0.01 IU/mL, as measured by in vivo neutralisation tests are 
protective. It has been previously demonstrated that a good correlation exists 
between in vivo neutralisation tests and the ELISA for antibodies to diphtheria and 
tetanus toxoid but this correlation may be reduced at antibody concentrations < 0.1 
IU/mL. For this reason, an antibody concentration of 0.1 IU/mL by ELISA 
(corresponding to approximately 3 times the lower quantitation limit of the assays) 
will be arbitrarily and conservatively set as the cut-off (for both anti-diphtheria and 

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anti-tetanus ELISAs [Camargo, 1984; Melville-Smith, 1983; WHO position paper, 
, 2006]. 
• 
Antibodies against poliovirus types 1, 2 and 3 will be determined by a virus micro- 
neutralisation 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. Titres will be expressed in terms of the reciprocal of the dilution resulting in 
50% inhibition. Antibody titres greater than or equal to this value are considered as 
protective. 
• 
No correlate of protection is defined for the immune response to pertussis antigens. 
Antibodies against the pertussis components PT and FHA will be measured by 
ELISA technique. The current assay cut-off for the pertussis antibodies is 
5 international units per mL (IU/mL) Subjects with antibody concentration below 
this cut-off will be considered seronegative [Plotkin, 2010]. 
• 
No immunological correlate of protection has been demonstrated so far for the 
antigen used as part of the HRV vaccine. However, a publication indicated that post- 
vaccination anti-RV IgA seropositivity (antibody concentration  20 U/mL) may 
serve as a useful correlate of vaccine efficacy in clinical trials of Rotarix [Cheuvart, 
2014]. 
The immunological assay results will be communicated to the investigator once they 
become available. 
 
The investigator is encouraged to share the immunological assay results for non- 
responders with the study subjects’ parent(s)/LAR(s). 
 
For the subjects identified as non-responders, it remains the responsibility of the 
investigator in charge of the subject’s clinical management to determine the medical need 
for re-vaccination and to re-vaccinate the subjects as per local/regional practices. 
 
6. 
STUDY VACCINES AND ADMINISTRATION 
 
6.1. 
Description of study vaccines 
The Quality Control Standards and Requirements for each candidate vaccine are 
described in separate Quality Assurance documents (e.g. release protocols, certificate of 
analysis) and the required approvals have been obtained. 
 
The vaccines are labelled and packed according to applicable regulatory requirements. 
 
Commercial vaccines are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics. 
 
The study vaccines are listed in Table 11. 

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Table 11 
Study vaccines 
 
Treatment 
name 
Vaccine name 
Formulation 
Presentation 
Volume to be 
administered 
Number 
of 
doses 
Squarekids 
Squarekids 
BP>=4Unit; 
DT>=14IU; TT>=9IU; 
Inactivated Poliovirus 
type 1=40DU; 
Inactivated Poliovirus 
type 2=8DU; 
Inactivated Poliovirus 
type 3=32DU; 
Sodium 
hydrate=210µg; 
Trisodium 
phosphate=810µg; 
Aluminum 
chloride=900µg 0.5 
ml 
Pre-filled syringe 
0.5 ml 
3 
Rotarix 
HRV 
HRV RIX4144 live 
attenuated 
>=10⁶⋅⁰CCID₅₀ 1.5 
ml 
Liquid in a pre-filled 
oral applicator 
1.5 ml 
2 
 
6.2. 
Medical Devices 
Medical device (not manufactured by or for GSK) is used for DPT-IPV vaccine 
(Squarekids) administered in this study. It is a combination product of a drug and a kit of 
a glass syringe pre-filled with drug solution, which is approved for marketing. 
 
Instructions for medical device usage are provided in the package insert of Squarekids. 
 
The medical device related incidents including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout the 
period of the study – see Section 8.7. 
 
6.3. 
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 authorised 
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 devices 
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 label 
storage condition) impacting investigational medicinal products (IMPs) must be reported 

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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 
label storage temperature conditions. The impacted IMP(s) may still be administered, but 
the site should avoid re-occurrence of such temperature excursion. Refer to the Module 
on Clinical Trial Supplies in the SPM for more details on actions to take. 
 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 
 
6.4. 
Dosage and administration of study vaccines 
The dosage and administration of study vaccines are given in Table 12. 
Table 12 
 Dosage and administration 
Type of contact 
and time point 
Volume to be 
administered 
Study group 
Treatment name 
Route 1 
Site 
Side 
Visit 1 (Day 0) 
1.5 ml 
Co-   
administration 
group, 
Staggered group 
Rotarix 
O 
Not applicable 
Not 
applicable 
Visit 2 (Month 1) 
1.5 ml 
Co-   
administration 
group 
Rotarix 
O 
Not applicable 
Not 
applicable 
Visit 2 (Month 1) 
0.5 ml 
Co-   
administration 
group, 
Staggered group 
Squarekids 
SC 
Upper arm, or 
Upper thigh 
- 
Visit 3 (Month 1.5) 
1.5 ml 
Staggered group 
Rotarix 
O 
Not applicable 
Not 
applicable 
Visit 4 (Month 2) 
0.5 ml 
Co-   
administration 
group 
Squarekids 
SC 
Upper arm, or 
Upper thigh 
- 
Visit 5 (Month 2.5) 
0.5 ml 
Staggered group 
Squarekids 
SC 
Upper arm, or 
Upper thigh 
- 
Visit 6 (Month 4) 
0.5 ml 
Co-   
administration 
group, 
Staggered group 
Squarekids 
SC 
Upper arm, or 
Upper thigh 
- 
1Oral (O)/ subcutaneous (SC) 
 
6.5. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 5% additional vaccine doses will be 
supplied to replace those that are unusable. 

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6.6. 
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 vaccine but may continue other study procedures at the discretion of 
the investigator. 
 
• 
Anaphylaxis following the administration of vaccines. 
• 
Hypersensitivity reaction following the administration of the vaccines. 
• 
Contraindications to Rotarix: 
 
Any uncorrected congenital malformation of the gastrointestinal tract (such as 
Meckel’s diverticulum) that would predispose for IS. 
 
Any history of IS. 
 
