A Phase IV, Single-blind, Randomised, Controlled, Multi-country Study to Evaluate the Immunogenicity and Safety of GSK's Infanrix Hexa (DTPa-HBV-IPV/Hib) Versus MCM Vaccine BV's Vaxelis (DTaP5-HBV-IPV Hib), When Administered Intramuscularly According to a 2-, 4- and 12-month Schedule in Healthy Infants and Toddlers
Phase: PHASE4
Conditions: Diphtheria
Sponsor: GlaxoSmithKline

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Protocol 212645, Amendment 1 
 
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TITLE PAGE 
Protocol Title: A phase IV, single-blind, randomised, controlled, multi-country study to evaluate the 
immunogenicity and safety of GSK’s Infanrix hexa (DTPa-HBV-IPV/Hib) versus MCM Vaccine BV’s 
Vaxelis (DTaP5-HBV-IPV-Hib), when administered intramuscularly according to a 2-, 4- and 12-month 
schedule in healthy infants and toddlers 
Protocol Number: 212645 
Amendment Number: 1  
Product: GlaxoSmithKline Biologicals SA’s (GSK) diphtheria, tetanus, acellular pertussis, hepatitis B, 
inactivated poliovirus vaccine and Haemophilus influenzae type b conjugate vaccine 
(DTPa-HBV-IPV/Hib) (GSK-217744, Infanrix hexa) 
Short Title: A Phase IV study to evaluate immunogenicity and safety of GSK’s Infanrix hexa 
(DTPa-HBV-IPV/Hib) versus MCM Vaccine BV’s Vaxelis (DTaP5-HBV-IPV-Hib) in healthy infants 
and toddlers 
Study Phase: IV 
Sponsor Name: GlaxoSmithKline Biologicals SA 
Legal Registered Address: Rue de l’Institut, 89, 1330 Rixensart, Belgium 
Regulatory Agency Identifying Number(s):  
EudraCT: 2019-002988-10 
Date of Protocol: 06 April 2021 
 
 

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Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
Nadia Meyer, MD 
Clinical and Epidemiology R&D Project Leader 
GlaxoSmithKline Biologicals SA 
 
Date 
 
 
 
 
 
 
 
 
Medical Monitor name and contact information can be found in Appendix 2. 
 
2 April 2021
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Table 1 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 1 
06 Apr 2021 
No 
Global 
Original Protocol 
21 Feb 2020 
- 
- 
 
Amendment 1 (06 April 2021) 
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of subjects nor the 
scientific value of the study. 
Overall Rationale for the Amendment: 
This amendment was made to clarify when to collect information regarding concomitant 
therapies and vaccines, and which therapies and vaccines must be recorded on the eCRF. In 
addition, there were minor editorial changes. 
Table 2 
Description of Changes in Amendment 
Section # and 
Name 
Description of Change 
Brief Rationale 
Synopsis, and 
3.0, Objectives 
and Endpoints 
 Added “≥” to secondary objective, 
preceding each number: “To assess the 
immunogenicity of Hib-components in 
terms of percentage of subjects above 
the thresholds for short-term 
(≥0.15 µg/mL) and long-term 
(≥1.0 µg/mL) protection…” 
Editorial 
6.6, Concomitant 
Therapy 
More detailed information regarding 
concomitant therapies and vaccines and 
which therapies or vaccines to record on 
eCRF  
Clarification 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................3 
TABLE OF TABLES ...............................................................................................................7 
TABLE OF FIGURES .............................................................................................................8 
1.0 
PROTOCOL SUMMARY ..........................................................................................9 
1.1 
Synopsis .............................................................................................................9 
1.2 
Schema ............................................................................................................12 
1.3 
Schedule of Activities .....................................................................................13 
2.0 
INTRODUCTION......................................................................................................15 
2.1 
Study Rationale ..............................................................................................15 
2.2 
Background ....................................................................................................16 
2.3 
Benefit/Risk Assessment ................................................................................16 
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................17 
4.0 
STUDY DESIGN ........................................................................................................19 
4.1 
Overall Design ................................................................................................19 
4.2 
Scientific Rationale for Study Design ...........................................................20 
4.3 
Justification for Dose .....................................................................................20 
4.4 
End of Study Definition .................................................................................20 
5.0 
STUDY POPULATION ............................................................................................21 
5.1 
Inclusion Criteria ...........................................................................................21 
5.2 
Exclusion Criteria ..........................................................................................21 
5.2.1 
Medical Conditions ...........................................................................21 
5.2.2 
Prior/Concomitant Therapy ...............................................................22 
5.2.3 
Prior/Concurrent Clinical Study Experience .....................................22 
5.2.4 
Other Exclusions ...............................................................................23 
5.3 
Lifestyle Considerations ................................................................................23 
5.4 
Screen Failures ...............................................................................................23 
6.0 
STUDY TREATMENT .............................................................................................24 
6.1 
Study Treatment(s) Administered ................................................................24 
6.2 
Contraindications to Subsequent Vaccination ............................................28 
6.2.1 
Criteria for Temporary Delay of Vaccination ...................................28 
6.2.2 
Other Contraindications to Subsequent Vaccination .........................28 

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6.2.3 
Warnings and Precautions .................................................................28 
6.3 
Preparation/Handling/Storage/Accountability ...........................................28 
6.4 
Measures to Minimise Bias: Randomisation and Blinding ........................29 
6.4.1 
Subject Identification .........................................................................29 
6.4.2 
Randomisation to Study Intervention ................................................29 
6.4.3 
Intervention Allocation to the Subject ...............................................29 
6.4.4 
Allocation Treatment Number for Subsequent Dose or 
Replacement ......................................................................................29 
6.4.5 
Blinding and Unblinding ...................................................................29 
6.5 
Study Treatment Compliance .......................................................................30 
6.6 
Concomitant Therapy ....................................................................................30 
6.7 
Dose Modification ..........................................................................................31 
6.8 
Treatment After the End of the Study .........................................................31 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ................................................................32 
7.1 
Discontinuation of Study Treatment ............................................................32 
7.2 
Subject Discontinuation/Withdrawal from the Study ................................32 
7.3 
Lost to Follow-up ...........................................................................................32 
7.4 
Reason for Discontinuation ...........................................................................33 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................34 
8.1 
Immunogenicity Assessments .......................................................................34 
8.2 
Safety Assessments .........................................................................................35 
8.2.1 
Physical Examinations .......................................................................35 
8.2.2 
Vital Signs .........................................................................................35 
8.3 
Adverse Events ...............................................................................................36 
8.3.1 
Time Period and Frequency for Collecting AE and SAE 
Information ........................................................................................36 
8.3.2 
Method of Detecting AEs and SAEs .................................................36 
8.3.3 
Follow-up of AEs and SAEs .............................................................37 
8.3.4 
Regulatory Reporting Requirements for SAEs .................................37 
8.3.5 
Subject Card ......................................................................................37 
8.4 
Treatment of Overdose ..................................................................................37 
8.5 
Pharmacokinetics ...........................................................................................37 
8.6 
Pharmacodynamics ........................................................................................38 
8.7 
Genetics ...........................................................................................................38 
8.8 
Biomarkers .....................................................................................................38 
8.9 
Medical Resource Utilisation and Health Economics .................................38 
9.0 
STATISTICAL CONSIDERATIONS .....................................................................38 
9.1 
Statistical Hypotheses ....................................................................................38 
9.2 
Sample Size Determination ...........................................................................39 
9.3 
Analysis Sets ...................................................................................................39 
9.4 
Statistical Analyses.........................................................................................41 
9.4.1 
Disposition .........................................................................................41 

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9.4.2 
Demographics and Other Baseline Characteristics ...........................41 
9.4.3 
Immunogenicity Analyses .................................................................41 
9.4.4 
Safety Analyses .................................................................................42 
9.4.5 
Sequence of analyses .........................................................................42 
9.4.6 
Interim Analyses ................................................................................42 
10.0 
REFERENCES ...........................................................................................................43 
11.0 
APPENDICES ............................................................................................................45 
Appendix 1 
Abbreviations and Glossary of Terms ...........................................46 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations ..........51 
Regulatory and Ethical Considerations ............................................................51 
Financial Disclosure .........................................................................................51 
Insurance ..........................................................................................................52 
Informed Consent Process ...............................................................................52 
Data Protection.................................................................................................52 
Administrative Structure ..................................................................................53 
Medical Monitor ..............................................................................................53 
Dissemination of Clinical Study Data ..............................................................53 
Data Quality Assurance ...................................................................................54 
Source Documents ...........................................................................................54 
Study and Study Centre Closure ......................................................................55 
Publication Policy ............................................................................................55 
Appendix 3 
Clinical Laboratory Tests ...............................................................56 
Appendix 4 
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ......................57 
Appendix 5 
Protocol Amendment History .........................................................62 
Appendix 6 
Signature of Investigator ................................................................64 
  

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TABLE OF TABLES 
Table 1 
Document History ..............................................................................................3 
Table 2 
Description of Changes in Amendment .............................................................3 
Table 3 
Schedule of Activities ......................................................................................13 
Table 4 
Study Objectives and Endpoints ......................................................................17 
Table 5 
Treatments Administered .................................................................................25 
Table 6 
Laboratory Assays ...........................................................................................35 
Table 7 
Analysis Sets ....................................................................................................40 
Table 8 
Intervals Between Study Visits ........................................................................41 
Table 9 
Study Administrative Structure ........................................................................53 
Table 10 
GSK Biologicals’ Laboratories ........................................................................56 
 

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TABLE OF FIGURES 
Figure 1 
Study Schema...................................................................................................12 
 
 

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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A phase IV, single-blind, randomised, controlled, multi-country study to evaluate the 
immunogenicity and safety of GSK’s Infanrix hexa (DTPa-HBV-IPV/Hib) versus MCM Vaccine BV’s 
Vaxelis (DTaP5-HBV-IPV-Hib), when administered intramuscularly according to a 2-, 4- and 12-month 
schedule in healthy infants and toddlers 
Short Title: A phase IV study to evaluate immunogenicity and safety of GSK’s Infanrix hexa 
(DTPa-HBV-IPV/Hib) versus MCM Vaccine BV’s Vaxelis (DTaP5-HBV-IPV-Hib) in healthy infants 
and toddlers 
Rationale: 
Aside from Infanrix hexa, 2 other hexavalent combination vaccines are currently available: 
Hexyon/Hexacima/Hexaxim™ (registered by Sanofi Pasteur in 2013) and Vaxelis™ (registered by MCM 
Vaccine BV in 2016). Available data from the clinical development of Vaxelis show numerical 
differences in the Haemophilus influenzae type b (Hib) immune response between Infanrix hexa and 
Vaxelis vaccines following the primary vaccination in infants; more specifically a higher 
anti-polyribosylribitol phosphate (anti-PRP) antibody response was demonstrated after Vaxelis as 
compared to Infanrix hexa. However, the observed anti-PRP geometric mean concentrations (GMCs) 
following Vaxelis booster dose in toddlers was lower as compared to Infanrix hexa booster dose increase. 
This study is intended to show both the non-inferiority of Infanrix hexa versus Vaxelis, as well as the 
superiority of Infanrix hexa versus Vaxelis in terms of anti-PRP GMCs and proportion of subjects with 
antibody concentrations above a threshold of 5 µg/mL 1 month after the booster dose. 
 

