Persistence of Hepatitis B Antibodies, Immunogenicity and Safety of GlaxoSmithKline (GSK) Biologicals' Hepatitis B Vaccine, Engerix™-B Kinder (SKF103860) Challenge Dose, in Adolescents Vaccinated With Four Doses of Infanrix™ Hexa (SB217744) During Infancy
Phase: PHASE4
Conditions: Hepatitis B
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l'Institut 89
1330 Rixensart, Belgium
Primary Study vaccine and 
number
GlaxoSmithKline (GSK) Biologicals’:
!
Hepatitis B vaccine, Engerix™-B Kinder
(SKF103860)
!
Combined diphtheria-tetanus-acellular pertussis
hepatitis B-inactivated poliovirus and
Haemophilus influenzae type b (DTPa-
HBVIPV/Hib) vaccine, Infanrix™ hexa 
(SB217744)
eTrack study number and 
Abbreviated Title
106794 (DTPA-HBV-IPV-115)
EudraCT number
2015-003391-74
Date of protocol
Final Version 01: 06 November 2015
Title
Persistence of hepatitis B antibodies, immunogenicity 
and safety of GSK Biologicals’ hepatitis B vaccine, 
Engerix™-B Kinder (SKF103860) challenge dose, in 
adolescents vaccinated with four doses of Infanrix™ 
hexa (SB217744) during infancy.
Detailed Title
A phase IV, open-label, multicentre study to assess the 
long-term persistence of antibodies against hepatitis B 
and the immunogenicity and safety of a challenge dose 
of hepatitis B vaccine (Engerix-B™ Kinder 
SKF103860) in children aged 14-15 years, previously 
primed and boosted in the first two years of life with 
four doses of GSK Biologicals’ DTPa-HBV-IPV/Hib 
(Infanrix™ hexa SB217744) vaccine.
Co-ordinating author
 Scientific Writer

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eTrack study number and 
Abbreviated Title
106794 (DTPA-HBV-IPV-115)
EudraCT number
2015-003391-74
Date of protocol
Final Version 01: 06 November 2015
Title
Persistence of hepatitis B antibodies, immunogenicity 
and safety of GSK Biologicals’ hepatitis B vaccine, 
Engerix™-B Kinder (SKF103860) challenge dose, in 
adolescents vaccinated with four doses of Infanrix™ 
hexa (SB217744) during infancy.
Detailed Title
A phase IV, open-label, multicentre study to assess the 
long-term persistence of antibodies against hepatitis B 
and the immunogenicity and safety of a challenge dose 
of hepatitis B vaccine (Engerix-B™ Kinder 
SKF103860) in children aged 14-15 years, previously 
primed and boosted in the first two years of life with 
four doses of GSK Biologicals’ DTPa-HBV-IPV/Hib 
(Infanrix™ hexa SB217744) vaccine.
Contributing authors
!
 Project-level Clinical 
Research and Development Lead
!
Clinical Research and 
Development Lead
!
 Project Statistician
!
 Lead Statistician
!
 Study Delivery Lead
!
 Study Delivery Manager
!
 Vaccine Supply Coordinator
!
 Clinical Safety representative
!
 Project Data Manager
!
 Study Data Manager
!
 Global Clinical Regulatory 
Affairs Representative
!
 Clinical Laboratory Sciences Read-
out Team Leader
!
Clinical Laboratory Sciences 
Study Manager
!
 Global Patent Representative
!
 Local Delivery Lead
GSK Biologicals’ Protocol DS v 14.1.1
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.

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Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
106794 (DTPA-HBV-IPV-115)
EudraCT number
2015-003391-74
Date of protocol
Final Version 01: 06 November 2015
Detailed Title 
A phase IV, open-label, multicentre study to assess 
the long-term persistence of antibodies against 
hepatitis B and the immunogenicity and safety of a 
challenge dose of hepatitis B vaccine (Engerix-B™ 
Kinder SKF103860) in children aged 14-15 years, 
previously primed and boosted in the first two years 
of life with four doses of GSK Biologicals’ DTPa-
HBV-IPV/Hib (Infanrix™ hexa SB217744) vaccine.
Sponsor signatory
Narcisa Elena Mesaros, MD
Project level Clinical Research and Development 
Lead, DTP/Polio Vaccines, Late Clinical 
Development, Vaccine Discovery and Development,
GlaxoSmithKline Biologicals, SA
Signature
Date
 
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Protocol Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
106794 (DTPA-HBV-IPV-115)
EudraCT number
2015-003391-74
Date of protocol
Final Version 01: 06 November 2015
Detailed Title
A phase IV, open-label, multicentre study to assess 
the long-term persistence of antibodies against 
hepatitis B and the immunogenicity and safety of a 
challenge dose of hepatitis B vaccine (Engerix-B™ 
Kinder SKF103860) in children aged 14-15 years, 
previously primed and boosted in the first two years 
of life with four doses of GSK Biologicals’ DTPa-
HBV-IPV/Hib (Infanrix™ hexa SB217744) vaccine.
Investigator name
Signature
Date
 
function and 
title
Signature
Date
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals, Rue de l'Institut 89, 1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.4.2
 
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SYNOPSIS
Detailed Title
A phase IV, open-label, multicentre study to assess the long-
term persistence of antibodies against hepatitis B and the 
immunogenicity and safety of a challenge dose of hepatitis B 
vaccine (Engerix-B™ Kinder SKF103860) in children aged 
14-15 years, previously primed and boosted in the first two 
years of life with four doses of GSK Biologicals’ DTPa-HBV-
IPV/Hib (Infanrix™ hexa SB217744) vaccine.
Indication
Immunisation against infection caused by all known subtypes 
of hepatitis B virus.
Rationale for the 
study and study 
design

Rationale for the study
In the global context of vaccination against hepatitis B, the 
European Medicines Agency (EMA) has requested GSK 
Biologicals to set up a long-term surveillance programme of 
vaccines containing a recombinant hepatitis B component. 
This study is the last study in a series of four studies, 
constituting a common follow-up programme of vaccination 
with Infanrix hexa. The previous studies conducted in this 
series are mentioned below: 

106789 (DTPA-HBV-IPV-112): The study was 
conducted in healthy subjects 4-5 years of age at the time 
of enrolment, who received four consecutive doses of 
Infanrix hexa [Steiner, 2010].

112688 (DTPA-HBV-IPV-113): The study was 
conducted in healthy subjects 7-8 years of age at the time 
of enrolment who received four consecutive doses of 
Infanrix hexa [Meeren, 2014].

106793 (DTPA-HBV-IPV-114): The study was 
conducted in healthy subjects 12-13 years of age at the 
time of enrolment who received four consecutive doses of 
Infanrix hexa.
This study aims to determine the persistence, from childhood 
to adolescence of immunity to hepatitis B that is conferred by 
4 doses vaccination with Infanrix hexa in the first 2 years of 
age. Persistent immunity to hepatitis B was assessed 
previously, in four to five year old, seven to eight year old and 
12-13 year old children who were vaccinated with four doses 
of Infanrix hexa, as part of routine vaccination in infancy, in 
Germany. More than 60% of subjects showed seroprotective 
persistent antibody concentrations and at least 96% of subjects 
in all age groups showed an anamnestic response to the single 
hepatitis B challenge dose [Steiner, 2010; Meeren, 2014; GSK 
 
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Biologicals’ Clinical Study Report (106793)]. Infanrix hexa
was licensed for use in Germany in 2000. The results 
observed in these studies are in line with the results observed 
when children and adolescents were primed with three doses 
of a monovalent hepatitis B vaccine [Behre,2012]. Infanrix 
hexa was licensed for use in Germany in 2000. Thus, children 
who received routine vaccination in the year 2001 with 
Infanrix hexa will reach an age of 14 to 15 years by 2016. 
These children will be invited to participate in this study in 
order to collect persistence data for hepatitis B antibodies and 
to assess the anamnestic response, immunogenicity, safety and 
reactogenicity of a single challenge dose of the hepatitis B 
vaccine (Engerix-B Kinder).

Rationale for the study design
This study will be conducted with a single group of subjects 
as all children recruited will receive a single challenge dose of 
HBV vaccine. A blood sample will be taken before and one 
month after the single challenge dose to evaluate:

The persistence of anti-HBs antibody concentrations in 
subjects 14-15 years of age previously vaccinated with 
four doses of Infanrix hexa in the first two years of life.

The ability to mount an anamnestic response to the single 
HBV challenge dose.

The safety and reactogenicity of the single challenge dose 
of HBV vaccine.
Since this study involves a single study group and all subjects 
will be administered the same vaccine, it is planned to be 
conducted in an open and non-randomised manner.
Objectives
Primary

To assess the immunological response to hepatitis B 
antigen, in terms of antibody concentrations 
≥100 mIU/ml, one month after the single challenge dose 
of the HBV vaccine in subjects 14-15 years of age, 
previously vaccinated with four doses of Infanrix hexa in 
the first two years of life.
Secondary

To assess the persistence of anti-HBs antibodies, in terms 
of seroprotection status and antibody concentrations, in 
subjects 14-15 years of age, previously vaccinated with 
four doses of Infanrix hexa in the first two years of life.
 
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
To assess the immunological response to hepatitis B 
antigen, in terms of anamnestic response, one month after 
the single challenge dose of the HBV vaccine in subjects 
14-15 years of age, previously vaccinated with four doses 
of Infanrix hexa in the first two years of life.

To assess the immunological response to the hepatitis B 
antigen, in terms of seroprotection status and antibody 
concentrations, one month after the single challenge dose 
of the HBV vaccine in subjects 14-15 years of age, 
previously vaccinated with four doses of Infanrix hexa in 
the first two years of life.

To evaluate the safety and reactogenicity of a single 
challenge dose of HBV vaccine (Engerix-B Kinder) in 
terms of solicited symptoms (local and general), 
unsolicited symptoms and serious adverse events (SAEs).
Study design

Experimental design: Phase IV, open-label, non-
randomised, multi-centric, single-country study with a 
single group.

Duration of the study: the intended duration of the study, 
per subject, will be approximately one month. The study 
will have a single epoch as follows:

Epoch 001: Primary starting at Visit 1 (Day 0) and 
ending at Visit 2 (Month 1).

Study groups: The study groups are presented in Synopsis 
Table 1 and Synopsis Table 2.
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epochs
Epoch 001
HBV Group
300
14 years – 15 years
x
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine name
HBV Group 
Engerix-B Kinder
HBV
●

Control: uncontrolled

Vaccination schedule: A single dose of HBV vaccine will 
be administered to all subjects, who were previously 
primed and boosted with four doses of Infanrix hexa in the 
first two years of life.

