Immunogenicity and Safety of GSK Biologicals' Combined Diphtheria-tetanus-acellular Pertussis-inactivated Poliovirus and Haemophilus Influenzae Type b (DTPa-IPV/Hib) Conjugate Vaccine
Phase: PHASE3
Conditions: Diphtheria, Tetanus, Pertussis, Hepatitis B, Haemophilus Influenzae Type b
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
11-OCT-2016 
1 
 
Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’Institut, 89 
1330 Rixensart, Belgium. 
Primary Study vaccine 
and number 
GlaxoSmithKline (GSK) Biologicals combined 
diphtheria-tetanus-acellular pertussis-inactivated 
poliovirus and Haemophilus influenzae type b (DTPa-
IPV/Hib) conjugate vaccine (Infanrix™-IPV/Hib). 
[213503 (DTPA-IPV)] 
eTrack study number 
and Abbreviated Title 
116194 [DTPA-IPV (INFANRIX-IPV)-061] 
EudraCT number 
2013-005577-43 
Date of protocol 
Protocol Version 3 Final: 21 January 2016  
Date of protocol 
amendment 
Protocol Amendment 1 Final: 11 October 2016 
Title 
Immunogenicity and safety of GSK Biologicals’ 
combined diphtheria-tetanus-acellular pertussis-
inactivated poliovirus and Haemophilus influenzae type b 
(DTPa-IPV/Hib) conjugate vaccine 
Detailed Title 
A phase III, open-label study to assess the immunogenicity 
and reactogenicity of GSK Biologicals’ DTPa-IPV/Hib 
vaccine administered as a three-dose primary vaccination 
course at 3, 4.5 and 6 months of age and a booster dose at 
18 months of age in healthy infants in Russia. 
Co-ordinating author 
, Scientific Writer, contractor for GSK 
Biologicals 
Contributing authors 
(Amended 11 October 
2016) 
• 
, Clinical Research and 
Development Lead (CRDL), contractor for GSK 
Biologicals 
• 
, CRDL 
• 
, Clinical and Epidemiology 
Project Leader (CEPL) 
• 
, Project Delivery Lead 
• 
, Study Delivery Lead, Aixial 
contractor for GSK Biologicals 
• 
, Study Delivery Manager 
• 
 Vaccine Supply Coordinator, 
contractor for GSK Biologicals 
• 
, Clinical Trial Supplies Manager, 
Aixial contractor for GSK Biologicals 
• 
, Safety Representative 
• 
, Study Statistician 
• 
, Project Statistician 
• 
, Lead Statistician 
• 
, Director Biostatistics 
• 
, Project Data Manager 
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CONFIDENTIAL 
116194 [DTPA-IPV (INFANRIX-IPV)-061] 
Protocol Amendment 1 Final 
11-OCT-2016 
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eTrack study number 
and Abbreviated Title 
116194 [DTPA-IPV (INFANRIX-IPV)-061] 
EudraCT number 
2013-005577-43 
Date of protocol 
Protocol Version 3 Final: 21 January 2016  
Date of protocol 
amendment 
Protocol Amendment 1 Final: 11 October 2016 
Title 
Immunogenicity and safety of GSK Biologicals’ 
combined diphtheria-tetanus-acellular pertussis-
inactivated poliovirus and Haemophilus influenzae type b 
(DTPa-IPV/Hib) conjugate vaccine 
Detailed Title 
A phase III, open-label study to assess the immunogenicity 
and reactogenicity of GSK Biologicals’ DTPa-IPV/Hib 
vaccine administered as a three-dose primary vaccination 
course at 3, 4.5 and 6 months of age and a booster dose at 
18 months of age in healthy infants in Russia. 
Contributing authors 
(continued) 
(Amended 11 October 
2016) 
• 
 and 
, Clinical 
Laboratory Sciences (CLS) Project Manager 
• 
, CLS Study Manager, Business 
& Decision Life Sciences contractor for GSK 
Biologicals 
• 
, Global Patent Representative 
• 
, Global Patent Representative 
• 
, Senior Medical Manager CIS 
• 
, Manager, Global RA 
• 
, Manager, Global RA 
• 
, Local Head of Clinical 
Operations 
• 
, Local Delivery Lead 
• 
, Study Data Manager 
• 
, Oversight Data Manager 
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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116194 [DTPA-IPV (INFANRIX-IPV)-061] 
Protocol Amendment 1 Final 
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Protocol Amendment 1 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
116194 [DTPA-IPV (INFANRIX-IPV)-061] 
EudraCT number 
2013-005577-43 
Date of protocol amendment 
Protocol Amendment 1 Final: 11 October 2016 
Detailed Title  
A phase III, open-label study to assess the 
immunogenicity and reactogenicity of GSK 
Biologicals’ DTPa-IPV/Hib vaccine administered as 
a three-dose primary vaccination course at 3, 4.5 and 
6 months of age and a booster dose at 18 months of 
age in healthy infants in Russia. 
Sponsor signatory 
Narcisa Mesaros, MD 
Clinical and Epidemiology Project Leader (CEPL), 
DTP, Polio, Hib containing vaccines 
R&D Center Belgium 
 
 
Signature 
 
 
 
Date 
 
 
 

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116194 [DTPA-IPV (INFANRIX-IPV)-061] 
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Protocol Amendment 1 Rationale 
Amendment number: 
Amendment 1 
Rationale/background for changes:  
• 
As per Russian legislation, only parents or adoptive parents can give consent for 
the enrolment of their child in a clinical trial. No other persons are allowed to give 
consent on behalf of a minor to participate in a clinical trial. Therefore the wording 
“parents/Legally Acceptable Representative(s) (LAR[s])” should be replaced by 
the wording “parents/adoptive parents”. This change was implemented by the local 
team in the Russian translation of the protocol and informed consent form after 
obtaining approval from competent authorities and ethics committees in order to 
meet Russian legislation requirements. The purpose of this amendment is to 
replace “parents/LAR(s)” by “parents/adoptive parents” in order to ensure 
consistency in wording between local protocol and central protocol. 
• 
The list of study personnel and the function names have been updated. 
 

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Protocol Amendment 1 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals investigational 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 parents/adoptive parents. 
• 
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. 
(Amended 11 October 2016) 

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116194 [DTPA-IPV (INFANRIX-IPV)-061] 
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eTrack study number and 
Abbreviated Title 
116194 [DTPA-IPV (INFANRIX-IPV)-061] 
EudraCT number 
2013-005577-43 
Date of protocol amendment 
Protocol Amendment 1 Final: 11 October 2016 
Detailed Title 
A phase III, open-label study to assess the 
immunogenicity and reactogenicity of GSK 
Biologicals’ DTPa-IPV/Hib vaccine administered as 
a three-dose primary vaccination course at 3, 4.5 and 
6 months of age and a booster dose at 18 months of 
age in healthy infants in Russia. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 

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Sponsor Information 
1. Sponsor  
GlaxoSmithKline Biologicals 
Rue de l'Institut 89, 1330 Rixensart, Belgium. 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 8.3.2. 

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SYNOPSIS 
Detailed Title 
A phase III, open-label study to assess the immunogenicity 
and reactogenicity of GSK Biologicals’ DTPa-IPV/Hib 
vaccine administered as a three-dose primary vaccination 
course at 3, 4.5 and 6 months of age and a booster dose at 18 
months of age in healthy infants in Russia. 
Indication 
Active immunisation against diphtheria, tetanus, pertussis, 
poliomyelitis and Haemophilus influenzae type b (Hib) 
diseases from the age of 2 months. 
Rationale for the 
study and study 
design 
Rationale for the study 
GlaxoSmithKline (GSK) Biologicals’ Infanrix-IPV/Hib is 
licensed for primary vaccination in 74 countries in the world, 
including most European countries. Infanrix-IPV/Hib has 
been extensively studied in clinical trials that established its 
immunogenicity and safety [Lim, 2011; Phua, 2008; Gilca, 
2006]. To date, more than 70 million commercial doses have 
been distributed, and routine use of the vaccine has confirmed 
its good safety profile. 
In the Russian Federation, a three-dose primary vaccination of 
infants is currently recommended against hepatitis B with 
doses administered at birth, 1 month and 6 months of age and 
against diphtheria, tetanus, pertussis, poliomyelitis and Hib 
with doses administered at 3, 4.5 and 6 months of age. The 
Russian Federation also recommends a booster vaccination of 
infants against diphtheria, tetanus, pertussis, poliomyelitis and 
Hib at 18 months of age. GSK Biologicals’ DTPa-IPV/Hib 
vaccine (Infanrix-IPV/Hib) combines antigens to diphtheria, 
tetanus, pertussis, poliomyelitis and Haemophilus influenzae 
type b diseases in one single injection and complements to the 
current local standard of care for the hepatitis B 
immunization. The present study is being performed to 
support the registration of Infanrix-IPV/Hib in the Russian 
Federation. 
Rationale for the study design 
The aim of the present study is to evaluate the immune 
response, safety and reactogenicity induced by the combined 
DTPa-IPV/Hib vaccine when administered as a three-dose 
primary vaccination course at 3, 4.5 and 6 months of age and 
as a booster dose at 18 months of age according to the Russian 
immunisation schedule. 

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The study will adopt a single group, open-label design. 
Objectives 
Primary 
• 
To assess the immune response to the study vaccine in 
terms of seroprotection status for diphtheria, tetanus, Hib 
and poliovirus types 1, 2 and 3 antigens, and in terms of 
seropositivity to the pertussis antigens, one month after 
the third dose of primary vaccination. 
 
Secondary 
• 
To assess the immune response to the study vaccine in 
terms of seroprotection to diphtheria, tetanus, Hib and 
poliovirus types 1, 2 and 3 antigens, and in terms of 
seropositivity to the pertussis antigens, one month after 
the booster vaccination. 
• 
To assess the immune response to the study vaccine in 
terms of antibody concentrations or titres against 
diphtheria, tetanus, Hib, poliovirus types 1, 2 and 3 
antigens, and pertussis antigens, one month after the third 
dose of primary vaccination and one month after the 
booster vaccination. 
• 
To assess the safety and reactogenicity of the study 
vaccine in terms of solicited symptoms, unsolicited 
symptoms and serious adverse events (SAEs). 
Study design 
• 
Experimental design: Phase III, open-label, multi-centric, 
single-country study with a single group. 
• 
Duration of the study: Approximately 16 months per 
subject. 
 Epoch 001 (Primary epoch): Primary phase starting at 
Visit 1 (Day 0) and ending at Visit 4 (Month 4). 
 Epoch 002 (Booster epoch): Booster phase starting at 
Visit 5 (Month 15) and ending at Visit 6 (Month 16). 
• 
Study group: The study group and epochs foreseen in the 
study are presented in Synopsis Table 1. 
Synopsis Table 1 
Study group and epochs foreseen in the study 
Study group 
Number of subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
(Primary epoch) 
Epoch 002 (Booster 
epoch) 
DTPa-IPV/Hib 
Group 
 235 
3 months - 4 months 
x 
 
DTPa-IPV/Hib 
Group 
 235 
18 months- 19 months 
 
x 

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Synopsis Table 2 presents the study group and treatment foreseen in the study. 
Synopsis Table 2 
Study group and treatment foreseen in the study 
Treatment name 
Vaccine/Product name 
Study Group 
DTPa-IPV/Hib Group 
Infanrix-IPV/Hib 
DTPa-IPV  
x  
Hib  
x  
 
• 
Control: This is an uncontrolled study. 
• 
Treatment group and vaccination schedule: All subjects 
will receive three doses of primary vaccination at 3, 4.5 
and 6 months of age and a single dose of booster 
vaccination at 18 months of age: 
 
DTPa-IPV/Hib Group: Subjects who will receive 
DTPa-IPV/Hib vaccine (Infanrix-IPV/Hib). 
• 
Blinding: (Refer to Synopsis Table 3). 
Synopsis Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 (Primary epoch) 
open 
Epoch 002 (Booster epoch) 
open  
 
• 
Sampling schedule: Two blood samples ( approximately3.5 
ml each) will be taken from all subjects: one blood sample 
will be taken one month after the primary vaccination course 
(Visit 4) and the second blood sample will be taken one 
month after the booster vaccination (Visit 6). 
• 
Type of study: self-contained. 
• 
Data collection: electronic Case Report Form (eCRF). 
Number of 
subjects 
Approximately 235 subjects aged three to four months at the time 
of first primary vaccination visit will be enrolled in this study. 
Endpoints 
Primary 
• Immunogenicity with respect to components of the study 
vaccine. 
 
Anti-diphtheria, anti-tetanus, anti-poliovirus types 1, 2 
and 3, and anti-PRP seroprotection status, one month 
after the third dose of primary vaccination. 
 
Anti- PT, anti-FHA and anti-PRN antibody 
seropositivity status, one month after the third dose of 
primary vaccination. 