SCID. 
• 
Contraindication for pertussis-containing vaccines: 
 
Encephalopathy of unknown aetiology, 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, generalised 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 
pertussis-containing vaccine until a treatment regimen has been established and 
the condition has stabilised. 
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 (see Section 5.5), within the time window 
specified in the protocol, or 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 ≥ 37.5°C on oral, axillary or tympanic setting, or 
≥ 38.0°C on rectal setting. The preferred route for recording temperature in this 
study will be axillary or tympanic. 
 
Subjects with a minor illness (such as mild upper respiratory infection) without 
fever can be administered all vaccines. 
• 
Diarrhoea or vomiting at the time of vaccination. 
 
6.7. 
Warnings and precautions 
Refer to the approved product label/package insert. 

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6.8. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit, the investigator should question the subject’s parent(s)/LAR(s) about 
any medications/products taken and vaccinations received by the subject. 
 
6.8.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
 
The following concomitant medications/products/vaccines must be recorded in the 
eCRF. 
 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting 30 days before and following each dose of 
study vaccine (Day -30 to Day 30). 
• 
Any concomitant vaccination administered in the period starting 30 days before the 
first dose of study vaccine and ending at the last study visit (Day -30 to Month 5). 
• 
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  37.5°C for oral, axillary or tympanic route, or  38.0°C for rectal 
route]. 
• 
Any concomitant medications/products/vaccines listed in Section 6.8.2. 
• 
Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered during the study period for the treatment of a SAE. In 
addition, concomitant medications relevant to SAEs need to be recorded on the 
expedited Adverse Event report. 
• 
Any antipyretic administered in the period starting 6 hours before vaccination and 
ending 12 hours after vaccination need to be recorded on the specific page of the 
eCRF. 
 
6.8.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP 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 
ATP analysis. 
 
• 
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 7. 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) during the study period between Visit 1 to Visit 7. For 

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corticosteroids, this will mean prednisone  0.5 mg/kg/day, or equivalent. Inhaled 
and topical steroids are allowed. 
• 
Immunoglobulins and/or any blood products administered during the study period 
between the first vaccination at Visit 1 to the blood sampling at Visit 7. 
• 
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 HRV vaccine administration and ending at 
blood sampling at Visit 7*, with the exception of other routinely administered 
vaccines like PCV, Hib, BCG, hepatitis B, meningococcal vaccine and inactivated 
influenza vaccines, which are allowed at any time during the study if administered at 
sites different from the sites used to administer the DPT-IPV vaccine. 
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the Sponsor is obtained. 
 
6.9. 
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses 
At each study visit subsequent to the first vaccination visit, it must be verified if the 
subject has experienced or is experiencing any intercurrent medical condition. If it is the 
case, the conditions must be recorded in the eCRF. 
 
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response or are 
confirmed to have an alteration of their initial immune status. 
 
7. 
HEALTH ECONOMICS 
Not applicable. 
 
8. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or SAE as 
provided in this protocol. 
 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs or symptoms they perceive as serious. 

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8.1. 
Safety definitions 
 
8.1.1. 
Definition of an adverse event 
 
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
 
Examples of an AE include: 
 
• 
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 investigational 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 
investigational vaccines or a concurrent medication (overdose per se should not be 
reported as an AE/SAE). 
• 
Signs, symptoms temporally associated with vaccines administration. 
• 
Significant failure of expected pharmacological or biological action. 
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen). 
 
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
 
Examples of an AE DO NOT include: 
 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• 
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. 

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8.1.2. 
Definition of a serious adverse event 
 
A SAE is any untoward medical occurrence that: 
 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation, 
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
d. Results in disability/incapacity. 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 
 
8.1.3. 
Solicited adverse events 
 
8.1.3.1. 
Solicited local (injection-site) adverse events 
 
All solicited local AEs are considered to be related to the vaccination. 

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The following local (injection-site) AEs associated with DPT-IPV vaccine will be 
solicited: 
 
Table 13 
Solicited local adverse events 
 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
 
8.1.3.2. 
Solicited general adverse events 
 
The following general AEs will be solicited after administration of the HRV vaccine: 
 
Table 14 
Solicited general adverse events (HRV vaccine) 
 
Fever 
Irritability/Fussiness 
Diarrhoea 
Vomiting 
Loss of appetite 
Cough/ runny nose 
 
The following general AEs will be solicited after administration of the DPT-IPV vaccine: 
 
Table 15 
Solicited general adverse events (DPT-IPV vaccine) 
 
Drowsiness 
Fever 
Irritability/Fussiness 
Loss of appetite 
 
Note: Temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF. 
 
8.1.4. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. vital signs etc.) that are 
judged by the investigator to be clinically significant will be recorded as AE or SAE if 
they meet the definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will also be reported as 
AEs or SAEs. However, clinically significant abnormal laboratory findings or other 
abnormal assessments that are associated with the disease being studied, unless judged by 
the investigator as more severe than expected for the subject’s condition, or that are 
present or detected at the start of the study and do not worsen, will not be reported as AEs 
or SAEs. 

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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. 
 
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 each dose of HRV vaccine 
and after the first dose of DPT-IPV vaccine (Day 0 to Day 30) must be recorded into the 
appropriate section of the eCRF, irrespective of intensity or whether or not they are 
considered vaccination-related. See Section 8.4 for instructions on reporting of causally 
AEs related to study vaccine. 
 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccines and will end at the end of the study (Visit 7), for each subject. 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 first receipt of study vaccines. 
 
SAEs that are related to the investigational vaccines will be collected and recorded from 
the time of the first receipt of study vaccines until the subject is discharged from the 
study. 
 
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. 
 
All causally related AEs from the first vaccination until the subject is discharged in the 
study will be recorded in the diary card and will be reported to Sponsor as mentioned in 
Section 8.4. 
 
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 16 and Table 17. 