Treatment allocation: non-randomised
 
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
Blinding: open-label
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
open

Sampling schedule: Blood samples will be taken from each 
subject at the following time-points: 

Pre-vaccination: at Visit 1, before the administration of 
the single challenge dose of HBV vaccine.

Post-vaccination: at Visit 2, approximately one month 
after the single challenge dose of HBV vaccine.

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF).
Number of subjects
Approximately 300 children aged 14-15 years will be enrolled 
in this study. They should have received four doses of Infanrix
hexa with the three primary vaccination doses received by 9 
months of age and the booster dose received between 11 and 18 
months of age as part of routine vaccination practice in 
Germany.
Endpoints
Primary

Immunogenicity to components of the study vaccine.

Anti-HBs antibody concentrations ≥100 mIU/ml, one 
month after the single challenge dose of HBV vaccine.
Secondary

Anti-HBs antibody persistence after previous vaccination 
with Infanrix hexa.

Anti-HBs antibody concentrations ≥10 mIU/ml, ≥100 
mIU/ml and anti-HBs antibody concentrations before 
the single challenge dose of HBV vaccine.

Immunogenicity to the components of the study vaccine.

Anti-HBs antibody concentrations ≥10 mIU/ml and 
anti-HBs antibody concentrations one month after the 
single challenge dose of HBV vaccine.

Anamnestic response to the single challenge dose of 
HBV vaccines.
 
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
Solicited local and general symptoms.

Occurrence of each solicited local and general 
symptom during the 4-day (Day 0–3) follow-up period 
after the single challenge dose of HBV vaccine.

Unsolicited adverse events

Occurrence of unsolicited AEs during the 31-day (Day 
0–30) follow-up period after the single challenge dose 
of HBV vaccine.

Serious adverse events

Occurrence of serious adverse events after the single 
challenge dose of HBV vaccine up to study end.
 
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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................6
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................18
GLOSSARY OF TERMS ...............................................................................................20
TRADEMARKS .............................................................................................................24
1.
INTRODUCTION....................................................................................................25
1.1.
Background ................................................................................................25
1.2.
Rationale for the study and study design ....................................................25
1.2.1.
Rationale for the study.................................................................25
1.2.2.
Rationale for the study design......................................................26
1.3.
Benefit : Risk Assessment ..........................................................................26
1.3.1.
Risk Assessment .........................................................................26
1.3.2.
Benefit Assessment .....................................................................27
1.3.3.
Overall Benefit: Risk Conclusion..................................................27
2.
OBJECTIVES.........................................................................................................28
2.1.
Primary objective ........................................................................................28
2.2.
Secondary objectives..................................................................................28
3.
STUDY DESIGN OVERVIEW ................................................................................29
4.
STUDY COHORT...................................................................................................30
4.1.
Number of subjects/centres ........................................................................30
4.2.
Inclusion criteria for enrolment....................................................................30
4.3.
Exclusion criteria for enrolment...................................................................31
5.
CONDUCT OF THE STUDY ..................................................................................33
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................33
5.2.
Subject identification and randomisation of treatment .................................34
5.2.1.
Subject identification....................................................................34
5.2.2.
Randomisation of treatment.........................................................34
5.2.2.1.
Randomisation of supplies..........................................34
5.2.2.2.
Treatment allocation to the subject.............................34
5.2.2.2.1.
Study group and treatment 
number allocation ...................................35
5.3.
Method of blinding ......................................................................................35
5.4.
General study aspects ................................................................................35
5.5.
Outline of study procedures ........................................................................35
5.6.
Detailed description of study procedures ....................................................37
5.6.1.
Informed consent and informed assent ........................................37
5.6.2.
Check inclusion and exclusion criteria .........................................37
5.6.3.
Collect demographic data ............................................................37
 
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5.6.4.
Medical and Vaccination history...................................................37
5.6.5.
Physical examination ...................................................................38
5.6.6.
Urine pregnancy test....................................................................38
5.6.7.
Check contraindications, warnings and precautions to 
vaccination...................................................................................38
5.6.8.
Assess pre-vaccination body temperature ...................................38
5.6.9.
Sampling......................................................................................38
5.6.9.1.
Blood sampling for safety or immune response 
assessments ..............................................................38
5.6.10.
Study Vaccine administration.......................................................39
5.6.11.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................39
5.6.12.
Recording of AEs, SAEs and pregnancies...................................39
5.6.13.
Study conclusion..........................................................................40
5.7.
Biological sample handling and analyses....................................................40
5.7.1.
Use of specified study materials ..................................................41
5.7.2.
Biological samples.......................................................................41
5.7.3.
Laboratory assays .......................................................................41
5.7.4.
Biological samples evaluation......................................................42
5.7.4.1.
Immunological read-outs ............................................42
5.7.5.
Immunological correlates of protection.........................................42
6.
STUDY VACCINE AND ADMINISTRATION...........................................................43
6.1.
Description of study vaccine .......................................................................43
6.2.
Storage and handling of study vaccine .......................................................43
6.3.
Dosage and administration of study vaccine...............................................44
6.4.
Replacement of unusable vaccine doses....................................................44
6.5.
Contraindications to vaccination .................................................................44
6.6.
Warnings and precautions ..........................................................................45
6.7.
Concomitant medications/products and concomitant vaccinations..............45
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................45
6.7.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................46
6.8.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses .........................................................................47
7.
HEALTH ECONOMICS ..........................................................................................47
8.
SAFETY.................................................................................................................47
8.1.
Safety definitions ........................................................................................47
8.1.1.
Definition of an adverse event......................................................47
8.1.2.
Definition of a serious adverse event ...........................................48
8.1.3.
Solicited adverse events..............................................................49
8.1.3.1.
Solicited local (injection-site) adverse events..............49
8.1.3.2.
Solicited general adverse events................................49
8.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................50
8.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events ...........................................................................................50
8.2.1.
Pregnancy ...................................................................................50
 
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8.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................51
8.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................51
8.3.2.
Post-Study adverse events and serious adverse events..............52
8.3.3.
Evaluation of adverse events and serious adverse events...........52
8.3.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................52
8.3.3.2.
Assessment of adverse events...................................53
8.3.3.2.1.
Assessment of intensity..........................53
8.3.3.2.2.
Assessment of causality .........................54
8.3.3.3.
Assessment of outcomes............................................56
8.3.3.4.
Medically attended visits.............................................56
8.4.
Reporting of serious adverse events, pregnancies, and other events .........56
8.4.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals............................................56
8.4.2.
Contact information for reporting serious adverse events, 
pregnancies.................................................................................57
8.4.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................57
8.4.3.1.
Back-up system in case the electronic reporting 
system does not work.................................................57
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................57
8.4.5.
Updating of SAE and pregnancy information after removal 
of write access to the subject’s eCRF ..........................................58
8.4.6.
Regulatory reporting requirements for serious adverse 
events..........................................................................................58
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies................................................................................................58
8.5.1.
Follow-up of adverse events and serious adverse events ............58
8.5.1.1.
Follow-up during the study..........................................58
8.5.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................59
8.5.2.
Follow-up of pregnancies.............................................................59
8.6.
Treatment of adverse events ......................................................................59
8.7.
Subject card................................................................................................59
9.
SUBJECT COMPLETION AND WITHDRAWAL.....................................................60
9.1.
Subject completion .....................................................................................60
9.2.
Subject withdrawal......................................................................................60
9.2.1.
Subject withdrawal from the study................................................60
10. STATISTICAL METHODS......................................................................................61
10.1.
Primary endpoint.........................................................................................61
10.2.
Secondary endpoints ..................................................................................61
10.3.
Determination of sample size......................................................................62
10.4.
Cohorts for Analyses...................................................................................63
10.4.1.
Total vaccinated cohort................................................................63
10.4.2.
According-to-protocol cohort for analyses of 
immunogenicity............................................................................64
 
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10.4.3.
According-to-protocol cohort for analyses of antibody 
persistence ..................................................................................64
10.5.
Derived and transformed data.....................................................................64
10.6.
Analyses of demographics..........................................................................65
10.7.
Analyses of immunogenicity........................................................................65
10.8.
Analyses of safety.......................................................................................66
10.9.
Conduct of analyses ...................................................................................67
10.9.1.
Sequence of analyses..................................................................67
10.9.2.
Statistical considerations for interim analyses..............................67
11. ADMINISTRATIVE MATTERS ...............................................................................67
11.1.
Electronic Case Report Form instructions...................................................67
11.2.
Study Monitoring by GSK Biologicals..........................................................68
11.3.
Record retention .........................................................................................69
11.4.
Quality assurance.......................................................................................69
11.5.
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................69
11.6.
Provision of study results to investigators ...................................................70
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................70
13. REFERENCES.......................................................................................................71
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................29
Table 2
Study groups and treatment foreseen in the study .................................29
Table 3
Blinding of study epochs ........................................................................30
Table 4
List of study procedures .........................................................................36
Table 5
Intervals between study visits.................................................................37
Table 6
Biological samples .................................................................................41
Table 7
Humoral Immunity (Antibody determination)...........................................42
Table 8
Immunological read-outs........................................................................42
Table 9
Study vaccine.........................................................................................43
Table 10
Dosage and administration.....................................................................44
Table 11
Solicited local adverse events ................................................................49
Table 12
Solicited general adverse events............................................................49
Table 13
Reporting periods for collecting safety information .................................52
Table 14
Intensity scales for solicited symptoms in children of 14-15 years 
of age.....................................................................................................53
Table 15
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals .................................................56
Table 16
Power to obtain a lower limit for the 95 percent CI for the 
response to HBV vaccine challenge (anti-HBs antibody 
concentration greater than or equal to 100 mIU per ml) greater 
than 90 percent or greater than a margin that would be 5 percent 
below the expected percentage for a sample size of 270 
evaluable subjects..................................................................................63
Table 17
GSK Biologicals’ laboratories .................................................................73
Table 18
Outsourced laboratories.........................................................................73
 
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LIST OF APPENDICES
PAGE
APPENDIX A CLINICAL LABORATORIES ..................................................................73
 