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Secondary 
• 
Immunogenicity with respect to components of the study 
vaccine. 
 
Anti-diphtheria, anti-tetanus, anti-poliovirus types 1, 2 
and 3, and anti-PRP seroprotection status, one month 
after the third dose of primary vaccination.  
 
Anti- PT, anti-FHA and anti-PRN antibody 
seropositivity status, one month after the third dose of 
primary vaccination. 
 
Anti-diphtheria, anti-tetanus, anti-poliovirus types 1, 2 
and 3, anti-PRP, anti-PT, anti-FHA, anti-PRN antibody 
concentrations or titres, one month after the third dose of 
primary vaccination and one month after the booster 
vaccination. 
• 
Solicited local and general symptoms. 
 
Occurrence of solicited local/general symptoms during 
the 4-day (Days 0-3) follow-up period after each primary 
vaccination dose and following the booster vaccination. 
• 
Unsolicited adverse events. 
 
Occurrence of unsolicited symptoms during the 31-day 
(Days 0-30) follow-up period after each primary 
vaccination dose and following the booster vaccination.  
• 
Serious adverse events. 
 
Occurrence of SAEs from Dose 1 up to study end. 

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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 7 
SYNOPSIS ...................................................................................................................... 8 
LIST OF ABBREVIATIONS ........................................................................................... 18 
GLOSSARY OF TERMS ............................................................................................... 21 
TRADEMARKS ............................................................................................................. 24 
1. 
INTRODUCTION .................................................................................................... 25 
1.1. 
Background ................................................................................................ 25 
1.2. 
Rationale for the study and study design .................................................... 25 
1.2.1. 
Rationale for the study ................................................................. 25 
1.2.2. 
Rationale for the study design ...................................................... 26 
1.3. 
Benefit : Risk Assessment .......................................................................... 26 
1.3.1. 
Risk Assessment ......................................................................... 26 
1.3.2. 
Benefit Assessment ..................................................................... 27 
1.3.3. 
Overall Benefit: Risk Conclusion .................................................. 28 
2. 
OBJECTIVES ......................................................................................................... 28 
2.1. 
Primary objective ........................................................................................ 28 
2.2. 
Secondary objectives .................................................................................. 28 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 29 
4. 
STUDY COHORT ................................................................................................... 30 
4.1. 
Number of subjects/centres ........................................................................ 30 
4.2. 
Inclusion criteria for enrolment .................................................................... 31 
4.3. 
Exclusion criteria for enrolment ................................................................... 31 
5. 
CONDUCT OF THE STUDY .................................................................................. 33 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process.......................................................................................... 33 
5.2. 
Subject identification and randomisation of treatment ................................. 34 
5.2.1. 
Subject identification .................................................................... 34 
5.2.2. 
Randomisation of treatment ......................................................... 34 
5.2.2.1. 
Randomisation of supplies .......................................... 34 
5.2.2.2. 
Treatment allocation to the subject ............................. 34 
5.2.2.2.1. 
Treatment number allocation .................. 34 
5.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 34 
5.3. 
Method of blinding ...................................................................................... 35 
5.4. 
General study aspects ................................................................................ 35 
5.5. 
Outline of study procedures ........................................................................ 35 
5.6. 
Detailed description of study procedures .................................................... 37 
5.6.1. 
Informed consent ......................................................................... 37 
5.6.2. 
Check inclusion and exclusion criteria ......................................... 37 

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5.6.3. 
Collect demographic data ............................................................ 37 
5.6.4. 
Medical and vaccination history ................................................... 37 
5.6.5. 
Physical examination ................................................................... 38 
5.6.6. 
Record gestational age ................................................................ 38 
5.6.7. 
Measure/record height and weight ............................................... 38 
5.6.8. 
Assess pre-vaccination body temperature ................................... 38 
5.6.9. 
Check contraindications, warnings and precautions to 
vaccination ................................................................................... 38 
5.6.10. 
Pre-vaccination measurement of limb circumference at the 
site of injection before booster vaccination at Visit 5 .................... 38 
5.6.11. 
Treatment number allocation ....................................................... 39 
5.6.12. 
Study Vaccine administration ....................................................... 39 
5.6.13. 
Sampling...................................................................................... 39 
5.6.13.1. Blood sampling for antibody determination ................. 39 
5.6.14. 
Check and record concomitant vaccination and 
intercurrent medical conditions .................................................... 39 
5.6.15. 
Recording of AEs and SAEs ........................................................ 40 
5.6.16. 
Study conclusion .......................................................................... 41 
5.7. 
Biological sample handling and analysis ..................................................... 41 
5.7.1. 
Use of specified study materials .................................................. 42 
5.7.2. 
Biological samples ....................................................................... 42 
5.7.3. 
Laboratory assays ....................................................................... 42 
5.7.4. 
Biological samples evaluation ...................................................... 43 
5.7.4.1. 
Immunological read-outs ............................................ 43 
5.7.5. 
Immunological correlates of protection ......................................... 44 
6. 
STUDY VACCINE AND ADMINISTRATION ........................................................... 45 
6.1. 
Description of study vaccine ....................................................................... 45 
6.2. 
Storage and handling of study vaccine ....................................................... 45 
6.3. 
Dosage and administration of study vaccine ............................................... 46 
6.4. 
Replacement of unusable vaccine doses .................................................... 47 
6.5. 
Contraindications to subsequent vaccination .............................................. 47 
6.6. 
Warnings and precautions .......................................................................... 48 
6.7. 
Concomitant medications/products and concomitant vaccinations .............. 48 
6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 48 
6.7.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses ........................ 49 
6.8. 
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses ......................................................................... 49 
7. 
HEALTH ECONOMICS .......................................................................................... 49 
8. 
SAFETY ................................................................................................................. 50 
8.1. 
Safety definitions ........................................................................................ 50 
8.1.1. 
Definition of an adverse event ...................................................... 50 
8.1.2. 
Definition of a serious adverse event ........................................... 51 
8.1.3. 
Solicited adverse events .............................................................. 52 
8.1.3.1. 
Solicited local (injection-site) adverse events .............. 52 
8.1.3.2. 
Solicited general adverse events ................................ 52 

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8.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 52 
8.2. 
Detecting and recording adverse events and serious adverse 
events ......................................................................................................... 53 
8.2.1. 
Time period for detecting and recording adverse events 
and serious adverse events ......................................................... 53 
8.2.2. 
Post-Study adverse events and serious adverse events .............. 55 
8.2.3. 
Evaluation of adverse events and serious adverse events ........... 55 
8.2.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 55 
8.2.3.2. 
Assessment of adverse events ................................... 56 
8.2.3.2.1. 
Assessment of intensity .......................... 56 
8.2.3.2.2. 
Assessment of causality ......................... 58 
8.2.3.3. 
Assessment of outcomes............................................ 59 
8.2.3.4. 
Medically attended visits ............................................. 59 
8.3. 
Reporting of serious adverse events ........................................................... 59 
8.3.1. 
Prompt reporting of serious adverse events and other 
events to GSK Biologicals ............................................................ 59 
8.3.2. 
Contact information for reporting serious adverse events 
and other events to GSK Biologicals ............................................ 60 
8.3.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................... 60 
8.3.3.1. 
Back-up system in case the electronic 
reporting system does not work .................................. 60 
8.3.4. 
Updating of SAE information after removal of write access 
to the subject’s eCRF................................................................... 60 
8.3.5. 
Regulatory reporting requirements for serious adverse 
events .......................................................................................... 61 
8.4. 
Follow-up of adverse events and serious adverse events ........................... 61 
8.4.1. 
Follow-up of adverse events and serious adverse events ............ 61 
8.4.1.1. 
Follow-up during the study .......................................... 61 
8.4.1.2. 
Follow-up after the subject is discharged from 
the study ..................................................................... 61 
8.5. 
Treatment of adverse events ...................................................................... 62 
8.6. 
Subject card ................................................................................................ 62 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 62 
9.1. 
Subject completion ..................................................................................... 62 
9.2. 
Subject withdrawal ...................................................................................... 62 
9.2.1. 
Subject withdrawal from the study ............................................... 62 
9.2.2. 
Subject withdrawal from investigational vaccine........................... 63 
10. STATISTICAL METHODS ...................................................................................... 64 
10.1. 
Primary endpoint ......................................................................................... 64 
10.2. 
Secondary endpoints .................................................................................. 64 
10.3. 
Determination of sample size ...................................................................... 65 
10.4. 
Cohorts for Analyses .................................................................................. 65 
10.4.1. 
Total vaccinated cohort for the primary epoch ............................. 66 
10.4.2. 
According-to-protocol cohort for analysis of 
immunogenicity of the primary epoch ........................................... 66 
10.4.3. 
Total vaccinated cohort for the booster epoch ............................. 66 

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10.4.4. 
According-to-protocol cohort for analysis of 
immunogenicity of the booster epoch ........................................... 66 
10.5. 
Derived and transformed data ..................................................................... 67 
10.6. 
Analysis of demographics ........................................................................... 68 
10.7. 
Analysis of immunogenicity ......................................................................... 68 
10.8. 
Analysis of safety ........................................................................................ 68 
10.9. 
Interpretation of analyses ............................................................................ 69 
10.10. Conduct of analyses ................................................................................... 70 
10.10.1. Sequence of analyses.................................................................. 70 
10.10.2. Statistical considerations for interim analyses .............................. 70 
11. ADMINISTRATIVE MATTERS ............................................................................... 70 
11.1. 
electronic Case Report Form instructions ................................................... 70 
11.2. 
Study Monitoring by GSK Biologicals .......................................................... 71 
11.3. 
Record retention ......................................................................................... 71 
11.4. 
Quality assurance ....................................................................................... 72 
11.5. 
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................ 72 
11.6. 
Provision of study results to investigators ................................................... 72 
12. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 73 
13. REFERENCES ....................................................................................................... 73 
 

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LIST OF TABLES 
PAGE 
Table 1 
Study group and epochs foreseen in the study ....................................... 30 
Table 2 
Study group and treatment foreseen in the study ................................... 30 
Table 3 
Blinding of study epochs ........................................................................ 30 
Table 4 
List of study procedures (Amended 11 October 2016)............................ 36 
Table 5 
Intervals between study visits ................................................................. 37 
Table 6 
Biological samples ................................................................................. 42 
Table 7 
Humoral Immunity (Antibody determination) ........................................... 43 
Table 8 
Immunological read-outs ........................................................................ 44 
Table 9 
Study vaccine ......................................................................................... 45 
Table 10 
Dosage and administration ..................................................................... 46 
Table 11 
Solicited local adverse events ................................................................ 52 
Table 12 
Solicited general adverse events ............................................................ 52 
Table 13 
Reporting periods for adverse events and serious adverse 
events .................................................................................................... 54 
Table 14 
Intensity scales for solicited symptoms in infants/toddlers ...................... 56 
Table 15 
Timeframes for submitting serious adverse event, reports to GSK 
Biologicals .............................................................................................. 59 
Table 16 
Exact 95 percentage CI for the different values of observed 
seroprotection / seropositivity rates for a sample size of 200 
evaluable subjects .................................................................................. 65 
Table 17 
GSK Biologicals laboratories .................................................................. 75 
Table 18 
Outsourced laboratories ......................................................................... 75 
 

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LIST OF APPENDICES 
PAGE 
APPENDIX A CLINICAL LABORATORIES .................................................................. 75 
APPENDIX B AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ........................................................................................... 76 
 

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LIST OF ABBREVIATIONS 
AE: 
Adverse Event 
ATP: 
According-To-Protocol 
BMI: 
Body Mass Index 
CDC: 
Centers for Disease Control and Prevention, USA 
CEPL: 
Clinical and Epidemiology Project Leader 
CI: 
Confidence Interval 
CLS: 
Clinical Laboratory Sciences 
cm: 
Centimetre 
CRDL: 
Clinical Research and Development Lead 
CSR: 
Clinical Study Report 
D: 
Diphtheria 
DTPa: 
Diphtheria-Tetanus-acellular Pertussis 
eCRF: 
electronic Case Report Form 
ELISA: 
Enzyme Linked Immunosorbant Assay 
eTDF: 
Electronic Temperature excursion Decision Form 
FHA: 
Filamentous Haemagglutinin 
GCP: 
Good Clinical Practice 
GMC: 
Geometric Mean Concentration 
GMT: 
Geometric Mean Titre 
GSK: 
GlaxoSmithKline 
Hib: 
Haemophilus influenzae type b 
IB: 
Investigator Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonisation 