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Table 16 
Reporting periods for collecting safety information (Co-administration group) 
 
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 
7 d 
post 
V4 
30 d 
post- 
V4 
Visit 5 7 d 
post 
V5 
30 d 
post- 
V5 
Visit 6 7 d 
post 
V6 
30 d 
post-
V6 
Visit 7 
Day 0 
M 1 
M 1.5 
M 2 
M 
2.5 
M 4 
M 5 
Solicited general 
AEs 
Solicited local AEs 
Unsolicited AEs 
AEs/SAEs leading 
to withdrawal from 
the study 
Causally related 
AEs/SAEs 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine 
* i.e. consent obtained. Pre-V: pre-vaccination; V: visit; d: day; M: Month 
Please refer to Section 5 for the detailed study design. Visit 3 and Visit 5 (shaded in grey) are not applicable for subjects in the Co-administered group. Solicited and unsolicited AEs 
will be recorded after each dose of the liquid HRV vaccine administration and after the first dose of DPT-IPV vaccine administration. 

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Table 17 
Reporting periods for collecting safety information (Staggered group) 
 
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 
7 d 
post 
V4 
30 d 
post- 
V4 
Visit 5 7 d 
post 
V5 
30 d 
post- 
V5 
Visit 6 7 d 
post 
V6 
30 d 
post-
V6 
Visit 7 
Day 0 
M 1 
M 1.5 
M 2 
M 
2.5 
M 4 
M 5 
Solicited general 
AEs 
Solicited local AEs 
Unsolicited AEs 
AEs/SAEs leading 
to withdrawal from 
the study 
Causally related 
AEs/SAEs 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine 
* i.e. consent obtained. Pre-V: pre-vaccination; V: visit; d: day; M: Month 
Please refer to Section 5 for the detailed study design. Visit 4 (shaded in grey) is not applicable for subjects in the Staggered group. Solicited and unsolicited AEs will be recorded after 
each dose of the liquid HRV vaccine administration and after the first dose of DPT-IPV vaccine administration 

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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 19. Investigators are not obligated to actively seek 
causally related AEs or SAEs in former study participants. However, if the investigator 
learns of any causally related AE and SAE at any time after a subject has been discharged 
from the study, and he/she considers the event reasonably related to the investigational 
vaccines, the investigator will promptly notify the Study Contact for Reporting SAEs. 
 
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?’ 
 
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 
 
The intensity of the following solicited AEs will be assessed as described: 
The intensity scales for solicited symptoms are listed in Table 18. 

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Table 18 
Intensity scales for solicited symptoms in infants 
 
Infants 
Adverse Event 
Intensity grade 
Parameter 
Pain at injection site 
0 
None 
1 
Mild: Minor reaction to touch 
2 
Moderate: Cries/protests on touch 
3 
Severe: Cries when limb is moved/spontaneously painful 
Redness at injection site 
Record greatest surface diameter in mm 
Swelling at injection site 
Record greatest surface diameter in mm 
Fever* 
Record temperature in °C 
Irritability/Fussiness 
0 
Behaviour as usual 
1 
Mild: Crying more than usual/no effect on normal activity 
2 
Moderate: Crying more than usual/interferes with normal activity 
3 
Severe: Crying that cannot be comforted/prevents normal 
activity 
Drowsiness 
0 
Behaviour as usual 
1 
Mild: Drowsiness easily tolerated 
2 
Moderate: Drowsiness that interferes with normal activity 
3 
Severe: Drowsiness that prevents normal activity 
Loss of appetite 
0 
Appetite as usual 
1 
Mild: Eating less than usual/no effect on normal activity 
2 
Moderate: Eating less than usual/interferes with normal activity 
3 
Severe: Not eating at all 
Diarrhoea¶ 
Record the number of looser than normal stools /day 
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§ 
Record the number of vomiting episodes/day 
0 
Normal (no emesis) 
1 
1 episode of vomiting/day 
2 
2 episodes of vomiting/day 
3 
 3 episodes of vomiting/day 
Cough/Runnynose 
0 
Normal 
1 
Mild: Cough/runny nose which is easily tolerated 
2 
Moderate: Cough/runny nose which interferes with daily activity 
3 
Severe: Cough/runny nose which prevents daily activity 
*Fever is defined as temperature  37.5°C for oral, axillary or tympanic route, or  38.0°C for rectal route. The 
preferred route for recording temperature in this study will be axillary or tympanic. ¶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. 

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The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals as follows: 
 
0 
: 
Absent 
 
1 
: 
 5 mm 
2 
: 
> 5 mm and  20 mm 
3 
: 
> 20 mm 
The maximum intensity of fever will be scored at GSK Biologicals as follows: 
 
0 
: 
Axillary < 37.5°C 
1 
: 
Axillary ≥ 37.5 – ≤ 38.0°C 
2 
: 
Axillary > 38.0 – ≤ 39.0°C 
3 
: 
Axillary > 39.0°C 
 
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 centre and would cause the 
parent(s)/LAR(s) to seek medical advice.) 
 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre- 
defined outcomes as described in Section 8.1.2. 
 
8.3.3.2.2. 
Assessment of causality 
 
The investigator is obligated to assess the relationship between investigational vaccines 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational vaccines will be considered and 

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investigated. The investigator will also consult the Prescribing Information for marketed 
products to determine his/her assessment. 
 
There may be situations when a causally related AE and/or 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 causally related AE and SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
 
In case of concomitant administration of multiple vaccines/products, it may not be 
possible to determine the causal relationship of general AEs to the individual vaccine 
administered. The investigator should, therefore, assess whether the AE could be causally 
related to vaccination rather than to the individual vaccines. 
 
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: 
 
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine? 
 
YES 
: 
There is a reasonable possibility that the vaccines contributed to the 
AE. 
NO 
: 
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccines. There are other, more 
likely causes and administration of the study vaccines is not 
suspected to have contributed to the AE. 
 
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
 
Possible contributing factors include: 
 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccines, if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 

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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 
hospitalisation, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF. 
 
8.4. 
Reporting of causally related adverse events and serious 
adverse events and other events 
 
8.4.1. 
Prompt reporting of related adverse event and serious adverse 
events to GSK Biologicals 
 
Both causally related solicited and unsolicited AEs and SAEs that occur in the time 
period defined in Section 8.3 will be reported promptly to GSK within the timeframes 
described in Table 19, once the investigator determines that the event meets the protocol 
definition of a causally related AE or SAE. 
 