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LIST OF ABBREVIATIONS
AE:
Adverse Event
Anti-HBc:
Antibodies against hepatitis B core antigen
Anti-HBs:
Antibodies against hepatitis B surface antigen
ATP:
According-To-Protocol
CDC:
Centers for Disease Control and Prevention, USA
CEVAC:
Center for Vaccinology, Ghent University Hospital
CI:
Confidence Interval
CLIA:
ChemiLuminescence ImmunoAssay
DTPa-HBV-IPV/Hib:
Combined diphtheria-tetanus-acellular pertussis-hepatitis
B-inactivated poliovirus vaccine and Haemophilus
influenzae type b conjugate (Infanrix hexa)
eCRF:
electronic Case Report Form
EDD:
Estimated Date of Delivery
EGA:
Estimated Gestational Age
EMA:
European Medicines Agency
GSK:
GlaxoSmithKline
ICF:
Informed Consent Form
IAF:
Informed Assent Form
ICH:
International Conference on Harmonisation
IEC:
Independent Ethics Committee
IM:
Intramuscular
IMP:
Investigational Medicinal Product
IRB:
Institutional Review Board
IU/ml:
International Units per millilitre
LAR:
Legally Acceptable Representative
 
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LL:
Lower Limit
LMP:
Last Menstrual Period
mg:
Milligram
g:
Microgram
MACDP:
Metropolitan Atlanta Congenital Defects Program
MedDRA:
Medical Dictionary for Regulatory Activities
RCC:
Reverse Cumulative Curves
RDE:
Remote Data Entry
SAE:
Serious Adverse Event
SBIR:
Randomisation System on Internet
SDV:
Source Document Verification
SmPC:
Summary of Product Characteristics
SPM:
Study Procedures Manual
TVC:
Total vaccinated cohort
WHO:
World Health Organization
 
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GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example: 

abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle,

oral contraceptives, either combined or progestogen 
alone,

injectable progestogen,

implants of etenogestrel or levonorgestrel,

estrogenic vaginal ring,

percutaneous contraceptive patches,

intrauterine device or intrauterine system,

male partner sterilisation prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject,
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository),

male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository). 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, when this 
is their preferred and usual lifestyle.
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product. 
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
 
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abuse or misuse.
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
open-label study, no blind is used. Both the investigator 
and the subject know the identity of the treatment 
assigned.
Child in care:
A child who has been placed under the control or 
protection of an agency, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epoch:
An epoch is a self-contained set of consecutive 
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion to define or precise the targeted 
label of the product. Typical examples of epochs are 
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analyses.
Immunological correlate 
of protection:
The defined immune response above which there is a high 
likelihood of protection in the absence of any host factors 
that might increase susceptibility to the infectious agent.
Investigational vaccine:
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
 
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(Synonym of 
Investigational Medicinal 
Product)
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:
(The terms legal 
representative or legally 
authorized 
representative are used 
in some settings.)
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
subject, to the subject's participation in the clinical trial.
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
female can become pregnant before her first menses. 
Thus, a conservative definition of non-childbearing 
potential in a pre-menarcheal female is a young female 
who has not yet entered puberty as evidenced by lack of 
breast development (palpable glandular breast tissue).
Randomisation:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine or as a control.
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 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
 
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event:
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event.
 
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TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the vaccines will 
be written without the superscript symbol ™ and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
Engerix™-B Kinder
Recombinant hepatitis B vaccine
Infanrix™hexa
Combined diphtheria-tetanus-acellular 
pertussis-hepatitis B-inactivated poliovirus 
and Haemophilus influenzae type b vaccine
 
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1.
INTRODUCTION
1.1.
Background
Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. 
It is a major global health problem and the most serious type of viral hepatitis. It can 
cause chronic liver disease and puts people at high risk of death from cirrhosis of the liver 
and liver cancer. An estimated 240 million people are chronically infected with hepatitis 
B. More than 780,000 people die every year due to the complications of hepatitis B, 
including cirrhosis and liver cancer [WHO, 2015].
A vaccine against hepatitis B has been available since 1982. The vaccine is 95% effective 
in preventing infection and the development of chronic disease and liver cancer due to 
hepatitis B. Protection against hepatitis B disease after immunisation relies on persistent
protective serum antibodies and on the ability of the immune system to mount an 
anamnestic response when confronted with the hepatitis B virus (HBV). Persisting 
immune memory to the hepatitis B virus surface antigen (HBsAg) is explored by
evaluating the effect of a HBV challenge vaccination of previously immunised subjects.
Studies conducted after primary immunisation with HBV vaccine in different populations 
have shown long-term persistence and immune memory induced by Engerix-B Kinder
against hepatitis B, extending up to 20 years after primary vaccination [Avdicova, 2012; 
Behre, 2012; Poovorawan, 2013].
Please refer to the Prescribing Information for information regarding the regarding the 
potential risks and benefits of Engerix-B Kinder.
1.2.
Rationale for the study and study design
1.2.1.
Rationale for the study
In the global context of vaccination against hepatitis B, the European Medicines Agency 
(EMA) has requested GSK Biologicals to set up a long-term surveillance programme of 
vaccines containing a recombinant hepatitis B component. This study is the last study in a 
series of four studies, constituting a common follow-up programme of vaccination with 
Infanrix hexa. The previous studies conducted in this series are mentioned below: 

106789 (DTPA-HBV-IPV-112): The study was conducted in healthy subjects 4-5 
years of age at the time of enrolment, who received four consecutive doses of 
Infanrix hexa [Steiner, 2010].

112688 (DTPA-HBV-IPV-113): The study was conducted in healthy subjects 7-8 
years of age at the time of enrolment who received four consecutive doses of Infanrix
hexa [Van Der Meeren, 2014].

106793 (DTPA-HBV-IPV-114): The study was conducted in healthy subjects 12-13 
years of age at the time of enrolment who received four consecutive doses of Infanrix
hexa.
 
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This study aims to determine the persistence, from childhood to adolescence of immunity 
to hepatitis B that is conferred by 4 doses of vaccination with Infanrix hexa in the first 2 
years of age. Persistent immunity to hepatitis B was assessed previously, in four to five 
year old, seven to eight year old and 12-13 year old children who were vaccinated with 
four doses of Infanrix hexa, as part of routine vaccination in infancy, in Germany. More 
than 60% of subjects showed seroprotective persistent antibody concentrations and at 
least 96% of subjects in all age groups showed an anamnestic response to the single 
hepatitis B challenge dose [Zinke M, 2010, Steiner, 2010; Van Der Meeren, 2014; GSK 
Biologicals’ Clinical Study Report (106793)]. The results observed in these studies are in 
line with the results observed when children and adolescents were primed with three 
doses of a monovalent hepatitis B vaccine [Behre,2012]. Infanrix hexa was licensed for 
use in Germany in 2000. Thus, children who received routine vaccination in the year 
2001 with Infanrix hexa will reach an age of 14 to 15 years by 2016. These children will 
be invited to participate in this study in order to collect persistence data for hepatitis B 
antibodies and to assess the anamnestic response, immunogenicity, safety and 
reactogenicity of a single challenge dose of the hepatitis B vaccine (Engerix-B Kinder).
1.2.2.
Rationale for the study design
This study will be conducted with a single group of subjects as all children recruited will 
receive a single challenge dose of HBV vaccine. A blood sample will be taken before and 
one month after the single challenge dose to evaluate:

The persistence of anti-HBs antibody concentrations in subjects 14-15 years of age 
previously vaccinated with four doses of Infanrix hexa in the first two years of life.

The ability to mount an anamnestic response to the single HBV challenge dose.
The safety and reactogenicity of the single challenge dose of HBV vaccine will also be 
evaluated in this study.
Since this study involves a single study group and all subjects will be administered the 
same vaccine, it is planned to be conducted in an open and non-randomised manner.
1.3.
Benefit : Risk Assessment
Engerix-B Kinder has demonstrated a good safety profile in the clinical studies performed 
to date.
Please refer to the Prescribing Information for information regarding the summary of 
potential risks and benefits of Engerix-B Kinder.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
1.3.1.
Risk Assessment
Based on substantial data available from clinical and non-clinical experience, the safety
profile of Engerix-B Kinder has been established. The vaccine is well tolerated without 
key safety findings.
 
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Important 
Potential/Identified Risk
Data/Rationale for Risk
Mitigation Strategy
Investigational study vaccine (Engerix-B Kinder)
Hypersensitivity
Spontaneous data/ hypersensitivity 
after administration of hepatitis B 
containing vaccines or to any 
component of the vaccine
Subjects will be observed for at least 
30 minutes after vaccine 
administration, with medical attention 
available in case of anaphylaxis 
reactions.
Adequate human data on use 
during pregnancy/lactation and 
adequate animal reproduction 
studies are not available
The effect of the vaccine on foetal 
development has not been 
assessed. 
Pregnant subjects will not be included 
in this study (see Section 4.2).
Female subjects of childbearing 
potential are to have a urine 
pregnancy test prior to the study 
vaccine administration and will not be 
vaccinated if the test is positive (see 
Section 4.2 and 4.3).
Study Procedures
Syncope
Spontaneous Syncope (fainting) 
can occur following, or even before, 
any vaccination as a psychogenic 
response to the needle injection.
Section 6.6 highlights that procedures 
should be in place to avoid injuries 
from falls following syncope.
1.3.2.
Benefit Assessment
When primed with Infanrix hexa, a vast majority of subjects get protected (>95%) against
hepatitis B disease. The persistence studies suggest that immune memory persists for at
least 20 years after vaccination. However, the immune response in some individuals
might wane more rapidly than expected. By taking part in this study, the subject will
know if he/she is still seroprotected against hepatitis 14-15 years after hepatitis B
vaccination.
This study will provide information about the duration of protection offered by three
primary doses and one booster dose in the first 2 years of life of Infanrix hexa against 
hepatitis B infection. This would also present an opportunity to facilitate better protection 
against the disease through hepatitis B vaccination, in the future.
The subject will also benefit from an additional vaccine dose, which is currently not
routinely offered, and which may help to keep him/her protected against hepatitis B even
longer.
1.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this
study, the potential or identified risks identified in association with Engerix-B Kinder are
justified by the potential benefits that may be afforded to subjects receiving the vaccine
for immunisation against hepatitis B infection.
 
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2.
OBJECTIVES
2.1.
Primary objective

To assess the immunological response to hepatitis B antigen, in terms of antibody 
concentrations ≥100 mIU/ml, one month after the single challenge dose of the HBV 
vaccine in subjects 14-15 years of age, previously vaccinated with four doses of 
Infanrix hexa in the first two years of life.
Refer to Section 10.1 for the definition of the primary endpoint.
2.2.
Secondary objectives

To assess the persistence of anti-HBs antibodies, in terms of seroprotection status 
and antibody concentrations, in subjects 14-15 years of age, previously vaccinated 
with four doses of Infanrix hexa in the first two years of life.