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Objectives and Endpoints 
Objectives 
Endpoints 
Co-primary 
Confirmatory 
1.To demonstrate that the Hib response in the 
Investigational Group (Inv_group) is non-inferior to the 
Comparator Group (Com_group), 1-month post-booster 
vaccination in terms of:  
• 
GMCs 
o 
Criterion: Lower limit (LL) of the 2-sided 
95% confidence interval (CI) on group 
GMC ratio (Inv_group over Com_group) 
is above 0.5. 
• 
Percentage of subjects with anti-PRP antibody 
concentrations ≥5 µg/mL.  
o 
Criterion: First primary objective is met 
and the LL of the 2-sided 95% CI on 
group difference in the percentage 
(Inv_group minus Com_group) is 
above -10%.  
2. To demonstrate that the Hib response in Inv_group is 
superior to Com_group, 1-month post-booster 
vaccination in terms of:  
• 
GMCs 
o 
Criterion: All previous objectives are met 
and the LL of the 2-sided 95% CI on 
group GMC ratio (Inv_group over 
Com_group) is above 1. 
• 
Percentage of subjects with anti-PRP antibody 
concentrations ≥5 µg/mL. 
o 
Criterion: All previous objectives are met 
and the LL of the 2-sided 95% CI on 
group difference in the percentage 
(Inv_group minus Com_group) is 
above 0.  
Note: A hierarchical procedure will be used to control 
the risk of concluding erroneously. 
• 
Anti-PRP antibody concentrations at 1-month 
post-booster vaccination. 
• 
Anti-PRP antibody concentration ≥5 µg/mL at 
1-month post-booster vaccination. 
 
Secondary 
Descriptive 
To assess the immunogenicity of Hib-components in 
terms of percentage of subjects above the thresholds for 
short-term (≥0.15 µg/mL) and long-term (≥1.0 µg/mL) 
protection as well as in terms of GMCs (post-primary, 
pre- and post-booster vaccination) 
Anti-PRP antibody concentrations at 1-month 
post-primary vaccination, pre-booster and 1-month 
post-booster vaccination. 
To assess the safety of Infanrix hexa and Vaxelis 
co-administered with Prevenar 13™ in terms of 
unsolicited adverse events (AEs) and serious adverse 
events (SAEs) 
• Occurrence of unsolicited AEs during the 31 day 
(Days 1-31) follow-up period after each vaccination. 
• Occurrence of SAEs after first dose up to study end. 

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Objectives 
Endpoints 
 
 
Tertiary 
The tertiary objective may be reported separately. 
 
Overall Design: 
This is a phase IV, single-blind, randomised, controlled and multi-country study with 2 parallel groups of 
healthy infants and toddlers aged 6 to 12 weeks at the time of first vaccination. 
Treatment allocation: The subjects will be randomised at a 1:1 ratio to Inv_group or Com_group using a 
minimisation algorithm with the study country and maternal immunisation of the infants as minimisation 
factors. This will be done at the study entry using an Interactive Voice Response System (IVRS) 
randomisation.  
Number of Investigators and Study Centres: 
Approximately 35 investigators and study centres in about 3 European countries are expected to 
participate in this study. 
Number of Subjects: 
The study will enrol 500 subjects in a 1:1 ratio. Assuming that 20% of the subjects would not be 
evaluable, the power was computed for 400 evaluable subjects (i.e., 200 subjects each in the Inv_group 
and Com_group). For more information, see Section 9.0, Statistical Considerations, and Section 9.2, 
Sample Size Determination. 
Treatment Groups and Duration: 
There will be 2 parallel groups of subjects: 
• 
Inv_group (Investigational group): All subjects in this group will receive 3 doses (2 primary 
doses+1 booster dose) of Infanrix hexa co-administered with 3 doses of Prevenar 13 at 2, 4, 
and 12 months. 
• 
Com_group (Comparator group): All subjects in this group will receive 3 doses (2 primary 
doses+1 booster dose) of Vaxelis co-administered with 3 doses of Prevenar 13 at 2, 4, and 
12 months. 
Duration of the study: The intended duration of the study per subject is approximately 11 months, 
divided into 2 study phases. 
• 
Study phase 1: Primary study phase, starting at Visit 1 (Day 1) and ending at Visit 3 (Month 
3); i.e., 1 month following the second primary dose. 
• 
Study phase 2: Booster study phase, starting at Visit 4 (Month 10) and ending at Visit 5 
(Month 11); i.e., 1 month after the booster dose. 
Data Monitoring Committee: No.  
CCI

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1.2 
Schema 
Figure 1 
Study Schema 
 
BST=booster, PRI=primary 
 

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1.3 
Schedule of Activities 
Table 3 
Schedule of Activities 
 
Age 
2 Months 
4 Months 
5 Months 
12 Months 
13 Months 
Study phase 
Study phase 1 (Primary) 
Study phase 2 (Booster) 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Sampling time points 
 
 
Post-primary 
Pre-booster 
Post-booster 
Informed consent by parents/LAR(s) 
● 
 
 
 
 
Check inclusion/exclusion criteria  
● 
 
 
 
 
Check contraindications to vaccination 
○ 
○ 
 
○ 
 
Collect demographic data (including gestational age) 
● 
 
 
 
 
Vaccination history and maternal dTpa immunisation 
● 
 
 
 
 
Vaccines 
Study group and treatment number allocation 
○ 
 
 
 
 
Treatment number allocation for subsequent doses 
 
○ 
 
○ 
 
Recording of administered treatment number 
● 
● 
 
● 
 
Vaccine administration  
● 
● 
 
● 
 
Clinical specimens for laboratory assays 
Blood sampling for antibody determination (2.5 mL) 
 
 
● 
● 
● 
 

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Age 
2 Months 
4 Months 
5 Months 
12 Months 
13 Months 
Study phase 
Study phase 01 (Primary) 
Study phase 02 (Booster) 
Type of contact 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Sampling time points 
 
 
Post-primary Pre-booster 
Post-booster 
Safety assessments 
Medical history 
● 
 
 
 
 
Check contraindications, warnings and precautions to 
vaccination 
○ 
● 
 
● 
 
Pre-vaccination body temperaturea 
● 
● 
 
● 
 
Record any concomitant medication/vaccination 
● 
● 
● 
● 
● 
Distribution of memory aids  
○ 
○ 
 
○ 
 
Return of memory aids 
 
○ 
○ 
 
○ 
Recording of unsolicited AEsb (including the review of 
memory aids) 
● 
● 
● 
● 
● 
Reporting of SAEsc 
● 
● 
● 
● 
● 
Study Conclusion 
 
 
 
 
● 
AEs=adverse events; SAEs=serious adverse events; dTpa=combined reduced-antigen-content diphtheria, tetanus and acellular pertussis; LAR=legally 
acceptable representative. 
a Fever is defined as temperature ≥38°C (regardless of route). Rectal temperature is preferred, but oral or axillary temperature is also allowed. 
b AEs collected during 31-day follow-up period after each vaccination. 
c SAEs collected throughout study. 
● = study procedure that requires documentation in the individual eCRF. 
○ = study procedure that does not require documentation in the individual eCRF. 
 

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2.0 INTRODUCTION 
Infanrix hexa was registered in Europe in 2000 and is currently licensed for primary and booster 
vaccination in more than 90 countries worldwide. Since launch more than 186 million doses of 
Infanrix hexa have been distributed worldwide. Infanrix hexa has a well-characterised safety 
profile and has a large cumulative post-marketing exposure suggesting the benefit/risk profile 
continues to be favourable. 
2.1 
Study Rationale 
Aside from Infanrix hexa, 2 other hexavalent combination vaccines are currently available: 
Hexyon/Hexacima/Hexaxim™ (registered by Sanofi Pasteur in 2013) and Vaxelis™ (registered 
by MCM Vaccine BV in 2016). The Haemophilus influenzae type b (Hib) component of 
Infanrix hexa is lyophilised, and it must be reconstituted with the sterile suspension containing 
the other vaccine antigens prior to its administration, while Hexyon/Hexacima/Hexaxim and 
Vaxelis are fully liquid vaccines.  
Available data from the clinical development of Vaxelis show that following the primary 
vaccination in infants, Vaxelis (containing a Hib-outer membrane protein [Hib-OMP] which is 
covalently bound to polyribosylribitol phosphate [PRP]) shows a higher anti-PRP antibody 
response than Infanrix hexa (PRP conjugated to tetanus toxoid [TT] carrier protein [Hib-TT]). 
However, the observed anti-PRP geometric mean concentrations (GMCs) following Vaxelis 
booster dose in toddlers was lower as compared to Infanrix hexa, [EMA, 2016; Vesikari, 2017; 
Silfverdal, 2016]. 
In Europe, there is evidence of successful Hib disease control with Infanrix hexa 3+1 and 2+1 
schedules, which also includes data between 2005 and 2013 when Infanrix hexa was the only 
hexavalent vaccine available in Europe [Wang, 2017]. The lower anti-PRP antibody response 
post-booster vaccination with Vaxelis could lead to rapid waning of immunity or have a negative 
effect on the Hib carriage/transmission rates in the population [EMA, 2016]. It is known that the 
presence of circulating anti-PRP antibodies at sufficient concentrations at the time of exposure to 
Hib is critical to prevent invasive disease [Barbour, 1996]. Therefore, the difference in the 
booster responses between the 2 vaccines may have significant implications on Hib disease 
control and public health. 
The co-primary objectives of this study are (1) to demonstrate non-inferiority of Infanrix hexa 
versus Vaxelis in terms of anti-PRP GMCs and proportion of subjects with antibody 
concentrations equal to or above 5 µg/mL following the booster dose in a 2+1 schedule (2-, 4-, 
and 12-month); (2) to demonstrate superiority of Infanrix hexa versus Vaxelis in terms of 
anti-PRP GMCs and proportion of subjects with antibody concentrations above 5 µg/mL 
following the booster dose in a 2+1 schedule (2-, 4-, and 12-month). The potential differences in 
anti-PRP antibody avidity for the 2 vaccines may also be explored in this study. 