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IEC: 
Independent Ethics Committee 
IM: 
Intramuscular 
IMP: 
Investigational Medicinal Product 
IPV: 
Inactivated Poliovirus vaccine 
IRB: 
Institutional Review Board 
IU: 
International Unit 
kg: 
Kilogram 
LSLV: 
Last Subject Last Visit 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mg: 
Milligram 
mIU: 
Milli-international units 
ml: 
Millilitre 
NEUTRA: 
Neutralising antibody assay 
PI: 
Prescribing Information 
PRN: 
Pertactin 
PT: 
Pertussis 
R: 
Right 
RCC: 
Reverse Cumulative distribution Curve 
RDE: 
Remote Data Entry 
SAE: 
Serious Adverse Event 
SBIR: 
Randomisation System on Internet 
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SPM: 
Study Procedures Manual 
T: 
Thigh 

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TVC: 
Total Vaccinated Cohort 
WHO: 
World Health Organization 
(Amended 11 October 2016) 

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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 parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian. 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
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 

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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 6.7.2 and 10.4 for details on criteria for 
evaluability). 
Immunological correlate 
of protection: 
The defined immune response above which there is a 
high likelihood of protection in the absence of any host 
factors that might increase susceptibility to the infectious 
agent. 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use.  
Primary completion 
date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated. 
Protocol amendment: 
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study. 
Protocol administrative 
change: 
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.  
Randomisation: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 

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more investigational sites. 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine or as a control. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation. 
Treatment number: 
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation. 
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. 
(Amended 11 October 2016) 

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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 ® and in italics. 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Generic description 
Infanrix® -IPV/Hib 
 
Combined diphtheria-tetanus-acellular 
pertussis-inactivated poliovirus and 
Haemophilus influenzae type b conjugate 
vaccine 
 

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1. 
INTRODUCTION 
1.1. 
Background 
Combination vaccines induce immunity against multiple diseases in a single injection. 
Therefore, they facilitate delivery of complex vaccinations in a simplified manner and 
promote better vaccine coverage, compliance and cost-effectiveness by decreasing the 
number of injections needed to immunise a child [Kalies, 2006; Zinke, 2010]. 
Combination vaccines, particularly the Diphtheria-Tetanus- Pertussis (DTP) based 
vaccines, have become a part of the routine paediatric practice as they are widely 
accepted as a means of conferring protection against several diseases simultaneously 
[Zepp, 2009]. 
Haemophilus influenzae type b (Hib) is a bacterium responsible for severe pneumonia, 
meningitis and other invasive diseases almost exclusively in children aged less than 5 
years. The World Health Organization (WHO) recommendation to immunise all infants 
with a Hib conjugate vaccine is now implemented in more than 100 countries [WHO, 
2009]. The importance of prevention of these bacterial infections through vaccination is 
gaining fast recognition among Health Authorities. 
Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the epidemiological information of Infanrix-IPV/Hib. 
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study 
GlaxoSmithKline (GSK) Biologicals’ Infanrix-IPV/Hib is licensed for primary 
vaccination in 74 countries in the world, including most European countries. Infanrix-
IPV/Hib has been extensively studied in clinical trials that established its immunogenicity 
and safety [Gilca, 2006; Lim, 2011; Phua, 2008]. To date, more than 70 million 
commercial doses have been distributed, and routine use of the vaccine has confirmed its 
good safety profile. 
In the Russian Federation, a three-dose primary vaccination of infants is currently 
recommended against hepatitis B with doses administered at birth, 1 month and 6 months 
of age and against diphtheria, tetanus, pertussis, poliomyelitis and Hib with doses 
administered at 3, 4.5 and 6 months of age. The Russian Federation also recommends a 
booster vaccination of infants against diphtheria, tetanus, pertussis, poliomyelitis and Hib 
at 18 months of age. GSK Biologicals’ DTPa-IPV/Hib vaccine (Infanrix-IPV/Hib) 
combines antigens to diphtheria, tetanus, pertussis, poliomyelitis and Hib diseases in one 
single injection. This complements the current local standard of care for the hepatitis B 
immunization in Russian infants. 
The present study is being performed to support the registration of Infanrix-IPV/Hib in 
the Russian Federation. 

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1.2.2. 
Rationale for the study design 
The aim of the present study is to evaluate the immune response, safety and 
reactogenicity induced by the combined DTPa-IPV/Hib vaccine when administered as a 
three-dose primary vaccination course at 3, 4.5 and 6 months of age and as a booster dose 
at 18 months of age according to the Russian immunisation schedule. 
The study will adopt a single group, open-label design as all the subjects will receive the 
same vaccine. 
1.3. 
Benefit : Risk Assessment 
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of Infanrix-IPV/Hib. 
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 (Infanrix-IPV/Hib) 
Important identified risk: 
Hypersensitivity 
People may develop allergic 
reactions to any type of vaccine 
and/or its components. 
Hypersensitivity reactions to vaccines 
highly vary in severity, ranging from 
mild to potentially life-threatening 
hypersensitivity reactions. Severe 
allergic reactions to vaccines are rare 
but tend to occur within hours after 
vaccination. 
The subjects will be observed closely 
for at least 30 minutes following the 
administration of the vaccine, with 
appropriate medical treatment readily 
available in case of anaphylaxis. 
History of any reaction or 
hypersensitivity likely to be 
exacerbated by any component of the 
vaccine is an exclusion criteria for 
enrolment to the study. 
Important identified risk: 
Apnoea in infants born 
prematurely 
Apnoea of prematurity is due to 
immaturity of the neurological and 
respiratory system in premature 
infants. The risk appears to be related 
to the degree of prematurity of the 
infant. 
Only subjects born full-term 
(gestation period of 37-42 weeks 
completed) will be enrolled. 
Important identified risk: 
Waning of acellular pertussis 
vaccine induced immunity 
Waning of pertussis immunity is 
considered a pharmacological class 
effect for acellular pertussis 
containing vaccine. Potential cases of 
break-through infections cannot be 
excluded after vaccination with 
Infanrix-IPV/Hib. 
GSK will continue close monitoring of 
waning of acellular pertussis vaccine 
induced immunity and post-marketing 
lack of efficacy cases through routine 
pharmacovigilance. 
Important identified risk: 
Temperature of ≥ 40.0 C 
In rare occasion, hyperpyrexia above 
40,0°C may occur after vaccination, 
particularly associated with booster 
vaccination. 
Acute disease and/or fever at the 
time of enrolment is an exclusion 
criteria; 
Temperature of  40.0°C (tympanic 
or axillary temperature) within 48 
hours of vaccination, not due to 
another identifiable cause is a 
contraindication to further 
administration of Infanrix-IPV/Hib 

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Important Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
Important identified risk: 
Hypotonic hyporesponsive 
episode 
HHE occurs more commonly in early 
childhood after primary vaccination 
and particularly after the first dose of 
vaccine. Most HHE events have been 
associated with whole cell pertussis-
containing vaccines (36-250 episodes 
per 100,000 doses). A much lower 
rate of HHE has been observed 
following vaccination with acellular 
pertussis vaccine (4-140 episodes 
per 100,000 doses) 
Collapse or shock-like state 
(hypotonic-hyporesponsive episode) 
within 48 hours of vaccination is a 
contraindication to further 
administration of Infanrix-IPV/Hib 
Important identified risk: 
Convulsions with or without fever 
Seizures occurring soon after 
immunization are mostly triggered by 
fever induced by the vaccine or are 
not vaccine related. Febrile 
convulsions usually occur in 
individuals aged between 3 months 
and 6 years with a peak incidence at 
18 months 
History of any neurological disorders 
or seizures is an exclusion criteria for 
enrolment to the study 
Important potential risk: 
Encephalopathy 
 
Encephalopathy defined as an acute, 
severe central nervous system 
disorder occurring within 7 days 
following vaccination 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 is a 
contraindication to further 
administration of Infanrix-IPV/Hib 
Study Procedures 
Syncope 
Spontaneous Syncope (fainting) can 
occur following, or even before, any 
vaccination as a psychogenic 
response to the needle injection. 
Syncope after vaccination itself is 
usually not a serious event, and 
patients generally recover within a 
few minutes, but can potentially 
produce serious harm from the 
trauma of falling or accidents. 
Procedures should be in place to 
avoid injuries from falls following 
syncope 
1.3.2. 
Benefit Assessment 
Diphtheria, tetanus, pertussis, poliomyelitis and diseases caused by Haemophilus 
influenzae type b are a common cause of disease in children worldwide, with significant 
morbidity and mortality. A dramatic decline in the incidence of diphtheria, tetanus, 
pertussis, poliomyelitis and diseases caused by Haemophilus influenzae type b has been 
evidenced in countries in which infants are routinely immunised against these diseases. 
Clinical trial and post-marketing data demonstrate the substantial benefit of Infanrix- 
IPV/Hib vaccination worldwide. 

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1.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential or identified risks identified in association with Infanrix-IPV/Hib are 
justified by the potential benefits (prevention) that may be afforded to subject(s) 
receiving Infanrix-IPV/Hib vaccine. 
2. 
OBJECTIVES 
2.1. 
Primary objective 
• 
To assess the immune response to the study vaccine in terms of seroprotection status 
for diphtheria, tetanus, Hib and poliovirus types 1, 2 and 3 antigens, and in terms of 
seropositivity to the pertussis antigens, one month after the third dose of primary 
vaccination. 
Refer to Section 10.1 for the definition of the primary endpoint. 
2.2. 
Secondary objectives 
• 
To assess the immune response to the study vaccine in terms of seroprotection to 
diphtheria, tetanus, Hib and poliovirus types 1, 2 and 3 antigens, and in terms of 
seropositivity to the pertussis antigens, one month after the booster vaccination. 
• 
To assess the immune response to the study vaccine in terms of antibody 
concentrations or titres against diphtheria, tetanus, Hib, poliovirus types 1, 2 and 3 
antigens, and pertussis antigens, one month after the third dose of primary 
vaccination and one month after the booster vaccination. 
• 
To assess the safety and reactogenicity of the study vaccine in terms of solicited 
symptoms, unsolicited symptoms and serious adverse events (SAEs). 
Refer to Section 10.2 for the definition of the secondary endpoints. 

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3. 
STUDY DESIGN OVERVIEW 
 
V = Primary vaccination 
BS = Blood Sample 
Post-Pri = One month after the third dose of primary vaccination course 
Post-Booster = One month after booster vaccination 
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 III, open-label, multi-centric, single-country study with a 
single group. 
• 
Duration of the study: The intended duration of the study is approximately 16 
months, per subject. 
 
Epoch 001 (Primary epoch): Primary phase starting at Visit 1 (Day 0) and 
ending at Visit 4 (Month 4). 
 
Epoch 002 (Booster epoch): Booster phase starting at Visit 5 (Month 15) and 
ending at Visit 6 (Month 16). 

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Study group: The study group and epochs foreseen in the study are presented in Table 1. 
Table 1 
Study group and epochs foreseen in the study 
Study group 
Number of subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
(Primary epoch) 
Epoch 002 (Booster 
epoch) 
DTPa-IPV/Hib 
Group 
 235 
3 months - 4 months 
x  
 
DTPa-IPV/Hib 
Group 
 235 
18 months – 19 
months 
 
x 
The study group and treatment foreseen in the study are presented in Table 2. 
Table 2 
Study group and treatment foreseen in the study 
Treatment name 
Vaccine/Product name 
Study Group 
DTPa-IPV/Hib Group 
Infanrix-IPV/Hib 
DTPa-IPV  
x  
Hib  
x  
• 
Control: uncontrolled. 
• 
Treatment group and vaccination schedule: All subjects will receive three doses of 
primary vaccination at 3, 4.5 and 6 months of age and a single dose of booster 
vaccination at 18 months of age. 
 
DTPa-IPV/Hib Group: Subjects who will receive DTPa-IPV/Hib vaccine 
(Infanrix-IPV/Hib). 
• 
Blinding: This is an open-label study (Refer Table 3). 
Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 (Primary epoch) 
open 
Epoch 002 (Booster epoch) 
open  
• 
Sampling schedule: Two blood samples (approximately 3.5 ml each) will be taken 
from all subjects: one blood sample will be taken one month after the primary 
vaccination course (Visit 4) and the second blood sample will be taken one month 
after the booster vaccination (Visit 6). 
• 
Type of study: This is a self-contained study. 
• 
Data collection: electronic Case Report Form (eCRF). 
4. 
STUDY COHORT 
4.1. 
Number of subjects/centres 
Approximately 235 subjects aged three to four months at the time of first dose of primary 
vaccination will be enrolled in this study. Refer to Section 10.3 for a detailed description 
of the criteria used in the estimation of sample size. 

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Overview of the recruitment plan: 
• 
This study will be conducted at multiple centers in Russia. 
• 
Enrolment will be terminated when at least 235 subjects have been enrolled. 
• 
Recruitment of subjects into the study will be tracked using GSK Biologicals’ central 
randomisation system on Internet (SBIR). 
• 
Recruitment will be monitored by the Study Monitor. 
4.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects’ parent(s)/adoptive parent(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 child between 3 and 4 months (between, and including, 90 and 120 
days) of age at the time of the first vaccination. 
• 
Written informed consent obtained from the parent(s)/adoptive parent(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. after a gestation period of at least 37 completed weeks). 
(Amended 11 October 2016) 
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 vaccine during the period starting 30 days before the first dose of study 
vaccine (Day-29 to Day 0), or planned use during the study period. 