To assess the immunological response to hepatitis B antigen, in terms of anamnestic 
response, one month after the single challenge dose of the HBV vaccine in subjects 
14-15 years of age, previously vaccinated with four doses of Infanrix hexa in the first 
two years of life.

To assess the immunological response to the hepatitis B antigen, in terms of 
seroprotection status and antibody concentrations, one month after the single 
challenge dose of the HBV vaccine in subjects 14-15 years of age, previously 
vaccinated with four doses of Infanrix hexa in the first two years of life.

To evaluate the safety and reactogenicity of a single challenge dose of HBV vaccine 
(Engerix-B Kinder) in terms of solicited symptoms (local and general), unsolicited 
symptoms and serious adverse events (SAEs).
Refer to Section 10.2 for the definition of the secondary endpoints.
 
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3.
STUDY DESIGN OVERVIEW
N: Number of subjects planned to be enrolled
* Pre-vaccination: Blood sampling before the administration of the single HBV vaccine challenge dose
** Post-vaccination: Blood sampling one month after the administration of the single HBV vaccine challenge dose
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 5.5), are essential and required for 
study conduct. 

Experimental design: Phase IV, open-label, non-randomised, multi-centric, single-
country study with a single group.

Duration of the study: the intended duration of the study, per subject, will be 
approximately one month. The study will have a single epoch as follows:

Epoch 001: Primary starting at Visit 1 (Day 0) and ending at Visit 2 (Month 1).

Study groups: the details are presented below in Table 1.
Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epochs
Epoch 001
HBV Group
300
14 years – 15 years
x
The treatment group details are provided in Table 2.
Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine name
HBV Group 
Engerix-B Kinder
HBV
●

Control: uncontrolled

Vaccination schedule: A single dose of HBV vaccine will be administered to all 
subjects, who were previously primed and boosted with four doses of Infanrix hexa in 
the first two years of life.

Treatment allocation: non-randomised

Blinding: Refer to Table 3.
 
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Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
open

Sampling schedule: Blood samples will be taken from each subject at the following 
time-points: 

Pre-vaccination: at Visit 1, before the administration of the single challenge dose 
of HBV vaccine.

Post-vaccination: at Visit 2, approximately one month after the single challenge 
dose of HBV vaccine.

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF).
4.
STUDY COHORT
4.1.
Number of subjects/centres
Approximately 300 children aged 14-15 years will be enrolled in this study. They should 
have received four doses of Infanrix hexa with the three primary vaccination doses 
received by 9 months of age and the booster dose received between 11 and 18 months of
age as part of routine vaccination practice in Germany.
Parents/Legally Acceptable Representative(s) [LAR(s)] of these children will be 
contacted and their children will be invited to participate in this challenge dose study.
Refer to Section 10.3 for a detailed description of criteria used to estimate the sample 
size.
Overview of the recruitment plan

The study will be conducted at multiple centres in Germany. 

Enrolment is expected to be completed within a period of approximately six months.

The study duration per subject will be approximately one month.

The follow-up of recruitment of subjects into the study will be performed using GSK 
Biologicals’ central randomisation system on Internet (SBIR).

The recruitment will be monitored by the site monitor.
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
 
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All subjects must satisfy ALL the following criteria at study entry:

Subjects’ parent(s)/Legally Acceptable Representative(s) [LAR(s)] who, in the 
opinion of the investigator, can and will comply with the requirements of the 
protocol (e.g. completion of the diary cards, return for follow-up visits).

Written informed consent obtained from the parent(s)/LAR(s) of the subject prior to 
performance of any study specific procedure.

In addition to the informed consent that will be signed by the parents/LAR(s), written 
informed assent of the subject will be sought.

A male or female between the ages of 14 to 15 (from and including the 14th birthday, 
up to but excluding the 16th birthday) at the time of vaccination.

Healthy subjects as established by medical history and clinical examination before 
entering into the study.

Subjects with documented evidence of previous vaccination with four consecutive 
doses of Infanrix hexa as part of routine vaccination in Germany: three doses of 
primary vaccination received by 9 months of age and one booster dose received 
between 11 and 18 months of age.

Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current tubal ligation, 
hysterectomy or ovariectomy. 
Please refer to the glossary of terms for the definition of menarche.

Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception for 30 days prior to vaccination, and

has a negative pregnancy test on the day of vaccination, and

has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series. 
Please refer to the glossary of terms for the definition of adequate contraception.
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care.
Please refer to the glossary of terms for the definition of child in care. 
 
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
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the dose of study vaccine 
(Day -29 to Day 0), or planned use during the study period.

Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the vaccine dose. For corticosteroids, this will mean prednisone ≥ 
0.5 mg/kg/day (for paediatric subjects), or equivalent. Inhaled and topical steroids 
are allowed.

Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab).

Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the dose and ending 30 days after the 
dose of HBV vaccine administration with the exception of tetanus toxoid, reduced 
diphtheria toxoid and acellular pertussis (dTpa) vaccine, which can be given as part 
of routine vaccination practice. Seasonal or pandemic influenza vaccine can be given 
at any time during the study, and according to the Summary of Product 
Characteristics and national recommendations.

Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device).

Evidence of previous hepatitis B booster vaccination since administration of the 
fourth dose of Infanrix hexa booster in the second year of life.

History of or intercurrent hepatitis B disease.

Hepatitis B vaccination at birth.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Family history of congenital or hereditary immunodeficiency.

History of any reaction or hypersensitivity (hypotone-hyperresponsiveness reaction) 
likely to be exacerbated by any component of the vaccine.

Major congenital defects or serious chronic illness including thrombocytopenia and 
bleeding disorders.

History of any neurological disorders or seizures.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature 37.5°C for oral, axillary or tympanic route, or 
38.0°C for rectal route.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.
 
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
Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by physical examination or laboratory 
screening tests.

Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the dose of study vaccine or planned administration during 
the study period.

Pregnant or lactating female.

Female planning to become pregnant or planning to discontinue contraceptive 
precautions.
5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki.
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject’s parent(s)/LAR(s) informed consent and subject informed assent, as 
appropriate.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject’s parent(s)/LAR(s) and subject informed assent, as appropriate, prior to 
participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
 
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that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
In accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice,
those subjects who can only be enrolled in the study with the consent of the subject’s
parent(s)/legally acceptable representative (e.g. minors), should be informed about the
study to the extent compatible with the subject’s understanding and, if capable, the
subject should sign and personally date a written Informed Assent Form (IAF). It is
required that the assent be signed by each subject, if capable, in addition to the informed
consent that is to be signed by his/her legal representative.
The investigator has the final responsibility for the final presentation of the ICF and IAF, 
respecting the mandatory requirements of local regulations. The ICF and IAF generated 
by the investigator with the assistance of the sponsor’s representative must be acceptable 
to GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
5.2.
Subject identification and randomisation of treatment
5.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects whose 
parent(s)/LAR(s) have consented to allow their child/ward to participate in the study, 
according to the range of subject identification numbers allocated to the study centre.
5.2.2.
Randomisation of treatment
5.2.2.1.
Randomisation of supplies
This is a single group non- randomised study. All eligible subjects will receive the 
challenge dose of HBV. A sequential list of treatment numbers will be generated by 
MATerial EXcellence (MATEX). The Randomisation System on Internet (SBIR) will be 
used to allocate treatment numbers to the subjects and also to track enrolment in the 
study. 
To allow GSK Biologicals to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation of supplies will be prepared.
5.2.2.2.
Treatment allocation to the subject
The treatment numbers will be allocated by dose.
 
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5.2.2.2.1.
Study group and treatment number allocation
Allocation of a treatment number to the subject at the investigator site will be performed 
using a randomisation system on internet (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for centre.
After obtaining the signed and dated ICF/IAF from the subject/subject’s parent(s)/LAR(s)
and having checked the eligibility of the subject, the site staff in charge of the vaccine 
administration will access SBIR. Upon providing the subject identification number, the 
randomisation system will provide the treatment number to be used for the dose.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
5.3.
Method of blinding 
This study is an open label study i.e. all subjects will receive a dose of the same vaccine, 
known to the investigator and to the parents/ LAR(s) of the subject.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
5.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects.
5.5.
Outline of study procedures
The burden of the study for the subject will be minimised as much as possible. For taking
blood samples, three attempts at most should be performed. If the physician is not
successful after the third attempt, he/she will make no further attempts. A local numbing
cream or patch will also be offered at the discretion of the investigator prior to blood
sampling, in order to minimise pain when blood samples are drawn.
The list of study procedures is presented in Table 4.
 
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Table 4
List of study procedures
Epoch
Epoch 001
Age
14-15 years
Visit
Visit 1
Visit 2
Timing
Day 0
Month 1 
Sampling time-points
Pre-HBV challenge
Post-HBV challenge 
Written informed consent from parent(s)/LAR(s)
●
Written informed assent from subject
O*
Check inclusion/exclusion criteria
●
Collect demographic data
●
Medical and Vaccination history
●
Physical examination
●
Urine pregnancy test
●**
Check contraindications, warnings and precautions
O
Measure/record height and weight
●
Pre-vaccination body temperature
●
Vaccine
Treatment number allocation
O
Hepatitis B vaccine challenge dose administration
●
Recording of administered treatment number
●
Laboratory Assays
Blood sampling for antibody determination (at least 2.5 mL)
●
●
Safety assessments
Recording of any concomitant medication/vaccination
●
●
Record any intercurrent medical conditions
●
Distribution of diary cards to the parents/LAR(s)
O
Recording of solicited symptoms (Days 0–3)
●
Recording of any non-serious adverse events within 30 days post-
vaccination
●
●
Recording of serious adverse events and pregnancies
●
●
Recording of SAEs related to study participation or to a concurrent 
GSK medication/vaccine
●
●
Return of diary cards
O
Diary card transcription by investigator
●
Study Conclusion
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
*This study procedure does not require documentation in the individual eCRF. The study purpose and procedures will 
be explained to the subject by appropriately trained personnel and the written informed assent will be obtained from the 
subject.
**This study procedure is to be performed for only female subjects of child bearing potential.
The intervals between study visits are presented in Table 5.
 