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2.2 
Background 
Barbour et al. report that the acquisition of Hib or the prolonged Hib carriage in the nasopharynx 
may occur only below a threshold concentration of serum or mucosal anti-PRP antibodies 
[Barbour, 1996]. Other literature reports that high anti-PRP antibody concentrations above the 
established correlates of clinical protection (0.15 µg/mL for short-term and 1.0 µg/mL for 
long-term protection) may be needed to reduce Hib nasopharyngeal colonisation and carriage 
[Peltola, 1977; Käyhty, 1983]. Also, the protection against colonisation seems to be well 
correlated with anti-PRP antibody concentrations ≥5 µg/mL at 1 month following the third 
vaccine dose in infants [Fernandez, 2000]. Comparative data on the proportion of subjects 
reaching the 5 µg/mL titre after Infanrix hexa or Vaxelis are not publicly available. In addition, 
little is known about antibody quality [Agbarakwe, 1995, Schlesinger, 1992]. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of Infanrix hexa, 
Vaxelis, and Prevenar 13™ are provided in the current Summaries of Product Characteristics 
(SmPCs). 
2.3 
Benefit/Risk Assessment 
Subjects’ parents or legally acceptable respresentative(s) (LARs) will be informed of the benefits 
and risks of participation in the study before they consent to the subjects’ participation.  
The benefit of vaccination in infants and toddlers includes protection from multiple diseases 
which have high morbidity and mortality rates. Both Infanrix hexa and Vaxelis are designed to 
prevent diphtheria, tetanus, pertussis, hepatitis B virus (HBV), polio, and diseases caused by Hib, 
and vaccination against these 6 diseases is recommended by the national health authorities in 
Europe.  
Risks may include injection site reactions, fever, hypersensitivity to vaccine ingredients and/or 
excipients.  
As applicable for all injectable vaccines, appropriate medical treatment and supervision should 
always be readily available in case of a rare anaphylactic event following the administration of 
the vaccine. 
As with any vaccine, a protective immune response may not be elicited in all vaccinees. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of Infanrix hexa, Vaxelis, and Prevenar 13 may be found in their respective 
SmPCs. 

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3.0 OBJECTIVES AND ENDPOINTS 
Objectives and endpoints are presented in Table 4. 
Table 4 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Co-primary 
Confirmatory 
1.To demonstrate that the Hib response in 
Investigational group (Inv_group) is non-inferior to 
Comparatory group (Com_group), 1-month 
post-booster vaccination in terms of:  
• 
GMCs 
o 
Criterion: Lower limit (LL) of the 2-sided 
95% confidence interval (CI) on group 
GMC ratio (Inv_group over Com_group) 
is above 0.5. 
• 
Percentage of subjects with anti-PRP antibody 
concentrations ≥5 µg/mL.  
o 
Criterion: First primary objective is met 
and the LL of the 2-sided 95% CI on 
group difference in the percentage 
(Inv_group minus Com_group) is more 
than -10%.  
2.To demonstrate that the Hib response in Inv_group is 
superior to Com_group, 1-month post-booster 
vaccination in terms of:  
• 
GMCs 
o 
Criterion: All previous objectives are met 
and the LL of the 2-sided 95% CI on 
group GMC ratio (Inv_group over 
Com_group) is above 1. 
• 
Percentage of subjects with anti-PRP antibody 
concentrations ≥5 µg/mL. 
o 
Criterion: All previous objectives are met 
and the LL of the 2-sided 95% CI on 
group difference in the percentage 
(Inv_group minus Com_group) is 
above 0.  
• 
Note: A hierarchical procedure will be used to 
control the risk of concluding erroneously. 
• 
Anti-PRP antibody concentrations at 1-month 
post-booster vaccination. 
• 
Anti-PRP antibody concentration ≥5 µg/mL at 
1-month post-booster vaccination. 
 
 

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Objectives 
Endpoints 
Secondary 
Descriptive 
To assess the immunogenicity of Hib-components in 
terms of percentage of subjects above the thresholds for 
short-term (≥0.15 µg/mL) and long-term (≥1.0 µg/mL) 
protection as well as in terms of GMCs (post-primary, 
pre- and post-booster vaccination). 
Anti-PRP antibody concentrations at 1-month 
post-primary vaccination, pre-booster and 1-month 
post-booster vaccination. 
To assess the safety of Infanrix hexa and Vaxelis 
co-administered with Prevenar 13 in terms of 
unsolicited adverse events (AEs) and serious adverse 
events (SAEs). 
• 
Occurrence of unsolicited AEs during the 31 day 
(Days 1-31) follow-up period after each 
vaccination. 
• 
Occurrence of SAEs after first dose up to study 
end. 
Tertiary/Exploratory 
The tertiary objective may be reported separately.  
CCI

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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a phase IV, single-blind, randomised, controlled and multi-country study in infants and 
toddlers 6 to 12 weeks of age at the time of first vaccination. 
The subjects will be assigned to 1 of 2 parallel groups: 
• Inv_group (Investigational group): All subjects in this group will receive 3 doses 
(2 primary doses+1 booster dose) of Infanrix hexa co-administered with 3 doses of 
Prevenar 13 at 2, 4, and 12 months. 
• Com_group (Comparator group): All subjects in this group will receive 3 doses 
(2 primary doses+1 booster dose) of Vaxelis co-administered with 3 doses of Prevenar 13 
at 2, 4, and 12 months. 
Duration of the study: The intended duration of the study per subject is approximately 
11 months, divided into 2 study phases. 
• Study phase 1: Primary study phase, starting at Visit 1 (Day 1) and ending at Visit 3 
(Month 3), i.e., 1 month following the second primary dose. 
• Study phase 2: Booster study phase, starting at Visit 4 (Month 10) and ending at Visit 5 
(Month 11), i.e., 1 month after the booster dose. 
Treatment allocation: The subjects will be randomised at a 1:1 ratio to Inv_group or Com_group 
using a minimisation algorithm with the study country and maternal immunisation status as 
minimisation factors. This will be done at study entry using an Interactive Voice Response 
System (IVRS) randomisation. 
Proposed countries: About 3 European countries. 
Sampling schedule: Blood samples will be collected from all subjects at the following time 
points: 
• Post-Primary (Visit 3): At 1 month after the second dose of primary vaccination, a 
volume of approximately 2.5 mL of whole blood will be collected. 
• Pre-Booster (Visit 4): Before the administration of the booster dose, a volume of 
approximately 2.5 mL of whole blood will be collected. 
• Post-Booster (Visit 5): At 1 month after the booster vaccination, a volume of 
approximately 2.5 mL of whole blood will be collected. 
Data collection: electronic Case Report Form (eCRF). 

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4.2 
Scientific Rationale for Study Design 
This study is designed to have 2 parallel groups to have a head-to-head comparison of Hib 
immune responses for Infanrix hexa versus Vaxelis as: 
• 
data from a literature review show differences in the Hib immune response between 
Infanrix hexa and Vaxelis post-primary and post-booster vaccination, and 
• 
this difference is seen both in fold change of anti-PRP antibody concentrations and in 
anti-PRP GMCs [EMA, 2016; Vesikari, 2017; Silfverdal, 2016].  
• 
It is also known that the presence of circulating anti-PRP antibodies at sufficient 
concentrations at the time of exposure to Hib is critical to prevent invasive disease 
[Barbour, 1996].  
Therefore, the difference in the booster responses between the 2 vaccines may have significant 
implications on Hib disease control and public health. 
Prevenar 13 is co-administered with both Infanrix hexa and Vaxelis in this study as vaccination 
with a pneumococcal conjugate vaccine is part of the national recommendations in Europe.  
This head-to-head study of Infanrix hexa versus Vaxelis is proposed to address: 
• 
the evidence gaps regarding the proportion of subjects ≥5 µg/mL anti-PRP antibody 
threshold, and, 
• 
the uncertainties regarding the quality of the anti-PRP antibodies generated by both 
vaccines. 
4.3 
Justification for Dose 
For this study, a 2+1 vaccination schedule (2-, 4- and 12-month) has been selected, as several 
European countries are either adopting and/or have implemented this schedule already in their 
national immunisation schedules [ECDC, 2019]. 
4.4 
End of Study Definition 
A subject is considered to have completed the study if he/she returns for the last visit as 
described in the protocol. 
End of study (EoS) is defined as the release date of the last testing results of samples collected at 
Visit 5.  

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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise the 
scientific integrity, regulatory acceptability of the study or subject safety. Therefore, adherence 
to the criteria as specified in the protocol is essential. 
Subjects are eligible to be included in the study only if ALL of the following criteria apply at 
study entry. 
1. Subjects’ parent(s)/ LAR(s) who, in the opinion of the investigator, can and will comply with 
the requirements of the protocol (e.g., return for follow-up visits) 
2. Written or witnessed/thumb printed informed consent obtained from the parent(s)/LAR(s) of 
the subject prior to performing any study specific procedure. 
3. A male or female child between and including 6 and 12 weeks of age (42 to 84 days) at the 
time of the first vaccination. 
4. Subject born after at least 37 weeks of gestation. 
5. Healthy subjects as established by the investigator based on medical history and the clinical 
examination before entering into the study.  
5.2 
Exclusion Criteria  
Deviations from exclusion criteria are not allowed because they can potentially jeopardise the 
scientific integrity, regulatory acceptability of the study or subject safety. Therefore, adherence 
to the criteria as specified in the protocol is essential. 
The following criteria should be checked at the time of study entry. If ANY exclusion criterion is 
met, the subject must not be included in the study.  
5.2.1 
Medical Conditions 
1. Any clinical condition that, in the opinion of the investigator, might pose any risk to the 
subject due to participation in the study. As with other vaccines, administration of 
Infanrix hexa should be postponed in subjects suffering from acute severe febrile illness. The 
presence of a minor infection is not a contraindication. 
2. Known history of diphtheria, tetanus, pertussis, HBV, poliomyelitis and Hib diseases since 
birth.   
3. History of any reaction or hypersensitivity likely to be caused or exacerbated by any 
excipient or active component of the vaccine(s). 