Table 19 
Timeframes for submitting related adverse event and serious 
adverse event reports to GSK Biologicals 
 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
Causally related 
solicited AE 
24 hours* 
electronic solicited AEs 
report 
24 hours* 
electronic solicited AEs report 
Causally related 
24 hours* 
electronic non-serious 
24 hours* 
electronic non-serious adverse 
unsolicited AE 
adverse event and 
event and intercurrent medical 
intercurrent medical 
conditions report 
conditions report 
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 causally related adverse events 
and serious adverse events 
 
Study Contact for Reporting Causally Related AEs and SAEs 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting Causally Related AEs and SAEs 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Fax: PPD 
or PPD 
 
Email address: PPD 
 
8.4.3. 
Completion and transmission of causally related AE reports and 
SAE reports to GSK Biologicals 
 
Once an investigator becomes aware that a causally related AE or a SAE has occurred in 
a study subject, the investigator (or designate) must complete the information in the 
electronic solicited AE report, unsolicited AE report or 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 causally related AE or 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 for a SAE. 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 report form (i.e. solicited AE report, unsolicited AE 
report or Expedited Adverse Events Report) and fax it to the Study Contact for Reporting 
SAEs (refer to the Medical Monitor/Sponsor Information) or to GSK Biologicals Clinical 
Safety and Pharmacovigilance department within 24 hours. 
 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
 
8.4.4. 
Updating of causally related AE and SAE information after 
removal of write access to the subject’s eCRF 
 
When additional causally related AE or SAE information is received after removal of the 
write access to the subject’s eCRF, new or updated information should be recorded on the 

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appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting causally related AEs 
or SAEs (refer to the Medical Monitor/Sponsor Information or to GSK Biologicals 
Clinical Safety and Pharmacovigilance department within the designated reporting time 
frames specified in Table 19. 
 
8.4.5. 
Regulatory reporting requirements for causally related AEs and 
SAEs 
 
The investigator will promptly report all causally related AEs and 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/or other regulatory agencies about the safety of a product under clinical investigation. 
Prompt notification of causally related AEs and SAEs by the investigator to the Study 
Contact for Reporting causally related AEs and 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 
SAE(s) that is both attributable to the investigational vaccines and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation. 
 
8.5. 
Follow-up of adverse events and serious adverse events 
 
8.5.1. 
Follow-up 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 causally related AEs and SAEs; refer to Table 19). 
 
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study. 
 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study (Visit 7). 
 
8.5.2. 
Follow-up after the subject is discharged from the study 
 
The investigator will follow subjects: 
 
• 
with causally related AEs, 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. 

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If the investigator receives additional relevant information on a previously reported 
causally related AE or SAE, he/she will provide this information to GSK Biologicals 
using solicited AE report, unsolicited AE report or electronic Expedited Adverse Events 
Report. 
 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
 
8.6. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.8). 
 
8.7. 
Medical Device Incidents (Including Malfunctions) 
The medical device is being provided for use in this study. The investigator is responsible 
for the detection and documentation of events which meet the definitions of incident or 
malfunction that occur during the study with such devices. 
 
The definition of a Medical Device Incident can be found in Section 8.7.1 of the Protocol. 
 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3 to 8.6 of the Protocol. 
 
8.7.1. 
Definitions of a Medical Device Incident 
 
• 
Any malfunction or deterioration in the characteristics and/or performance of a 
device, as well as any inadequacy in the labelling or the instructions for use which, 
directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health. 
• 
Not all incidents lead to death or serious deterioration in health. The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel. 
It is sufficient that: 
 
• 
an incident associated with a device happened and 
• 
the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health. 

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A serious deterioration in state of health can include: 
 
• 
life-threatening illness 
• 
permanent impairment of body function or permanent damage to a body structure 
• 
a condition necessitating medical or surgical intervention to prevent one of the above 
• 
foetal distress, foetal death or any congenital abnormality or birth defects 
Examples of medical device incidents: 
• 
a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse 
• 
a patient’s treatment is interrupted or compromised by a medical device failure 
• 
misdiagnosis due to medical device failure leads to inappropriate treatment 
• 
a patient’s health deteriorates due to medical device failure 
8.7.2. 
Procedures for Documenting Medical Device Incidents 
 
The detection and documentation procedures described in this protocol apply to all 
medical devices provided for use in the study (see Section 6.2 for the medical device used 
in this study). 
 
8.7.2.1. 
Time Period for Detecting Medical Device Incidents 
 
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented and reported during all periods of the study. 
 
If the investigator learns of any incident at any time after a subject has been discharged 
from the study, and such incident is reasonably related to a medical device provided for 
the study, the investigator will promptly notify GSK. 
 
NOTE: The method of documenting Medical Device Incidents is provided in Section 
8.7.2.2. 
 
8.7.2.2. 
Documenting Medical Device Incidents 
 
Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical practice, 
and on the appropriate form. For incidents fulfilling the definition of an AE or an SAE, 
the appropriate AE/SAE eCRF screen will be completed as described in Section 8.3to 
8.6. 
 
The form will be completed as thoroughly as possible and signed by the investigator 
before it is transmitted to GSK by fax. 
 
It is very important that the investigator provides his/her assessment of causality to the 
medical device provided by GSK at the time of the initial report, and describes any 

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corrective or remedial actions taken to prevent recurrence of the incident. A remedial 
action is any action other than routine maintenance or servicing of a device where such 
action is necessary to prevent recurrence of an incident. This includes any amendment to 
the design to prevent recurrence. 
 
8.7.3. 
Prompt Reporting of Medical Device Incidents to GSK 
 
Medical device incidents will be reported to GSK within 24 hours once the investigator 
determines that the event meets the protocol definition of a medical device incident. 
 
Facsimile transmission of the "Medical Device Incident Report Form" is the preferred 
method to transmit this information to the Study Contact for Reporting Medical Device 
Incidents (Section 8.4.2). The Study Contact for Reporting Medical Device Incidents is 
same as the Study Contact for Reporting Causally Related AEs and SAEs. 
 
In the absence of facsimile equipment, notification by telephone is acceptable for 
incidents, with a copy of the "Medical Device Incident Report Form" sent by overnight 
mail. 
 