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Table 5
Intervals between study visits
Interval
Optimal length of interval*
Maximum interval allowed**
Birth Visit 1
14-15 days of age
From the 14th up to, but excluding the 16th
birthday
Visit 1 Visit 2
30 days
21 – 48 days
* Whenever possible the investigator should arrange study visits within this interval
** Subjects will not be eligible for inclusion in one or more cohorts for analyses if they make the study visit outside this 
interval. An interval of 21–48 days will be considered for the According-to-Protocol (ATP) cohort of immunogenicity.
Refer to Section 10.4 for the definition of the cohorts for analyses.
If a subject returns for the Visit 2 blood draw prior to completion of the 31-day safety follow-up period, the subject 
should continue to record this information on the diary card until 31 days post-vaccination and mail the diary card to the 
site. The investigator will make an attempt to obtain this information as soon as possible after the 31-day follow-up 
period if it is not mailed.
5.6.
Detailed description of study procedures
The following procedure will be conducted prior to study entry.
5.6.1.
Informed consent and informed assent
The signed/witnessed/thumb printed informed consent of the subject’s parent(s)/LAR(s) 
must be obtained before study participation. The signed informed assent of the subject 
below the age of consent (i.e. minor) should be obtained in addition to the signed 
informed consent by his/her parent(s)/LAR(s) according to local rules and regulations.
Refer to Section 5.1 for the requirements on how to obtain informed consent and assent, 
as appropriate.
The following procedures will be conducted at the time of study entry.
5.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment. 
5.6.3.
Collect demographic data
Record demographic data such as age [in years], gender, geographic ancestry, height [in 
cm] and weight [kg] in the subject’s eCRF.
5.6.4.
Medical and Vaccination history
Obtain the subject’s medical and vaccination history by interview and/or review of the 
subject’s medical records and record any pre-existing conditions or signs and/or 
symptoms present in a subject prior to the study vaccination in the eCRF.
 
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5.6.5.
Physical examination
Perform a physical examination of the subject, including assessment of body temperature. 
Collected information needs to be recorded in the eCRF.
Physical examination at the study visit subsequent to the vaccination visit, will be
performed only if the subject indicates during questioning that there might be some
underlying pathology(ies) or if deemed necessary by the Investigator or delegate.
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
5.6.6.
Urine pregnancy test
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccine may only be administered if the 
pregnancy test is negative. Note: The urine pregnancy test must be performed even if the 
subject is menstruating at the time of the study visit.
5.6.7.
Check contraindications, warnings and precautions to 
vaccination 
Contraindications, warnings and precautions to vaccination must be checked at the 
beginning of the vaccination visit. Refer to Sections 6.5 and 6.6 for more details.
5.6.8.
Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccine administration. The preferred route for recording 
temperature in this study will be axillary. If the subject has fever [fever is defined as 
temperature 37.5°C for oral, axillary or tympanic route, or 38.0°C for rectal route] on 
the day of vaccination, the vaccination visit will be rescheduled within the allowed 
interval for this visit (see Table 5).
5.6.9.
Sampling
As specified in the List of Study Procedures (see Table 4), blood samples will be taken 
during both study visits. Refer to the Module on Biospecimen Management in the SPM 
for detailed instructions for the collection, handling and processing of the blood samples.
5.6.9.1.
Blood sampling for safety or immune response assessments 
Blood samples will be taken during Visit 1 and Visit 2 as specified in Section 5.5.
 
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A volume of at least 2.5 mL of whole blood (to provide at least 0.8 mL of serum) should 
be drawn from all subjects included in the study for analyses of humoral immune 
response. After centrifugation, serum samples should be kept at –20°C or below until 
shipment. Refer to the SPM for more details on sample storage conditions.
5.6.10.
Study Vaccine administration

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly (IM) in the deltoid region of the non-
dominant arm (refer to Section 6.3 for detailed description of the vaccine
administration procedure). If the investigator or delegate determines that the 
subject’s health on the day of administration temporarily precludes vaccine
administration, the visit will be rescheduled within the allowed interval for this visit 
(see Table 5)

The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccine, with appropriate medical treatment readily available in 
case of anaphylaxis.
5.6.11.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.7.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.8.
5.6.12.
Recording of AEs, SAEs and pregnancies 

Refer to Section 8.3 for procedures for the investigator to record AEs, SAEs and 
pregnancies. Refer to Section 8.4 for guidelines and how to report SAE and 
pregnancy reports to GSK Biologicals.

The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 

At the vaccination visit (Visit 1), diary cards will be provided to the subject’s 
parent(s)/LAR(s). The subject’s parent(s)/LAR(s) will record body (axillary) 
temperature and any solicited local/general AEs (i.e. on the day of vaccination and 
during the next 3 days) or any unsolicited AEs (i.e. on the day of vaccination and 
during the next 30 occurring after vaccination. The subject’s parent(s)/LAR(s) will 
be instructed to return the completed diary card to the investigator at the next study 
visit.
Note: Diary cards can be filled in by a minor subject under the supervision of the 
subject’s parent(s)/LAR(s) provided that the minor has the competency to assess and 
report the information to be provided in the diary card. The ultimate accountability 
for the completion of the diary cards remains with the subject’s parent(s)/LAR(s). 
 
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The investigator should discuss this accountability with the subject’s 
parent(s)/LAR(s).

Collect and verify completed diary cards during discussion with the subject’s
parent(s)/LAR(s) on Visit 2.
Note: If the diary card has been filled in by a minor subject, the investigator or 
delegate should verify the reported information during a discussion with the minor 
subject preferably in the presence of his/her parent(s)/LAR(s).

Any unreturned diary cards will be sought from the subject’s parent(s)/LAR(s) 
through telephone call(s) or any other convenient procedure. The investigator will 
transcribe the collected information into the eCRF in English.
5.6.13.
Study conclusion
At Visit 2 the investigator will:

review data collected to ensure accuracy and completeness.

complete the Study Conclusion screen in the eCRF.
5.7.
Biological sample handling and analyses
Please refer to the SPM for details on biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed, will be asked to give a specific 
consent to allow GSK or a contracted partner to use the samples for future research. 
Future research will be subject to the laws and regulations in the respective countries 
and will only be performed once an independent Ethics Committee or Review Board 
has approved this research.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject’s 
parent(s)/LAR(s).
 
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Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
If additional testing is performed, the marker priority ranking given in Section 5.7.4 may 
be changed.
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
5.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all clinical 
samples (including serum samples) be collected and stored exclusively using those 
materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analyses (See Section 10.4 for the definition of 
cohorts to be analysed). The investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when 
GSK Biologicals does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
5.7.2.
Biological samples
The biological samples to be collected in the study are presented in Table 6.
Table 6
Biological samples
Sample type
Quantity
Unit
Timepoint
Blood
At least 2.5
mL
Visit 1 (pre-HBV challenge)
Visit 2 (post-HBV challenge)
5.7.3.
Laboratory assays
Please refer to APPENDIX A for the address of the clinical laboratories used for sample 
analyses.
Serological assays for the determination of anti-HBc and anti-HBs antibodies will be 
performed by ChemiLuminescence ImmunoAssay (CLIA) at a GSK Biologicals’ 
laboratory or in a laboratory designated by GSK Biologicals using standardised and 
validated procedures (see Table 7).
 
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Table 7
Humoral Immunity (Antibody determination)
System
Component
Scale
Method
Test kit/ 
Manufacturer
Unit
Cut-off
Laboratory*
SER
Hepatitis B 
Virus.Core Ab
Ordinal
CLIA
Immulite 
(Siemens 
Healthcare)
No unit
N/A
CEVAC
SER
Hepatitis B 
Virus.Surface 
Ab
Quantitative
CLIA
Centaur 
(Siemens 
Healthcare)
mIU/ml
6.2
GSK 
Biologicals**
*Refer to APPENDIX A for the laboratory addresses
CEVAC: Center for Vaccinology
**GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium Wavre, Belgium
SER: Serum
CLIA: ChemiLuminescence ImmunoAssay (CLIA)
mIU/ml: Milli-International units per millilitre
N/A: Not applicable
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
5.7.4.
Biological samples evaluation
5.7.4.1.
Immunological read-outs
The immunological read-outs are presented in Table 8.
Table 8
Immunological read-outs
Blood sampling timepoint
No. subjects
Component
Components priority rank
Type of contact and 
timepoint
Sampling 
timepoint
Visit 1 (Day 0)
Pre-HBV 
vaccination
Approximately 300
Anti-HBs
(1)
Visit 2 (Month 1)
Post-HBV 
vaccination
Approximately 300
Anti-HBs
Anti-HBc
(1)
(2)
In case of insufficient blood sample volume to perform assays for all antibodies, the 
samples will be analysed according to priority ranking provided in Table 8. 
5.7.5.
Immunological correlates of protection
The assay cut-off used for the detection of anti-HBs antibodies has been set at 
6.2 mIU/ml. The cut-off of 10 mIU/ml provides a conservative estimate of the percentage 
of subjects deemed to be protected for antibodies against hepatitis B antibodies [CDC, 
1991; WHO, 1988; Frisch-Niggemeyer, 1986].
Assessment of the protection level will be done at least 4 weeks after the administration 
of the challenge dose.
 
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The immunological assay results will be communicated to the investigator as soon as they 
become available.
The investigator is encouraged to share the immunological assay results for non-
responders with the study subjects’ parent(s)/LAR(s).
For the subjects identified as non-responders, it remains the responsibility of the 
investigator in charge of the subject’s clinical management to determine the medical need 
for re-vaccination and to re-vaccinate the subjects as per local/regional practices.
Non-responders are defined as subjects with anti-HBs antibody concentration < 10 
mIU/mL, one month after the HBV challenge.
6.
STUDY VACCINE AND ADMINISTRATION
6.1.
Description of study vaccine
The HBV vaccine (Engerix-B Kinder) to be used has been developed and manufactured 
by GSK Biologicals.
The Quality Control Standards and Requirements for the study vaccine are described in 
separate Quality Assurance documents (e.g. release protocols, certificate of analyses) and 
the required approvals have been obtained.
The vaccine is labelled and packed according to applicable regulatory requirements.
The commercial vaccine is assumed to comply with the specifications given in the 
manufacturer’s Summary of Product Characteristics.
The description of study vaccine is presented in Table 9.
Table 9
Study vaccine
Treatment 
name
Vaccine/product 
name
Formulation
Presentation
Volume
Number of 
doses
Engerix-B 
Kinder
HBV
HBsAg=10µg; 
Al(OH)₃=250µg 
Al3+
Suspension 
for injection in 
pre-filled 
syringes
0.5 ml
1
6.2.
Storage and handling of study vaccine
The study vaccine must be stored at the respective label storage temperature conditions in 
a safe and locked place. Access to the storage space should be limited to authorized study 
personnel. The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccine.
 