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4. Any confirmed or suspected immunosuppressive or immunodeficient condition, including 
malignancies, based on medical history and physical examination (no laboratory testing 
required). 
5. Family history of congenital or hereditary immunodeficiency. 
6. Major congenital defects, as assessed by the investigator. 
7. Acute or chronic clinically significant pulmonary, cardiovascular, hepatic or renal functional 
abnormality, as determined via medical history including physical examination. 
8. Medical history of neurological disorder, including seizures.  
5.2.2 
Prior/Concomitant Therapy 
9. Previous vaccination for diphtheria, tetanus, pertussis, HBV, poliomyelitis, Hib diseases and 
previous vaccination against pneumococcal infection with pneumococcal conjugate vaccine, 
with the exception of a birth dose of HBV vaccine, which may be given in accordance with 
local recommendations. 
10. Use of any investigational or nonregistered product (drug, vaccine, or medical device) other 
than the study vaccine(s) during the period starting 30 days before the first dose of study 
vaccine(s) (Day -29 to Day 1), or planned use during the study period. 
11. 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(s) with the exception of administration of vaccines given as part of the national 
immunisation schedule and as part of routine vaccination practice, e.g., rotavirus vaccine, 
that are allowed at any time during the study period. In case emergency mass vaccination for 
an unforeseen public health threat (e.g., a pandemic) is organised by public health authorities 
outside the routine immunisation programme, the time period described above can be 
reduced if necessary for that mass vaccination vaccine, provided this vaccine/product(s) is 
licensed and used according to its Product Information. 
12. Administration of long-acting immune-modifying drugs in the period starting 30 days before 
the first dose and at any time during the study period. 
13. Administration of immunoglobulins and/or any blood products or plasma derivatives from 
birth or planned administration during the study period. 
14. Chronic administration (defined as more than 14 days in total) of immunosuppressants or 
other immune-modifying drugs during the period starting 3 months prior to the first vaccine. 
For corticosteroids, this will mean prednisone ≥0.5 mg/kg/day (for paediatric subjects), or 
equivalent. Inhaled and topical steroids are allowed. 
5.2.3 
Prior/Concurrent Clinical Study Experience  
15. 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 (drug or medical device). 

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5.2.4 
Other Exclusions 
16. Child in care. 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
Screen failures are defined as subjects whose parent(s) or LAR(s) give consent for the subject to 
participate in the clinical study, but are not subsequently entered in the study. Screen failure 
information is maintained by the investigator as source data.  

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6.0 STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a subject according to the study protocol. Study 
treatments administered are presented in Table 5.  
6.1 
Study Treatment(s) Administered

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Table 5 
Treatments Administered 
Study Treatment  
Infanrix hexa 
Vaxelis  
Prevenar 13 
Vaccine/ Product 
DTPa-HBV-IPV 
Hib 
Vaxelis 
Prevenar 13 
Presentation 
Suspension for injection, Syringe 
Powder for 
suspension for 
injection, Vial 
Suspension for injection, Syringe 
Suspension for injection, Syringe 
Number of Doses  
3 
3 
3 
Dose Volume 
~0.5 mLa 
0.5 mL 
0.5 mL 
Route of 
Administration  
IM injection, right thigh 
IM injection, right thigh 
IM injection, left thigh 
Dosing Instructions 
Refer to and follow the SmPC or directions for handling 
and administration. 
Refer to and follow the SmPC or directions for 
handling and administration. 
Refer to and follow the SmPC or directions for 
handling and administration. 
Packaging and 
Labelling 
Study treatment will be provided in a carton, containing 
1 vial and 1 prefilled syringe without needles. Each 
carton will be clinically labeled as required per country 
requirement.   
Study treatment will be provided in a carton, 
1 prefilled syringe without needles. Each carton 
will be clinically labeled as required per country 
requirement. 
Study treatment will be provided in a carton, 
1 prefilled syringe without needles. Each carton will 
be clinically labeled as required per country 
requirement. 
Manufacturer 
GSK Biologicals 
MCM Vaccine BV 
Pfizer 
QA Release for 
Study 
GSK Biologicals 
GSK Biologicals 
GSK Biologicals 

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Study Treatment  
Infanrix hexa 
Vaxelis  
Prevenar 13 
Vaccine/ Product 
DTPa-HBV-IPV 
Hib 
Vaxelis 
Prevenar 13 
Dosage Formulation 
Diphtheria toxoid (≥30 I.U.) 
adsorbed on aluminium hydroxide; 
Tetanus toxoid (≥40 I.U.) adsorbed 
on aluminium hydroxide; 
Bordetella pertussis antigens-
Pertussis toxoid (PT) (25 µg) 
adsorbed on aluminium hydroxide; 
Bordetella pertussis antigens-
Filamentous Haemagglutinin 
(FHA) (25 µg) adsorbed on 
aluminium hydroxide; Bordetella 
pertussis antigens-Pertactin (PRN) 
(8 µg) adsorbed on aluminium 
hydroxide; Hepatitis B surface 
antigen (HBs) (10 µg) adsorbed on 
aluminium phosphate; Poliovirus 
(inactivated) (IPV) type 1 
(Mahoney strain) (40 DAgU); 
Poliovirus (inactivated) (IPV) 
type 2 (MEF-1 strain) (8 DAgU); 
Poliovirus (inactivated) (IPV) 
type 3 (Saukett strain) (32 DAgU); 
Aluminium hydroxide 
(Al(OH)₃)/Aluminium phosphate 
(AlPO₄) (0.7 mg Al³⁺); Medium 
199; Sodium chloride; Water for 
injections q.s. 0.5 mL 
Haemophilus 
influenzae type b 
polysaccharide 
(polyribo-
sylribitol 
phosphate, PRP) 
(10 µg) 
conjugated to 
tetanus toxoid 
(~25 µg) 
adsorbed on 
aluminium 
phosphate; 
Aluminium 
phosphate; 
Lactose 
Diphtheria toxoid (not less than 20 I.U.) 
adsorbed on aluminium phosphate; Tetanus 
toxoid  (not less than 40 µg I.U.) adsorbed on 
aluminium phosphate; Bordetella pertussis 
antigens - Pertussis toxin (20 µg) adsorbed on 
aluminium phosphate; Bordetella pertussis 
antigens - Filamentous haemagglutinin (20 µg) 
adsorbed on aluminium phosphate; Bordetella 
pertussis antigens - Pertactin (3 µg) adsorbed 
on aluminium phosphate; Bordetella pertussis 
antigens - Fimbriae type 2 and 3 (5 µg) 
adsorbed on aluminium phosphate; Hepatitis B 
surface antigen (10 µg) adsorbed on amorphous 
aluminium hydroxyphosphate sulfate; 
Poliovirus (Inactivated) Type 1 (Mahoney) 
(40 D antigen units); Poliovirus (Inactivated) 
Type 2 (MEF-1) (8 D antigen units); Poliovirus 
(Inactivated) Type 3 (Saukett) (32 D antigen 
units); Haemophilus influenzae type b 
polysaccharide (Polyribosylribitol Phosphate) 
(3 µg) conjugated to meningococcal protein 
(50 µg) adsorbed on amorphous aluminium 
hydroxyphosphate sulfate; Aluminium 
phosphate (0.17 mg Al³⁺); Amorphous 
aluminium hydroxyphosphate sulfate (0.15 mg 
Al³⁺); Glutaraldehyde (Traces); Formaldehyde 
(Traces); Neomycin (Traces); Streptomycin 
(Traces); Polymyxin B (Traces); Sodium 
phosphate; Water for injections q.s. 0.5 mL 
Pneumococcal polysaccharide serotype 1 (2.2 µg) 
conjugated to CRM₁₉₇ carrier protein, adsorbed on 
aluminium phosphate; Pneumococcal polysaccharide 
serotype 3 (2.2 µg) conjugated to CRM₁₉₇ carrier 
protein, adsorbed on aluminium phosphate; 
Pneumococcal polysaccharide serotype 4 (2.2 µg) 
conjugated to CRM₁₉₇ carrier protein, adsorbed on 
aluminium phosphate; Pneumococcal polysaccharide 
serotype 5 (2.2 µg) conjugated to CRM₁₉₇ carrier 
protein, adsorbed on aluminium phosphate; 
Pneumococcal polysaccharide serotype 6A (2.2 µg) 
conjugated to CRM₁₉₇ carrier protein, adsorbed on 
aluminium phosphate; Pneumococcal polysaccharide 
serotype 6B (4.4 µg) conjugated to CRM₁₉₇ carrier 
protein, adsorbed on aluminium phosphate; 
Pneumococcal polysaccharide serotype 7F (2.2 µg) 
conjugated to CRM₁₉₇ carrier protein, adsorbed on 
aluminium phosphate; Pneumococcal polysaccharide 
serotype 9V (2.2 µg) conjugated to CRM₁₉₇ carrier 
protein, adsorbed on aluminium phosphate; 
Pneumococcal polysaccharide serotype 14 (2.2 µg) 
conjugated to CRM₁₉₇ carrier protein, adsorbed on 
aluminium phosphate; Pneumococcal polysaccharide 
serotype 18C (2.2 µg) conjugated to CRM₁₉₇ carrier 
protein, adsorbed on aluminium phosphate; 
Pneumococcal polysaccharide serotype 19A (2.2 µg) 
conjugated to CRM₁₉₇ carrier protein, adsorbed on 
aluminium phosphate; Pneumococcal polysaccharide 
serotype 19F (2.2 µg) conjugated to CRM₁₉₇ carrier 
protein, adsorbed on aluminium phosphate; 
Pneumococcal polysaccharide serotype 23F (2.2 µg) 
conjugated to CRM₁₉₇ carrier protein, adsorbed on 
aluminium phosphate; Total CRM₁₉₇ carrier protein 
(32 µg [EU]/34 µg [US]); Aluminium phosphate 
(0.125 mg Al³⁺); Sodium chloride; Succinic acid; 
Polysorbate 80; Water for injections q.s. 0.5 mL 

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Subjects must be observed closely for at least 30 minutes after the administration of the vaccines. Appropriate medical treatment must be readily available during 
the observation period in case of anaphylaxis and/or syncope. 
Infanrix hexa and Vaxelis are administered IM to the right thigh; Prevenar 13 is administered to the left thigh.  
Abbreviations: IPV=inactivated poliovirus vaccine.  
a. Full volume after reconstitution (approximately 0.5 mL) to be administered.