8.7.3.1. 
Regulatory Reporting Requirements for Medical Device Incidents 
 
The investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution in Japan), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC. 
 
8.7.4. 
Follow-up of Medical Device Incidents 
 
All medical device incidents involving an AE will be followed until resolution of the 
event, until the condition stabilises, until the condition is otherwise explained, or until the 
subject is lost to follow-up. This applies to all subjects, including those withdrawn 
prematurely. 
 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature 
and/or causality of the incident. 
 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator. 
 
8.8. 
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. 

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Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times. 
 
9. 
SUBJECT COMPLETION AND WITHDRAWAL 
 
9.1. 
Subject completion 
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study. 
 
9.2. 
Subject withdrawal 
Withdrawals will not be replaced. 
 
9.2.1. 
Subject withdrawal from the study 
 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol. 
 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
 
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up. 
 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made, by 
the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
 
• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 

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*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’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). 
 
9.2.2. 
Subject withdrawal from investigational vaccines 
 
A ‘withdrawal’ from the investigational vaccines refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccines may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol. 
 
Information relative to premature discontinuation of the investigational vaccines will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/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: 
 
• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
Other (specify). 
 
10. 
STATISTICAL METHODS 
 
10.1. 
Primary endpoint 
• 
Immunogenicity with respect to components of the DPT-IPV vaccine 1 month after 
administration of the third dose of the vaccine (Visit 7): 
 
anti-diphtheria antibody concentrations ≥ 0.1 IU/mL, 
 
anti-tetanus antibody concentrations ≥ 0.1 IU/mL, 
 
anti-PT and anti-FHA antibody concentrations ≥ 10 IU/mL, 
 
anti-poliovirus serotypes 1, 2 and 3 antibody titre ≥ 8 ED50. 
 
10.2. 
Secondary endpoints 
• 
Serum anti-RV IgA antibody concentration 20 U/mL and seropositivity in a sub- 
cohort of subjects, 1 month after the second dose of the liquid HRV vaccine. 

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• 
Serum GMCs/GMTs for anti-diphtheria, anti-tetanus, anti-poliovirus serotypes 1, 2 
and 3, anti-PT and anti-FHA antibodies, 1 month after the third dose of the DPT-IPV 
vaccine. 
• 
Occurrence of solicited general symptoms during the 8-day (Days 0-7) follow-up 
period after each dose of liquid HRV vaccine. 
• 
Occurrence of solicited local and general symptoms during the 8-day (Days 0-7) 
follow-up period after the first dose of DPT-IPV vaccine. 
• 
Occurrence of unsolicited AEs during the 31-day (Days 0-30) follow-up period after 
each dose of the liquid HRV vaccine and the first dose of DPT-IPV vaccine, 
according to the Medical Dictionary for Regulatory Activities (MedDRA) 
classification. 
• 
Occurrence of SAEs from the first dose of the study vaccine up to study end (Visit 
7). 
10.3. 
Determination of sample size 
The target enrolment will be at least 292 subjects (146 subjects in each of the groups) to 
obtain 262 evaluable subjects (131 subjects in each of groups) for the evaluation of the 
co-primary objectives assuming that approximately 10% of the enrolled subjects will not 
be evaluable. 
 
A sub-cohort of subjects which includes half the number of enrolled subjects from each 
study group (a total of 146 subjects, with 73 from the co-ad group and 73 from the 
staggered group), will be used for evaluating immunogenicity of the liquid HRV vaccine 
in terms of serum anti-RV IgA antibody seropositivity and GMCs. 
 
10.3.1. 
Reference for sample size 
 
Table 20 presents the reference response rates. 

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Table 20 
Reference response rates 
 
Reference 
Timing 
Cut-off 
N 
% 
LL 
UL 
DPT-IPV group (DPT-IPV (SQK) 
Phase 2 Study*) 
4 weeks after primary 
vaccination 
D  0.01 IU/ml 
114 
100.0% 96.7% 100.0% 
T  0.01 IU/ml 
114 
100.0% 96.7% 100.0% 
PT≥ 10 EU/ml 
114 
99.1% 95.2% 99.8% 
FHA≥ 10 EU/ml 
114 
100.0% 96.7% 100.0% 
Anti-Polio-1  8 
114 
100.0% 96.7% 100.0% 
Anti-Polio-2  8 
114 
100.0% 96.7% 100.0% 
Anti-Polio-3  8 
114 
100.0% 96.7% 100.0% 
DPT-IPV group (DPT-IPV (SQK) 
Phase 3 Study*) 
D  0.1 IU/ml 
235 
99.1% 97.0% 99.9% 
T  0.01 IU/ml 
235 
100.0% 98.4% 100.0% 
PT≥ 10 EU/ml 
235 
98.7% 96.3% 99.7% 
FHA≥ 10 EU/ml 
235 
100.0% 98.4% 100.0% 
Anti-Polio-1  8 
235 
100.0% 98.4% 100.0% 
Anti-Polio-2  8 
235 
100.0% 98.4% 100.0% 
Anti-Polio-3  8 
235 
100.0% 98.4% 100.0% 
DPT group (DPT-IPV (SQK) 
Phase 3 Study*) 
D  0.1 IU/ml 
120 
100.0% 97.0% 100.0% 
T  0.01 IU/ml 
120 
100.0% 97.0% 100.0% 
PT≥ 10 EU/ml 
120 
98.3% 94.1% 99.8% 
FHA≥ 10 EU/ml 
120 
100.0% 97.0% 100.0% 
N= Number of subjects with available results, % = Percentage of subjects with titre/concentration within the specified 
range, LL = Lower Limit, UL = Upper Limit 
*Regulatory review report of DPT-IPV (SQK). 
 
 
10.3.2. 
Power computation 
 
The sample size has been estimated in order to obtain at least 90% power to demonstrate 
the confirmatory primary objectives (Bonferroni adjustment of type II error). A 
hierarchical procedure will be used for the multiple study objectives. 
 