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• 
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe. 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 
since birth. For corticosteroids, this will mean prednisone 0.5 mg/kg/day (for 
paediatric subjects), or equivalent. Inhaled and topical steroids are allowed. 
• 
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab). 
• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose and ending 30 days after 
the last dose of vaccine administration, with the exception of hepatitis B and other 
vaccines given as part of the national immunisation schedule and as part of routine 
vaccination practice, that are allowed at any time during the study period. Seasonal 
or pandemic influenza vaccine can be given at any time during the study, and 
according to the Summary of Product Characteristics and national recommendations.  
• 
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). 
• 
Previous vaccination against diphtheria, tetanus, pertussis, poliomyelitis and Hib 
diseases. 
• 
History of diphtheria, tetanus, pertussis, poliomyelitis and Hib diseases. 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
• 
Family history of congenital or hereditary immunodeficiency. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine. 
• 
Major congenital defects. 
• 
Serious chronic illness. 
• 
History of any neurological disorders or seizures. 
• 
Acute disease and/or fever at the time of enrolment. 
 
Fever is defined as temperature 37.5°C for oral, axillary or tympanic route, or 
38.0°C for rectal route. 
 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may, be enrolled at the discretion of the investigator. 
• 
Administration of immunoglobulins and/or any blood products since birth or planned 
administration during the study period. 

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5. 
CONDUCT OF THE STUDY 
5.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with the 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)/adoptive parent(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 informed consent must be obtained from each subject’s 
parent(s)/adoptive parent(s), as appropriate, prior to participation in the study. 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF. 
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. 
(Amended 11 October 2016) 

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5.2. 
Subject identification and randomisation of treatment 
5.2.1. 
Subject identification 
Subject identification numbers will be assigned sequentially to subjects on whose behalf 
consent has been provided to participate in the study, according to the range of subject 
identification numbers allocated to each study centre. 
5.2.2. 
Randomisation of treatment 
This is a single group non- randomised study. All eligible subjects will receive the 
primary and booster doses of DTPa-IPV/Hib vaccine in the primary and booster epochs 
respectively. The central randomisation system (SBIR) will be used to allocate treatment 
numbers to the subjects and also to track enrolment in the study. 
5.2.2.1. 
Randomisation of supplies 
Randomisation of supplies will not be performed. A sequential list of treatment numbers 
will be generated and the supplies will be sent to the centres /warehouses. 
5.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by dose. 
5.2.2.2.1. Treatment number allocation 
Allocation of a treatment number to a subject at the investigator site will be performed 
using a randomisation system on internet (SBIR). 
After obtaining the signed and dated ICF from the subject’s parent(s)/adoptive parent(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 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. 
(Amended 11 October 2016) 
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 for the subsequent doses. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 

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5.3. 
Method of blinding 
The study will be conducted in an open-label manner since this is a single-group study. 
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample. 
5.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
5.5. 
Outline of study procedures 
The list of study procedures is presented in Table 4. 

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Table 4 
List of study procedures (Amended 11 October 2016) 
Age of subjects 
3 
months 
4.5 
months 
6 
months 
7 
months 
18 
months 
19 
months 
Epochs 
Epoch 001 
(Primary epoch) 
Epoch 002 
(Booster epoch) 
Type of contact 
Visit 1 
Visit 2 Visit 3 Visit 4 
Visit 5 
Visit 6 
Time-points 
Day 0 
Month 
1.5 
Month 
3 
Month 
4 
Month 
15  
Month 
16  
Sampling time-points 
 
 
 
Post-
Pri 
 
Post-
Boost  
Informed consent 
●  
 
 
 
 
 
Check inclusion/exclusion criteria 
●  
 
 
 
 
 
Collect demographic data 
●  
 
 
 
 
 
Medical history, including vaccination history 
●  
 
 
 
 
 
Physical examination 
●  
 
 
 
 
 
Record gestational age 
●  
 
 
 
 
 
Measure/record height and weight  
●  
 
 
 
 
 
Pre-vaccination body temperature  
●  
●  
●  
 
●  
 
Check warnings and precautions  
○ 
○ 
○ 
 
○ 
 
Check contraindications to subsequent vaccination  
 
○ 
○ 
○ 
○ 
 
Pre-vaccination measurement of limb circumference at site 
of injection by investigator  
 
 
 
 
● 
 
Vaccine 
 
 
 
 
 
 
Treatment number allocation 
○ 
 
 
 
 
 
Treatment number allocation with subsequent doses 
 
○ 
○  
 
○ 
 
Recording of administered treatment number 
● 
● 
● 
 
● 
 
Vaccine administration 
● 
● 
● 
 
● 
 
Post- vaccination observation for at least 30 minutes 
○  
○  
○  
 
○  
 
Laboratory Assays 
 
 
 
 
 
 
Blood sampling for antibody determination (approximately 
3.5 ml)  
 
 
 
● 
 
● 
Safety Assessments 
 
 
 
 
 
 
Record any concomitant medication/vaccination 
● 
●  
●  
●  
● 
● 
Record any intercurrent medical conditions 
 
● 
● 
● 
● 
● 
Distribution of diary cards 
● 
● 
● 
 
● 
 
Recording of solicited adverse events (AEs) (Days 0-3) by 
subjects’ parent(s)/adoptive parent(s) in the diary cards 
● 
● 
● 
 
●  
 
Recording of non-serious adverse events (AEs) (Days 0-30) 
by subjects’ parent(s)/adoptive parent(s) in the diary cards 
● 
● 
●  
 
●  
 
Recording of Large injection site reaction 
 
 
 
 
● 
 
Return of diary cards 
 
○ 
○ 
○ 
 
○ 
Diary card transcription by investigator 
 
● 
●  
● 
 
● 
Recording of serious adverse events (SAEs) 
● 
● 
● 
● 
● 
● 
Recording of SAEs related to study participation or to a 
concurrent GSK vaccine 
● 
● 
● 
● 
● 
● 
Recording of withdrawal due to AEs 
●  
● 
● 
 ● 
● 
● 
Study Conclusion 
 
 
 
 
 
● 
Note: The double-line border following Month 4 and Month 16 indicate the analyses which will be performed separately 
on all data (i.e. data that are as clean as possible) obtained up to Month 4 (primary epoch) and Month 16 (booster 
epoch), respectively.  
V = vaccination; Post-Pri = One month after the third dose of primary vaccination course; Post-Boost = One month 
after booster vaccination; ml = millilitres 
● 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. 
# Refer to Section 8.1.3.1 and 5.6.10 for detailed explanation on the reporting of large injection site reactions  

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The intervals between study visits are presented in Table 5. These intervals determine 
each subject’s evaluability in the according-to-protocol analyses. 
Table 5 
Intervals between study visits 
Interval 
Optimal length of interval1 
Allowed interval2 
Birth  Visit 1 
90 days 
90-120 days 
Visit 1 Visit 2 
45 days 
28-62 days 
Visit 2 Visit 3 
45 days 
28-62 days 
Visit 3 Visit 4 
30 days 
21-48 days 
Birth Visit 5 
 540 days 
540-570 days 
Visit 5  Visit 6 
30 days 
21-48 days 
1 Whenever possible the investigator should arrange study visits within this interval. 
2 Subjects will not be eligible for inclusion in the analyses of the according-to-protocol (ATP) cohort of immunogenicity 
for the respective epochs if they make the study visit outside this interval. An interval of 21-48 days between Visit 3 and 
Visit 4, and between Visit 5 and Visit 6 will be considered for the ATP cohort of immunogenicity for the analysis of 
respective epochs. Refer Section 10.4 for the definition of the cohorts for analysis. 
 If a subject returns for the Visit 4 or the Visit 6 blood draw prior to completion of the 31-day safety follow-up period, the 
subject should continue to record this information in the diary card until 31 days post-vaccination and mail the diary 
card to the site. The investigator will make an attempt to obtain this information as soon as possible after the 31-day 
follow-up period if it is not mailed in. 
5.6. 
Detailed description of study procedures 
5.6.1. 
Informed consent 
The signed informed consent of the subject’s parent(s)/adoptive parent(s) must be 
obtained before study participation. 
(Amended 11 October 2016) 
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 geographic ancestry in the subject’s 
eCRF. 
5.6.4. 
Medical and vaccination history 
Obtain the subject’s vaccination/medical history by interview and/or review of the 
subject’s medical records and record any previous vaccines administered or pre-existing 
conditions or signs and/or symptoms present in a subject prior to the first study 
vaccination in the eCRF. 

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5.6.5. 
Physical examination 
Perform physical examination of the subject, including assessment of body temperature. 
Collected information needs to be recorded in the eCRF. 
Physical examination at each study visit subsequent to the vaccination visit, will be 
performed only if the subject’s parent/adoptive parent indicates during questioning that 
there might be some underlying pathology(ies) or if deemed necessary by the Investigator 
or delegate. 
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
(Amended 11 October 2016) 
5.6.6. 
Record gestational age 
Record the gestational age of the subject in the eCRF. 
5.6.7. 
Measure/record height and weight 
Measure the height and weight of the subject and record in the eCRF. 
5.6.8. 
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. 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 5). 
5.6.9. 
Check contraindications, warnings and precautions to 
vaccination 
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of each vaccination visit. Refer to Sections 6.5 and 6.6 for more details. 
5.6.10. 
Pre-vaccination measurement of limb circumference at the site of 
injection before booster vaccination at Visit 5 
During Epoch 002 (Visit 5), baseline measurement of limb circumference at the level of 
the injection site should be obtained to measure the intensity of swelling. Clothing should 
be removed so as not to interfere with the measurement of the limb circumference. For 
measuring leg circumference the child should be standing or lying flat, as appropriate, as 
long as the leg is straight. 

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5.6.11. 
Treatment number allocation 
Treatment number allocation will be performed as described in Section 5.2.2.2.1. The 
number of each administered treatment must be recorded in the eCRF. 
5.6.12. 
Study Vaccine administration 
• 
The study vaccine will be administered at Visits 1, 2, 3 and 5 as specified in Section 
5.5 List of Study Procedures.  
• 
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly at a 90-degree angle into the upper side 
of the thigh [CDC, 2002] on the side stated in Table 10. The vaccine should not be 
administered in the buttock. (Refer to Section 6.3 for detailed description of the 
vaccine administration procedure). If the investigator or delegate determines that the 
subject’s health on the day of administration temporarily precludes vaccine 
administration, the visit will be rescheduled within the allowed interval for this visit 
(Refer to Table 5). 
The subjects will be observed closely for at least 30 minutes following the administration 
of the vaccine, with appropriate medical treatment readily available in case of 
anaphylaxis. 
5.6.13. 
Sampling 
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples. 
5.6.13.1. 
Blood sampling for antibody determination 
Blood samples will be taken at Visits 4 and 6 as specified in Section 5.5 List of Study 
Procedures. 
A volume of approximately 3.5 ml of whole blood (to provide approximately 1.2 ml of 
serum) should be drawn from all subjects for the analysis of humoral immune response at 
each pre-defined time point. 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. 
5.6.14. 
Check and record concomitant vaccination and intercurrent 
medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7. 
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8. 

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5.6.15. 
Recording of AEs and SAEs 
• 
Refer to Section 8.2 for procedures for the investigator to record AEs and SAEs, 
Refer to Section 8.3 for guidelines and how to report SAE reports to GSK 
Biologicals. 
• 
The subjects’ parent(s)/adoptive parent(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)/adoptive parent(s). The subject’s parent(s)/adoptive parent(s) will record 
body temperature (preferably axillary) and any solicited local/general AEs (i.e. on 
the day of vaccination and during the next 3 days) or any unsolicited AEs (i.e. on the 
day of vaccination and during the next 30 days) occurring after vaccination. The 
subject’s parent(s)/adoptive parent(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)/adoptive parent(s) at Visits 2, 3, 4 and 6. 
• 
In preparation for Epoch 002, the sites should be provided with a measurement 
device for recording circumference of injected limb at the level of the injection site 
on the day of vaccination (baseline measurement - prior to vaccination) and in case 
of a large swelling reaction during the next three days. The site staff should be 
instructed on how and where to perform the measurement of the circumference of the 
vaccinated limb. 
• 
If the parent(s) /adoptive parent(s) of subjects observe any large injection site 
reaction (defined as swelling with a diameter > 50 mm, noticeable diffuse swelling 
or noticeable increase of limb circumference) during the 4-day follow-up (Day 0-
Day 3) period, they are to contact study personnel and to visit the investigator's 
office for evaluation as soon as possible. 
• 
In addition to the diameter of the swelling and the circumference of the limb, the 
investigator will record the following additional symptoms/characteristics that may 
be associated with large injection site swelling reactions: 
 
Type of swelling (local swelling only around the injection site, diffuse swelling 
not involving the knee joint, swelling involving the knee joint) 
 
Induration at injection site (largest diameter) 
 
Functional impairment (intensity – scale and description provided) 
The intensity scale is provided in section 8.2.3.2.1. 
• 
The largest or most intense score for a given day will be recorded in the eCRF at the 
level of the solicited symptoms and at the level of the large swelling report form. 
• 
Any unreturned diary cards will be sought from the subject’s parent(s)/adoptive 
parent(s) through telephone call(s) or any other convenient procedure. The 
investigator will transcribe the collected information into the eCRF in English. 

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(Amended 11 October 2016) 
5.6.16. 
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 
• 
Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably. 
• 
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects parent’s/adoptive parent’s in countries where this is allowed, will be 
asked to give a specific consent to allow GSK or a contracted partner to use the 
samples for future research. Future research will be subject to the laws and 
regulations in the respective countries and will only be performed once an 
independent Ethics Committee or Review Board has approved this research. 
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/adoptive parent(s). 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed. 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
(Amended 11 October 2016) 

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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 in this study are presented in Table 6. 
Table 6 
Biological samples 
Sample type 
Quantity 
Unit 
Time point 
Sampling timepoint 
Blood  
Approximately 3.5 
ml 
 Visit 4 
(Post-Pri) 
Blood  
Approximately 3.5 
ml 
 Visit 6  
(Post Boost) 
Post-Pri = One month after the third dose of primary vaccination course; Post-Boost = One month after booster 
vaccination; ml = millilitres 
5.7.3. 
Laboratory assays 
Please refer to APPENDIX A for the address of the clinical laboratories used for sample 
analysis. 
The details of the humoral immunity (antibody determination) is listed in Table 7. 

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Table 7 
Humoral Immunity (Antibody determination) 
System 
Component 
Method 
Kit/ 
Manufacturer 
Unit 
Cut-
off** 
Laboratory* 
Serum 
Corynebacterium 
diphtheriae.Diphtheria 
Toxoid Ab.IgG  
ELISA 
In-house 
IU/ml 
0.1 
GSK Biologicals 
Serum 
Clostridium 
tetani.Tetanus Toxoid 
Ab.IgG  
ELISA 
In-house 
IU/ml 
0.1 
GSK Biologicals 
Serum 
Bordetella 
pertussis.Pertussis 
Toxin Ab.IgG  
ELISA 
In-house 
ELU/ml*** 
5 
GSK Biologicals 
Serum 
Bordetella 
pertussis.Filamentous 
Hemaglutinin Ab.IgG  
ELISA 
In-house 
ELU/ml*** 
5 
GSK Biologicals 
Serum 
Bordetella 
pertussis.Pertactin 
Ab.IgG  
ELISA 
In-house 
ELU/ml*** 
5 
GSK Biologicals 
Serum 
Poliovirus Sabin Type 
1 Ab 
NEUTRA 
In-house 
ED50 
8 
GSK Biologicals 
Serum 
Poliovirus Sabin Type 
2 Ab  
NEUTRA 
In-house 
ED50 
8 
GSK Biologicals 
Serum 
Poliovirus Sabin Type 
3 Ab  
NEUTRA 
In-house 
ED50 
8 
GSK Biologicals 
Serum 
Haemophilus 
influenzae type 
b.Polyribosyl Ribitol 
Phosphate Ab  
ELISA 
In-house 
µg/ml 
0.15 
GSK Biologicals 
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart or Wavre, Belgium. 
ELISA = Enzyme Linked Immuno Sorbent Assay; NEUTRA = Neutralizing antibody assay 
ELU/ml = ELISA Unit/millilitre 
IU/ml = International Unit/millilitre 
g/ml = microgram/millilitre 
**The assay cut-off for D, T and PRP may be subject to change 
***The unit for the assay cut-offs may be subject to change 
The laboratory that will perform ELISA and Neutralisation is not yet identified and will 
be defined before study start. 
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department. 
5.7.4. 
Biological samples evaluation 
5.7.4.1. 
Immunological read-outs 
The immunological read-outs are represented in Table 8. 

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Table 8 
Immunological read-outs 
Blood sampling time-point 
No. of subjects 
Component 
Components 
priority rank 
Type of contact and 
time-point 
Sampling time-point 
Visit 4 (Month 4) 
Post-Pri 
All 
PT, FHA, PRN 
PRP 
D, T 
Poliovirus types 1, 2, 3 
1 
2 
3 
4 
Visit 6 (Month 16) 
Post-Boost 
All 
PT, FHA, PRN 
 
 PRP 
D, T 
Poliovirus types 1, 2, 3 
1 
2 
3 
4 
Post-Pri = One month after the third dose of primary vaccination course 
Post-Boost: One month after booster vaccination 
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 8. 
5.7.5. 
Immunological correlates of protection 
For the following antigens in the DTPa-IPV/Hib vaccine, an immunological correlate of 
protection has been established: 
• 
Specific antibodies against diphtheria toxoid (anti-diphtheria) and tetanus toxoid 
(anti-tetanus) will be measured by ELISA. The assay cut-off of ELISA is set at 0.1 
International Units per ml (IU/ml), which provides a conservative estimate of the 
percentage of subjects deemed to be protected [Melville-Smith, 1983; Camargo, 
1984]. 
• 
Data from subjects given unconjugated Hib vaccine suggest that, in the absence of 
induction of immunological memory, a concentration of 0.15 g/ml is indicative of 
short-term protection, with 1 g/ml considered indicative of long-term protection 
[Käyhty, 1983; Anderson, 1984]. 
• 
Antibodies against poliovirus types 1, 2 and 3 will be determined by a virus micro-
neutralisation test adapted from the W H O Guidelines for WHO/EPI Collaborative 
Studies on Poliomyelitis [WHO, 1993]. Titres will be expressed in terms of the 
reciprocal of the dilution resulting in 50% inhibition. Samples with a titre greater 
than or equal to 1:8 will be considered as sero-positive and protective.  
• 
No serological correlate of protection against pertussis has been established 
[Granström, 1987; Karpinsky, 1987]. Antibodies against the pertussis components 
pertussis toxoid (PT), filamentous haemagglutinin (FHA) and pertactin (PRN) will 
be measured by ELISA. The seropositivity cut-off for all three pertussis antibodies in 
ELISA is 5 EL.U/ml. Subjects with antibody concentration below the cut-off will be 
considered seronegative. 
Assessment of the protection level will be done at least 4 weeks after completing the 
primary vaccination course and at least 4 weeks after the administration of the booster 
dose. 

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The immunological assay results will be communicated to the investigator as soon as 
they become available. 
The investigator is encouraged to share the immunological assay results for non-
responders with the study subject’s parent(s)/adoptive parent(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. 
(Amended 11 October 2016) 
6. 
STUDY VACCINE AND ADMINISTRATION 
6.1. 
Description of study vaccine 
The candidate vaccine to be used has been developed and manufactured by GSK 
Biologicals. 
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained. 
The vaccine is labelled and packed according to applicable regulatory requirements. 
Commercial vaccine are assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics. 
The details of the study vaccine is presented in Table 9. 
Table 9 
Study vaccine 
Treatment 
name 
Vaccine name 
Formulation 
Presentation 
Volume to be 
administered 
Number 
of doses 
Infanrix-
IPV/Hib  
DTPa-IPV  
DT>=30IU; TT>=40IU; 
PT=25µg; FHA=25µg; 
PRN=8µg; Inactivated 
Poliovirus type 1=40DU; 
Inactivated Poliovirus 
type 2=8DU; Inactivated 
Poliovirus type 3=32DU; 
Al(OH)₃=500µg Al3+ 
The DTPa-IPV 
component is presented 
as a turbid white 
suspension in a pre-
filled syringe.  
0.5 ml 
4 
Hib  
PRP=10µg; TT~=25µg  
The lyophilised Hib 
component is presented 
as a white pellet in a 
glass vial; it must be 
reconstituted before use 
with the liquid DTPa-
IPV component.  
6.2. 
Storage and handling of study vaccine 
The study vaccine must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorized study 

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personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine. 
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 
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 vaccine. 
6.3. 
Dosage and administration of study vaccine 
The vaccine must be administered intramuscularly, at a 90-degree angle into the upper 
side of the thigh [CDC, 2002] on the right side. The vaccine should not be administered 
in the buttock. 
In order to ensure proper intramuscular injection of the vaccine, a needle of at least 1 inch 
(2.54 cm) length, 25 gauge will be used [Diggle, 2006; Zuckerman, 2000]. 
If the other allowed vaccine (i.e. hepatitis B) is administered at the same visit, the 
hepatitis B vaccine will be administered at a different injection site.  
The dosage and administration of the study vaccine is presented in Table 10. 
Table 10 
Dosage and administration 
Type of contact and 
time-point 
volume to be 
administered 
Study Group 
Treatment 
name 
Route 1 
Site 2 
Side 3 
Visit 1 (Day 0) 
Visit 2 (Month 1.5) 
Visit 3 (Month 3) 
Visit 5 (Month 15) 
0.5 ml 
DTPa-IPV/Hib 
Group  
Infanrix-IPV/Hib  
IM 
T* 
R/L 
1 Intramuscular (IM) 
2 Thigh (T) 
3 Right (R)/Left (L) 
* upper side of thigh. 
 Note: Vaccination can be performed in the opposite side in case of medical indication preventing vaccination in the 
side stated in the table, as judged by the investigator. 

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6.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
extra doses to allow flexibility in enrolment at the different sites), at least 5% additional 
vaccine doses will be supplied to replace those that are unusable. 
6.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of 
Infanrix-IPV/Hib. 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 (see Section 8.4). 
• 
Anaphylaxis following the administration of vaccine. 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV infection. 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
• 
Encephalopathy defined as an acute, severe central nervous system disorder 
occurring within 7 days following vaccination 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. 
• 
Temperature of  40.0°C (tympanic or axillary temperature) within 48 hours of 
vaccination, not due to another identifiable cause. 
• 
Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours of 
vaccination. 
• 
Persistent, inconsolable crying occurring within 48 hours of vaccination and lasting 
3 hours. 
• 
Seizures with or without fever occurring within 3 days of vaccination. 
Note: A history of febrile convulsions, a family history of convulsions, a family history 
of Sudden Infant Death Syndrome or a family history of an AE following DTP 
vaccination do not constitute contraindications. 
The following events constitute contraindications to administration of Infanrix-IPV/Hib 
at that point in time; if any of these events occur at the time scheduled for vaccination, 
the subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 5.5), or the subject may be withdrawn at the discretion of the 
investigator (see Section 9.2). 
• 
Acute disease and/or fever at the time of vaccination. 
 
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. 

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Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) 
without fever can be administered the vaccine. 
6.6. 
Warnings and precautions 
As with all injectable vaccines, appropriate medical treatment should always be readily 
available in case of anaphylactic reactions following the administration of the vaccine. 
For this reason, the vaccinee should remain under medical supervision for 30 minutes 
after vaccination. 
DTP vaccination should be administered with caution to subjects with thrombocytopenia 
or a bleeding disorder since bleeding may occur following an intramuscular (IM) 
administration to these subjects. 
DTP vaccination should under no circumstances be administered intravenously. 
6.7. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit, the investigator should question the subject’s parent(s)/adoptive 
parent(s) about any medications/products taken and vaccinations received by the subject. 
(Amended 11 October 2016) 
6.7.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF. 
• 
All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting from the administration of the study vaccine 
(Day 0) up to Day 30 post booster vaccination. 
• 
Any concomitant vaccination administered during the period starting from the 
administration of the study vaccine and ending at the last study visit/contact (Day 0) 
up to Day 30 post booster vaccination. 
• 
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 6.7.2. 
• 
Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 

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a SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report. 
6.7.2. 
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. See Section 10.4 for cohorts to be analysed. 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period. 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) during the study period. For corticosteroids, this will mean 
prednisone 0.5 mg/kg/day, or equivalent. Inhaled and topical steroids are allowed. 
• 
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab). 
• 
A vaccine not foreseen by the study protocol administered during the period starting 
from 30 days before each dose of vaccine and ending 30 days after*, with the 
exception of hepatitis B vaccine and other vaccines given as part of the national 
immunisation schedule, that are allowed at any time during the study period. 
Seasonal or pandemic influenza vaccine can be given at any time during the study, 
and according to the Summary of Product Characteristics and national 
recommendations. 
*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 SmPC or Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the Sponsor is obtained. 
• 
Immunoglobulins and/or any blood products administered during the study period. 
6.8. 
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 condition(s) 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 (i.e. 
pertussis infection) or are confirmed to have an alteration of their initial immune status. 
7. 
HEALTH ECONOMICS 
Not applicable. 

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8. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol.  
Each subject’s parent(s)/adoptive parent(s) will be instructed to contact the investigator 
immediately should the subject manifest any signs or symptoms they perceive as serious. 
(Amended 11 October 2016) 
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 vaccine administration. 
• 
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 are an AE/SAE. 

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

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8.1.3. 
Solicited adverse events 
A 4-day follow-up (Day 0-3) of solicited local (at each injection site) and general AEs 
will be performed after each study vaccine administration. Data concerning the following 
AEs will be solicited using diary cards provided by the Sponsor. 
8.1.3.1. 
Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited (Table 11): 
Table 11 
Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
N.B. If parent(s)/adoptive parent(s) of infants observe any large injection site reaction 
(defined as swelling with a diameter > 50 mm, noticeable diffuse swelling or noticeable 
increase of limb circumference) after the booster dose at Visit 5, they will be asked to 
contact study personnel and to visit the investigator's office for evaluation as soon as 
possible. The investigator will record detailed information describing the AE on a 
specific large injection site reaction screen in the eCRF. In addition to the diameter of the 
swelling and the circumference of the limb, the investigator will need to record additional 
symptoms/characteristics as mentioned in Section 5.6.15. 
(Amended 11 October 2016) 
8.1.3.2. 
Solicited general adverse events 
The following general AEs will be solicited: (Table 12): 
Table 12 
Solicited general adverse events 
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. X-ray, 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 

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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. 
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. 
Detecting and recording adverse events and serious 
adverse events 
8.2.1. 
Time period for detecting and recording adverse events and 
serious adverse events 
All AEs starting following administration of each dose of study vaccine (Day 0 to Day 
30) must be recorded into the appropriate section of the eCRF, irrespective of intensity or 
whether or not they are considered vaccination-related. 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine and will end 30 days following administration of the last dose of study vaccine 
for each subject. See Section 8.3 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 vaccine. 
SAEs that are related to the investigational vaccine will be collected and recorded from 
the time of the first receipt of study vaccine 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’s parent/adoptive parent consents to participate in the study until she/he 
is discharged from the study. 
An overview of the protocol-required reporting periods for AEs and SAEs is given in 
Table 13. 
(Amended 11 October 2016) 
 

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Table 13 
Reporting periods for adverse events and serious adverse events 
Event 
Pre- 
V1* 
 
V1 
3 d 
post 
V1 
30 d  
post-
V1 
 
V2 
3 d 
post 
V2 
30 d  
post-
V2 
 
V3 
3 d 
post 
V3 
30 d post- 
V3 
V4 
 
B 
3 d post B 30 d 
 post-B
 
(Study Conclusion) 
Time-point 
D0 
 
 
M1.5 
 
 
M3 
 
 
M4 
M15 
 
 
M16 
Age of subject 
3m 
3m 
 
 
4.5m 
 
 
6m 
 
 
7m 
18m 
 
 
19m 
Study Visit 
Visit 1 
Visit 1 
 
 
Visit 2 
 
 
Visit 3
 
 
Visit 4 
Visit 5 
 
 
Visit 6 
Solicited local 
and general 
AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Large injection 
site reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs 
leading to 
withdrawal from 
the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
the 
investigational 
vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* i.e. consent obtained. Pre-V: pre-vaccination; V: vaccination; Post-V: post-vaccination; B: Booster vaccination; d: days; D: Day; m: months; M: Month 
Large injection site reactions are defined as swelling with a diameter > 50 mm, noticeable diffuse swelling or noticeable increase of limb circumference after the booster vaccination.  

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8.2.2. 
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 Section 8.2. Investigators are not obligated to actively seek 
AEs or SAEs in former study participants. However, if the investigator learns of any SAE 
at any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccine, the investigator will promptly 
notify the Study Contact for Reporting SAEs. 
8.2.3. 
Evaluation of adverse events and serious adverse events 
8.2.3.1. 
Active questioning to detect adverse events and serious adverse 
events 
As a consistent method of collecting AEs, the subject’s parent(s)/adoptive parent(s) 
should be asked a non-leading question such as: 
‘Has your child acted differently or felt different in any way since receiving the vaccine 
or since the last visit?’ 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals. 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 
(Amended 11 October 2016) 

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8.2.3.2. 
Assessment of adverse events 
8.2.3.2.1. Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
Table 14 
Intensity scales for solicited symptoms in infants/toddlers 
Infant (below 12 months of age ) /Toddler (15–24 months) 
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 
Increase in limb circumference post-dose 4 
(according to where vaccine was administered) 
Record the limb circumference at the level of the injection site 
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 
*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. 
Mm = millimetre 
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 

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The maximum intensity of fever will be scored at GSK Biologicals as follows: 
Axillary 
0 
: 
< 37.5C 
1 
: 
37.5C and  38.0C 
2 
: 
> 38.0C and  39.0C 
3 
: 
> 39.0C 
Prior to analysis, the increase in limb circumference as compared to the baseline pre-
vaccination measurement will be scored for each subject at GSK Biologicals' as follows: 
Grade 0 = Increase in limb circumference 5 mm 
1 = Increase in limb circumference >5 mm but 20 mm 
2 = Increase in limb circumference >20 mm but 40 mm 
3 = Increase in limb circumference >40 mm 
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. 
For unsolicited symptoms and adverse events associated with large injection site 
reactions (e.g. induration and functional impairment), the intensity should be assigned to 
one of the following categories: 
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)/adoptive parent(s) 
to seek medical advice.  
(Amended 11 October 2016) 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 8.1.2. 

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8.2.3.2.2. Assessment of causality 
The investigator is obligated to assess the relationship between investigational vaccine 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational vaccine will be considered and 
investigated. The investigator will also consult the IB to determine his/her assessment. 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the SAE report to GSK Biologicals. The investigator may change 
his/her opinion of causality in light of follow-up information and update the SAE 
information accordingly. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
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 vaccines 
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 vaccine contributed to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine. There are other, more likely causes 
and administration of the study vaccine 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 vaccine, if applicable. 

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• 
Erroneous administration. 
• 
Other cause (specify). 
8.2.3.3. 
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). 
8.2.3.4. 
Medically attended visits 
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/adoptive parent(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. 
(Amended 11 October 2016) 
8.3. 
Reporting of serious adverse events 
8.3.1. 
Prompt reporting of serious adverse events and other events to 
GSK Biologicals 
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 13, once the investigator determines that 
the event meets the protocol definition of a SAE. 
Table 15 
Timeframes for submitting serious adverse event, reports to GSK 
Biologicals 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a Previous 
Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse Events 
Report 
* Timeframe allowed after receipt or awareness of the information. 
Note: 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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8.3.2. 
Contact information for reporting serious adverse events and 
other events to GSK Biologicals 
Back-up Study Contact for Reporting SAEs  
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Fax: 
 or 
 
Email address: 
 
8.3.3. 
Completion and transmission of SAE reports to GSK Biologicals 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
8.3.3.1. 
Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the section 8.3) 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. 
8.3.4. 
Updating of SAE information after removal of write access to the 
subject’s eCRF 
When additional SAE information is received after removal of the write access to the 
subject’s eCRF, new or updated information should be recorded on the appropriate paper 
report, with all changes signed and dated by the investigator. The updated report should 
be faxed to the Study Contact for Reporting SAEs (refer to the section 8.3) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within the designated 
reporting time frames specified in Table 15. 
PPD
PPD
PPD

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8.3.5. 
Regulatory reporting requirements for serious adverse events 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.3.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation. 
8.4. 
Follow-up of adverse events and serious adverse events 
8.4.1. 
Follow-up of adverse events and serious adverse events  
8.4.1.1. 
Follow-up during the study 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 15). 
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination. 
8.4.1.2. 
Follow-up after the subject is discharged from the study 
The investigator will follow subjects: 
• 
with SAEs, or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up.  
• 
with other non-serious AEs, until 30 days or they are lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/ electronic 
Expedited Adverse Events Report as applicable. 

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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. 
8.5. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7). 
8.6. 
Subject card 
Study subjects’ parent(s)/adoptive parent(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)/adoptive parent(s). In an emergency situation this card serves to inform the 
responsible attending physician that the subject is in a clinical study and that relevant 
information may be obtained by contacting the investigator. 
Subjects’ parent(s)/adoptive parent(s) must be instructed to keep subject cards in their 
possession at all times. 
(Amended 11 October 2016) 
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. 

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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 parents/adoptive parent(s) of 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)/adoptive parent(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because the subject’s parent(s)/adoptive 
parent(s) has withdrawn consent, the investigator will document the reason for 
withdrawal of consent, if specified by the subject’s parent(s)/adoptive parent(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 8.4.1.2). 
(Amended 11 October 2016) 
9.2.2. 
Subject withdrawal from investigational vaccine 
A ‘withdrawal’ from the investigational vaccine 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 vaccine 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 vaccine will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination was made by the 
subject’s parent(s)/adoptive parent(s), or by the investigator, as well as which of the 
following possible reasons was responsible for withdrawal: 

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• 
Serious adverse event. 
• 
Non-serious adverse event. 
• 
Other (specify). 
(Amended 11 October 2016) 
10. 
STATISTICAL METHODS 
10.1. 
Primary endpoint 
• 
 Immunogenicity with respect to components of the study vaccine. 
 
Anti-diphtheria, anti-tetanus, anti-poliovirus types 1, 2 and 3, and anti-PRP 
seroprotection status, one month after the third dose of primary vaccination. 
 
Anti- PT, anti-FHA and anti-PRN antibody seropositivity status, one month after 
the third dose of primary vaccination.  
10.2. 
Secondary endpoints 
• 
Immunogenicity with respect to components of the study vaccine. 
 
Anti-diphtheria, anti-tetanus, anti-poliovirus types 1, 2 and 3, and anti-PRP 
seroprotection status, one month after the booster vaccination. 
 
Anti- PT, anti-FHA and anti-PRN antibody seropositivity status one month after 
the booster vaccination. 
 
Anti-diphtheria, anti-tetanus, anti-poliovirus types 1, 2 and 3, anti-PRP, anti-PT, 
anti-FHA, anti-PRN antibody concentrations or titres, one month after the third 
dose of primary vaccination and one month after the booster vaccination. 
• 
 Solicited local and general symptoms. 
 
Occurrence of solicited local/general symptoms during the 4-day (Days 0-3) 
follow-up period after each primary vaccination dose and following the booster 
vaccination. 
• 
Unsolicited adverse events. 
 
Occurrence of unsolicited symptoms during the 31-day (Days 0-30) follow-up 
period after each primary vaccination dose and following the booster 
vaccination. 
• 
Serious adverse events. 
 
Occurrence of SAEs from Dose 1 up to study end. 

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10.3. 
Determination of sample size 
The target sample size is 200 subjects evaluable for analysis of immunogenicity. 
Considering that approximately 15% of enrolled subjects may not be evaluable for 
analysis of immunogenicity, 235 subjects are estimated to be enrolled. The number of 
evaluable subjects for the analysis of immunogenicity is not derived from any power 
based computations. The number of evaluable subjects for the study is based on the 
requirement from local regulatory authorities.  
The primary objective of this study is to assess the immunogenicity of the study vaccines, 
in terms of seroprotection rates for antibodies against diphtheria, tetanus, PRP, poliovirus 
types 1, 2, 3 antigens, and seropositivity rates for antibodies against PT, FHA and PRN 
antigens one month after the third dose of primary vaccination. 
Table 16 presents the exact 95% confidence interval (CI) for a sample size of 200 
evaluable subjects according to the value observed for the seroprotection / seropositivity 
rates: 
Table 16 
Exact 95 percentage CI for the different values of observed 
seroprotection / seropositivity rates for a sample size of 200 
evaluable subjects 
Observed seroprotection / seropositivity 
rates expressed as a percentage 
Exact 2-sided 95% CI for this observed rate for a sample size of 200 
evaluable subjects 
Lower Limit (LL) 
Upper Limit (UL) 
92 
87.3 
95.4 
93 
88.5 
96.1 
94 
89.8 
96.9 
95 
91.0 
97.6 
96 
92.3 
98.3 
97 
93.6 
98.9 
98 
95.0 
99.5 
99 
96.4 
99.9 
100 
98.2 
100 
CI: Confidence interval 
Reference study: DTPa-HBV-IPV-109 (105910), Group HexaNEW: Subjects received the new formulation of DTPa-
HBV IPV/Hib at 3, 4 and 5 months of age. 
10.4. 
Cohorts for Analyses 
Four cohorts are defined for the purpose of the analyses: 
• 
Total vaccinated cohort for the primary epoch 
• 
ATP cohort for analysis of immunogenicity of the primary epoch 
• 
Total vaccinated cohort for the booster epoch 
• 
ATP cohort for analysis of immunogenicity of the booster epoch. 

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10.4.1. 
Total vaccinated cohort for the primary epoch 
The Total vaccinated cohort for the primary epoch will include all subjects who received 
at least one primary vaccine dose. Thus, the Total vaccinated cohort for analysis of safety 
of the primary epoch will include all subjects with at least one primary vaccine dose 
administration documented and the Total vaccinated cohort for analysis of 
immunogenicity will include vaccinated subjects for whom data concerning primary 
immunogenicity endpoint measures are available. 
10.4.2. 
According-to-protocol cohort for analysis of immunogenicity of 
the primary epoch 
• 
The ATP cohort for analysis of immunogenicity of the primary epoch will include all 
evaluable subjects (i.e. those meeting all eligibility criteria, complying with the 
procedures and intervals relative to the primary epoch defined in the protocol, with 
no elimination criteria during the primary epoch of the study) from the ATP cohort 
for safety of the primary epoch for whom data concerning primary immunogenicity 
endpoint measures are available. This will include subjects for whom assay results 
are available for antibodies against at least one study vaccine antigen component one 
month after Dose 3. The interval between Dose 3 and blood sampling at Visit 4, 
considered for inclusion of a subject will be 21-48 days. 
10.4.3. 
Total vaccinated cohort for the booster epoch 
The Total vaccinated cohort for the booster epoch will include all subjects who received 
the booster dose of study vaccine.  
• 
The TVC for the analysis of safety of booster epoch will include all subjects with 
booster vaccine dose administration documented.  
• 
The Total vaccinated cohort for analysis of immunogenicity of the booster epoch 
will include vaccinated subjects for whom data concerning booster immunogenicity 
endpoint measures are available. 
10.4.4. 
According-to-protocol cohort for analysis of immunogenicity of 
the booster epoch 
• 
The ATP cohort for analysis of immunogenicity of the booster epoch will include all 
evaluable subjects (i.e. those meeting all eligibility criteria, complying with the 
procedures and intervals relative to the booster epoch defined in the protocol, with 
no elimination criteria during the primary epoch of the study) from the ATP cohort 
for safety of the booster epoch for whom data concerning immunogenicity endpoint 
measures of booster epoch are available. This will include subjects for whom assay 
results are available for antibodies against at least one study vaccine antigen 
component one month after the booster dose of vaccination. The interval between 
study visits that will be considered for inclusion in the ATP cohort for 
immunogenicity of booster epoch will be 15–18 months from date of birth to booster 
vaccination visit and 21-48 days between the booster vaccination visit and the blood 
sampling at one month post-booster vaccination. 

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10.5. 
Derived and transformed data 
The cut-off value is defined by the laboratory before the analysis and is described in the 
laboratory assays section (Section 5.7.3). 
• 
A seronegative subject is a subject whose antibody concentration/titre is below the 
assay cut-off. 
• 
A seropositive subject is a subject whose antibody concentration/titre is greater than 
or equal to the assay cut-off. 
• 
A seroprotected subject is a subject whose antibody concentration/titre is greater than 
or equal to the level defining clinical protection. The following seroprotection 
thresholds are applicable: 
 
Anti-diphtheria antibody concentrations 0.1 IU/ml. 
 
Anti-tetanus antibody concentrations 0.1 IU/ml. 
 
Anti-poliovirus types 1, 2 and 3 antibody titres 8. 
 
Anti-PRP antibody concentrations 0.15 µg/ml. 
• 
The geometric mean concentrations (GMCs) /geometric mean titres (GMTs) 
calculations will be performed by taking the anti-log of the mean of the log10 
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: 
Immunogenicity 
For a given subject and a given immunogenicity measurement, missing or non-evaluable 
measurements will not be replaced. Therefore, an analysis will exclude subjects with 
missing or non-evaluable measurements. 
Safety/reactogenicity 
• 
For a given subject and the analysis of solicited AEs 3 days post-vaccination, 
missing or non-evaluable measurements will not be replaced. Therefore the analysis 
of the solicited AEs based on the Total Vaccinated cohort will include only 
vaccinated subjects and doses with documented safety data (i.e. symptom screen 
completed). 
• 
For analysis of unsolicited AEs, such as SAEs or AEs by primary Medical 
Dictionary for Regulatory Activities (MedDRA) term, and for the analysis of 
concomitant medications, all vaccinated subjects will be considered. Subjects who 
did not report the event or the concomitant medication will be considered as subjects 
without the event or the concomitant medication respectively. 

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For summaries reporting both solicited and unsolicited AEs, all vaccinated subjects will 
be considered. Subjects who did not report the event or the concomitant medication will 
be considered as subjects without the event or the concomitant medication respectively. 
10.6. 
Analysis of demographics 
The analysis of demographics will be performed separately for each epoch: 
• 
The distribution of subjects enrolled among the study centers will be tabulated. 
• 
The number of subjects who withdraw from the study will be tabulated according to 
the reason for drop-out. 
• 
The deviations from specifications for age and intervals between study visits will be 
tabulated. 
The median, mean, range and standard deviation of age (in weeks) at each vaccine dose 
will be computed. The median, mean and standard deviation of height in centimeter (cm) 
and weight in kilograms (kg) at Visit 1 will be computed. The Body Mass Index (BMI) at 
Visit 1 will also be computed as weight (in kg) / height² (in meters). The gender 
composition and geographic ancestry will be presented. 
10.7. 
Analysis of immunogenicity 
The analysis of immunogenicity will be performed separately for each epoch. 
The primary analysis will be based on the ATP cohort for analysis of immunogenicity for 
both primary and booster epochs. If the percentage of enrolled subjects excluded from 
this ATP cohort is more than 5%, a second analysis based on the Total vaccinated cohort 
will be performed on both primary and booster epochs to complement the ATP analysis. 
All analyses are descriptive. 
Where appropriate, at each time-point that a blood-sample result is available: 
• 
Seroprotection rates against diphtheria toxoid, tetanus toxoid, PRP antigen and 
poliovirus types 1, 2 and 3 antigens (with exact 95% CI [Clopper, 1934]) will be 
calculated. 
• 
Seropositivity rates against PT, FHA and PRN antigens (with exact 95% CI 
[Clopper, 1934]) will be calculated. 
• 
GMCs/GMTs with 95% CI will be tabulated for antibodies against each antigen. 
The distribution of antibody concentrations/titres for each antigen will be displayed using 
reverse cumulative distribution curves (RCCs). 
10.8. 
Analysis of safety 
Analysis of safety relative to the primary epoch will include analysis of safety data 
collected following administration of the three primary doses of study vaccine. Analysis 
of safety relative to the booster epoch will include analysis of safety data collected 
following administration of the booster dose of study vaccine. At this second stage, in 

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order to avoid missing SAEs that have been reported, an SAE summary table including 
all the events reported during the entire study period will also be generated. 
The analysis will be based on the Total vaccinated cohort for both primary and booster 
epochs. All analyses are descriptive. 
• 
The overall percentage of subjects/doses with at least one local symptom (solicited 
or unsolicited), with at least one general symptom (solicited or unsolicited) and with 
any symptom (solicited or unsolicited) during the 4-day (Days 0-3) solicited follow-
up period will be tabulated with exact 95% CI [Clopper, 1934] after each vaccine 
dose and overall primary doses. The same calculations will be done for symptoms 
(solicited or unsolicited) rated as grade 3 in intensity, for symptoms (solicited or 
unsolicited) leading to medical advice and for symptoms (solicited or unsolicited) 
assessed as causally related to vaccination. 
• 
The overall percentage of subjects/doses and of subjects reporting each individual 
solicited local and general symptom during the 4-day (Days 0-3) solicited follow-up 
period will be tabulated after each vaccine dose and overall primary doses, with 
exact 95% CI [Clopper, 1934] after each vaccine dose and overall primary doses. 
The same calculations will be done for each individual solicited symptom rated as 
grade 3 in intensity and for each individual solicited symptom assessed as causally 
related to vaccination. 
• 
Occurrence of fever will be reported per 0.5°C cumulative increments. 
• 
The verbatim reports of unsolicited AEs will be reviewed by a physician and the 
signs and symptoms will be coded according to MedDRA. Every verbatim term will 
be matched with the appropriate Preferred Term. The percentage of subjects with 
unsolicited AEs occurring within 31-day (Days 0-30) follow-up period after any dose 
(after primary or booster vaccination) with its exact 95% CI [Clopper, 1934] will be 
tabulated by preferred term. Similar tabulation will be done for unsolicited AEs rated 
as grade 3, for unsolicited AEs with causal relationship to vaccination and 
AE(s)/SAE(s) leading to withdrawal from the study. 
• 
The percentage of subjects who receive at least one concomitant medication during 
the 4-day (Days 0-3) solicited follow-up period and during the entire primary/booster 
epoch will be tabulated (with exact 95% CI [Clopper, 1934]) after each vaccine dose 
and overall. 
• 
Any large injection site reaction (defined as a swelling with a diameter > 50 mm, 
noticeable diffuse swelling or noticeable increase in limb circumference) after 
booster vaccination will be described in detail. 
• 
SAE(s) will be described in detail. 
10.9. 
Interpretation of analyses 
All analyses will be conducted in a descriptive manner. 

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10.10. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 
10.10.1. 
Sequence of analyses 
The analyses will be performed stepwise: 
• 
A final analysis of the primary epoch will be conducted on all immunogenicity and 
safety data obtained up to one month after administration of the third primary dose of 
study vaccine (Visit 4), as soon as the data will be as clean as possible. This will 
include the analysis of the primary immunogenicity objectives related to the primary 
epoch and analysis of solicited symptoms and unsolicited symptoms reported within 
the 4-day (Days 0-3) period and 31-day (Days 0-30) period following the primary 
vaccination, respectively, and the SAEs reported during the primary epoch. 
• 
 Analysis of the booster epoch will be conducted on all cleaned immunogenicity and 
safety data obtained up to one month after administration of the booster dose of 
study vaccine (Visit 6). This will include analysis of the secondary immunogenicity 
objectives related to the booster epoch and analysis of solicited symptoms and 
unsolicited symptoms reported within the 4-day (Days 0-3) period and 31-day (Days 
0-30) period following administration of the booster dose of study vaccine, 
respectively, and the SAEs reported during the booster epoch. At this second stage, 
in order to avoid missing SAEs that have been reported, an SAE summary table 
including all the events reported during the entire study period will also be 
generated. 
10.10.2. 
Statistical considerations for interim analyses 
All analysed data will be reported in an integrated clinical study report that will be 
written at the end of the study. 
11. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
11.1. 
electronic Case Report Form instructions 
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 

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While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
11.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst others, the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a 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 

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other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
11.4. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
11.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines. 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. 
11.6. 
Provision of study results to investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 

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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
12. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable. 
13. 
REFERENCES 
Anderson P. The protective levels of serum antibodies to the capsular polysaccharide of 
Haemophilus influenzae type b. J Infect Dis 1984;149:1034-1035. 
Camargo ME, Silveira L, Furuta JA, et al. Immunoenzymatic assay of anti-diphtheria 
toxin antibodies in human serum. J Clin Microbiol 1984;20(4):772-4. 
Centre for Disease Control and Prevention (CDC), General recommendations on 
immunisation: recommendations of the Advisory Committee on Immunization Practices 
(ACIP) and the American Academy of Family Physicians (AAFP). Morb Mortal Wkly 
Rep 2002; 51(RR02): 1-36. 
Clopper C J, Pearson E S. The Use Of Confidence Or Fiducial Limits Illustrated In The 
Case Of The Binomial. Biometrika 1934;26(4):404-13. 
Diggle L, Deeks JJ and Pollard AJ. Effect of needle size on immunogenicity and 
reactogenicity of vaccines in infants: randomised controlled trial. BMJ 2006;333 
(7568):571. 
Gilca V, Duval B, Deeks S, et al. Penta- And Hexavalent DTaP Based Vaccines 
Approved For Use In Canada: A Systematic Literature Review Of Immunogenicity And 
Reactogenicity. Can J Infect Dis Med Microbiol 2006;7(6):358. 
Granström M, Thoren M, Blennow M, et al. Acellular Pertussis Vaccine in Adults: 
Adverse Reactions and Immune Response. Eur J Clin Microbiol 1987;6(1):18-21. 
Kalies H, Grote V, Verstraeten T, et al. The Use of Combination Vaccines Has Improved 
Timeliness of Vaccination in Children. Pediatr Infect Dis J 2006;25(6):507-12. 
Karpinsky KF, Hayward S and Tryphonas H. Statistical considerations in the quantitation 
of serum immunoglobulin levels using the enzyme-linked immunosorbent assay 
(ELISA). J Immunol Methods 1987;103:189-94. 
Käyhty H, Peltola H, Karanko V,et al. The protective level of serum antibodies to the 
capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 1983; 147:1100. 