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6.2 
Contraindications to Subsequent Vaccination 
6.2.1 
Criteria for Temporary Delay of Vaccination 
Vaccination may be delayed temporarily in the case of acute disease and/or fever at the time of 
vaccination.  
• 
Fever is defined as temperature 38.0°C.  
• 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) 
without fever may be enrolled at the discretion of the investigator. 
In case of fever at the time of vaccination, the vaccination visit could be rescheduled, within the 
time window specified in [Table 8]. 
6.2.2 
Other Contraindications to Subsequent Vaccination 
For additional information regarding contraindications to subsequent vaccination, refer to the 
respective SmPCs for Infanrix hexa, Vaxelis, and Prevenar 13. 
6.2.3 
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 
subject should remain under medical supervision for 30 minutes after vaccination. 
6.3 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
2. Only subjects enrolled in the study may receive study treatment and only authorised study 
centre staff may supply or administer study treatment. All study treatments must be stored in 
a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator and 
authorised study centre staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment are 
provided in the site study reference manual.  
The investigator, a member of the study centre staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study treatment using the Drug 
Accountability Form. These forms must be available for inspection at any time. 

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To maintain blinding, vaccination doses will be prepared in a separate room, out of sight of 
subjects/LARs.  
6.4 
Measures to Minimise Bias: Randomisation and Blinding 
6.4.1 
Subject Identification 
After checking the inclusion and exclusion criteria, subject identification numbers will be 
assigned sequentially to the subjects who have consented to participate in the study, according to 
the range of subject identification numbers allocated to the/each study centre. 
6.4.2 
Randomisation to Study Intervention 
All eligible subjects will be centrally randomised using IVRS randomisation. Before the study is 
initiated, log-in information and directions for the IVRS will be provided to each site. As this is a 
randomised single-blind study, the study treatment assigned to the subject will be known by the 
investigator, but the subject will be blinded to the treatment received.  
Once a treatment number has been assigned it cannot be re-assigned. 
6.4.3 
Intervention Allocation to the Subject 
Treatment allocation: The subjects will be randomised in a 1:1 ratio to either the Inv_group or 
Com_group (Section 1.2 and Section 6.1) using a minimisation algorithm with the study country 
and maternal immunisation as minimisation factors. This will be done at study entry, i.e., on 
Day 1 after consent was obtained and subjects were determined to be eligible, using IVRS 
randomisation. 
6.4.4 
Allocation Treatment Number for Subsequent Dose or Replacement 
For all subsequent doses, new treatment numbers will be obtained through the IVRS. 
6.4.5 
Blinding and Unblinding 
The laboratory in charge of sample testing will be blinded to the intervention assignment. Codes 
will be used to link the subject and study (without any link to the intervention attributed to the 
subject) to each sample. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment is warranted. Subject safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted and subject 
treatment is unblinded, GSK must be notified within 24 hours after breaking the blind. The date 
and reason that the blind was broken must be recorded in the source documentation and eCRF, as 
applicable. A subject may continue in the study if that subject’s intervention assignment is 
unblinded. 

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Unblinded monitors and, in the event of a Quality Assurance audit, the auditor(s), will be 
allowed access to unblinded study treatment information records at the site(s) to verify that 
randomisation/dispensing has been done accurately. 
Despite the fact that this is a single-blind study, the data management and biostatistics teams will 
remain blinded to the study treatment until after the final database lock. No unblinded data 
summaries (presented by treatment) will be available prior to the final database lock. An 
independent unblinded Biostatistician will be identified to review potentially unblinding 
information ahead of the final database lock, e.g., randomisation specifications and schedule. 
6.5 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. Any departures 
from the intended regimen must be recorded in the eCRFs. For dosing instructions and route, 
refer to Table 5. 
6.6 
Concomitant Therapy 
Exclusionary concomitant therapies are described in exclusion criteria Section 5.2.2.  
At each trial visit/contact, the investigator or delegate should question the participant’s 
parent(s)/LAR(s) about any medications/products taken and vaccinations received by the 
participant. The following concomitant medications/products/vaccines must be recorded in the 
eCRF: 
• All concomitant medications/products associated with an AE, except vitamins and 
dietary supplements, administered following each dose of investigational vaccine 
(Day 1 to Day 31). 
• Any vaccination administered in the period from birth until 30 days after the last dose 
of study vaccines. 
• Prophylactic medication (i.e., medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination or blood sampling), for 
example: 
− An antipyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom to prevent fever from occurring (fever is 
defined as temperature ≥ 38.0°C [100.4°F] regardless of the location of 
measurement). 
− A topical local anesthetic used prior to a blood sampling is considered to be 
prophylactic. 
• Any concomitant medications/products/vaccines listed in Section 5.2.2. 

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• Any concomitant medications/products/vaccines relevant to an SAE or administered 
at any time during the trial period for the treatment of an SAE. In addition, 
concomitant medications relevant to SAEs need to be recorded on the Expedited AE 
Report. 
These medications/products/vaccines must be recorded on the eCRF along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Prophylactic administration of antipyretics (paracetamol/acetaminophen and ibuprofen) before or 
immediately after vaccine administration can reduce the incidence and intensity of post-
vaccination febrile reactions.  
If the subject has a history of febrile seizures, prophylactic antipyretic treatment should be 
initiated according to local treatment guidelines.  
(Section 6.6 amended 06 April 2021) 
6.7 
Dose Modification 
This protocol does not allow alteration from the currently outlined dosing schedule. 
6.8 
Treatment After the End of the Study 
The investigator is encouraged to share immunological assay results for non-responders with the 
subjects’ parent(s)/LAR(s). 
For subjects identified as non-responders, it is the responsibility of the investigator in charge of 
the subject’s clinical management to determine the medical care needed as per local/regional 
practices (such as re-vaccination of the subject[s]). 
• 
Immunological correlate of protection: Data from subjects given unconjugated Hib vaccine 
suggest that, in the absence of induction of immunological memory, a concentration of 
0.15 µg/mL is indicative of short-term protection, with 1 µg/mL considered indicative of 
long-term protection [Anderson, 1984; Käyhty, 1983].  
During the study conclusion visit, the investigator will ask each subject’s parent(s)/LAR(s) if 
they are interested in participating in a potential study to evaluate the persistence of the Hib 
immune response. If they are not interested in participating in such a study the reason for refusal 
will be documented, when available, in the subject’s eCRF. 

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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Treatment  
Discontinuation of study vaccine(s) means any subject who has not received all planned doses of 
vaccine(s). A subject who discontinued study vaccine(s) may, if deemed appropriate by the 
investigator, continue other study procedures (e.g., safety or immunogenicity) if planned in the 
study protocol. 
7.2 
Subject Discontinuation/Withdrawal from the Study 
• Parents or LARs may withdraw a subject from the study at any time on request, or a subject 
may be withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. 
• If the subject’s parents or LARs withdraw consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a subject is withdrawn from the study, the subject’s parents or LARs may request 
destruction of any samples taken and not tested, and the investigator must document this in 
the study centre study records. 
Subjects who discontinue study treatment or are withdrawn will not be replaced. The eCRF 
should be completed as much as possible. 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if his or her parents or LARs fail to return the 
subject for scheduled visits and are unable to be contacted by the study centre.  
The following actions must be taken if a subject’s parents or LARs fail to return him or her to the 
clinic for a required study visit: 
• The study centre must attempt to contact the parents/LARs and reschedule the missed visit as 
soon as possible, and counsel the parents/LARs on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the parents/LARs wish the subject to 
continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the parents or LARs (where possible, 3 telephone calls and, if 
necessary, a certified letter to the parents’/LAR’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s medical 
record. 

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• Should the parents or LARs continue to be unreachable, the subject will be considered to 
have withdrawn from the study.  
7.4 
Reason for Discontinuation 
Subjects may be withdrawn from the treatment and the study for any of the following reasons: 
• The parents or LARs withdraw consent on behalf of the subject. 
• The parents or LARs are unwilling or unable to comply with the protocol. 
• Adverse event(s). 
• Lost to follow-up. 
• Protocol deviation(s). 
• Occurrence of contraindications that were not present at enrolment. 
• If, in the clinical judgment of the investigator, it is not in the subject’s best interest to 
continue with the study treatment. 
The reason for the subject’s withdrawal from the study or from treatment must be recorded in the 
subject’s eCRF. When a subject is withdrawn, the date of last contact and reason for 
treatment/study withdrawal (see above) should be clearly described in the relevant sections of the 
eCRF. If a subject is removed from study or treatment because of an AE, the reason for treatment 
withdrawal should always be stated as “adverse event” irrespective of whether this was the 
investigator’s or the parents’ or LARs’ decision. The subject should be followed until the event 
has resolved, stabilised, or returned to baseline. 

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8.0 STUDY ASSESSMENTS AND PROCEDURES 
 Study procedures and their timing are summarised in the Schedule of Activities (SoA)  
[Table 3].  
 Protocol waivers or exemptions are not allowed unless necessary for the management of an 
immediate safety concerns. 
 Immediate safety concerns should be discussed with the Sponsor upon occurrence or 
awareness to determine if the subject should continue or discontinue study treatment. 
 Adherence to the study design requirements, as specified in the SoA, is essential and required 
for study conduct. 
 The investigator is not allowed to do testing on samples outside of what has been agreed 
upon by the Independent Ethics Committee (IEC)/Institutional Review Board (IRB). 
 All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
 An overall blood volume of 7.5 mL will be collected during the entire study period. Refer to 
the SoA for details of volumes collected for different assessments as presented in Table 6 
(laboratory assays). 
8.1 
Immunogenicity Assessments  
Blood samples of approximately 2.5 mL each will be obtained at Visit 3, Visit 4 and Visit 5 
[Table 6]. Please refer to the Laboratory Manual for details on biospecimen management 
(handling, storage and shipment). Tests will be conducted at the Sponsor’s laboratory, or 
laboratories designated by the Sponsor. All blood sample testing is based on in-house assays. 
GSK clinical laboratories have established a Quality System supported by procedures. The 
activities of GSK clinical laboratories are audited regularly for quality assessment by an internal 
(sponsor-dependent) but laboratory-independent Quality Department. 
Refer to Table 6 for the laboratory assays to be performed and the SoA [Table 3] for the timing 
and frequency. See Table 10 for addresses of the clinical laboratories used for sample analysis.  
Collected biological 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.  
Future findings may make it desirable to use the samples acquired in this study for future 
research not described in this protocol, such as immunogenicity testing of the other study 
vaccines’ antigens. Therefore, all subjects in countries where this is allowed will be asked to give 
a specific consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to prior IEC/IRB approval if required per local legislation. 

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 Collected samples will be stored for a maximum of 20 years. This storage period begins 
when the last subject performs the last study visit, unless local rules, regulations or guidelines 
require different timeframes or procedures, which would then be in line with subject consent. 
These extra requirements need to be communicated formally to, and discussed and agreed on 
with, GSK. 
Table 6 
Laboratory Assays 
Sampling 
Time Points 
System 
Component 
Method 
Unit 
Number of 
Subjects 
 
Humoral immunity 
Month 3, 
Month 10, and 
Month 11 
Serum 
anti-PRP antibody 
ELISAa 
 µg/mL 
All 
 ELISA=enzyme linked immunosorbent assay  
8.2 
Safety Assessments  
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE [Appendix 4]. The investigator and any 
designees remain responsible for following up AEs that are serious, considered related to the 
study intervention or the study, or that caused the subject to discontinue the study intervention or 
discontinue from study. 
8.2.1 
Physical Examinations 
 A brief history-directed physical examination will include, at a minimum, assessment of 
body temperature and vital signs.  
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 Subject vaccination history and maternal dTpa immunisation history will be collected. 
8.2.2 
Vital Signs 
Temperature will be taken before each vaccination (i.e., at Visit 1, Visit 2 and Visit 4). Rectal 
temperature is preferred, but oral or axillary temperature is also allowed. Fever is defined as 
≥38˚C, regardless of route. 
If the subject has a fever, the vaccination should be postponed and a new visit scheduled 
considering the allowed visit windows. 
CCI
CCI
CCI

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8.3 
Adverse Events 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from Visit 1 through study end, at the time points specified in the 
SoA [Table 3]. 
All AEs will be collected from vaccination through the 31-day follow-up period after each 
vaccination, as specified in the SoA [Table 3]. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 4. The investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing the causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
8.3.2 
Method of Detecting AEs and SAEs 
Memory aids used by subjects’ parent(s)/LAR(s) will be reviewed for health related issues of 
subjects and for potential AEs which will be transcribed in eCRFs. Care will be taken not to 
introduce bias when detecting AEs and/or SAEs. Open-ended and nonleading verbal questioning 
of the subject’s parents or LARs is the preferred method to inquire about AE occurrences.  
For any unplanned/routine laboratory investigation performed, the investigator must review the 
laboratory report, document that he/she did so, and record any clinically relevant changes 
occurring during the study in the AE Section of the CRF/eCRF. Clinically significant abnormal 
laboratory findings are those which are not associated with an underlying disease, unless judged 
by the investigator to be more severe than expected for the participant's condition. 
• All clinically significant abnormal laboratory test values during the study or within 31 days 
after the last dose of study intervention should be repeated until the values return to normal 
or baseline, or are no longer considered significantly abnormal by the investigator or LML. 
Refer to Appendix 4 for more information on clinically abnormal laboratory assessments that 
qualify as an AE or SAE. 

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• If such values do not return to normal/baseline after an interval judged reasonable by the 
investigator, the aetiology should be identified and the sponsor notified. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilisation, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met. For SAEs, the investigator will always provide 
an assessment of causality at the time of the initial report, as defined in the Appendix 4. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will review 
and then file it and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Subject Card 
The investigator (or designee) must provide the subjects’ parent(s)/LAR(s) with a “subject card” 
containing information about the clinical study. The subject’s parent(s)/LAR(s) must be 
instructed to keep the subject card in his/her/their possession at all times throughout the study. In 
an emergency, this card serves to inform the responsible attending physician/LAR/care 
giver/family member that the subject is in a clinical study and that relevant information may be 
obtained by contacting the investigator. 
8.4 
Treatment of Overdose 
Not applicable. 
8.5 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 

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8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
 Genetics 
Genetics are not evaluated in this study. 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Medical Resource Utilisation and Health Economics 
Medical Resource Utilisation and Health Economics parameters are not evaluated in this study. 
9.0 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
For the co-primary endpoints, a hierarchical procedure will be used to control the risk of 
concluding erroneously. 
To demonstrate that the Hib response in Inv_group is non-inferior to Com_group, 1-month 
post-booster vaccination in terms of: 
• GMCs 
o Criterion: Lower limit (LL) of the 2-sided 95% confidence interval (CI) on group 
GMC ratio (Inv_group over Com_group) is above 0.5. 
• Percentage of subjects with anti-PRP antibody concentrations ≥5 µg/mL.  
o Criterion: First primary objective is met and the LL of the 2-sided 95% CI on 
group difference in the percentage (Inv_group minus Com_group) is above -10%.  
To demonstrate that the Hib response in Inv_group is superior to Com_group, 1-month 
post-booster vaccination in terms of:  
• GMCs 
o Criterion: All previous objectives are met and the LL of the 2-sided 95% CI on 
group GMC ratio (Inv_group over Com_group) is above 1. 
• Percentage of subjects with anti-PRP antibody concentrations ≥5 µg/mL. 
o Criterion: All previous objectives are met and the LL of the 2-sided 95% CI on 
group difference in the percentage (Inv_group minus Com_group) is above 0. 

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9.2 
Sample Size Determination  
The study will enrol approximately 500 subjects in a 1:1 ratio. Assuming that 20% of the 
subjects would not be evaluable, the power was computed for 400 evaluable subjects (i.e., 
200 subjects each in the Inv_group and Com_group). Evaluable is defined as: meeting all 
eligibility criteria, complying with the procedures defined in the protocol, and, therefore, 
qualified for inclusion in the according-to-protocol analysis. 
A 2.5% nominal type I error was used for each co-primary evaluation. To control the overall 
type I error below 2.5%, a hierarchical procedure will be used for the multiple study objectives. 
The study has: 
 
More than 99% power to reach the first co-primary objective. This power is obtained from 
PASS 2012, 1-sided t-test (non-inferiority with 0.5 group ratio as margin, i.e., -0.301 in log10 
Scale) for 2 independent means with common 0.63 variance of log10 transformed anti-PRP 
concentration, under the specific alternative that the group GMC ratio is 1.75  
[Silfverdal, 2016], i.e., 0.2430 in log10 scale, and 
 
More than 99% power to reach the second co-primary objective. This power is obtained 
from PASS 2012, 1-sided Miettinen and Nurminen [Miettinen, 1985] test (non-inferiority 
with -10% margin) for 2 independent proportions under the specific alternative that the 
proportions are 46% after Vaxelis and 62% after Infanrix hexa [Silfverdal, 2016] while 
accounting for the power to meet the first co-primary objective. 
 
Approximately 97% power to reach the third co-primary objective. This power is obtained 
from PASS 2012, 1-sided t-test (inequality) for 2 independent means with common 
0.63 variance in log10 scale, under the specific alternative that the group GMC ratio is 1.75 
[Silfverdal, 2016], i.e., 0.2430 in log10 scale while accounting for the power to meet the first 
co-primary objective. 
 
At least 80% power to reach all co-primary objectives. This power is obtained from PASS 
2012, 1-sided Z test (inequality) with pooled variance for 2 independent proportions under 
the specific alternative that the proportions are 46% after Vaxelis and 62% after 
Infanrix hexa [Silfverdal, 2016] while accounting for the power to meet the first 
3 co-primary objectives. 
9.3 
Analysis Sets 
For purposes of analysis, the analysis sets are defined in Table 7. 

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Table 7 
Analysis Sets 
Analysis Set 
Description 
Enrolled set 
All subjects with a study intervention (either randomised or vaccinated or with 
a blood draw). 
Exposed set (ES) 
All vaccinated subjects. Subjects will be analysed according to the 
intervention they received at Dose 1. 
Per protocol set (PPS) 
All eligible subjects who received all DTPa-combination study vaccines as per 
protocol, who had anti-PRP results post-vaccination, who complied with 
vaccination/blood draw intervals (Table 8), without intercurrent conditions 
that may interfere with immunogenicity and without prohibited concomitant 
medication/vaccination. Subjects will be analysed according to the 
intervention they received at Dose 1. 
 
 
 

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Table 8 
Intervals Between Study Visits 
Interval 
Length of interval 
Allowed interval 
Birth (age is 0 day on birth 
date)→ Visit 1 
6 to 12 weeks  
42 to 84 days 
Visit 1 → Visit 2 
60 days  
52, 78 days 
Visit 2 → Visit 3 
30 days  
21, 48 days  
Birth → Visit 4 
365 days  
335, 395 days  
Visit 4 → Visit 5 
30 days  
21, 48 days  
 
9.4 
Statistical Analyses 
The Statistical Analysis Plan will be developed and finalised before database lock and will 
describe the subject analysis sets to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 
All analyses, summaries, and listings will be performed using SAS® software (version 9.4 or 
higher). 
Individual subject data will be presented in listings. 
9.4.1 
Disposition 
The number of subjects screened, randomised, treated and who completed the study will be 
presented. For subjects who discontinue the treatment/study, the reason for discontinuing early 
will also be presented. 
9.4.2 
Demographics and Other Baseline Characteristics 
Baseline and demographic information will be summarised using descriptive statistics for 
continuous and ordinal variables (e.g., age, weight, height [Day 1 only]) and counts and 
percentages for categorical variables (e.g., sex, race). 
9.4.3 
Immunogenicity Analyses 
The confirmatory analyses of non-inferiority will be based on the PPS while the confirmatory 
analyses of superiority will be based on the ES. 
• 
Method for non-inferiority and superiority in anti-PRP antibody concentration at 1-month 
post-booster vaccination: 

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o The 2-sided 95% CI for group GMC ratio derived from an ANOVA model on 
log10 transformed concentration will be used. The model will include country, 
maternal immunisation and group as fixed effects. (Missing data will not be 
replaced. Concentration below assay cut-off will be replaced by half the assay 
cut-off). 
• 
Method for non-inferiority and superiority in the percentage of subjects with anti-PRP 
antibody concentration ≥5.0 µg/mL at 1-month post-booster vaccination: 
o The 2-sided 95% CI on group difference in seroconversion rate (Inv_group 
minus Com_group) will be computed based on Miettinen and Nurminen 
method [Miettinen, 1985]. 
• Descriptive analysis for each study group will be provided by country for Anti-PRP antibody 
concentrations at 1-month post-primary vaccination, pre-booster and 1-month post-booster 
vaccination, and for the percentage of subjects with anti-PRP antibody concentration 
≥5.0 µg/mL at 1-month post-booster vaccination. 
9.4.4 
Safety Analyses 
Descriptive analyses for the AEs and SAEs will be provided by study group. Safety data will be 
analysed on the ES population. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). For each study treatment, numbers of AEs and percentage of subjects with AE 
within 31 days post-vaccination will be tabulated by preferred term and system organ class.  
9.4.5 
Sequence of analyses 
An integrated clinical study report containing all data will be written and made available to the 
investigators. The data for tertiary objectives may be reported in an annex report if not available 
at the time the integrated clinical study report is prepared 
Data from subjects who withdraw from the study, including AEs and any follow-up, will be 
included in the analyses of primary and secondary outcomes. 
9.4.6 
Interim Analyses  
No interim analysis for efficacy is planned. 

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10.0 REFERENCES 
1. Agbarakwe AE, Griffiths H, Begg N, Chapel HM. Avidity of specific IgG antibodies elicited 
by immunisation against Haemophilus influenzae type b. J Clin Pathol. 1995;48:206-209. 
2. Anderson P. The protective levels of serum antibodies to the capsular polysaccharide of 
Haemophilus influenzae type b. J Infect Dis. 1984;149:1034-1035. 
3. Barbour ML. Conjugate vaccines and the carriage of Haemophilus influenzae type b. Emerg 
Infect Dis. 1996;2:176-182. 
4. ECDC. Haemophilus Influenzae Type B Infection and Diphtheria: Recommended 
vaccinations Web site. https://vaccine-
schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=5&SelectedCountryIdBy
Disease=-1; https://vaccine-
schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=1&SelectedCountryIdBy
Disease=-1. Accessed 13 May 2019. 
5. EMA. Vaxelis – European Public Assessment Report (EPAR) summary for the public. 
EMA/CHMP/72003/2016 Web site. https://www.ema.europa.eu/en/documents/assessment-
report/vaxelis-epar-public-assessment-report_en.pdf. Accessed 13 May 2019. 
6. Fernandez J, Levine OS, Sanchez J, Balter S, LaClaire L, Feris J, et al. Prevention of 
Haemophilus influenzae Type b Colonization by Vaccination: Correlation with Serum 
Anti-Capsular IgG Concentration. J Infect Dis. 2000;182:1553-1556. 
7. Käyhty H, Peltola H, Karanko V, Mäkelä PH. The protective level of serum antibodies to the 
capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis.1983;147:1100. 
8. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4:213-226. 
9. Peltola H, Käyhty H, Sivonen A, Mäkelä H . Haemophilus influenzae Type b Capsular 
Polysaccharide Vaccine in Children: A Double-Blind Field Study of 100000 Vaccinees 3 
Months to 5 Years of Age in Finland. Pediatrics. 1977;60(5):730-737. 
10. Schlesinger Y, Granoff DM. Avidity and bactericidal activity of antibody elicited by 
different Haemophilus influenzae type b conjugate vaccines. The vaccine study group. 
JAMA. 1992;267:1489-1494. 
11. Silfverdal SA, Icardi G, Vesikari T, Flores SA, Pagnoni MF, Xu J, et al. A Phase III 
randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at 2, 4, 
and 11-12 months. Vaccine. 2016;19;34(33):3810-3816. doi: 10.1016/j.vaccine.2016.05.054.  

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12. Vesikari T, Silfverdal SA, Jordanov E, Feroldi E. A Randomized, Controlled Study of DTaP-
IPV-HB-PRP-T, a Fully Liquid Hexavalent Vaccine, Administered in a 3-, 5- and 11- to 12-
month Schedule. Pediatr Infect Dis. 2017;36(1):87-93. 
13. Wang S, Tafalla M, Hanssens L, Dolhain J. A review of Haemophilus influenzae disease in 
Europe from 2000-2014: challenges, successes and the contribution of hexavalent 
combination vaccines. Expert Rev Vaccines. 2017;16(11):1095-1105. doi: 
10.1080/14760584.2017.1383157.  

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11.0 APPENDICES 

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Appendix 1 
Abbreviations and Glossary of Terms 
AE: 
Adverse Event 
CI: 
Confidence Interval 
Com_group: Comparator group 
dTpa: 
Combined reduced-antigen-content diphtheria, tetanus and acellular 
pertussis vaccine 
DTPa-
HBV-
IPV/Hib 
Diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus 
vaccine and Haemophilus influenzae type b conjugate vaccine 
eCRF: 
electronic Case Report Form 
EoS 
End of Study 
ES: 
Exposed Set 
GCP: 
Good Clinical Practice 
GMC: 
Geometric Mean Concentration 
GSK: 
GlaxoSmithKline Biologicals SA 
HBV 
Hepatitis B virus 
Hib: 
Haemophilus influenzae type b 
Hib-OMP: 
Hib component of Vaxelis; outer membrane protein (OMP) that is 
covalent bound to polyribosylribitol phosphate (PRP) 
Hib-TT: 
PRP conjugated to tetanus toxoid (TT) carrier protein 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
Inv_group: 
Investigational group 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
LAR: 
Legally acceptable representative 
LL: 
Lower limit 
µg 
Microgram 
mL 
Millilitre 
PPS: 
Per Protocol Set 
PRP: 
Polyribosylribitol phosphate 

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SAE: 
Serious Adverse Event 
SoA 
Schedule of Activities 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 

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Glossary of Terms 
Adverse event: 
Any untoward medical occurrence in a subject or clinical 
investigation subject, temporally associated with the use of a 
medicinal product, whether or not considered related to the 
medicinal product. 
An adverse event (AE) can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed 
medicinal products, this also includes failure to produce 
expected benefits (i.e., lack of efficacy), abuse or misuse. 
Blinding: 
A procedure in which one or more parties to the trial are kept 
unaware of the treatment assignment in order to reduce the risk 
of biased study outcomes. The level of blinding is maintained 
throughout the conduct of the trial, and only when the data are 
cleaned to an acceptable level of quality will appropriate 
personnel be unblinded or when required in case of a serious 
adverse event. In a single-blind study, the investigator knows 
the identity of the treatment assigned while the subject’s 
parent(s)/legally acceptable representatives(s) don’t know. 
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. 
End of Study:  
(Synonym of End of Trial) 
For studies without collection of human biologicals samples or 
imaging data End of Study (EoS) is the Last Subject Last Visit 
(LSLV). 
For studies with collection of Human Biologicals Samples or 
imaging data, EoS is defined as the date of the last 
testing/reading released of the Human Biological Samples or 
imaging data, related to primary and secondary endpoints. EoS 
must be achieved no later than 8 months after LSLV 
Study phase: 
A study phase 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 

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within that study phase allows to draw a complete conclusion 
to define or precise the targeted label of the product. Typical 
examples of study phases are primary vaccinations, boosters, 
yearly immunogenicity follow-ups, and surveillance periods 
for efficacy or safety. 
Evaluable: 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol, and, therefore, included in the Per 
Protocol Set (PPS). 
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. 
Intercurrent medical 
condition: 
A condition that has the capability of altering a subject’s 
immune response or are confirmed to have an 
immunodeficiency condition during the study. 
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.  
Legally Acceptable 
Representative (LAR) 
(The terms legal 
representative or legally 
authorised representative are 
used in some settings.) 
An individual or juridical or other body authorised under 
applicable law to consent, on behalf of a prospective subject, 
to the subject's participation in the clinical trial. 
Primary completion date: 
The date that the final subject was examined or received an 
intervention for the purpose of final collection of data for all 
primary outcomes, whether the clinical trial was concluded 
according to the pre-specified protocol or was terminated. 
Randomisation: 
Process of random attribution of treatment to subjects in order 
to reduce bias of selection. 
Site Monitor: 
An individual assigned by the sponsor who is responsible for 
assuring proper conduct of clinical studies at one or more 
investigational sites. 
Study vaccine: 
Any investigational vaccine being tested and/or any authorised 
use of a vaccine as a reference or administered concomitantly, 
in a clinical trial that evaluates the use of an investigational 
vaccine. 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 

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Subject: 
Term used throughout the protocol to denote an individual 
who has been contacted in order to participate or participates 
in the clinical study, either as a recipient of the vaccines or as a 
control. 
Treatment number: 
A number identifying a treatment to a subject, according to the 
study randomisation or treatment allocation. 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or placebo 
intended to be administered to a subject, identified by a unique 
number, according to the study randomisation or treatment 
allocation. 
Unsolicited adverse event: 
Any AE reported in addition to those solicited during the 
clinical study. Also, any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse event. 
 

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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
Companies/organisations responsible for conducting the study are presented in Table 9. 
 
 This study will be conducted in accordance with the protocol and with the following: 
Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines. 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines. 
Applicable laws. 
 The protocol, protocol amendments, Informed Consent Form (ICF), SmPCs, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IRB/IEC and regulatory authority approval, 
when applicable, before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to subjects.  
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
o Providing oversight of the conduct of the study at the study centre and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
 After reading the protocol, each investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 6). The study will not 
start at any study centre at which the investigator has not signed the protocol. 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 

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Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects in this study. The terms of the insurance will be kept in the study files. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the subject 
subject’s parents or LARs and answer all questions regarding the study.  
 The subject’s parents or LARs must be informed that participation is voluntary. The subject’s 
parents or LARs will be required to sign a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines, and the IRB/IEC or study centre.  
 The medical record must include a statement that written informed consent was obtained 
before the subject was entered in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF. 
 Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
 A copy of the ICF(s) must be provided to the subject or the subject’s LAR.  
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorised designee will explain to each 
subject the objectives of the exploratory research. Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a subject’s agreement to allow 
any remaining specimens to be used for exploratory research. Subjects who decline to participate 
in this optional research will not provide this separate signature. 
Data Protection 
 Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
 The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.  
 The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
 

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Administrative Structure 
Table 9 
Study Administrative Structure 
Function 
Responsible Organisation 
Study Operations Management 
Medical Monitoring, Study Master File 
IQVIA 
Randomisation Code 
Cenduit 
Clinical Supply Management, Quality Assurance 
Auditing 
GSK 
Biostatistics 
Medical Writing 
IQVIA 
Laboratory Assessments 
GSK 
Electrocardiogram Collection, Review, and Analysis 
Not applicable 
Pharmacokinetic Sample Testing 
Not applicable 
 
Medical Monitor 
Refer to study reference manual. 
Dissemination of Clinical Study Data 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study register in compliance with the applicable 
regulations/GSK policy. GSK will aim to register protocol summaries prior to study start and 
target result summaries submission within 12 months of primary/ study completion date. Where 
external regulations require earlier disclosure, GSK will follow those timelines.  
Where required by regulation, summaries will also be posted on applicable national or regional 
clinical trial registers. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and provided reasonable access to statistical 
tables, figures, and relevant reports. GSK will also provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary results with 
study subjects, as appropriate. 
GSK will provide the investigator with randomisation codes for their site only after completion 
of the full statistical analysis. 
GSK intends to make anonymised subject-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 

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science or improve subject care. This helps ensure the data provided by trial subjects are used to 
maximum effect in the creation of knowledge and understanding. 
Data Quality Assurance 
 All subject data relating to the study will be recorded on printed or eCRFs unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.  
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised study centre personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.  
 Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
Source Documents 
The investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study centre’s subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (e.g., via an audit trail). 
 Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s study centre. 
 Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
 Source data are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for 

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the reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies). 
 Source documents are defined as original legible documents, data, and records (e.g., hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects' memory aids or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical trial).  
Study and Study Centre Closure 
The Sponsor designee reserves the right to close the study centre or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centres will be closed upon study 
completion. A study centre is considered closed when all required documents and study supplies 
have been collected and a study centre closure visit has been performed. 
The investigator may initiate study centre closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study centre by the Sponsor or investigator may include but are 
not limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines. 
 Inadequate recruitment of subjects by the investigator. 
 Discontinuation of further study treatment development. 
Publication Policy 
GSK aims to submit for publication the results of the study in searchable, peer reviewed 
scientific literature within 18 months from Last Subject Last Visit (LSLV) for interventional 
studies and follows the guidance from the International Committee of Medical Journal Editors. 