The power computations are based on the following method: 
 
• 
Non-inferiority on percentage of subjects with titre/concentration above pre- 
specified cut-off: Type II error is obtained using PASS 12, one-sided non-inferiority 
test for two proportions, under the alternative of equal proportions. Miettinen and 
Nurminen method. It corresponds to method 6 described in a paper by Newcombe 
[Newcombe, 1998]. 
To account for the multiplicity of comparison, the global type II errors are conservatively 
estimated as the sum of individual type II errors. 
 
Table 21 details the power for non-inferiority of DPT-IPV vaccine co-administered with 
Rotarix compared to DPT-IPV vaccine with staggered administration of Rotarix 
following 3 primary vaccine doses in terms of immune response to diphtheria, tetanus, 
PT, FHA and 3 serotypes of poliovirus. During the redevelopment of the PT and FHA 
assays, an international standard was included as an internal reference. This led to the 
conversion of the unit concentration from EU/mL to IU/mL. The unit standard of IU/mL 
is a conservative reference and considering that most subjects are anticipated to achieve a 

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post vaccination titre significantly above 10, there is no expected impact on the 
calculations in Table 21, which uses the EU/mL unit for the PT and FHA assays. 
 
Table 21 
Power for non-inferiority 
 
Endpoint 
N evaluable in Co- 
administration 
group 
N evaluable 
in Staggered group 
Estimated sero- 
positive rate in 
both groups 
Power* 
Anti-D 0.1 IU/mL 
131 
131 
97.0% 
97.3% 
Anti-T 0.1 IU/mL** 
131 
131 
98.4% 
99.7% 
Anti-PT 10 EU/mL 
131 
131 
96.3% 
95.2% 
Anti-FHA 10 EU/mL 
131 
131 
98.4% 
99.7% 
Anti-Polio-1  8 
131 
131 
98.4% 
99.7% 
Anti-Polio-2  8 
131 
131 
98.4% 
99.7% 
Anti-Polio-3  8 
131 
131 
98.4% 
99.7% 
Global power for Non-inferiority 
91.0% 
* PASS 12, non-inferiority test for two proportions using differences, 1-sided, alpha=0.025, power under the alternative 
hypothesis of equal rates between groups. 
** Anti-T percentage of subjects above the cut off 0.01 =100% (N=235 95%CI 98.4- 100.0) from DPT-IPV(SQK) reports 
of the phase 3 study. 
 
10.4. 
Cohorts for Analyses 
Two cohorts are defined for the purpose of the analysis: 
• 
Total vaccinated cohort. 
• 
ATP cohort for analysis of immunogenicity. 
 
10.4.1. 
Total vaccinated cohort 
 
The TVC will include all subjects with at least one dose of the study vaccines 
administration documented: 
 
• 
A safety and reactogenicity analysis based on the TVC will include all subjects with 
at least one vaccine administration documented. 
 
• 
An immunogenicity analysis based on the TVC will include all subjects from this 
cohort for whom immunogenicity data were available. 
The TVC analysis will be performed per treatment actually administered. 
 
10.4.2. 
According-to-protocol cohort for analysis of immunogenicity 
 
The ATP cohort for immunogenicity will include all subjects: 
• 
who comply with vaccination schedule of DPT-IPV and HRV vaccines, 
• 
who have not received medication forbidden by the protocol (up to Visit 7), 
• 
whose underlying medical condition was not forbidden by the protocol (up to Visit 
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• 
who complied with the blood sampling schedule, 
• 
who had no concomitant infection related to the vaccine which may have influenced 
the immune response, 
• 
who had no concomitant infection unrelated to the vaccine which may have 
influenced the immune response, 
• 
for whom immunogenicity data are available at least one of the post-sampling time 
points. 
 
10.5. 
Derived and transformed data 
• 
Immunogenicity 
 
The cut-off value is defined by the laboratory before the analysis and is 
described in Section 5.7.3. 
 
A seronegative subject is a subject whose antibody titre is below the cut-off 
value. 
 
A seropositive subject is a subject whose antibody titre is greater than or equal 
to the cut-off value. 
 
The Geometric Mean Concentrations/Titres (GMC/GMTs) calculations are 
performed by taking the anti-log of the mean of the log concentration/titre 
transformations. Antibody concentrations/titres below the cut-off of the assay 
will be given an arbitrary value of half the cut-off for the purpose of GMC/GMT 
calculation. 
 
Handling of missing data: for a given subject and a given immunogenicity 
measurement, missing or non-evaluable measurements will not be replaced. 
 
• 
Reactogenicity and safety 
 
Handling of missing data: subjects who missed reporting symptoms 
(solicited/unsolicited or concomitant medications) will be treated as subjects 
without symptoms (solicited/unsolicited or concomitant medications, 
respectively). In case of significant non-compliance of study procedures for 
reporting symptoms, the analysis plan will be reassessed to ensure more accurate 
reporting of study data by further analysis. 
 
For the analysis of solicited symptom, missing or non-evaluable measurements 
will not be replaced. Therefore the analysis of the solicited symptoms based on 
the Total vaccinated cohort will include only subjects/doses with documented 
safety data (i.e. symptom screen/sheet completed). 
 
10.6. 
Analysis of demographics/baseline characteristics 
The distributions of subjects enrolled by centre will be tabulated by group. The numbers 
of subjects who are withdrawn from the study will be tabulated by group according to the 
reason for withdrawal. The median, mean, range and standard deviation (SD) of age at 

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each study vaccine dose (in weeks) will be computed by group. The median, mean and 
SD of height in centimetre (cm) and weight in kilograms (kg) at Visit 1 will be computed 
by group. The Body Mass Index (BMI) at Visit 1 will also be computed as weight (in 
kg)/height Index (BMI). The number of doses of the liquid HRV vaccine and DPT-IPV 
vaccine administered will be tabulated per group. The gender composition per group will 
also be presented. The deviations from specifications for age and intervals between study 
visits will be tabulated by group. 
 
10.7. 
Analysis of immunogenicity 
The ATP cohort for immunogenicity will be used for the primary analysis of 
immunogenicity. An analysis of immunogenicity based on the TVC will be performed 
only if more than 5% of the vaccinated subjects with immunogenicity results available 
were excluded from the ATP cohort for immunogenicity. In such a case, the TVC 
analyses will evaluate whether exclusion from the ATP cohort has biased the results. 
 