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Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C label 
storage condition) impacting investigational medicinal products (IMPs) must be reported 
in the appropriate (electronic) temperature excursion decision form ([e]TDF). The 
impacted IMPs must not be used and must be stored in quarantine at label temperature 
conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to +8°C
label storage temperature conditions. The impacted IMP(s) may still be administered, but 
the site should avoid re-occurrence of such temperature excursion. Refer to the Module 
on Clinical Trial Supplies in the SPM for more details on actions to take.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccine.
6.3.
Dosage and administration of study vaccine
All subjects will receive one dose of the HBV vaccine. The vaccine will be administered 
as an IM injection at a 90-degree angle into the deltoid region of the non-dominant arm
(preferably). In order to ensure proper IM injection of the study vaccine, a needle of at 
least 1 inch (2.54 cm) length, 25 gauge will be used [CDC, 2002].
The dosage and administration of study vaccines is presented in Table 10.
Table 10
Dosage and administration
Type of contact and 
timepoint
Volume to be 
administered
Treatment name
Route 1
Site
Side
Visit 1 (Day 0)
0.5 ml
HBV
IM
Deltoid region of 
arm
Preferably 
Non-dominant
1IM: Intramuscular 
6.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 5% additional vaccine doses will be 
supplied to replace those that are unusable. 
6.5.
Contraindications to vaccination
Since this is a single-dose study, contraindications have been included as part of the 
exclusion criteria (see Section 4.3)
The following events constitute contraindications to administration of HBV vaccine at 
that point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
 
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protocol (see Section 5.5), or withdrawn at the discretion of the investigator (see Section 
8.5).

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 37.5°C for oral, axillary or tympanic route, or 
38.0°C for rectal route. The preferred route for recording temperature in this 
study will be axillary.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines.
6.6.
Warnings and precautions

Engerix-B Kinder should not be administered in the buttock or intradermally since 
this may result in lower immune response.

Engerix-B Kinder should under no circumstances be administered intravenously.

Syncope (fainting) can occur following, or even before any vaccination especially in 
adolescents as a psychogenic response to the needle injection. It is important that 
procedures are in place to avoid injury from syncope.

Due to the long incubation period of hepatitis B, it is possible for unrecognised 
infection to be present at the time of vaccination. The vaccine may not prevent 
hepatitis B in such cases.
Refer to the approved product label/package insert.
6.7.
Concomitant medications/products and concomitant 
vaccinations
At each study visit, the investigator should question the subject’s parent(s)/LAR(s) about 
any medication/product taken and vaccination received by the subject.
6.7.1.
Recording of concomitant medications/products and 
concomitant vaccinations
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in 
the eCRF.

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period starting from the administration of the study vaccine 
(Day 0) up to 30 days post-vaccination (Day 30).

Any concomitant vaccination administered in the period starting 30 days before the 
dose of study vaccine and ending at the last study visit [Day 30 (Visit 2)].

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
 
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E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 37.5°C for oral, axillary or tympanic route, or 38.0°C for rectal 
route].

Any concomitant medications/products/vaccines listed in Section 6.7.2.

Any concomitant medications/products/vaccines relevant to a SAE to be reported as 
per protocol or administered at any time during the study period for the treatment of 
a SAE. In addition, concomitant medications relevant to SAEs need to be recorded 
on the expedited Adverse Event report.
6.7.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analyses. See Section 10.4 for cohorts to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period. 

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days in total) during the study period. For corticosteroids, this will 
mean prednisone 0.5 mg/kg/day (for paediatric subjects) or equivalent. Inhaled and 
topical steroids are allowed

Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).

A vaccine not foreseen by the study protocol administered during the period starting 
from the dose of the study vaccine and ending 30 days after the dose of vaccine 
administration (Visit 2)*, with the exception of tetanus toxoid, reduced diphtheria 
toxoid and acellular pertussis (dTpa) vaccine, which can be given as part of routine 
vaccination practice. Seasonal or pandemic influenza vaccine can be given at any 
time during the study, and according to the Summary of Product Characteristics and 
national recommendations.
*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its SmPC or Prescribing 
Information and according to the local governmental recommendations and provided 
a written approval of the Sponsor is obtained.

Immunoglobulins and/or any blood products administered during the study period.
 
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6.8.
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses
At each study visit subsequent to the vaccination visit, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition. If it is the case, the 
condition(s) must be recorded in the eCRF.

Subjects may be eliminated from the ATP cohort for immunogenicity if, during the 
study, they incur a condition that has the capability of altering their immune response 
(i.e. HBV infection) or are confirmed to have an alteration of their initial immune 
status.

Previous hepatitis B infection as evidenced by testing seropositive for antibodies
against hepatitis B core antigen (anti-HBc) at post-HBV vaccine challenge blood
sampling time point.
7.
HEALTH ECONOMICS
Not applicable.
8.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol. 
Each subject’s parent(s)/LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs or symptoms they perceive as serious.
8.1.
Safety definitions
8.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
Examples of an AE include:

Significant or unexpected worsening or exacerbation of the condition/indication
under study.
 
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
New conditions detected or diagnosed after investigational vaccine administration 
even though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccine or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with vaccine administration.

Significant failure of expected pharmacological or biological action. 

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
Examples of an AE DO NOT include:

Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
study vaccination. These events will be recorded in the medical history section of the 
eCRF.
8.1.2.
Definition of a serious adverse event 
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
 
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serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity,
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect in the offspring of a study subject.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
8.1.3.
Solicited adverse events
8.1.3.1.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 11
Solicited local adverse events
Pain at injection site
Redness at injection site
Swelling at injection site
8.1.3.2.
Solicited general adverse events
The following general AEs will be solicited:
Table 12
Solicited general adverse events
Fatigue
Fever
Gastrointestinal symptoms †
Headache
†Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain.
 
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Note: Temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF.
8.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments (e.g. vital signs) that are judged 
by the investigator to be clinically significant will be recorded as AE or SAE if they meet 
the definition of an AE or SAE (refer to Sections 8.1.1and 8.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs. However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are associated with the disease being studied, unless judged by the 
investigator as more severe than expected for the subject’s condition, or that are present 
or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
8.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events 
8.2.1.
Pregnancy
Female subjects who become pregnant after the vaccination may continue the study at the 
discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on an electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 8.4.1 and 8.4.3:

Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation)

ectopic and molar pregnancy

stillbirth (intrauterine death of foetus after 22 weeks of gestation).
 
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Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the investigational vaccine will be reported 
to GSK Biologicals as described in Section 8.4.3. While the investigator is not obligated 
to actively seek this information from former study participants, he/she may learn of a 
pregnancy through spontaneous reporting.
8.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
8.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting 30 days following administration of the dose of study vaccine (Day 0 to 
Day 30) must be recorded into the appropriate section of the eCRF, irrespective of 
intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the receipt of study 
vaccine and will end 30 days following administration of the dose of study vaccine for 
each subject. See Section 8.4 for instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from
the time of the receipt of study vaccine.
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
The time period for collecting and recording pregnancies will begin at the receipt of study
vaccine and will end 30 days following administration of the dose of study vaccine. See
section 8.4 for instructions on reporting of pregnancies.
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 13.
 
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Table 13
Reporting periods for collecting safety information
Event
Pre HBV 
challenge(Consent 
obtained)
HBV challenge
(Visit 1)
4-day post HBV 
challenge follow-up
31-day post HBV 
challenge follow-
up
(Visit 2)
Study conclusion
Time in study
Day 0
Day 3
Day 30
Solicited local and general 
AEs
Unsolicited AEs
AEs/SAEs leading to 
withdrawal from the study
SAEs 
SAEs related to study 
participation or concurrent 
GSK medication/vaccine 
Pregnancies 
8.3.2.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 13. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccine, the investigator will promptly 
notify the Study Contact for Reporting SAEs.
8.3.3.
Evaluation of adverse events and serious adverse events
8.3.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject’s parent(s)/LAR(s) should be asked 
a non-leading question such as:
‘Has your child acted differently or felt different in any way since receiving the vaccine 
or since the last visit?’
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
 
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AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the subject’s 
medical records to GSK Biologicals instead of appropriately completing the eCRF. 
However, there may be instances when copies of medical records for certain cases are 
requested by GSK Biologicals. In this instance, all subject identifiers will be blinded on 
the copies of the medical records prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
8.3.3.2.
Assessment of adverse events
8.3.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 14
Intensity scales for solicited symptoms in children of 14-15 years of 
age
Child (14-15 years)
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing 
normal every day activities.
2
Moderate: Painful when limb is moved and interferes with 
every day activities.
3
Severe: Significant pain at rest. Prevents normal every 
day activities.
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Gastrointestinal symptoms
0
Normal
(nausea, vomiting, diarrhoea and/or 
abdominal pain)
1
Mild: Gastrointestinal symptoms that are easily tolerated
2
Moderate: Gastrointestinal symptoms that interfere with 
normal activity
3
Severe: Gastrointestinal symptoms that prevent normal 
activity
*Fever is defined as temperature 37.5°C for oral, axillary or tympanic route, or 38.0°C for rectal route. The 
preferred route for recording temperature in this study will be axillary.
 
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The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals as follows:
0
:
Absent
1
:
20 mm
2
:
>20 and 50 mm
3
:
> 50 mm
The maximum intensity of fever will be scored at GSK Biologicals as follows:
Axillary
0
:
< 37.5C
1
:
37.5C and 38.0C
2
:
> 38.0C and 39.0C
3
:
> 39.0C
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities. In adolescents, 
such an AE would, for example, prevent attendance at school and 
would necessitate the administration of corrective therapy.
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 8.1.2
8.3.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between investigational vaccine 
and the occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship 
of the event to the investigational vaccine will be considered and investigated. The 
 
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investigator will also consult the SmPC and/or Prescribing Information for marketed 
products to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccine administered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines.
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine?
YES
:
There is a reasonable possibility that the vaccine contributed to the 
AE. 
NO
:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccine. There are other, more 
likely causes and administration of the study vaccine is not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).
 