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Lim FS, Phua KB, Lee BW, et al. Safety and reactogenicity of DTPa-HBV-IPV/Hib and 
DTPa-IPV/I-Hib vaccines in a post-marketing surveillance setting. Southeast Asian J 
Trop Med Public Health 2011;42(1):138-47. 
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. 
Phua KB, Quak SH, Lim FS, et al. Immunogenicity, reactogenicity and safety of a 
diphtheria-tetanus-acellular pertussis-inactivated polio and Haemophilus influenzae type 
b vaccine in a placebo-controlled rotavirus vaccine study. Ann Acad Med Singapore 
2008;37(7):546–53. 
World Health Organization (WHO). Standard Procedure for Determining Immunity to 
Poliovirus using the Microneutralization Test (WHO/EPI/GEN 93.9) 1993. 
WHO. Immunisation, Vaccines and Biologicals, Haemophilus influenzae type b 2009 
http://www.who.int/immunization/topics/hib/en/index.html. Accessed on 20-January-
2016. 
Zepp F, Schmitt HJ, Cleerbout J, et al. Review of 8 years of experience with Infanrix 
hexa™ (DTPa-HBV-IPV/Hib hexavalent vaccine). Expert Rev. Vaccines 2009;8(6):663-
78. 
Zinke M, Disselhoff J, Gartner B, et al. Immunological persistence in 4–6 and 7–9 year 
olds previously vaccinated in infancy with hexavalent DTPa-HBV-IPV/Hib. Hum Vaccin 
2010;6(2):189-93. 
Zuckerman JN. The importance of injecting vaccines into muscles. BMJ 2000;321:1237-
8. 

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APPENDIX A 
CLINICAL LABORATORIES 
Table 17 
GSK Biologicals laboratories 
Laboratory 
Address 
GSK Biologicals Clinical Laboratory 
Sciences, Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium 
GSK Biologicals Clinical Laboratory 
Sciences, Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre – Belgium 
Table 18 
Outsourced laboratories 
Laboratory 
Address 
NEOMED- LABS Inc 
525 Cartier blvd West- Laval- Quebec 
Canada- H7V 3S8 
CERBA 
7/11 rue de l’Equerre 
Parc d’activités « les Béthunes » 
F-95310 Saint Ouen L’Aumone 
France 
BARC NV 
Industriepark Zwijnaarde 3b 
B-9052 Gent 
Belgium 
CEVAC - University of Gent 
De Pintelaan, 185 Gent 
Belgium 
ImmuneHealth asbl 
Rue Adrienne Bolland 8/B.2, Gosselies 
Belgium 
SGS Wavre 
Vieux Chemin du Poète 10 
1300 Bierges 
Belgium 
Retroscreen Virology Ltd 
Royal College Street 
London Biosciences Innovation Centre 2 
London 
United Kingdom 
Biomnis 
Avenue Tony Garnier 17/19 
BP7322 – Lyon Cedex 07 
France 

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APPENDIX B 
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL 
GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 1 
eTrack study number 
and Abbreviated Title 
116194 [DTPA-IPV (INFANRIX-IPV)-061] 
EudraCT number 
2013-005577-43 
Amendment number: 
Amendment 1 
Amendment date: 
11 October 2016 
Co-ordinating author: 
 (Project Manager Scientific Writer, Keyrus 
Biopharma Contractor for GSK Biologicals) 
Rationale/background for changes:  
• 
As per Russian legislation, only parents or adoptive parents can give consent for 
the enrolment of their child in a clinical trial. No other persons are allowed to give 
consent on behalf of a minor to participate in a clinical trial. Therefore the wording 
“parents/Legally Acceptable Representative(s) (LAR[s])” should be replaced by 
the wording “parents/adoptive parents”. This change was implemented by the local 
team in the Russian translation of the protocol and informed consent form after 
obtaining approval from competent authorities and ethics committees in order to 
meet Russian legislation requirements. The purpose of this amendment is to 
replace “parents/LAR(s)” by “parents/adoptive parents” in order to ensure 
consistency in wording between local protocol and central protocol. 
• 
The list of study personnel and the function names have been updated. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
• 
On the protocol cover page, the following contributing authors have been added and 
the following function names have been updated. 
 
, CRDL 
 
, Project Level CRDL Clinical and Epidemiology 
Project Leader (CEPL) 
 
, Study Delivery Lead Project Delivery Lead 
 
, Study Delivery Lead, Aixial contractor for GSK Biologicals 
 
, Clinical Trial Supplies Manager, Aixial contractor for GSK 
Biologicals 
 
, Study Statistician 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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 
, Director Biostatistics 
 
 and 
, Clinical Laboratory Sciences (CLS) CLS 
Project Manager 
 
, CLS Study Manager, Business & Decision Life Sciences 
contractor for GSK Biologicals 
 
, Global Patent Representative 
 
, Senior Medical Manager CIS Regional Clinical 
Operations Head 
 
, Manager Specialist, Global RA 
 
, Manager, Global RA 
 
, Local Head of Clinical Operations Senior Local Study 
Manager 
 
, Local Delivery Lead 
 
, Oversight Data Manager 
• 
On the Protocol Amendment 1 Investigator Agreement page, the following 
change has been done: 
 
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 parents/adoptive parents. 
• 
In the List of abbreviations, the following changes have been done: 
CEPL: 
Clinical and Epidemiology Project Leader 
CLS: 
Clinical Laboratory Sciences 
CRDL: 
Clinical Research and Development Lead 
CLS: 
Clinical Laboratories Sciences 
LAR: 
Legally Acceptable Representative 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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• 
In the Glossary of terms, the following changes have been done: 
Legally acceptable 
representative 
(The terms legal 
representative or 
legally authorized 
representative are 
used in some 
settings.) 
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial. 
• 
In Section 4.2 Inclusion criteria for enrolment, the following changes have been 
done: 
 
Subjects’ parent(s)/Legally Acceptable Representative(s) [LAR(s)] adoptive 
parent(s) who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards, return for 
follow-up visits). 
 
Written informed consent obtained from the parent(s)/LAR(s) adoptive 
parent(s) of the subject prior to performing any study specific procedure. 
• 
In Section 5.1 Regulatory and ethical considerations, including the informed 
consent process, the following changes have been done: 
 
Subject’s parent(s)/LAR(s) adoptive parent(s) informed consent. 
Freely given and written informed consent must be obtained from each subject’s 
parent(s)/LAR(s) adoptive parent(s), as appropriate, prior to participation in the 
study. 
• 
In Section 5.2.2.2.1 Treatment number allocation, the following changes have 
been done: 
After obtaining the signed and dated ICF from the subject’s parent(s)/LAR(s) 
adoptive parent(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 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. 
• 
In Table 4 List of study procedures, the following changes have been done: 
Recording of solicited adverse events (AEs) (Days 0-3) 
by subjects’ parent(s)/LAR(s) adoptive parent(s) in the 
diary cards 
● 
● 
● 
 
●  
 
Recording of non-serious adverse events (AEs) (Days 0-
30) by subjects’ parent(s)/LAR(s) adoptive parent(s) in 
the diary cards 
● 
● 
●  
 
●  
 
• 
In Section 5.6.1 Informed consent, the following changes have been done: 
The signed informed consent of the subject’s parent(s)/LAR(s) adoptive parent(s) 
must be obtained before study participation. 

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• 
In Section 5.6.5 Physical examination, the following changes have been done: 
Physical examination at each study visit subsequent to the vaccination visit, will be 
performed only if the subject’s parent/LAR adoptive parent indicates during 
questioning that there might be some underlying pathology(ies) or if deemed 
necessary by the Investigator or delegate. 
• 
In Section 5.6.15 Recording of AEs and SAEs, the following changes have been 
done: 
 
The subjects’ parent(s)/LAR(s) adoptive parent(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) adoptive parent(s). The subject’s parent(s)/LAR(s) adoptive 
parent(s) will record body temperature (preferably axillary) and any solicited 
local/general AEs (i.e. on the day of vaccination and during the next 3 days) or 
any unsolicited AEs (i.e. on the day of vaccination and during the next 30 days) 
occurring after vaccination. The subject’s parent(s)/LAR(s) adoptive parent(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) adoptive parent(s) at Visits 2, 3, 4 and 6. 
 
If the parent(s) /LAR(s) adoptive parent(s) of subjects observe any large 
injection site reaction (defined as swelling with a diameter > 50 mm, noticeable 
diffuse swelling or noticeable increase of limb circumference) during the 4-day 
follow-up (Day 0-Day 3) period, they are to contact study personnel and to visit 
the investigator's office for evaluation as soon as possible. 
 
Any unreturned diary cards will be sought from the subject’s parent(s)/LAR(s) 
adoptive parent(s) through telephone call(s) or any other convenient procedure. 
The investigator will transcribe the collected information into the eCRF in 
English. 
• 
In Section 5.7 Biological sample handling and analysis, the following changes 
have been done 
 
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. 
Therefore, all subjects parent’s/LAR’s adoptive parent’s in countries where this 
is allowed, will be asked to give a specific consent to allow GSK or a contracted 
partner to use the samples for future research. Future research will be subject to 
the laws and regulations in the respective countries and will only be performed 
once an independent Ethics Committee or Review Board has approved this 
research. 
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s) adoptive parent(s). 

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• 
In Section 5.7.5 Immunological correlates of protection, the following changes 
have been done: 
The investigator is encouraged to share the immunological assay results for non-
responders with the study subject’s parent(s)/LAR(s) adoptive parent(s). 
• 
In Section 6.7 Concomitant medications/products and concomitant vaccinations, 
the following changes have been done: 
At each study visit, the investigator should question the subject’s parent(s)/LAR(s) 
adoptive parent(s) about any medications/products taken and vaccinations received 
by the subject. 
• 
In Section 8 Safety, the following changes have been done: 
Each subject’s parent(s)/LAR(s) adoptive parent(s) will be instructed to contact the 
investigator immediately should the subject manifest any signs or symptoms they 
perceive as serious. 
• 
In Section 8.1.3 Solicited adverse events, the following changes have been done: 
N.B. If parent(s) /LAR(s) adoptive parent(s) of infants observe any large injection 
site reaction (defined as swelling with a diameter > 50 mm, noticeable diffuse 
swelling or noticeable increase of limb circumference) after the booster dose at Visit 
5, they will be asked to contact study personnel and to visit the investigator's office 
for evaluation as soon as possible. The investigator will record detailed information 
describing the AE on a specific large injection site reaction screen in the eCRF. In 
addition to the diameter of the swelling and the circumference of the limb, the 
investigator will need to record additional symptoms/characteristics as mentioned in 
Section 5.6.15. 
• 
In Section 8.2.1 Time period for detecting and recording adverse events and 
serious adverse events, the following changes have been done: 
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from 
the time the subject’s parent/LAR adoptive parent consents to participate in the 
study until she/he is discharged from the study. 
• 
In Section 8.2.3.1 Active questioning to detect adverse events and serious 
adverse events, the following changes have been done: 
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) adoptive 
parent(s) should be asked a non-leading question such as: 
• 
In Section 8.2.3.2.1 Assessment of intensity, the following changes have been done: 
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) adoptive 
parent(s) to seek medical advice. 

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• 
In Section 8.2.3.4 Medically attended visits, the following changes have been done: 
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) adoptive parent(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. 
• 
In Section 8.6 Subject card, the following changes have been done: 
Study subjects’ parent(s)/LAR(s) adoptive parent(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) adoptive parent(s). In an emergency situation this card 
serves to inform the responsible attending physician that the subject is in a clinical 
study and that relevant information may be obtained by contacting the investigator. 
Subjects’ parent(s)/LAR(s) adoptive parent(s) must be instructed to keep subject 
cards in their possession at all times. 
• 
In Section 9.2.1 Subject withdrawal from the study, the following changes have 
been done: 
Investigators will make an attempt to contact parents/LARs adoptive parent(s) of 
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) adoptive parent(s), or by the 
investigator, as well as which of the following possible reasons was responsible for 
withdrawal: 
*In case a subject is withdrawn from the study because the subject’s 
parent(s)/LAR(s) adoptive parent(s) has withdrawn consent, the investigator will 
document the reason for withdrawal of consent, if specified by the subject’s 
parent(s)/LAR(s) adoptive parent(s), in the eCRF. 
• 
In Section 9.2.2 Subject withdrawal from investigational vaccine, the following 
changes have been done: 
Information relative to premature discontinuation of the investigational vaccine will 
be documented on the Vaccine Administration screen of the eCRF. The investigator 
will document whether the decision to discontinue further vaccination was made by 
the subject’s parent(s)/LAR(s) adoptive parent(s), or by the investigator, as well as 
which of the following possible reasons was responsible for withdrawal: 

PPD