10.7.1. 
Within groups assessment 
 
For each treatment group and each antigen: 
• 
Percentage of subjects with antibody concentrations/ titres greater than or equal to 
the pre-specified cut-off will be calculated with exact 95% CI (Refer Table 9). Anti- 
PT and anti-FHA antibody concentrations ≥ 10 IU/mL will also be calculated with 
exact 95% CI. 
• 
GMC/GMTs, as applicable with 95% CIs will be tabulated. 
• 
The distribution of antibody concentrations/ titres, as applicable, will be presented 
using reverse cumulative curves (RCC). 
 
10.7.2. 
Between groups assessment 
 
For each antigen in the DPT-IPV vaccine: 
• 
The two-sided asymptotic standardised 95% CIs for the difference between groups 
(Co-administration group minus Staggered group) in terms of percentage of subjects 
with antibody concentrations/ titres greater than or equal to the pre-specified cut-off 
will be computed. Anti-PT and anti-FHA antibody concentrations ≥ 10 IU/mL will 
also be calculated with exact 95% CI. 
 
10.8. 
Analysis of safety 
The safety analysis will be based on the TVC. 
 
The incidence by dose, overall per dose and overall per subject, with its exact 95% CI of 
 
• 
any adverse event (solicited or unsolicited, local or general), 
• 
at least one local adverse event (solicited or unsolicited), and, 

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• 
at least one general adverse event (solicited or unsolicited), 
during the 8-day (Days 0-7) follow-up period will be tabulated. The same calculations 
will be performed for any Grade 3 (solicited or unsolicited) symptoms, related and for 
any adverse event requiring medical attention. 
 
For each type of solicited symptom, the incidence during the 8-day (Days 0-7) follow-up 
period of the symptom (any grade, Grade 3, related, Grade 3 related, requiring medical 
advice) will be tabulated as follows: 
 
• 
at each dose, the percentage of doses followed by the reporting of a symptom and its 
exact 95% CI, 
• 
over all the doses, the percentage of subjects reporting the symptom and its exact 
95% CI, 
• 
over all the doses, the percentage of doses followed by the reporting of a symptom 
and its exact 95% CI, 
• 
for fever, additional analyses will be performed by 0.5C increments. 
The percentage of subjects who receive concomitant medication, who receive antipyretic 
medication and prophylactic antipyretic medication during the 8-day (Days 0-7) and 31- 
day (Days 0-30) follow-up period post-vaccination will be tabulated by dose, overall per 
subject and over all the doses. 
 
The verbatim reports of unsolicited symptoms 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 
symptoms occurring during the 31 days (Days 0-30) with its exact 95% CI will be 
tabulated by preferred term. Similar tabulation will be done for Grade 3 unsolicited 
symptoms and for unsolicited symptoms causally related to vaccination. 
 
Subjects who experienced at least one SAE during the entire study period (from the first 
dose till the end of the study [Visit 7]) will be reported and the SAEs will be described in 
detail. 
 
10.9. 
Interpretation of analyses 
Except for the analyses addressing the criteria specified in the objectives, no comparative 
analyses will be performed. 
 
10.10. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 

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10.10.1. 
Sequence of analyses 
 
The final data analysis will include all data up to one month after the third dose of DPT- 
IPV vaccine. These analyses will include the final analysis of immunogenicity and the 
final analysis of solicited and unsolicited symptoms and SAEs from the first dose up to 
Visit 7. 
 
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 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 of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
 
11.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst others, the: 
 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 

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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 monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
 
For eCRF, the monitor freezes completed and approved screens at each visit. 
 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 
 
11.3. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 

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11.4. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
 
11.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations. 
 
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry (ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the Last Subject Last Visit 
(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 
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. 
 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy. 
 
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 

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11.7. 
Regulatory and Ethical Considerations, including the 
Informed Consent Process 
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy. 
 
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following: 
 
• 
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable 
• 
Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable) 
• 
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC) 
GSK will provide full details of the above procedures, either verbally, in writing, or both. 
 
11.8. 
Study and site closure 
• 
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures. 
• 
GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites. 
• 
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the investigator 
or the head of the medical institution, where applicable, of the impending action. 
• 
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. 
• 
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation. 

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12. 
COUNTRY SPECIFIC REQUIREMENTS 
 
12.1. 
Japan specific requirements – Study conduct 
considerations 
 
12.1.1. 
Regulatory and Ethical Considerations 
 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27th March, 1997)” and Law for Ensuring the Quality, Efficacy, and Safety 
of Drugs and Medical Devices. 
 
The statement “I acknowledge that I am responsible for the overall study conduct.” on the 
Investigator Protocol Agreement Page means the investigator’s responsibility as defined 
by Japanese GCP. 
 
Prompt notification by the investigator to GSK of unsolicited AEs assessed as related to a 
investigational products (even for non- interventional post-marketing studies) is essential 
so that legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a product under clinical investigation are met. 
 
12.1.2. 
Informed Consent 
 
Prior to participation in the study, the investigator (or sub-investigator) should fully 
inform the potential subject and/or the subject’s legally acceptable representative of the 
study including the written information. The investigator (or sub-investigator) should 
provide the subject and/or the subject's legally acceptable representative ample time and 
opportunity to inquire about details of the study. The subject and/or the subject’s legally 
acceptable representative should sign and personally date the consent form. If the subject 
wishes to consider the content of the written information at home, he/she may sign the 
consent form at home. The person who conducted the informed consent discussion and 
the study collaborator giving supplementary explanation, where applicable, should sign 
and personally date the consent form. If an impartial witness is required, the witness 
should sign and personally date the consent form. The investigator (or sub-investigator) 
should retain this signed and dated form (and other written information) together with the 
source medical records, such as clinical charts (in accordance with the rules for records 
retention, if any, at each medical institution) and give a copy to the subject and/or the 
subject’s legally acceptable representative. 
 
12.1.3. 
Study period 
 
September 2016 (First Subject First Visit) - December 2017 (PCD). 