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8.3.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
8.3.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject’s 
parent(s)/LAR(s) will be asked if the subject received medical attention defined as 
hospitalisation, or an otherwise unscheduled visit to or from medical personnel for any 
reason, including emergency room visits. This information will be recorded in the eCRF. 
8.4.
Reporting of serious adverse events, pregnancies, and 
other events
8.4.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 15, once the investigator determines that 
the event meets the protocol definition of a SAE.
Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 15, once the investigator becomes 
aware of the pregnancy. 
Table 15
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a 
Previous Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
Pregnancies 
2 weeks*
electronic pregnancy report
2 weeks*
electronic pregnancy report
* Timeframe allowed after receipt or awareness of the information.
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE.
 
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8.4.2.
Contact information for reporting serious adverse events, 
pregnancies 
Study Contact for Reporting SAEs and pregnancies
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs and pregnancies
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: 
 or 
Email address: 
8.4.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE.
8.4.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system. 
8.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
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Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
8.4.5.
Updating of SAE and pregnancy information after removal of 
write access to the subject’s eCRF
When additional SAE or pregnancy information is received after removal of the write 
access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance
department within the designated reporting time frames specified in Table 15.
8.4.6.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine and unexpected. The 
purpose of the report is to fulfil specific regulatory and GCP requirements, regarding the 
product under investigation.
8.5.
Follow-up of adverse events, serious adverse events, and 
pregnancies
8.5.1.
Follow-up of adverse events and serious adverse events 
8.5.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 15).
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
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All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination.
8.5.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs or subjects withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilised, disappeared, or until the event is otherwise 
explained, or the subject is lost to follow-up. 

with other non-serious AEs, until they are lost to follow-up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using an electronic Expedited 
Adverse Events Report and/or pregnancy report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
8.5.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals electronic pregnancy report and the 
Expedited Adverse Events Report if applicable. Generally, the follow-up period doesn’t 
need to be longer than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
8.6.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 6.7).
8.7.
Subject card
Study subjects’ parent(s)/LAR(s) must be provided with the address and telephone 
number of the main contact for information about the clinical study.
 
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The investigator (or designate) must therefore provide a “subject card” to each subject’s 
parent(s)/LAR(s). In an emergency situation this card serves to inform the responsible 
attending physician that the subject is in a clinical study and that relevant information 
may be obtained by contacting the investigator.
Subjects’ parent(s)/LAR(s) must be instructed to keep subject cards in their possession at 
all times.
9.
SUBJECT COMPLETION AND WITHDRAWAL
9.1.
Subject completion
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study.
9.2.
Subject withdrawal
Withdrawals will not be replaced.
9.2.1.
Subject withdrawal from the study
From an analyses perspective, a ‘withdrawal’ from the study refers to any subject who 
did not come back for the concluding visit foreseen in the protocol. 
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analyses.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subject’s parent(s)/LAR(s) who do 
not return for scheduled visits or follow-up.
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject’s parent(s)/LAR(s), or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.
 
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
Other (specify).
*In case a subject is withdrawn from the study because the subject’s parent(s)/LAR(s) has 
withdrawn consent, the investigator will document the reason for withdrawal of consent, 
if specified by the subject’s parent(s)/LAR(s), in the eCRF.
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.5.1.2).
10.
STATISTICAL METHODS
10.1.
Primary endpoint

Immunogenicity to components of the study vaccine.

Anti-HBs antibody concentrations ≥100 mIU/ml, one month after the single 
challenge dose of HBV vaccine.
10.2.
Secondary endpoints

Anti-HBs antibody persistence after previous vaccination with Infanrix hexa.

Anti-HBs antibody concentrations ≥10 mIU/ml, ≥100 mIU/ml and anti-HBs 
antibody concentrations before the single challenge dose of HBV vaccine.

Immunogenicity to the components of the study vaccine.

Anti-HBs antibody concentrations ≥10 mIU/ml and anti-HBs antibody 
concentrations one month after the single challenge dose of HBV vaccine.

Anamnestic response to the single challenge dose of HBV vaccines.
For the definition of anamnestic response, refer to Section 10.5.

Solicited local and general symptoms.

Occurrence of each solicited local and general symptom during the 4-day (Day 
0–3) follow-up period after the single challenge dose of HBV vaccine.

Unsolicited adverse events

Occurrence of unsolicited AEs during the 31-day (Day 0–30) follow-up period 
after the single challenge dose of HBV vaccine.

Serious adverse events

Occurrence of serious adverse events after the single challenge dose of HBV 
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10.3.
Determination of sample size
The primary objective of the study is to assess the anti-HBs antibody response to a single 
challenge dose of HBV vaccine (Engerix-B Kinder) in subjects at 14-15 years of age, 
previously vaccinated with four doses of Infanrix hexa in the first two years of life. The 
objectives of the study are descriptive as given in Section 2. However for the computation 
of sample size, the anti-HBs antibody response to the challenge dose of Engerix-B Kinder
is expected to be above 90%.
Approximately 300 children aged 14-15 years who were previously primed and boosted 
with four doses of Infanrix hexa in the first two years of life will be enrolled in this study.
It is assumed that 10% of subjects enrolled in this study may be non-evaluable for the 
analyses of the primary endpoint (e.g., drop-outs, non-compliance with protocol, etc.). 
Thus, a sample size of 270 evaluable subjects provides a power of at least 86% for the 
lower limit (LL) of the 95% confidence interval (CI) for the percentage of subjects who 
are expected to respond to the HBV vaccine challenge (i.e. anti-HBs antibody 
concentrations 100 mIU/ml one month after HBV vaccine challenge) to be more than 
90%, if the true percentage of subjects who have responded to the HBV vaccine 
challenge is 95%, as shown in Table 16.
In addition, should the true percentage of response to the HBV vaccine challenge be 
greater than 95% (for example 96% to 98%), Table 16 shows that the study is adequately 
powered to lead to a LL of the 95% CI not more than 5% below that true percentage (i.e. 
a LL above 91% to 93%, respectively). For instance, if the true percentage of response to 
the HBV vaccine challenge is 97%, a sample size of 270 subjects provides a power of at 
least 93% for the LL of the 95% CI, for the percentage of subjects who have responded to 
the HBV vaccine challenge (i.e. anti-HBs antibody concentrations 100 mIU/ml one 
month after HBV vaccine challenge) to be more than 92%. 
 
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Table 16
Power to obtain a lower limit for the 95 percent CI for the response 
to HBV vaccine challenge (anti-HBs antibody concentration greater 
than or equal to 100 mIU per ml) greater than 90 percent or greater 
than a margin that would be 5 percent below the expected 
percentage for a sample size of 270 evaluable subjects
Expected percentage
Power (%) to obtain a lower limit 
greater than 5% below the expected 
percentage
Power (%) to obtain a lower limit 
greater than 90%
**94%
80%
64%
^95%
86%
86%
96%
92%
97%
97%
93%
99%
*97.5%
95%
99%
98%
97%
> 99%
Note: All computations were performed in Pass 2005 based on a one-sided binomial test with a target one sided 
significance level of 0.025.
References data from studies: 
^DTPa-HBV-IPV-112 (106789): Subjects who received a single dose of HBV vaccine in the age group of 4-5 years and 
were previously primed and boosted with four doses of Infanrix hexa in the first two years of life. (Percentage of 
subjects 100 mIU/ml post challenge dose 95.8%, 95%CI [92.8%, 97.8%])
*DTPA-HBV-IPV-113 (112688): Subjects who received a single dose of HBV vaccine in the age group of 7-8 years 
and were previously primed and boosted with four doses of Infanrix hexa in the first two years of life. (Percentage of 
subjects 100 mIU/ml post challenge dose 95.8%, 95%CI [92.6%, 97.9%])
**DTPA-HBV-IPV-114 (106793): Subjects who received a single dose of HBV vaccine in the age group of 12-13 years 
and were previously primed and boosted with four doses of Infanrix hexa in the first two years of life. (Percentage of 
subjects 100 mIU/ml post challenge dose 94.1%, 95%CI [90.7%, 96.5%])
10.4.
Cohorts for Analyses
Three cohorts are defined for the purpose of analyses:

Total vaccinated cohort (TVC)

ATP cohort for analyses of immunogenicity

ATP cohort for analyses of antibody persistence
10.4.1.
Total vaccinated cohort
The TVC will include all subjects who received the single challenge dose of HBV 
vaccine. 

The TVC for the analyses of safety will include all subjects with study vaccine 
administration documented. 

The TVC for the analyses of immunogenicity will include all subjects who have 
received a single challenge dose of HBV vaccine and for whom data concerning 
immunogenicity endpoint measures are available at the post-HBV challenge blood 
sampling time point.
 
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10.4.2.
According-to-protocol cohort for analyses of immunogenicity
The ATP cohort for analyses of immunogenicity will include all subjects who satisfy the 
below criteria:

who meet all eligibility criteria

who comply with the procedures and intervals defined in the protocol.

who do not meet any of the elimination criteria during the study

for whom post-vaccination immunogenicity (Visit 2) results are available.
The interval between vaccination at Visit 1 and blood sampling at Visit 2, considered for 
inclusion of a subject in the ATP cohort for analyses of immunogenicity will be 21-48 
days.
10.4.3.
According-to-protocol cohort for analyses of antibody 
persistence
The ATP cohort for analyses of antibody persistence will include all enrolled subjects:

aged 14–15 years (from and including the 14th birthday up to but excluding the 16th
birthday) at the time of enrolment.

who have not received any additional dose of hepatitis B vaccine (or any other 
vaccine with this antigen component) other than the four doses of Infanrix hexa
during the first two years of life. 

with no evidence of hepatitis B infection or disease (including anti-HBc at post-HBV 
challenge dose time point). 

for whom serological results are available at the pre-HBV challenge blood sampling 
time point.
10.5.
Derived and transformed data

A seronegative subject is a subject with anti-HBs antibody concentration below the 
assay cut-off (< 6.2 mIU/ml).

A seropositive subject is a subject with anti-HBs antibody concentrations above the 
assay cut-off (6.2 mIU/ml).

A seroprotected subject is a subject with anti-HBs antibody concentrations above the 
protection level (10 mIU/ml).

Anamnestic response to the single challenge dose is defined as:

At least (i.e. greater than or equal to) 4-fold rise in post-vaccination anti-HBs 
antibody concentrations in subjects seropositive at the pre-vaccination time 
point.

Post-vaccination, anti-HBs antibody concentrations 10 mIU/ml in subjects 
seronegative at the pre-vaccination time point.
 
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
The Geometric mean antibody concentrations (GMCs) calculations will be
performed by taking the anti-log of the mean of the log10 concentration 
transformations. All subjects will be considered. Subjects whose antibody 
concentrations are below the cut-off of the assay will be given an arbitrary value of 
half the cut-off for the purpose of GMC calculation. Note that as per assay 
specification, results between the assay cut-off of 6.2 mIU/ml and 7.65 mIU/ml (=
Lower limit of Quantification) will be quantified as 6.2 mIU/ml.

For a given subject and a given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced. Therefore, an analysis will exclude 
subjects with missing or non-evaluable measurements.
Safety/Reactogenicity

For the analyses of solicited symptoms, missing or non-evaluable measurements will 
not be replaced. Therefore the analyses of the solicited symptoms based on the TVC 
will include only subjects with documented safety data (i.e. symptom screen 
completed).

For the analyses of unsolicited adverse events/concomitant medication, all 
vaccinated subjects will be considered and subjects who did not report an event will 
be considered as subjects without an event.
10.6.
Analyses of demographics
Demographic characteristics (age at study entry [in years], gender, geographic ancestry, 
height [in cm] and weight [kg]), cohort description and drop outs/withdrawals will be 
summarised using descriptive statistics: 

Frequency tables will be generated for categorical variable such as centre.

Mean, median, standard deviation will be provided for continuous variable such as 
age.
10.7.
Analyses of immunogenicity
Analyses for antibody persistence
The analyses for antibody persistence will be performed on the ATP cohort for analyses
of antibody persistence. 

Prior to the single dose of HBV vaccine:

Percentage of subjects with anti-HBs antibody concentrations 6.2 mIU/ml, 
10 mIU/ml, 10 mIU/ml to < 100 mIU/ml, and 100 mIU/ml, with exact 
95% CI will be calculated [Clopper, 1934].

GMCs with 95% CI will be calculated for anti-HBs antibodies.

The distribution of anti-HBs antibody concentrations will be displayed using 
reverse cumulative curves (RCCs).
 
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Response to challenge dose
The primary analyses will be based on the ATP cohort for analyses of immunogenicity. 
If, the percentage of vaccinated subjects with serological results excluded from the ATP 
cohort for analyses of immunogenicity is 5% or more, a second analyses based on the 
TVC will be performed to complement the ATP analyses.

One month after the single challenge dose of HBV vaccine:

Percentage of subjects with anti-HBs antibody concentrations 6.2 mIU/ml, 
10 mIU/ml and 100 mIU/ml, with exact 95% CI will be calculated [Clopper, 
1934].

GMCs with 95% CI will be calculated for anti-HBs antibodies.

The distribution of anti-HBs antibody concentrations will be displayed using 
RCCs.

The percentage of subjects with anti-HBs concentrations 6.2 mIU/ml, 
10 mIU/ml, and 100 mIU/ml (with exact 95% CI) and GMCs at the post-HBV 
challenge dose time-point, in relation to their pre-challenge dose status 
(< 6.2 mIU/ml, < 10 mIU/ml, 10 mIU/ml) will be tabulated [Clopper, 1934].

Percentage of subjects (with 95% CI) who mount an anamnestic response to the 
single challenge dose of HBV vaccine will be calculated overall and in relation to 
their pre-vaccination status (< 6.2 mIU/ml, < 10 mIU/ml, 10 mIU/ml) [Clopper, 
1934].

Post-challenge anti-HBs antibody concentrations as a function of pre-challenge
concentrations, with regression line will be computed using linear regression method
for ATP cohort for immunogenicity only. The model will include pre-challenge log
transformed concentrations as regressor (independent or explanatory variable) and
post-challenge log-transformed concentrations as an outcome (dependent or
response) variable.antibody concentrations observed at the pre-challenge dose time 
point will be presented graphically.
10.8.
Analyses of safety
The primary analyses of safety and reactogenicity will be based on the TVC.

The percentage of subjects with at least one local AE (solicited and unsolicited), with 
at least one general AE (solicited and unsolicited) and with any AE during the 4-day 
(Day 0 to Day 3) follow-up period after the vaccination will be tabulated with exact 
95% CI [Clopper, 1934]. The same calculations will be performed for any Grade 3 
(solicited or unsolicited) symptoms, relationship to the vaccination and any 
symptoms requiring medical attention.

The percentage of subjects reporting each individual solicited symptom during the 4-
day follow-up period with exact 95% CI [Clopper, 1934], by type of adverse event; 
by severity (any grade, Grade 3 only); by relationship to vaccination (any 
relationship, related only) will be tabulated.
 
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
The occurrence of fever will be tabulated per 0.5°C cumulative increments as well as 
the occurrence of Grade 3 fever (> 39.0 °C axillary temperature) with causal 
relationship to vaccination. 

The percentage of subjects with at least one report of unsolicited adverse event 
classified by the Medical Dictionary for Regulatory Activities and reported within 
the 31-day (Day 0 to Day 30) follow-up period after vaccination will be tabulated 
with exact 95% CI [Clopper, 1934]. The same tabulation will be performed for 
Grade 3 unsolicited adverse events and for unsolicited adverse events with a causal 
relationship to vaccination.

The percentage of subjects who started receiving at least one concomitant medication 
(i.e. any medication, antipyretic medication, prophylactic antipyretics) during the 4-
day and 31-day follow-up period after vaccination will be tabulated (with exact 95% 
CI) [Clopper, 1934].

SAEs and withdrawals due to AEs and SAEs reported during the study will be 
described in detail
10.9.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
10.9.1.
Sequence of analyses
The analyses will be performed when all data up to one month after the vaccine dose will 
be available. All analyses and associated individual data will be presented in a Clinical 
Study Report, which will be shared with the investigator(s) involved in the conduct of 
this study.
10.9.2.
Statistical considerations for interim analyses
All analyses will be conducted on final data and therefore no statistical adjustment for 
interim analyses is required.
11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
11.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analyses and reporting will be entered/transmitted into a validated database 
 
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or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
11.2.
Study Monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose. 
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. 
For eCRF, the monitor freezes completed and approved screens at each visit.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
 
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11.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
11.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
11.5.
Posting of information on publicly available clinical trial 
registers and publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 6 months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines. 
 
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GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. At the time of publication, this protocol will be fully disclosed.
11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
12.
COUNTRY SPECIFIC REQUIREMENTS
Refer to the Explanatory Statement concerning Gender Distribution.
 
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13.
REFERENCES
Avdicova M, Crasta P, Hardt K et al. Lasting immune memory against hepatitis B 10 
years after the 2+1 primary vaccination schedule with DTPa-HBV-IPV/Hib or DTPa-
IPV/Hib+HBV. 30th Annual Meeting of the ESPID. 2012, Congress abstract presented at 
Thessaloniki; Greece Start date: 08/05/2012.
Behre U, Bleckmann G, Crasta PD et al. Long-term anti-HBs antibody persistence and 
immune memory in children and adolescents who received routine childhood hepatitis B 
vaccination. Hum Vaccin Immunother. 2012, 8(6).
Centers for Disease Control (CDC). Hepatitis B virus: A comprehensive strategy for 
eliminating transmission in the United States through universal childhood vaccination:
Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR. 
1991; 40(RR-13): 1–19.
Centre for Disease Control (CDC) General recommendations on immunization: 
recommendations of the Advisory Committee on Immunization Practices (ACIP) and the 
American Academy of Family Physicians (AAFP). MMWR; 2002, 51(RR02); 1–36.
Clopper C. J, Pearson E.S. The Use Of Confidence Or Fiducial Limits Illustrated In The 
Case Of The Binomial. Biometrika. 1934: 26, 404-413.
Centers for Disease Control and  Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005 ) ‘adopted at Community level 
in May 2006);
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf.
Frisch-Niggemeyer W, Ambrosch F and Hofmann H. The assessment of immunity 
against hepatitis B after vaccination. J Biol Stand. 1986; 14: 255–258.
GSK Biologicals’ Clinical Study Report (106793) DTPA-HBV-IPV-114. An open, phase 
IV, multicentre study to assess the long-term persistence of antibodies against hepatitis B 
and the immune response to a hepatitis B (Engerix-B Kinder) vaccine challenge in 
children aged 12-13 years, previously primed and boosted in the first two years of life 
with GlaxoSmithKline (GSK) Biologicals’ DTPa-HBV-IPV/Hib (Infanrix hexa) vaccine.
Data on file.
Van Der Meeren O, Bleckmann G, Crasta PD. Immune memory to hepatitis B persists in 
children aged 7-8 years who were vaccinated in infancy with 4 doses of hexavalent 
DTPa-HBV-IPV/Hib (Infanrix hexa) vaccine. Hum Vacc Immunother. 2014; 10(6): 1682-
87.
 
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Poovorawan Y, Chongsrisawat, Theamboonlers A, et al. Long-term anti-HBs antibody 
persistence following infant vaccination against hepatitis B and evaluation of anamnestic 
response: a 20-year follow-up study in Thailand. Hum Vaccin Immunother. 2013;
9(8):1679-84.
Steiner M, Ramakrishnan G, Gartner B et al. Lasting immune memory against hepatitis B 
in children after primary immunization with 4 doses of DTPa-HBV-IPV/Hib in the first 
and 2nd year of life. BMC Infect Dis. 2010; 10:9.
World Health Organization (WHO). Progress in the control of viral hepatitis: 
Memorandum from a WHO Meeting. Bull WHO 1988; 66(4): 443–445.
WHO. Hepatitis B Fact sheet N°204. July 2015. 
http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed on 06 November 2015.
Zinke M, Disselhoff J, Gartner B, et al. Immunological persistence in 4–6 and 7–9 year
olds previously vaccinated in infancy with hexavalent DTPa-HBV-IPV/Hib. Hum Vacci
2010;6(2):189-93.
 
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APPENDIX A
CLINICAL LABORATORIES
Table 17
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Clinical Laboratory 
Sciences, Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium
GSK Biologicals Clinical Laboratory, 
Sciences, Wavre-Nord Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 18
Outsourced laboratories
Laboratory
Address
CEVAC - University of Gent
De Pintelaan, 185 Gent
Belgium
Néomed Lab Inc
Biospecimen Reception - Clinical Serology
525 Cartier blvd West - Laval - Quebec - Canada -
H7V 3S8
 
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PPD