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Appendix 3 
Clinical Laboratory Tests  
• The immunogenicity tests detailed in Table 6 will be performed. 
All laboratory testing will be performed at GSK’s laboratory or in a laboratory designated by 
GSK. All blood sample testing is based on in-house assays. 
Laboratory/analyte results that could unblind the study will not be reported to study centres or 
other blinded personnel until the study has been unblinded. 
Table 10 
GSK Biologicals’ Laboratories 
Laboratory 
Address 
GSK Biologicals Global Vaccine Clinical Laboratory, 
Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Global Vaccine Clinical Laboratory, 
Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
 

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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a subject or subject, temporally associated with the use 
of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: 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 
study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (i.e., not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE 
or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the 
definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the subject’s condition, or that present or are detected at the start of the study and do not 
worsen. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the subject’s condition. 
• 
Hospitalisation for elective treatment of a pre-existing condition (known or diagnosed prior to 
informed consent signature) that did not worsen from baseline. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
 

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Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
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 inpatient hospitalisation or prolongation of existing hospitalisation 
In general, hospitalisation signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or an outpatient setting. Complications that occur during 
hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any other serious criteria, the 
event will also be considered as serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious. 
d) Results in persistent disability/incapacity 
• 
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, and accidental trauma (e.g., sprained 
ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 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 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include 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. 
If an event meets the criteria to be determined as “serious”, 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. 
• 
Erroneous administration. 
• 
Other cause (specify). 
Assessment of Outcome 
The Investigator will assess the outcome of all unsolicited AEs (including SAEs) recorded during the study 
as: 
• 
Recovered/resolved. 

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•
Recovering/resolving.
•
Not recovered/not resolved.
•
Recovered with sequelae/resolved with sequelae.
•
Fatal (SAEs only).
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g.,
hospital progress notes, laboratory reports, and diagnostics reports) related to the event.
•
The investigator will then record all relevant AE/SAE information in the eCRF. Each event must be
recorded separately.
•
It is not acceptable for the investigator to send photocopies of the subject’s medical records to IQVIA
in lieu of appropriate completion of the IQVIA/AE/SAE eCRF page.
•
There may be instances when copies of medical records for certain cases are requested by IQVIA. In
this case, all subject identifiers, with the exception of the subject number, will be redacted on the
copies of the medical records before submission to IQVIA.
•
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will
be documented as the AE/SAE.
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to one of the following categories:  
•
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering
with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities.
•
Severe: An event that prevents normal everyday activities.
An AE that is assessed as severe should not be confused with an SAE. Severe is a category utilised for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 

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Assessment of Causality 
The Investigator is obligated to assess the relationship between study vaccine(s) and the occurrence of each 
AE/SAE using clinical judgment. In case of concomitant administration of multiple vaccines, if possible, 
the Investigator should specify if the AE could be causally related to a specific vaccine administered (i.e., 
investigational or co-administered vaccine). When causal relationship to a specific vaccine(s) cannot be 
determined, the Investigator should indicate the AE to be related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the event to the study vaccine(s) will be considered and 
investigated. The Investigator will also consult the SmPC and/or Prescribing Information (PI) for marketed 
products to determine his/her assessment. 
There may be situations when an SAE has occurred and the Investigator has minimal information to 
include in the initial report to IQVIA. However, it is very important that the Investigator always makes an 
assessment of causality for every event prior to submission of the Expedited Adverse Events Report to 
IQVIA. The Investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
Causality of all unsolicited AEs should be assessed by the Investigator using the following question: 
Is there a reasonable possibility that the AE may have been caused by the study vaccine? 
YES: There is a reasonable possibility that the study vaccine(s) contributed to the AE. 
NO: There is no reasonable possibility that the AE is causally related to the administration of the study 
vaccine(s). There are other, more likely causes and administration of the study vaccine(s) is not suspected 
to have contributed to the AE. 
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well
as the temporal relationship of the event to study treatment administration will be considered and
investigated.
•
The investigator will also consult the SmPC and/or Product Information, for marketed products, in
his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the
AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred, and the investigator has minimal information
to include in the initial report to IQVIA. However, it is very important that the investigator always
make an assessment of causality for every event before the initial transmission of the SAE data to
IQVIA.
•
The investigator may change his/her opinion of causality in light of follow-up information and send an
SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
Follow-up of AEs and SAEs 
The investigator will provide any new or updated relevant information on previously reported SAE to GSK 
using a paper/electronic Expedited Adverse Events Report as applicable. The investigator is obliged to 
perform or arrange for the conduct of supplemental clinical examinations/tests and/or evaluations to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. 

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Reporting of SAEs 
SAE Reporting to IQVIA via an Electronic Data Collection Tool 
•
The primary mechanism for reporting an SAE to IQVIA will be the electronic data collection tool.
•
If the electronic system is unavailable for more than 24 hours, then the study centre will use the paper
SAE data collection tool (see next section).
•
The study centre will enter the SAE data into the electronic system as soon as it becomes available.
•
After the study is completed at a given study centre, the electronic data collection tool will be taken
off-line to prevent the entry of new data or changes to existing data.
•
If a study centre receives a report of a new SAE from a subject or receives updated data on a
previously reported SAE after the electronic data collection tool has been taken off-line, then the study
centre can report this information on a paper SAE form (see next section) or to the medical
monitor/SAE coordinator by telephone.
•
Contacts for SAE reporting can be found in the study reference manual.
Back-up SAE Reporting to IQVIA via Paper (in Case of Electronic System Failure) 
•
Facsimile transmission of the SAE paper eCRF is the preferred method to transmit this information to
the medical monitor or the SAE coordinator.
•
In rare circumstances and in the absence of facsimile equipment, notification by telephone is
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to complete and sign the
SAE eCRF pages within the designated reporting time frames.
•
Contacts for SAE reporting can be found in the study reference manual.

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Appendix 5 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Protocol Amendment 1 (additions bold and italic; deletions strikethrough and): 
Synopsis and Section 3.0: Addition of “≥” to the secondary immunogenicity objective, preceding 
the numbers of the thresholds for short-term and long-term protection: 
To assess the immunogenicity of Hib-components in terms of percentage of subjects above the 
thresholds for short-term (≥0.15 µg/mL) and long-term (≥1.0 µg/mL) protection as well as in 
terms of GMCs (post primary, pre- and post-booster vaccination). 
Section 6.6: 
Exclusionary concomitant therapies are described in exclusion criteria Section 5.2.2.  
At each trial visit/contact, the investigator or delegate should question the participant’s 
parent(s)/LAR(s) about any medications/products taken and vaccinations received by the 
participant. The following concomitant medications/products/vaccines must be recorded in the 
eCRF: 
• All concomitant medications/products associated with an AE, except vitamins and 
dietary supplements, administered following each dose of investigational vaccine 
(Day 1 to Day 31). 
• Any vaccination administered in the period from birth until 30 days after the last dose 
of study vaccines. 
• Prophylactic medication (i.e., medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination or blood sampling), for 
example: 
− An antipyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom to prevent fever from occurring (fever is 
defined as temperature ≥ 38.0°C [100.4°F] regardless of the location of 
measurement). 
− A topical local anesthetic used prior to a blood sampling is considered to be 
prophylactic. 
• Any concomitant medications/products/vaccines listed in Section 5.2.2. 
• Any concomitant medications/products/vaccines relevant to an SAE or administered 
at any time during the trial period for the treatment of an SAE. In addition, 

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concomitant medications relevant to SAEs need to be recorded on the Expedited AE 
Report. 
These Concomitant medications/vaccinations information will be collected at each study visit. 
medications/products/or vaccines (including over-the-counter or prescription medicines) that the 
subject is receiving at the time of enrolment (or within 14 to 30 days before the time of 
enrolment, as detailed in Section 5.2.2) or receives during the study must be recorded on the 
eCRF along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
A list of excluded medications/therapy is provided in Section 5.2.2. 
Prophylactic administration of antipyretics (paracetamol/acetaminophen and ibuprofen) before or 
immediately after vaccine administration can reduce the incidence and intensity of post-
vaccination febrile reactions.  
 
 

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Appendix 6 
Signature of Investigator 
PROTOCOL TITLE: A phase IV, single-blind, randomised, controlled, multi-country study to 
evaluate the immunogenicity and safety of GSK’s Infanrix hexa (DTPa-HBV-IPV/Hib) versus 
MCM Vaccine BV’s Vaxelis (DTaP5-HBV-IPV-Hib), when administered intramuscularly 
according to a 2-, 4- and 12-month schedule in healthy infants and toddlers  
PROTOCOL NO: 
212645 
VERSION:  
 
Amendment 1  
This protocol is a confidential communication of GlaxoSmithKline Biological SA. I confirm that 
I have read this protocol, I understand it, and I will work according to this protocol. I will also 
work consistently with the ethical principles that have their origin in the Declaration of Helsinki 
and that are consistent with Good Clinical Practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from the Sponsor. 
Instructions to the investigator:  Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
centre in which the study will be conducted. Return the signed copy to IQVIA.  
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      __________________________            Date:  ________ 
Printed Name:                                ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Centre:               
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________