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12.1.4. 
Study administrative structure 
 
Sponsor information and List of Medical Institutions and Investigators are included in 
Exhibit 1. 
 
13. 
REFERENCES 
Atherly D, Dreibelbis R, Parashar U D, et al. Rotavirus Vaccination: Cost-Effectiveness 
and Impact on Child Mortality in Developing Countries The Journal of Infectious 
Diseases 2009; 200:S28–38. 
 
Camargo ME, Silveira L, Furuta JA, et al. Immunoenzymatic assay of anti-diphtheric 
toxin antibodies in human serum. J Clin Microbiol. 1984; 20(4): 772-774. 
 
Cheuvart B, Neuzil KM, Steele AD, et al. Association of serum anti-rotavirus 
immunoglobulin A antibody seropositivity and protection against severe rotavirus 
gastroenteritis: Analysis of clinical trials of human rotavirus vaccine. Hum Vaccin 
Immunother. 2014; 10: 505-511. 
 
Cunliffe N, Zaman K., Rodrigo C. et al. Early exposure of infants to natural rotavirus 
infection: a review of studies with human rotavirus vaccine RIX441, BMC Pediatrics 
2014, 14:295. 
 
Dennehy PH, Bertrand HR, Silas PE, et al. Coadministration of RIX4414 oral human 
rotavirus vaccine does not impact the immune response to antigens contained in routine 
infant vaccines in the United States. Pediatrics. 2008;122(5):e1062-6. 
 
Desselberger U. Updating prevaccination rotavirus-associated mortality Lancet Infect Dis 
2012; 12: 94-96. 
 
Glass R I, Parashar U D, Bresee J S, et al. Rotavirus vaccines: current prospects and 
future challenges, Lancet 2006; 368: 323–32. 
 
Kamiya H, Nakano T, Kamiya H, et al. Rotavirus-associated acute gastroenteritis 
hospitalizations among Japanese children aged <5 years: active rotavirus surveillance in 
Mie Prefecture, Japan. Jpn J Infect Dis. 2011; 64(6): 482-7. 
 
Kawamura N, Tokoeda Y, Oshima M, et al. Efficacy, safety and immunogenicity of 
RIX4414 in Japanese infants during the first two years of life. Vaccine. 2011; 29(37): 
6335-41. 
 
Linhares AC, Velázquez FR, Pérez-Schael I, et al. Efficacy and safety of an oral live 
attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 
years of life in Latin American infants: a randomised, double-blind, placebo-controlled 
phase III study. Lancet. 2008; 371(9619): 1181-9. 
 
Melville-Smith ME, Seagroatt VA and Watkins JT. A comparison of enzyme-linked 
immunosorbent assay (ELISA) with the toxin neutralization test in mice as a method for 
the estimation of tetanus antitoxin in human sera. J Biol Stand. 1983; 11: 137-44. 

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Nakagomi O, Nakagomi T. Rotarix in Japan: Expectations and Concerns. Biol Ther. 
2011; 1(1): 4. 
 
Newcombe R G, Two-sided confidence intervals for the single proportion: Comparison 
of seven methods. Statistics in Medicine. 1998; 17(8):857–72. 
 
Phua KB, Lim FS, Lau YL et al. Rotavirus vaccine RIX4414 efficacy sustained during 
the third year of life: A randomized clinical trial in an Asian population, Vaccine 2012; 
30: 4552– 4557. 
 
Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol. 
2010; 17(7):1055-65. 
 
Vesikari T, Karvonen A, Korhonen T, et al. Safety and immunogenicity of RIX4414 live 
attenuated human rotavirus vaccine in adults, toddlers and previously uninfected infants. 
Vaccine 2004(a); 22: 2836–42. 
 
Vesikari T, Karvonen A, Puustinen L, et al. Efficacy of RIX4414 live attenuated human 
rotavirus vaccine in Finnish infants. Pediatr Infect Dis J 2004(b); 23: 937–43. 
 
Vesikari T, Karvonen A, Prymula R. et al. Efficacy of human rotavirus vaccine against 
rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, 
double-blind controlled study. Lancet 2007; 370:1757–63. 
 
WHO. Standard Procedure for Determining Immunity to Poliovirus using the 
Microneutralisation Test (WHO/EPI/GEN 93.9) 1993. 
 
WHO position paper. Weekly epidemiological record. Outbreak news. Cholera, Angola. 
2006; 81(20): 197-208. 
 
WHO position paper. Weekly epidemiological record. Rotavirus vaccines WHO position 
paper - 2013; 88: 49–64. 

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APPENDIX A 
LABORATORY ASSAYS 
Anti-Rotavirus antibody concentrations are determined by a validated anti-Rotavirus IgA 
ELISA. Micro titre plates (96-well) are coated with an anti-Rotavirus monoclonal 
antibody. The wells are washed and incubated with (positive wells) or without (negative 
wells) Rotavirus. Following incubation, the plates are washed and serum, standard and 
control dilutions are incubated in both types of wells (positive and negative). Bound anti- 
Rotavirus IgA in the well are detected by incubation with peroxidase conjugated anti- 
human IgA polyclonal antibodies. Colour development proportional to the quantity of 
bound anti-Rotavirus IgA occurs in the presence of a chromogen, TMB 
(TetraMethylBenzidine), and measured spectrophotometrically. Specific optical densities 
are calculated for each sample / control / standard dilution by measuring the difference 
between positive and negative wells, the use of negative wells allowing to assess non- 
specific IgA binding. Concentrations of the samples expressed in units per millilitre are 
calculated relative to the four-parameter logistic function generated from the standard 
curve. 

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APPENDIX B 
CLINICAL LABORATORIES 
Table 22 
GSK Biologicals’ laboratories 
 
Laboratory 
Address 
Clinical Laboratory Sciences (CLS), 
Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
Clinical Laboratory Sciences (CLS), 
Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
Table 23 
Outsourced laboratories 
 
Laboratory 
Address 
Q² Solutions Clinical Trials (US) 
27027 Tourney Road, Suite 2E 
Valencia, CA 91355 
USA 
Q² Solutions Clinical Trials (UK) 
Simpson Parkway 
The Alba Campus 
Rosebank 
Livingston 
EH54 7EG 
UK 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD