Long Term Hepatitis A Virus (HAV) Antibody Persistence in Children Vaccinated With 1 Dose and Those Vaccinated With 2 Doses of Havrix in Panama
Phase: NA
Conditions: Hepatitis A Vaccine
Sponsor: GlaxoSmithKline

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201630 (EPI-HAV-007 BOD PA)
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Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89
1330 Rixensart, Belgium
eTrack study number and 
Abbreviated Title
201630 (EPI-HAV-007 BOD PA)
Date of protocol
Final Version 3: 02 October 2015
Date of protocol 
amendment
Amendment 1 Final: 05 April 2016
Amendment 2 Final: 24 July 2017
Title
Long term hepatitis A virus (HAV) antibody 
persistence in children vaccinated with 1 dose and 
those vaccinated with 2 doses of Havrix® in Panama.
Detailed Title
Epidemiological, prospective, interventional, multi-
centre, long term HAV antibody persistence in 
children vaccinated with 1 dose and those vaccinated 
with 2 doses of Havrix® in Panama.
Co-ordinating author
, Scientific Writer
Contributing authors
(Amended: 24 July 2017)
!
, Regional Manager, Epidemiology 
LATAM
!
, Senior Manager, Epidemiology 
Travellers/
, Senior Manager, 
Epidemiology
!
, Study Delivery Lead, Synteract 
HCR for GSK Biologicals,
!
,
, Study Delivery 
Leads
!
, 
, Project 
Statisticians
!
, 
, Lead 
Statisticians
!
, Project Data Manager
!
, Study Data Manager, Tata 
Consultancy Services for GSK Biologicals
!
/
, CLS Study 
Manager
!
/
, CLS Study 
Manager
!
, Clinical Read-out leader
!
, Cluster Medical 
Lead, Caricam-Andina

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eTrack study number and 
Abbreviated Title
201630 (EPI-HAV-007 BOD PA)
Detailed Title
Epidemiological, prospective, interventional, multi-
centre, long term HAV antibody persistence in
children vaccinated with 1 dose and those vaccinated 
with 2 doses of Havrix® in Panama.
Co-ordinating author
!
, Scientific Writer
Contributing authors
!
, Clinical Safety representative
!
, Study Delivery Manager
!
/
, Vaccine Supply 
Coordinator, Aprova for GSK Biologicals
!
, Local Delivery Lead
GSK Biologicals’ protocol template for observational studies and interventional studies 
without administration of medicinal products as described in a research protocol based 
on the Protocol Document Standard version 14.1.2
Copyright 2015-2017 of the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.

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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
201630 (EPI-HAV-007 BOD PA)
Date of protocol amendment
Amendment 2 Final: 24 July 2017
Detailed Title
Epidemiological, prospective, interventional, multi-
centre, long term HAV antibody persistence in 
children vaccinated with 1 dose and those vaccinated 
with 2 doses of Havrix® in Panama.
Sponsor signatory
Frank Struyf,
Clinical and Epidemiology Project Leader 
Hepatitis/HPV
Signature
Date
 
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Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes:

The date of birth requirement has been eliminated from the study as it is not
necessary for the design or the objectives of the study and will ease the recruitment 
constraint observed in the study.

The post last dose interval will be updated due to low number of eligible subjects 
identified within the existing intervals which puts at risk achieving adequate 
sample size.

For the Year 8 survey: The new post last dose time interval may include 
children with ≥ 7 years and < 10 years between last dose.

For the Year 10 survey: The new post last dose time interval may include 
children with ≥ 10 years and < 13 years between last dose.

This post last dose time criteria has been added to inclusion criteria section for 
clarification.
 
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Protocol Amendment 2 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, with the terms of the study 
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) or other 
applicable guidelines such as International Society for Pharmacoepidemiology 
(ISPE) guidelines for Good Pharmacoepidemiology Practices (GPP) and all 
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
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 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 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, 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
201630 (EPI-HAV-007 BOD PA)
Date of protocol amendment
Amendment 2 Final: 24 July 2017
Detailed Title
Epidemiological, prospective, interventional, multi-
centre, long term HAV antibody persistence in 
children vaccinated with 1 dose and those vaccinated 
with 2 doses of Havrix® in Panama.
Investigator name
Signature
Date
 
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Sponsor Information
Sponsor
GlaxoSmithKline Biologicals
GlaxoSmithKline Biologicals
Rue de l’Institut 89
1330 Rixensart, Belgium
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
Sponsor Study Monitor
Refer to the local study contact information document.
Study Contact for Reporting of a Serious Adverse Event (SAE)
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 7.3.2.
 
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SYNOPSIS
Detailed Title
Epidemiological, prospective, interventional, multi-centre, 
long term HAV antibody persistence in children vaccinated 
with 1 dose and those vaccinated with 2 doses of Havrix® in 
Panama.
Objectives
Primary

To assess the persistence of anti-hepatitis A virus (HAV) 
antibodies, approximately 8 years and 10 years post 
vaccination with the last received vaccine dose of the 
complete series of Havrix (2 doses) and the partial series 
completion (1 dose) in Panama.
Secondary

To assess geometric mean concentration (GMC) of anti-
HAV antibodies, approximately 8 years and 10 years post 
vaccination with the last received dose of the complete 
series of Havrix (2 doses) and the partial series 
completion (1 dose) in Panama.

To explore the non-inferiority of the 1-dose schedule of 
Havrix when compared to the 2-dose schedule in terms of 
the percentage of subjects with anti-HAV antibody 
concentrations ≥ 15 mIU/mL, approximately 8 years and 
10 years after the last received vaccination dose.
Criteria for evaluation: The lower limit of the 2-sided 95% CI 
for the difference (1-dose group minus the 2-dose group) of 
percentage of subjects with anti-HAV antibody concentrations 
≥ 15 mIU/mL is greater than or equal to the pre-defined 
clinical non-inferiority limit of -10%.
Rationale for the 
study
Due to limited financial resources, most countries in Latin 
America (LatAm) have not included Havrix as part of the 
Universal Mass Vaccination (UMV) program. A possible 
solution to this problem is to offer a one dose series which 
would be more economical and logistically feasible in these 
resource limited countries. Many countries within LatAm 
have shown interest in this possible new vaccination schedule 
but evidence is limited on the long term protection of 1-dose 
schedule of Havrix compared to the demonstrated long term 
protection of the recommended 2-dose schedule, especially in 
the paediatric population.
In LatAm, Argentina was the first country that introduced an 
off label schedule for Havrix. In Argentina, there was a 
nationwide outbreak of hepatitis and the rate of infection 
 
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increased from 55.3 cases per 100,000 inhabitants in 2002 to 
107.5 and 113.3 cases per 100,000 inhabitants in 2003 and 
2004, respectively. Additionally, hepatitis A virus (HAV) was 
the leading cause of fulminant hepatic failure (FHF) and liver 
transplantation in children. To reduce the health burden 
associated with HAV disease, the Ministry of Health decided 
to implement a mandatory one-dose vaccination strategy into 
the Argentinean regular immunisation schedule for all 
children aged 12 months in June 2005.
Recent published data show that since 2006, the mean 
Argentinean hepatitis A incidence rate has dropped to 7.9 per 
100,000 inhabitants in the post-vaccination period (2006-
2011), which represents an 88.1% reduction compared to the 
pre-vaccination period (2000-2002), with mean incidence rate 
of 66.5 per 100,000 inhabitants. There was a striking decrease 
in HAV-related FHF and resulting liver failure, with no new 
HAV-related FHF/liver failure cases recorded after end of 
2006 / March 2007.
Universal hepatitis A vaccination was introduced in Panama 
in April 2007. Two doses of the vaccine were given to 
children at 12 and 18 months of age. The Expanded Program 
of Immunisation (EPI) of Panama had reportedly provided 
53,417 and 7,104 doses of Havrix in Panama (first and second 
dose) during 2007 for an estimated coverage of 81% of the 
population receiving at least one dose of Havrix and 11% 
receiving both doses (complete series). In 2008, vaccination 
coverage rose as 99% of the eligible population received at 
least one dose of Havrix and 65% received the complete 
vaccination series (two doses).
Panama is an ideal setting to conduct the present study since it 
consists of an adequate size cohort of children who had 
received both doses of Havrix as well as children who had 
received one dose of Havrix. In addition, this population 
provides an adequate time interval to measure long term 
antibody persistence since the children were vaccinated 
approximately 8 years ago.
The present study will be conducted to evaluate the 
persistence of hepatitisA antibodies, approximately 8 years 
and 10 years post vaccination with the complete series of 
Havrix (2 doses) and the partial series completion (1 dose).
Study design
(Amended: 24 July 
2017)

Type of design: Epidemiological, serial, cross-sectional, 
interventional, multi-centre study in Panama.

Study population comprises of children who had received 
 
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Havrix at selected health centres of Panama.

Eligible children affiliated with the study sites will be 
enrolled in the study.

Biological samples: A blood sample (5mL) will be 
collected from all subjects at each cross-sectional survey 
(Year 8 and Year 10).

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Duration of the study: This study involves only one study 
visit per subject. However, since the study comprises of 
two independent cross-sectional surveys (Year 8 and 
Year 10), the same subject who participated in the Year 8 
cross-sectional survey may be randomly enrolled for the 
Year 10 cross-sectional survey. In that case, the subject 
will be enrolled as a new subject and will not be 
associated to his/her participation in the Year 8 cross-
sectional survey. The overall duration of the study is 
estimated to be approximately 2 years.

Epochs foreseen in the study:

Epoch 001: Persistence Visit 1 (Year 8)

Epoch 002: Persistence Visit 1’ (Year 10)

Definition of the cohorts foreseen in the study:

Year 8 cohort: All subjects participating in the Year 
8 cross-sectional survey (Visit 1 Epoch 001) - May 
include children with ≥ 7 years and < 10 years 
between last Havrix dose and Persistence Visit 1 
(Year 8)

Year 10 cohort: All subjects participating in the Year 
10 cross-sectional survey (Visit 1’ Epoch 002) - May 
include children with ≥ 10 years and < 13 years 
between last Havrix dose and Persistence Visit 1’ 
(Year 10)
Synopsis Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of subjects
Epochs
Epoch 001
Epoch 002
Yr 8 Havrix_1 dose 
~300
x 
Yr 8 Havrix_2 dose 
~300 
X
Yr 10 Havrix_1 dose  
~300
x 
Yr 10 Havrix_2 dose 
~300 
x 
 
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Discussion of study 
design
A serial, cross-sectional, serological study will allow 
evaluating the long term persistence of anti-HAV antibodies 
and GMCs in children who had received 1 dose of Havrix
vaccine (partial series) and children who had received 2 doses 
of Havrix vaccine (complete series) during the same time 
point.
The first cross-sectional serousurvey will evaluate the long 
term persistence of immunity approximately 8 years post 
vaccine administration and provide preliminary data on the 
non-inferiority of 1 dose versus 2 doses, in terms of long term 
persistence. The second cross-sectional study will evaluate 
long term persistence, approximately 10 years post vaccine 
administration, since the duration of protection beyond 10 
years remains unknown and provide preliminary data on the 
non-inferiority of 1 dose versus 2 doses, in terms of long term 
persistence. However, the sampling and testing for Year 8 and 
Year 10 cross-sectional surveys will be independent of each 
other.
Persistence of immunity to HAV will be assessed by 
measuring the persisting, circulating anti-HAV antibodies by 
Enzyme-Linked Immunosorbent Assay (ELISA). Since only 
subjects who were previously vaccinated with Havrix are 
being followed up in this long term persistence study, a 
control group will not be available for comparison. No 
vaccine will be administered during the study period.
Number of subjects
(Amended: 24 July
2017)
Approximately 600 subjects (about 300 subjects vaccinated 
with one dose of Havrix and about 300 subjects vaccinated 
with two doses of Havrix) are planned to be enrolled at each 
cross-sectional survey time points (Year 8 and Year 10). Two 
different cohorts of subjects will be enrolled at each epoch, 
therefore about 600 subjects will be enrolled at Epoch 001 
(Year 8 cohort) and another cohort of about 600 subjects will 
be enrolled at Epoch 002 (Year 10 cohort). In total, 
approximately 1200 subjects will be enrolled in the study. 
Subjects in the Year 8 cross-sectional survey may be 
randomly enrolled for the Year 10 cross-sectional survey. In 
this case, the subject will not be associated to his / her 
previous participation and a new subject number will be re-
assigned.
Endpoints
Primary

Anti-HAV seropositivity status at approximately 8 years 
and 10 years after administration with the last received 
dose of Havrix.
 
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Secondary

Anti-HAV concentrations (GMC) at approximately 8 
years and 10 years after administration with the last 
received dose of Havrix

Anti-HAV seropositivity status at approximately 8 years 
and 10 years after administration with the last received 
dose of Havrix.
Subjects are defined as being seropositive if their anti-HAV 
antibody concentration is 15 mIU/mL.
 
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TABLE OF CONTENTS
PAGE
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................18
GLOSSARY OF TERMS ...............................................................................................19
TRADEMARKS .............................................................................................................21
1.
INTRODUCTION....................................................................................................22
1.1.
Background ................................................................................................22
1.2.
Rationale for the study................................................................................22
2.
BENEFIT: RISK ASSESSMENT.............................................................................23
2.1.
Risk Assessment ........................................................................................23
2.2.
Benefit Assessment ....................................................................................23
2.3.
Overall Benefit: Risk Conclusion.................................................................24
3.
OBJECTIVES.........................................................................................................24
3.1.
Primary objective ........................................................................................24
3.2.
Secondary objectives..................................................................................24
4.
STUDY DESIGN OVERVIEW (AMENDED: 24 JULY 2017) ...................................24
4.1.
Discussion of study design..........................................................................26
5.
STUDY POPULATION ...........................................................................................26
5.1.
Number of subjects/centres (Amended: 24 July 2017)................................26
5.2.
Inclusion criteria for enrolment (Amended: 24 July 2017)............................27
5.3.
Exclusion criteria/criterion for enrolment .....................................................28
6.
CONDUCT OF THE STUDY ..................................................................................28
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................28
6.2.
Subject identification...................................................................................29
6.3.
General study aspects ................................................................................29
6.4.
Outline of study procedures (Amended: 24 July 2017)................................30
6.5.
Detailed description of study procedures ....................................................30
6.5.1.
Reporting of subjects in the individual screening log sheet ..........30
6.5.2.
Informed consent/assent..............................................................30
6.5.3.
Check inclusion and exclusion criteria .........................................31
6.5.4.
Subject number attribution ...........................................................31
6.5.5.
Collect socio-demographic data...................................................31
6.5.6.
Study group allocation .................................................................31
6.5.7.
Record medical history including hepatitis A disease or 
vaccination history .......................................................................31
6.5.8.
Blood sampling for antibody determination ..................................31
6.5.9.
Recording of SAEs related to study participation .........................32
6.5.10.
Study conclusion..........................................................................32
6.6.
Biological sample handling and analysis.....................................................32
 
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6.6.1.
Use of specified study materials ..................................................33
6.6.2.
Biological samples.......................................................................33
6.6.3.
Laboratory assays .......................................................................33
6.6.4.
Biological samples evaluation......................................................34
6.6.4.1.
Immunological read-outs ............................................34
7.
SAFETY.................................................................................................................34
7.1.
Safety definitions ........................................................................................35
7.1.1.
Definition of a serious adverse event ...........................................35
7.1.2.
Clinical laboratory parameters and other abnormal 
assessments qualifying as SAEs .................................................35
7.2.
Detecting and recording SAEs....................................................................36
7.2.1.
Time periods for detecting and recording SAEs ...........................36
7.2.2.
Evaluation of SAEs......................................................................36
7.2.2.1.
Active questioning to detect SAEs..............................36
7.2.2.2.
Assessment of causality .............................................37
7.2.2.3.
Assessment of outcomes............................................38
7.3.
Reporting of SAEs ......................................................................................38
7.3.1.
Prompt reporting of SAEs related to study participation ...............38
7.3.2.
Contact information for reporting SAEs........................................38
7.3.3.
Completion and transmission of SAEs reports related to 
study participation........................................................................39
7.3.3.1.
Back-up system in case the electronic reporting 
system does not work.................................................39
7.3.4.
Updating of SAE information after freezing of the subject’s 
eCRF ...........................................................................................39
7.3.5.
Regulatory reporting requirements for SAEs................................39
7.4.
Follow-up of SAEs ......................................................................................40
7.4.1.
Follow-up during the study...........................................................40
7.4.2.
Follow-up after the subject is discharged from the study..............40
8.
STATISTICAL METHODS......................................................................................40
8.1.
Endpoints....................................................................................................40
8.1.1.
Primary endpoint..........................................................................40
8.1.2.
Secondary endpoints ...................................................................40
8.2.
Determination of sample size......................................................................41
8.3.
Cohorts for Analyses at Years 8 and 10......................................................42
8.3.1.
Total cohort at Year 8 or Year 10.................................................42
8.3.2.
Total effective cohort at Year 8 or Year 10...................................42
8.3.3.
According-to-Protocol (ATP) cohort for persistence at 
Years 8 or 10 (Amended: 24 July 2017).......................................42
8.4.
Derived and transformed data.....................................................................43
8.5.
Analysis of demographics/baseline characteristics .....................................43
8.6.
Analysis of primary and secondary objectives.............................................43
8.7.
Interpretation of analyses............................................................................44
8.8.
Conduct of analyses ...................................................................................45
8.8.1.
Sequence of analyses..................................................................45
8.8.2.
Statistical considerations for interim analyses..............................45
9.
ADMINISTRATIVE MATTERS ...............................................................................45
9.1.
Electronic Case Report Form instructions...................................................45
9.2.
Study monitoring by GSK Biologicals..........................................................46
 
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9.3.
Record retention .........................................................................................46
9.4.
Quality assurance.......................................................................................47
9.5.
Posting of information on publicly available registers and publication 
policy ..........................................................................................................47
9.6.
Provision of study results to investigators ...................................................47
10. COUNTRY SPECIFIC REQUIREMENTS...............................................................48
11. REFERENCES.......................................................................................................48
 
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LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study.....................................26
Table 2
List of study procedures .........................................................................30
Table 3
Intervals between study visits/contacts/observations (Amended: 
24 July 2017) .........................................................................................30
Table 4
Biological samples .................................................................................33
Table 5
Humoral immunity (antibody determination) ...........................................34
Table 6
Immunological read-outs........................................................................34
Table 7
Reporting periods for SAEs....................................................................36
Table 8
Timeframes for submitting SAEs related to study participation...............38
Table 9
Exact 95% confidence intervals of the percentage of subjects 
with anti-HAV concentrations greater than or equal to 15 mIU/mL..........41
Table 10
Power to show non-inferiority of the immunogenicity of 1-dose 
compared to 2-doses of Havrix...............................................................42
Table 11
GSK Biologicals’ laboratories .................................................................51
 
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LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .......................................................................50
APPENDIX B CLINICAL LABORATORIES ..................................................................51
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................52
 
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LIST OF ABBREVIATIONS
ANOVA:
Analysis of Variance
ATP:
According-To-Protocol
CI:
Confidence Interval
eCRF:
electronic Case Report Form
ELISA:
Enzyme-Linked Immunosorbent Assay
EPI:
Expanded Program of Immunisation
FHF:
Fulminant Hepatic Fever
GCP:
Good Clinical Practice
GMC:
Geometric Mean Concentration
GPP:
Good Pharmacoepidemiology Practices
GSK:
GlaxoSmithKline
HAV:
Hepatitis A Virus
ICF:
Informed Consent Form
ICH:
International Conference on Harmonisation
IEC:
Independent Ethics Committee
IRB:
Institutional Review Board
ISPE:
International Society for Pharmacoepidemiology
LAR:
Legally Acceptable Representative
LatAm:
Latin America
SAE:
Serious Adverse Event
SAP:
Statistical Analysis Plan
SBIR:
GSK Biologicals’ Central randomisation system on 
Internet
SDV:
Source Document Verification
SPM:
Study Procedures Manual
UMV:
Universal Mass Vaccination
 
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GLOSSARY OF TERMS
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.
Enrolled subject:
Enrolled subjects are subjects that have signed an ICF 
(valid or not) and have data entered in the database.
Epidemiological study:
An observational or interventional study without 
administration of medicinal product(s) as described in a 
research protocol.
Epoch:
An epoch is a self-contained set of consecutive time 
points or a single time point from a single protocol. Self-
contained means that data collected for all subjects at all 
time points within that epoch allows to draw a complete 
conclusion. Typical examples of epochs are retrospective 
data collection and prospective data collection, etc.
eTrack:
GSK Biologicals’ tracking tool for clinical/ 
epidemiological trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Section 8.3 for details on criteria for evaluability).
Interventional Human 
Subject Research:
Studies in which participants are administered medical 
care, medicinal products and/or medical/scientific 
procedures as described in a research protocol.
Prospective study:
A study in which the subjects/cases are identified and 
then followed forward in time in order to address one or 
more study objectives.
 
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Research protocol:
A document that describes the objective(s), design, 
methodology, statistical considerations, and organisation 
of a study. The protocol usually also gives the 
background and rationale for the study, but these could be 
provided in other protocol referenced documents.
Self-contained study:
Study with objectives not linked to the data of another 
study.
Study population:
Sample of population of interest.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the epidemiological study or a person 
about whom some medical information has been recorded 
in a database.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
 
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TRADEMARKS
The following trademark is used in the present protocol.
Note: In the body of the protocol (including the synopsis), the name of the vaccine will be 
written without the superscript symbol ™ or ® and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
Havrix®
Hepatitis A vaccine
 
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1.
INTRODUCTION
1.1.
Background
Due to limited financial resources, most countries in Latin America (LatAm) have not 
included Havrix as part of the Universal Mass Vaccination (UMV) program. A possible 
solution to this problem is to offer a one dose series which would be more economical 
and logistically feasible in these resource limited countries. Many countries within 
LatAm have shown interest in this possible new vaccination schedule but evidence is 
limited on the long term protection of 1-dose schedule of Havrix compared to the 
demonstrated long term protection of the recommended 2-dose schedule, especially in the 
paediatric population [Ott, 2013; WHO, 2011].
In LatAm, Argentina was the first country that introduced an off label schedule for 
Havrix. In Argentina, there was a nationwide outbreak of hepatitis and the rate of 
infection increased from 55.3 cases per 100,000 inhabitants in 2002 to 107.5 and 113.3 
cases per 100,000 inhabitants in 2003 and 2004, respectively [Vizzotti, 2014]. 
Additionally, hepatitis A virus (HAV) was the leading cause of fulminant hepatic failure 
(FHF) and liver transplantation in children [Ciocca, 2004; Ciocca, 2007; Ciocca, 2008]. 
To reduce the health burden associated with HAV disease, the Ministry of Health decided 
to implement a mandatory one-dose vaccination strategy into the Argentinean regular 
immunisation schedule for all children aged 12 months in June 2005 [Hendrickx, 2008].
Recent published data show that since 2006, the mean Argentinean hepatitis A incidence 
rate has dropped to 7.9 per 100,000 inhabitants in the post-vaccination period (2006-
2011), which represents an 88.1% reduction compared to the pre-vaccination period 
(2000-2002), with mean incidence rate of 66.5 per 100,000 inhabitants [Vizzotti, 2014]. 
There was a striking decrease in HAV-related FHF and resulting liver failure, with no 
new HAV-related FHF/liver failure cases recorded after end of 2006 / March 2007 
[Cervio, 2011; Vizzotti, 2014].
Universal hepatitis A vaccination was introduced in Panama in April 2007. Two doses of 
the vaccine were given to children at 12 and 18 months of age. The Expanded Program of 
Immunisation (EPI) of Panama had reportedly provided 53,417 and 7,104 doses of 
Havrix in Panama (first and second dose) during 2007 for an estimated coverage of 81% 
of the population receiving at least one dose of Havrix and 11% receiving both doses 
(complete series). In 2008, vaccination coverage rose as 99% of the eligible population 
received at least one dose of Havrix and 65% received the complete vaccination series 
(two doses) [GlaxoSmithKline Biologicals Clinical Study Report 112263].
1.2.
Rationale for the study
Panama is an ideal setting to conduct the present study since it consists of an adequate 
size cohort of children who had received both doses of Havrix as well as children who 
had received one dose of Havrix. In addition, this population provides an adequate time 
interval to measure long term antibody persistence since the children were vaccinated 
approximately 8 years ago.
 
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The present study will be conducted to evaluate the persistence of hepatitis A antibody, 
approximately 8 years and 10 years post vaccination with the complete series of Havrix
(2 doses) and the partial series completion (1 dose).
2.
BENEFIT: RISK ASSESSMENT
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:
2.1.
Risk Assessment
Risks associated with blood collection (such as pain at blood sampling site, haematoma 
or thrombus, vasovagal reaction, syncope or fainting) can be reduced by following best 
practices listed in the [WHO guidelines] for drawing blood (2010). Some examples are 
provided in the table below.
Important 
Potential/Identified Risk
Data/Rationale for 
Risk
Mitigation Strategy
Study Procedures 
Study procedure: Blood 
sample collection.
Pain at blood sampling 
site

Well-trained person should take 
the blood sample

Use needle of smaller gauge 
than the vein
Haematoma or 
thrombus

Enter vessel at an angle of 30 
degrees or less

Use gauge of needle smaller 
than the vein

Apply pressure to a straight arm 
for 3–5 minutes after drawing 
blood
Vasovagal reaction, 
Syncope, fainting

Hydrate patient, take postural 
blood pressure if dehydrated

Reduce anxiety

Have patient lie down if the 
person expresses concern

Provide audio-visual distraction
Please refer to WHO guidelines for drawing blood (2010): Best practices in phlebotomy, 
in particular section 8.5.3 on risk assessment and risk reduction strategies.
2.2.
Benefit Assessment
Most people vaccinated against hepatitis A are protected against the disease. By taking 
part in this study, the subject will know his/her anti-hepatitis A antibody levels. If the 
subject is not protected, the subject maybe offered hepatitis A vaccination as per routine 
practice in Panama.
 
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This study will provide information about the duration of protection offered by Havrix
against hepatitis A infection.
2.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimise the risk to subjects participating in 
this study, the potential or identified risks identified are justified by the potential benefits 
that will be provided to the subjects.
3.
OBJECTIVES
3.1.
Primary objective

To assess the persistence of anti-hepatitis A virus (HAV) antibodies, approximately 8 
years and 10 years post vaccination with the last received vaccine dose of the 
complete series of Havrix (2 doses) and the partial series completion (1 dose) in 
Panama.
Refer to Section 8.1.1 for the definition of the primary endpoint.
3.2.
Secondary objectives

To assess geometric mean concentration (GMC) of anti-HAV antibodies, 
approximately 8 years and 10 years post vaccination with the last received dose of 
the complete series of Havrix (2 doses) and the partial series completion (1 dose) in 
Panama.

To explore the non-inferiority of the 1-dose schedule of Havrix when compared to 
the 2-dose schedule in terms of the percentage of subjects with anti-HAV antibody 
concentrations ≥ 15 mIU/mL, approximately 8 years and 10 years after the last 
received vaccination dose.
Criteria for evaluation: The lower limit of the 2-sided 95% CI for the difference (1-dose 
group minus the 2-dose group) of percentage of subjects with anti-HAV antibody 
concentrations ≥ 15 mIU/mL is greater than or equal to the pre-defined clinical non-
inferiority limit of -10%.
Refer to Section 8.1.2 for the definition of the secondary endpoints.
4.
STUDY DESIGN OVERVIEW (AMENDED: 24 JULY 2017)
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 6.4), are essential and required for 
study conduct.
 
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
Type of design: Epidemiological, serial, cross-sectional, interventional, multi-centre 
study in Panama.

Study population comprises of children who had received Havrix at selected health 
centres of Panama.

Eligible children affiliated with the study sites will be enrolled in the study.

Biological samples: A blood sample (5mL) will be collected from all subjects at 
each cross-sectional survey (Year 8 and Year 10).

Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

Duration of the study: This study involves only one study visit per subject. However, 
since the study comprises of two independent cross-sectional surveys (Year 8 and 
Year 10), the same subject who participated in the Year 8 cross-sectional survey may 
be randomly enrolled for the Year 10 cross-sectional survey. In that case, the subject 
will be enrolled as a new subject and will not be associated to his/her participation in 
the Year 8 cross-sectional survey. The overall duration of the study is estimated to be 
approximately 2 years.

Epochs foreseen in the study:

Epoch 001: Persistence Visit 1 (Year 8)

Epoch 002: Persistence Visit 1’ (Year 10)

Definition of the cohorts foreseen in the study:

Year 8 cohort: All subjects participating in the Year 8 cross-sectional survey 
(Visit 1 Epoch 001) - May include children with ≥ 7 years and < 10 years 
between last Havrix dose and Persistence Visit 1 (Year 8)

Year 10 cohort: All subjects participating in the Year 10 cross-sectional survey 
(Visit 1’ Epoch 002) - May include children with ≥ 10 years and < 13 years 
between last Havrix dose and Persistence Visit 1’ (Year 10)
Table 1 presents the study groups and epochs foreseen in the study.
 
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Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of subjects
Epochs
Epoch 001
Epoch 002
Yr 8 Havrix_1 dose  
~300
x
Yr 8 Havrix_2 dose 
~300
x
Yr 10 Havrix_1 dose  
~300
x
Yr 10 Havrix_2 dose 
~300
x
4.1.
Discussion of study design
A serial, cross-sectional, serological study will allow evaluating the long term persistence 
of anti-HAV antibodies and GMCs in children who had received 1 dose of Havrix
vaccine (partial series) and children who had received 2 doses of Havrix vaccine 
(complete series) during the same time point.
The first cross-sectional serosurvey will evaluate the long term persistence of immunity 
approximately 8 years post vaccine administration and provide preliminary data on the 
non-inferiority of 1 dose versus 2 doses, in terms of long term persistence. The second 
cross-sectional study will evaluate long term persistence, approximately 10 years post 
vaccine administration, since the duration of protection beyond 10 years remains 
unknown and provide preliminary data on the non-inferiority of 1 dose versus 2 doses, in 
terms of long term persistence. However, the sampling and testing for Year 8 and Year 10 
cross-sectional surveys will be independent of each other.
Persistence of immunity to HAV will be assessed by measuring the persisting, circulating 
anti-HAV antibodies by Enzyme-Linked Immunosorbent Assay (ELISA). Since only 
subjects who were previously vaccinated with Havrix are being followed up in this long 
term persistence study, a control group will not be available for comparison. No vaccine 
will be administered during the study period.
5.
STUDY POPULATION
5.1.
Number of subjects/centres (Amended: 24 July 2017)
Approximately 600 subjects (about 300 subjects vaccinated with one dose of Havrix and 
about 300 subjects vaccinated with two doses of Havrix) are planned to be enrolled at 
each cross-sectional survey time points (Year 8 and Year 10). Two different cohorts of 
subjects will be enrolled at each epoch, therefore about 600 subjects will be enrolled at 
Epoch 001 (Year 8 cohort) and another cohort of about 600 subjects will be enrolled at 
Epoch 002 (Year 10 cohort). In total, approximately 1200 subjects will be enrolled in the 
study. Subjects in the Year 8 cross-sectional survey may be randomly enrolled for the 
Year 10 cross-sectional survey. A new subject number will be re-assigned.
If needed, the recruitment period for each cross-sectional survey may be extended to 
ensure the target sample size is achieved.
 
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Overview of the recruitment plan:

The parent(s)/legally acceptable representative (s) [LAR(s)] of eligible children 
attending the schools will be contacted by the school management and informed of 
the study rationale and procedures.

The parent(s) or LAR(s) along with the preselected children will be asked to visit the 
study site at a scheduled appointment where the informed consent process will be 
initiated and the children will be formally enrolled into the study.

The parent(s) or LAR(s) will need to sign the informed consent form (ICF) and all 
children-as they are above 7 years of age will be asked to provide informed assent.

However, the recruitment of subjects will not be limited to schools. Some subjects 
maybe enrolled directly at the study site also.

The recruitment will be performed using the SBIR application. The aim is to control 
the enrolment per group at each epoch and stop the enrolment once the defined target 
has been reached. After having checked the eligibility of the subject and obtaining 
the ICF/informed assent form, the study site staff will access SBIR. When SBIR is 
not available, please refer to the SBIR user guide or the Study Procedures Manual
(SPM) for specific instructions.

Note that as soon as the target number of 300 subjects per study group per epoch has 
been reached, the enrolment will be frozen.
5.2.
Inclusion criteria for enrolment (Amended: 24 July 2017)
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects whose parent(s)/ LAR(s), in the opinion of the investigator, can and will 
comply with the requirements of the protocol.

Written informed assent/consent obtained from the subject or subject’s parent(s)/ 
LAR(s) of the subject.

Available HAV vaccination records.

Children who have received either 1 or two doses of Havrix at selected health centres 
of Panama.

Children with ≥ 7 years and < 10 years between last dose and Persistence Visit 1 
(Year 8) and children ≥ 10 years and < 13 years between last dose and Persistence 
Visit 1’ (Year 10).
 
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5.3.
Exclusion criteria/criterion for enrolment
Deviations from exclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Child in care
Please refer to the glossary of terms for the definition of child in care.

Subjects with history of vaccination with other hepatitis A vaccines other than 
Havrix.

Subjects with known past history of hepatitis A infection, both without vaccination 
and after they received the last dose of Havrix (1 dose or the complete 2 dose 
schedule).
6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) or other applicable 
guidelines, such as Guidelines for Good Pharmacoepidemiology Practices (GPP) 
[International Society for Pharmacoepidemiology (ISPE), 2007], 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 prior to a site initiating 
the study in that country or will document that neither a favourable opinion nor an 
approval to conduct the study is needed.
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 Biologicals will provide full details of the above procedures to the investigator, 
either verbally, in writing, or both.
 
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Freely given and written informed consent must be obtained from each subject’s 
parent(s)/LAR(s) or the impartial witness 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 applicable ICH GCP or other applicable guidelines, such as ISPE guidelines for GPP 
and GSK Biologicals required elements. While it is strongly recommended that this 
model ICF 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, 
a subject who can only be enrolled in the study with the consent of his/her parent(s) or 
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. 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 parent or legal representative. It should be assessed whether an assent is 
required depending on the age of the study population and the local requirements.
GSK Biologicals strongly recommends that if the subject reaches the age of consent 
during the study they will be asked to provide consent at the next study visit (if 
applicable). This procedure should be applied according to local laws and regulations.
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
6.2.
Subject identification
Subject numbers will be assigned sequentially to subjects to be included in the study, 
according to the range of subject numbers allocated to each study centre.
6.3.
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.
 
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6.4.
Outline of study procedures (Amended: 24 July 2017)
Table 2
List of study procedures
Epochs
001 and 002
Visits
Visit 1 – Year 8 and Visit 1’ – Year 10
Time points
Day 0 and Year 2
Reporting of subjects in the individual screening log sheet
O 
Informed consent/assent
● 
Check inclusion/exclusion criteria
● 
Subject number attribution
O 
Collect socio-demographic data
● 
Study group allocation
O 
Record medical history including hepatitis A disease/ vaccination history
● 
Blood sampling for antibody determination (~5mL)
● 
Recording of SAEs related to study participation
● 
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.
*The study conclusion is applicable to both epochs, Epoch 001 and Epoch 002. Different set of subjects will visit the 
study centre at Year 8 (Epoch 001) and Year 10 (Epoch 002). However, the study conclusion page will be filled for all 
the subjects in the eCRF.
Table 3
Intervals between study visits/contacts/observations (Amended: 24 
July 2017)
Interval
Allowed interval 1
Last Havrix dose vaccination date 
Visit 1 Epoch 001 (Year 8 Survey)
≥ 2555 days to <3650 days (7.0-
9.9 years)
Last Havrix dose vaccination date 
Visit 1’ Epoch 002 (Year 10 Survey)
≥3650 days to < 4745 days 
(10.0-12.9 years)
1Subjects will not be eligible for inclusion in the ATP cohort for analysis of each survey if they make the study visit 
outside this interval
6.5.
Detailed description of study procedures
6.5.1.
Reporting of subjects in the individual screening log sheet
All subjects who are approached for the trial will be reported in this sheet (including non-
eligible subjects). This is a log sheet to be maintained only by the sites for their reference.
6.5.2.
Informed consent/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 a 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 6.1 for the requirements on how to obtain informed consent and assent, 
as appropriate.
 
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6.5.3.
Check inclusion and exclusion criteria
Check all applicable inclusion and exclusion criteria as described in Sections 5.2 and 5.3
before enrolment.
6.5.4.
Subject number attribution
Subject numbers will be assigned sequentially to subjects to be included in the study, 
according to the range of subject numbers allocated to each study centre.
Two different cohorts of subjects will be enrolled at each epoch. About 600 subjects will 
be enrolled at Epoch 001 and another cohort of about 600 subjects will be enrolled at 
Epoch 002. Subjects in the Year 8 cross-sectional survey may be randomly enrolled for 
the Year 10 cross-sectional survey. In this case, the subject will not be associated to his / 
her previous participation and a new subject number will be re-assigned.
6.5.5.
Collect socio-demographic data
Record demographic data such as date of birth, gender, geographic ancestry, urban or 
rural residency in the subject’s eCRF.
6.5.6.
Study group allocation
After obtaining the ICF and informed assent form (as applicable) and confirming 
eligibility, the subject will be entered in to the SBIR enrolment module. SBIR will keep 
track of the enrolment status in each group during the enrolment in an epoch and freeze 
enrolment once the defined target per group is reached.
6.5.7.
Record medical history including hepatitis A disease or 
vaccination history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to participation in the study in the eCRF. Record any previous history of 
hepatitis A disease or vaccination. The investigator will also record if the subject received 
1 dose or 2 doses of Havrix previously along with the vaccination dates, in order to assign 
the subject to the appropriate study group.
6.5.8.
Blood sampling for antibody determination
About 5 mL of blood samples will be collected at each serosurvey for the determination 
of antibodies against HAV. Refer to the Module on Biospecimen Management in the 
SPM for general handling of blood samples.
 
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6.5.9.
Recording of SAEs related to study participation

Refer to Section 7.2 for procedures for the investigator to record SAEs related to 
study participation. Refer to Section 7.3 for guidelines on how to submit SAE reports 
to GSK Biologicals.

The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should they manifest any signs or symptoms they perceive as serious.
6.5.10.
Study conclusion
The investigator will:

review all the data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
The study conclusion is applicable to both epochs, Epoch 001 and Epoch 002. Different 
set of subjects will visit the study centre at Year 8 (Epoch 001) and Year 10 (Epoch 002). 
However, the study conclusion will be filled by all the subjects in the eCRF.
6.6.
Biological sample handling and analysis
Please refer to the SPM for details of biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subjects but will 
be coded with the identification number for the subject (subject number).

Collected samples will be used for protocol mandated research. In addition, these 
samples may be used to perform research 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 invited to give another specific 
consent to allow GSK or a contracted partner use the samples for future research 
including development of tests and their quality assurance. 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).
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.
6.6.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all samples 
(including serum samples) be collected and stored exclusively using those materials in 
the appropriate manner. The use of other materials could result in the exclusion of the 
subject from the ATP analysis (See Section 8.3 for the definition of study cohort’s/data 
sets 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 samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
6.6.2.
Biological samples
Table 4
Biological samples
Sample type
Quantity
Unit
Time point
Blood
5
ml
Visit 1 – Year 8 and Visit 1’ – Year 10
6.6.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis.
Serological assays for the determination of antibodies against HAV will be performed by
ELISA using standardised and validated procedures at GSK Biologicals’ laboratory or in 
a laboratory designated by GSK Biologicals. Subjects will be defined as being 
seropositive if their anti-HAV antibody concentration is 15 mIU/mL
 
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Table 5
Humoral immunity (antibody determination)
System
Component
Method
Kit / Manufacturer
Cut-off
Unit
Laboratory*
SER
Hepatitis A Virus 
Antibodies
ELI
Enzygnost (Siemens 
Healthcare)
15
mIU/mL
GSK Biologicals**
SER = Serum
ELI = Enzyme-linked immunosorbent assay
*Refer to APPENDIX B for the laboratory addresses.
**GSK Biologicals laboratory refers to the Clinical Laboratories Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium
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.
6.6.4.
Biological samples evaluation
6.6.4.1.
Immunological read-outs
Table 6
Immunological read-outs
Blood sampling time point
No. subjects
Component
Components priority 
rank
Year 8 – Visit 1 
All (Year 8 cohort)
Anti-HAV antibodies
Not applicable
Year 10 – Visit 1’
All (Year 10 cohort)
Anti-HAV antibodies
Not applicable
Investigators will be provided with the immunogenicity results for individual subjects 
enrolled at their site after the statistical analyses of each epoch have been completed.
If subjects have anti-HAV levels below the seropositivity cut-off of 15 mIU/ml (anti-
HAV antibody concentration is < 15 mIU/mL), the investigator will refer them to the 
appropriate point of care to assess if an extra dose of the Havrix vaccine needs be 
administered.
7.
SAFETY
All SAEs related to the study procedure (blood sample collection) will be collected from 
the time of sample collection up to study conclusion.
The investigator or site staff is/are responsible during the study for the detection and 
documentation of events meeting the criteria and definition of an SAE as provided in this 
protocol
Each subject’s parent(s)/ LAR(s) will be instructed to contact the investigator 
immediately should they manifest any signs or symptoms they perceive as serious/ of 
concern or indicating a change in their health status.
 
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7.1.
Safety definitions
7.1.1.
Definition of a serious adverse event
An SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
NB: 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 an existing hospitalisation,
NB: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting.
Complications that occur during hospitalisation are also considered AEs. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event 
will also be considered serious. When in doubt as to whether ‘hospitalisation’ 
occurred or was necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an SAE.
d.
Results in disability/incapacity,
NB: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
7.1.2.
Clinical laboratory parameters and other abnormal assessments 
qualifying as SAEs
In absence of diagnosis, abnormal laboratory findings (e.g., clinical chemistry, 
haematology, urinalysis) or other abnormal assessments that are judged by the 
investigator to be clinically significant will be recorded as SAEs if they meet the 
 
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definition of an SAE (refer to Section 7.1.1). 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 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.
7.2.
Detecting and recording SAEs
7.2.1.
Time periods for detecting and recording SAEs
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) will be collected and recorded from the time the study start until she/he is 
discharged from the study.
An overview of the protocol-required reporting periods for SAEs is given in Table 7.
Table 7
Reporting periods for SAEs
Epoch 001:
Study activity
Year 8 (Visit 1)
Study Conclusion
SAEs related to study procedure
Epoch 002:
Study activity
Year 10 (Visit 1’)
Study Conclusion
SAEs related to study procedure
7.2.2.
Evaluation of SAEs
7.2.2.1.
Active questioning to detect SAEs
Each subject’s parents/ LAR(s) will be instructed to contact the investigator immediately 
should the subject manifest any signs and symptoms they perceive as serious.
All SAEs either observed by the investigator or his/ her staff or reported by the subject’s 
parents/ LAR(s) spontaneously or in response to a direct question will be evaluated by the 
investigator. The nature of each event, date and time of onset, outcome, intensity and 
possible relationship to the study procedures should be established.
When an 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 the 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, 
 
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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 SAE and not the individual signs/symptoms.
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all 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 SAE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An SAE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An SAE which prevents normal, everyday activities
An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as 
described in Section 7.1.1.
7.2.2.2.
Assessment of causality
The investigator should assess the causality of each SAE. The investigator will use 
clinical judgement to determine the relationship between the SAEs and study 
participation. Alternative causes, such as natural history of the underlying diseases, other 
concomitant therapy and other risk factors will be considered and investigated.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the SAE report to GSK Biologicals. The investigator may change 
his/her opinion of causality in light of follow-up information and update the SAE 
information accordingly.
If an event meets the criteria to be considered as ‘serious’ (see Section 7.1.1), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possibly contributing factors to each SAE.
Possibly contributing factors include:

Medical history.

Concomitant medication.

Protocol required procedure.
 
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!
Other procedure not required by the protocol.
!
Lack of efficacy of the vaccine
7.2.2.3.
Assessment of outcomes
The investigator will assess the outcome of all SAEs recorded during the study as:
!
Recovered/ resolved
!
Recovering/ resolving
!
Not recovered/ not resolved
!
Recovered with sequelae/ resolved with sequelae
!
Fatal (SAEs only)
7.3.
Reporting of SAEs
7.3.1.
Prompt reporting of SAEs related to study participation
SAEs that occur in the time period defined in Section 7.2.1 will be reported promptly to 
GSK within the timeframes described in Table 8 once the investigator determines that 
the event meets the protocol definition of an SAE.
Table 8
Timeframes for submitting SAEs related to study participation
Type of event
Initial reports
Follow-up of relevant information
on a previous report
Timeframe
Documents
Timeframe
Documents
SAEs related to 
study participation
24 hours*‡
electronic 
Expedited Adverse 
Event Report
24 hours*
electronic Expedited Adverse 
Event 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
7.3.2.
Contact information for reporting SAEs
Study Contact for Reporting SAEs
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: 
 or 
Email address: 

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7.3.3.
Completion and transmission of SAEs reports related to study 
participation
Once an investigator becomes aware that an SAE has occurred in a study subject, the 
investigator (or designee) must complete the information in the electronic Expedited 
Adverse Event 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 an SAE, the report should still be completed within 24 
hours. Once additional 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.
7.3.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designee) must 
complete, then date and sign a paper Expedited Adverse Event Report and fax it to the 
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 designee) must complete the electronic Expedited Adverse 
Event Report within 24 hours. The final valid information for regulatory reporting will be 
the information reported through the electronic reporting system.
7.3.4.
Updating of SAE information after freezing of the subject’s eCRF
When additional SAE information is received after freezing of the subject’s eCRF, new 
or updated information should be recorded on a paper Expedited Adverse Event Report, 
with all changes signed and dated by the investigator. The updated report should be faxed 
to the GSK Biologicals Clinical Safety and Pharmacovigilance department or to the 
Study Contact for Reporting SAEs (see the Sponsor Information) within the designated 
reporting time frames specified in Table 8.
7.3.5.
Regulatory reporting requirements for SAEs
The investigator will promptly report all SAEs to GSK Biologicals in accordance with the 
procedures detailed in Section 7.3.1. GSK Biologicals has a legal responsibility to 
promptly notify, as appropriate, both the local regulatory authority and other regulatory 
agencies about the safety of a product under epidemiological 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.
 
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7.4.
Follow-up of SAEs
7.4.1.
Follow-up during the study
After the initial SAE report, the investigator is required to proactively follow each subject 
and provide further relevant information on the subject’s condition to GSK Biologicals 
(within 24 hours for SAEs, refer to Table 8)
7.4.2.
Follow-up after the subject is discharged from the study
The investigator will follow-up subjects:

With SAEs until the event has resolved, subsided, stabilised, disappeared, or until the 
event is otherwise explained, or the subject is lost to follow-up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/ she will provide this information to GSK Biologicals using a paper Expedited 
Adverse Event Report.
GSK Biologicals may request that the investigator performs or arranges for the conduct 
of additional clinical examinations/ tests and/ or evaluations to elucidate as fully as 
possible the nature and/ or causality of the 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.
STATISTICAL METHODS
8.1.
Endpoints
8.1.1.
Primary endpoint

Anti-HAV seropositivity status at approximately 8 years and 10 years after 
administration with the last received dose of Havrix.
Subjects are defined as being seropositive if their anti-HAV antibody concentration is ≥ 
15 mIU/mL.
8.1.2.
Secondary endpoints

Anti-HAV concentrations (GMC) at approximately 8 years and 10 years after 
administration with the last received dose of Havrix.

Anti-HAV seropositivity status at approximately 8 years and 10 years after 
administration with the last received dose of Havrix.
Subjects are defined as being seropositive if their anti-HAV antibody concentration is ≥ 
15 mIU/mL.
 
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8.2.
Determination of sample size
The primary objective of this study is to evaluate the persistence of anti-HAV antibodies, 
approximately 8 years and 10 years post vaccination with the last vaccination of the 
complete series of Havrix (2 doses) and the partial series (1 dose). Around 300 subjects 
will be enrolled in each group at Year 8 and Year 10 visits. Considering that 10-15% of 
the subjects will be non-evaluable or will not have any available immunogenicity result, 
it will be assumed that around 260 subjects per group will be included in the ATP cohort 
of persistence at Year 8 and at Year 10 for the analysis of the primary endpoint.
Table 9 illustrates the accuracy that can be expected from sample size of 260 evaluable 
subjects in each group at Year 8 and Year 10 visits for evaluating the percentage of 
subjects with anti-HAV concentrations 15 mIU/mL. With 260 subjects per group, the 
width of the 95% CI giving a precision of approximately 5% around the point estimate is 
considered meaningful.
Table 9
Exact 95% confidence intervals of the percentage of subjects with 
anti-HAV concentrations greater than or equal to 15 mIU/mL
At Year 8 and Year 10
Percentage (%)
N=260
20
[15.3; 25.4]
30
[24.5; 36.0]
40
[34.0; 46.2]
50
[43.8; 56.2]
60
[53.8; 66.0]
70
[64.0; 75.5]
80
[74.6; 84.7]
90
[85.7; 93.4]
100
[98.6; 100.0]
N: Total number of eligible subjects with available immunogenicity results
Table 10 illustrates the sample size and the power associated with the objective below at 
each epoch. The power to meet the criteria associated the objective below is at least 80% 
with 260 evaluable subjects in each group at each cross-sectional survey time period 
(Year 8 and Year 10 visits).
In terms of seropositivity rates: To explore the non-inferiority of the 1-dose of Havrix
when compared to 2-doses in terms of the percentage of subjects with anti-HAV antibody 
concentrations ≥ 15 mIU/mL, approximately 8 years and 10 years after the last 
vaccination dose.
Criteria for evaluation: The lower limit of the 2-sided 95% CI for the difference (1-dose 
group minus the 2-dose group) of percentage of subjects with anti-HAV antibody 
concentrations ≥ 15 mIU/mL is greater than or equal to the pre-defined clinical non-
inferiority limit of -10%.
 
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Table 10
Power to show non-inferiority of the immunogenicity of 1-dose 
compared to 2-doses of Havrix
Endpoint
% in the two 
group**

Power* 
N=260/group
Anti-HAV 15 mIU/mL
80%
-10%
80.9%
* Pass 2005, one-sided equivalence test of proportions (non-inferiority), alpha = 2.5%, power under equal proportions.
H0: group difference in expected % of subjects with anti-HAV concentrations < (P1-dose– P2-dose < -10%)
Ha: group difference in expected % of subjects with anti-HAV concentrations (P1-dose– P2-dose >= -10%) 
**References used for the sample size calculation: [Raczniak, 2013 and Hammitt, 2008]
8.3.
Cohorts for Analyses at Years 8 and 10
The following cohorts will be defined separately for each epoch.
8.3.1.
Total cohort at Year 8 or Year 10
The total cohort at Year 8 or at Year 10 will include all subjects enrolled in the study at 
Year 8 or Year 10 serosurveys, respectively. For the analysis of persistence, this will 
include subjects for whom data concerning persistence endpoint measures are available.
8.3.2.
Total effective cohort at Year 8 or Year 10
The total effective cohort at Year 8 or Year 10 will include all enrolled subjects who have 
a valid ICF at Year 8 or Year 10 serosurveys, respectively.
8.3.3.
According-to-Protocol (ATP) cohort for persistence at Years 8 or 
10 (Amended: 24 July 2017)
The ATP cohort for persistence at Year 8 or at Year 10 will include all enrolled subjects:

who have a valid ICF

who have available assay results at Year 8 or Year 10 serosurveys, respectively.

who have not received a hepatitis A vaccine other than Havrix.

who do not have a history hepatitis A infection prior to study.

who have available HAV vaccination records.

who received either 1 or two doses of Havrix at selected health centres of Panama.

who have ≥ 7 years and < 10 years between last dose and Persistence Visit 1 (Year 8)
and children ≥ 10 years and < 13 years between last dose and Persistence Visit 1’
(Year 10).
 
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8.4.
Derived and transformed data

Age at time of enrolment in the study will be computed as the difference between the 
date of enrolment [date when the ICF was signed by the parent(s)/ LAR(s)] and the 
date of birth. The age will be expressed in years.

For a given subject and given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced. Therefore, the analysis will exclude 
subjects with missing or non-evaluable measurements.

The GMC calculations are performed by taking the anti-log of the mean of the log 
concentrations transformations. Antibody concentrations below the cut-off of the 
assay will be given an arbitrary value of half the cut-off for the purpose of GMC 
calculation. The cut-off value is defined by the laboratory before the analysis and is 
described in Section 6.6.3.

A seronegative subject is a subject whose antibody concentration is below the cut-off 
value of the assay. A seropositive subject is a subject whose antibody concentration 
is greater than or equal to the cut-off value of the assay. The cut-off value is defined 
in Section 6.6.3.
8.5.
Analysis of demographics/baseline characteristics
At each cross-sectional survey (Year 8 and 10 visits):

Demographic characteristics such as age at the study visit, gender, geographic 
ancestry, rural and urban residency of the subjects enrolled will be tabulated per dose 
group and overall.

The mean age (with the range and standard deviation) as well as the proportion of 
males and females will be calculated and presented for subjects enrolled at Year 8 
visit and Year 10 visit per dose group and overall.
8.6.
Analysis of primary and secondary objectives
All statistical analyses will be performed using statistical analysis system version 9.2 or 
later. All the analyses will be described in detail in the statistical analysis plan (SAP).
The analysis for persistence at Year 8 and at Year 10 serosurveys will be based on the 
ATP cohort. If the percentage of enrolled subjects with available serological results 
excluded from this ATP cohort is more than 5%, a second analysis based on the Total 
effective cohort will be performed to support the ATP analysis.
 
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Analysis of persistence
For the subjects who had received either one dose or two doses of Havrix, at each 
serosurvey (approximately 8 years and 10 years after the last vaccine dose):

Percentage of subjects with concentrations above the proposed cut-off with exact 
95% CI will be calculated.

GMCs with 95% CI will be tabulated.

The distribution of antibody concentrations will be tabulated and also presented 
using reverse cumulative curves.
Exploratory between groups analysis:
An exploratory evaluation of the differences in the immune response approximately 8 
years and 10 years after the last vaccination dose with Havrix between the subjects who 
received only one dose of Havrix and subjects who received two doses of Havrix at each 
serosurvey (approximately 8 years and 10 years after the last received vaccine dose) will 
be performed in terms of:

Differences in anti-HAV antibody concentrations between the subjects who received 
only one dose of Havrix and subjects who received two doses of Havrix at each 
serosurvey.
Computation of the asymptotic standardised 2-sided 95% CIs for the difference in 
the percentage of subjects with anti-HAV antibody concentrations ≥ 15 mIU/mL at 
Year 8 or at Year 10 after the last received Havrix vaccination dose (1-dose group 
minus the 2-dose group): if the lower limit of the 2-sided 95% CI for the difference 
in the percentage of subjects with anti-HAV antibody concentrations ≥ 15 mIU/mL 
at Year 8 or at Year 10 serosurveys, (1-dose group minus the 2-dose group) is greater 
than or equal to the pre-defined clinical limit of -10%, the pre-defined criteria for the 
exploratory objective is considered met and the 1-dose group non-inferior to the 2-
dose group in terms of seropositivity rate).

Ratio of the anti-HAV GMCs between the subjects who received only one dose of
Havrix and subjects who received two doses of Havrix with their standardised 
asymptotic 95% CI at each serosurvey.
Computation of the GMC ratio and its 95% CI:
For all analyses (exploration evaluation of differences between groups), the GMC ratio 
and its 95% CI will be computed using an analysis of variance (ANOVA) model on the 
log10-transformed concentration with the group and area of residence as fixed effects in 
the model.
8.7.
Interpretation of analyses
All the analyses will be descriptive with the aim to characterise the immunogenicity 
within and between study groups. Because of the exploratory nature of the comparisons 
no conclusions can be made.
 
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There will be no comparison between the two serosurveys (Year 8 and Year 10). It will 
be descriptive in nature.
8.8.
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.
8.8.1.
Sequence of analyses
All statistical analysis will be performed at the end of each cross-sectional survey (at 
Year 8 (Epoch 001) and Year 10 (Epoch 002)) on clean data and carried out on the final 
dataset, following recruitment of the last subject of each serosurvey.
The statistical analysis will be described in detail in the SAP.
8.8.2.
Statistical considerations for interim analyses
No interim analysis is planned. However, the analysis will be done separately for the two 
epochs. As all analyses are descriptive, no adjustment of type I error is needed.
9.
ADMINISTRATIVE MATTERS
To comply with ICH GCP or other applicable guidelines such as ISPE guidelines for 
GPP, administrative obligations relating to data collection, monitoring, archiving data, 
audits, confidentiality, ownership and publications must be met.
9.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/ transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data.
Once the database is archived and the clinical study report is complete and approved by 
all parties, each participating investigator will be provided with a CD-ROM of the final 
version of the data generated at his/her investigational site.
 
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9.2.
Study monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form.
For eCRF, the monitor will mark 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.
9.3.
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.
 
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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 or other applicable 
guidelines such as ISPE guidelines for GPP any institutional requirements or applicable 
laws or regulations, or GSK standards/procedures; otherwise, the minimum retention 
period will default to 15 years.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility and transfer of 
ownership of the records in the event the investigator leaves the site.
9.4.
Quality assurance
To ensure compliance with GCP or other applicable guidelines such as ISPE guidelines 
for GPP 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.
9.5.
Posting of information on publicly available registers and 
publication policy
Study information from this protocol will be posted on public registers before enrolment 
of subjects begins.
Observational studies that do not evaluate vaccines/products are progressed for 
publication in the scientific literature when the results provide important scientific or 
medical knowledge.
9.6.
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 Biologicals site or other 
mutually-agreed 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.
 
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10.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
11.
REFERENCES
Cervio G, Trentadue J, D’Agostino D et al. Decline in HAV-associated fulminant hepatic 
failure and liver transplant in children in Argentina after the introduction of a universal 
hepatitis A vaccination program. Hepatic Medicine: Evidence and Research
2011;3:99-106.
Ciocca ME, Ramonet MD, Cuarterolo ML et al. Acute liver failure in 
children:Experience with 210 patients. J Pediatr Gastroenterol &Nutr. 2004; 39 (suppl 
1):S31-O0062. URL: 
http://journals.lww.com/jpgn/Fulltext/2004/06001/O0062_Acute_Liver_Failure_in_Child
ren__Experience.64.aspx. Last accessed:05 April 2016.
Ciocca M, Moreira-Silva SF, Alegria S et al. Hepatitis A as an etiologic agent of acute 
liver failure in Latin America. Pediatric Infectious Disease Journal 2007;26(8):711-715.
Ciocca M, Ramonet M, Cuarterolo M et al. Prognostic factors in paediatric acute liver 
failure. Arch Dis Child. 2008;93:48–51.
GlaxoSmithKline Biologicals Clinical Study Report 112263. Time trend analysis of the 
incidence of hepatitis-related outcomes (viral hepatitis A and unspecified viral hepatitis) 
by monitoring the reports received by the surveillance system of Panama, 2000-2010.
Hammitt LL, Bulkow L, Hennessy TW et.al. Persistence of Antibody to Hepatitis A 
Virus 10 Years after Vaccination among Children and Adults. Int J Infect Dis. 2008; 198 
(12): 1776-82.
Hendrickx G, Van Herck K, Vorsters A et al.Has the time come to control hepatitis A 
globally? Matching prevention to the changing epidemiology. Journal of Viral Hepatitis
2008;15(Suppl 2):1-15.
International Society for Pharmacoepidemiology (ISPE). Guidelines for Good 
Pharmacoepidemiology Practices. GPP, 
http://www.pharmacoepi.org/resources/guidelines_08027.cfm; 2007. Accessed 17 April 
2014.
Ott JJ and Wiersma ST. Single-dose administration of inactivated hepatitis A vaccination 
in the context of hepatitis A vaccine recommendation. Int J Infect Dis. 2013; 17(11): 
e939-44.
Raczniak GA, Bulkow LR, Bruce MG et.al. Long-Term Immunogenicity of Hepatitis A 
Virus Vaccine in Alaska 17 Years After Initial Childhood Series. J Infect Dis. 2013; 
207(3):493-6.
 
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Vizzotti C, González J, Gentile A et al. Impact of the single-dose immunisation strategy 
against hepatitis A in Argentina. Pediatr Infect Dis J. 2014;33(1): 84-8.
World Health Organisation (WHO). Meeting of the Strategic Advisory Group of Experts 
on Immunization, November 2011. URL: http://www.who.int/wer/2012/wer8701.pdf. 
Last accessed: 05 April 2016.
WHO guidelines on drawing blood. Best practices in phlebotomy. 2010.  URL: 
http://apps.who.int/iris/bitstream/10665/44294/1/9789241599221_eng.pdf. Last accessed: 
05 April 2016.
 
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APPENDIX A
LABORATORY ASSAYS
The Enzygost ELISA kit from Siemens Healthcare is a commercial labelled kit for the 
qualitative detection of anti-HAV antibodies in serum.
Performance characteristics of the assay are described in the GSK Vaccines internal 
validation document.
 
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APPENDIX B
CLINICAL LABORATORIES
Table 11
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
 
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APPENDIX C
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
201630 (EPI-HAV-007 BOD PA)
Amendment number:
Amendment 1
Amendment date:
05 April 2016
Co-ordinating author:
, Scientific Writer for GSK Biologicals
Rationale/background for changes:
!
The mitigation strategy for risks associated with blood sample collection was 
revised based on the WHO guidelines on drawing blood.
!
Due to unexpected low number of eligible subjects identified with 8 years post 
vaccination of the last dose of Havrix in the first survey (and subsequently 
10 years post vaccination for the second survey), the post last dose vaccination 
period criteria will be expanded in order to increase the pool of eligible children 
and reach the adequate sample size for the study:
∀
For the Year 8 survey: The new post last dose time interval may include 
children with ≥7 years and < 9 years between last dose.
∀
For the Year 10 survey: The new post last dose time interval may include 
children with ≥9 years and < 11 years between last dose.
This post last dose time criteria have been added to inclusion criteria section for 
clarification.
!
The date of birth requirement has also been expanded to include the 2005 birth 
cohort in order to increase the pool of eligible children and reach the adequate 
sample size for the study. The new date of birth inclusion criteria will include 
children born January 1, 2005 to December 31, 2007
!
The age requirement has been eliminated from the study as it is neither necessary 
for the design nor the objectives of the study.
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!
The typographical error identified by the local ethics committee in section 6.6.3 
Laboratory assays” of the protocol was updated accordingly:
∀
“Please refer to APPENDIX A for a detailed description of the assays 
performed in the study. Please refer to APPENDIX B for the address of the 
clinical laboratories used for sample analysis. Serological assays for the 
determination of antibodies against HAV will be performed by ELISA using 
standardised and validated procedures at a local laboratory”. The correct 
sentence should be “…at GSK Biologicals’ laboratory or in a laboratory 
designated by GSK Biologicals.
Amended text has been included in bold italics and deleted text in strikethrough in the
Title page:
Contributing authors
!
, Senior Manager, Epidemiology 
Travellers/
, Senior Manager, 
Epidemiology
!
/
, GVCL CLS 
Study Manager
!
, Project Data Manager
!
/
, GVCL CLS
Study Manager
!
, Cluster Area
Medical Lead, Caricam-Andina
!
, Study Delivery Manager
!
/
, Vaccine Supply 
Coordinator, Aprova for GSK Biologicals
!
, Local Delivery 
Lead
Synopsis and Section 1.2 Rationale for the study
Panama is an ideal setting to conduct the present study since it consists of an adequate 
size cohort of children who had received both doses of Havrix as well as children who 
had received one dose of Havrix. In addition, this population provides an adequate time 
interval to measure long term antibody persistence since the children were vaccinated 
approximately 8 years ago.
The present study will be conducted to evaluate the persistence of hepatitis A antibodies, 
approximately 8 years and 10 years post vaccination with the complete series of Havrix
(2 doses) and the partial series completion (1 dose).
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Section 2.1 Risk Assessment
Risks associated with blood collection (such as pain at blood sampling site, haematoma 
or thrombus, vasovagal reaction, syncope or fainting) can be reduced by following best 
practices listed in the [WHO guidelines] for drawing blood (2010). Some examples are 
provided in the table below.
Important Potential/Identified 
Risk
Data/Rationale for 
Risk
Mitigation Strategy
Study Procedures 
Blood sample collection- While 
giving blood the subject may 
feel faint, or locally experience 
mild pain, bruising, irritation or 
redness.
Spontaneous data
Subjects will be observed for at least 
30 minutes after blood sample 
collection.
Study procedure: Blood 
sample collection.
Pain at blood 
sampling site

Well-trained person should 
take the blood sample

Use needle of smaller gauge 
than the vein
Haematoma or 
thrombus

Enter vessel at an angle of 
30 degrees or less

Use gauge of needle smaller 
than the vein

Apply pressure to a straight 
arm for 3–5 minutes after 
drawing blood
Vasovagal 
reaction, Syncope, 
fainting

Hydrate patient, take 
postural blood pressure if 
dehydrated

Reduce anxiety

Have patient lie down if the 
person expresses concern

Provide audio-visual 
distraction
Please refer to WHO guidelines for drawing blood (2010): Best practices in 
phlebotomy, in particular section 8.5.3 on risk assessment and risk reduction strategies.
Synopsis and Section 3 Objectives
Primary
To assess the persistence of anti- HAV antibodies, approximately 8 years and 10 years 
post vaccination with the last received vaccine dose of the complete series of Havrix (2 
doses) and the partial series completion (1 dose) in Panama.
 
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Secondary

To assess geometric mean concentration (GMC) of anti-HAV antibodies, 
approximately 8 years and 10 years post vaccination with the last received dose of 
the complete series of Havrix (2 doses) and the partial series completion (1 dose) in 
Panama.

To explore the non-inferiority of the 1-dose schedule of Havrix when compared to 
the 2-dose schedule in terms of the percentage of subjects with anti-HAV antibody 
concentrations ≥ 15 mIU/mL, approximately 8 years and 10 years after the last 
received vaccination dose.
Synopsis and Section 4 Study design overview

Study population comprises of children who had received Havrix at selected health 
centres of Panama in 2007-2009.

Definition of the cohorts foreseen in the study:

Year 8 cohort: All subjects participating in the Year 8 cross-sectional survey 
(Visit 1 Epoch 001) - May include children with ≥ 7 years and < 9 years 
between last Havrix dose and Persistence Visit 1 (Year 8)

Year 10 cohort: All subjects participating in the Year 10 cross-sectional survey 
(Visit 1’ Epoch 002) - May include children with ≥ 9 years and < 11 years 
between last Havrix dose and Persistence Visit 1’ (Year 10)
Synopsis and Table 1 Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age (Min/Max)
Epochs
Epoch 001
Epoch 002
Yr 8 Havrix_1 dose  
~300
8 years - 9 years 
x 
Yr 8 Havrix_2 dose 
~300 
8 years - 9 years
x
Yr 10 Havrix_1 dose  
~300
10 years -11 years 
x 
Yr 10 Havrix_2 dose 
~300 
10 years -11 years
x 
Synopsis and Section 4.1 Discussion of study design
A serial, cross-sectional, serological study will allow evaluating the long term persistence 
of anti-HAV antibodies and GMCs in children who had received 1 dose of Havrix
vaccine (partial series) and children who had received 2 doses of Havrix vaccine 
(complete series) during the same time point.
The first cross-sectional serosurvey will evaluate the long term persistence of immunity 
approximately 8 years post vaccine administration and provide preliminary data on the 
non-inferiority of 1 dose versus 2 doses, in terms of long term persistence. The second 
cross-sectional study will evaluate long term persistence, approximately 10 years post 
vaccine administration, since the duration of protection beyond 10 years remains 
unknown and provide preliminary data on the non-inferiority of 1 dose versus 2 doses, in 
terms of long term persistence. However, the sampling and testing for Year 8 and Year 10 
cross-sectional surveys will be independent of each other.
 
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Synopsis and Section 5.1 Number of subjects/centres
Approximately 600 subjects born between 1st January 2006 2005 and 31st December 
2007 (i.e., 8 to 9 years of age at Year 8 visit and 10 to 11 years of age at Year 10 visit)
(about 300 subjects vaccinated with one dose of Havrix and about 300 subjects 
vaccinated with two doses of Havrix) are planned to be enrolled at each cross-sectional 
survey time points (Year 8 or 2015 and Year 10 or 2017). Two different cohorts of 
subjects will be enrolled at each epoch, therefore about 600 subjects will be enrolled at 
Epoch 001 (Year 8 cohort) and another cohort of about 600 subjects will be enrolled at 
Epoch 002 (Year 10 cohort). In total, approximately 1200 subjects will be enrolled in the 
study. Subjects in the Year 8 cross-sectional survey may be randomly enrolled for the 
Year 10 cross-sectional survey. In this case, the subject will not be associated to his / her 
previous participation and a new subject number will be re-assigned.
Synopsis and Section 5.2 Inclusion criteria for enrolment

Children born between 1st January 2006 2005 and 31st December 2007 (i.e., 8 to 9 
years of age at Year 8 visit and 10 to 11 years of age at Year 10 visit) that received 
either 1 or two doses of Havrix at selected health centres of Panama.

Available HAV vaccination records.

Children who have received either 1 or two doses of Havrix at selected health 
centres of Panama

Children with ≥ 7 years and < 9 years between last dose and Persistence Visit 1 
(Year 8) and children ≥ 9 years and < 11 years between last dose and Persistence 
Visit 1’ (Year 10)
Section 6.4 Outline of study procedures
Table 2 List of study procedures
Age 
8-9 years and 10-11 years
Epochs
001 and 002
Visits
Visit 1 – Year 8 and Visit 1’ – Year 10
Time points
Day 0 and Year 2
Reporting of subjects in the individual screening log sheet 
O 
Informed consent/assent
● 
Check inclusion/exclusion criteria
● 
Subject number attribution 
O 
Collect socio-demographic data
● 
Study group allocation 
O 
Record medical history including hepatitis A disease/ vaccination history
● 
Blood sampling for antibody determination (~5mL)
● 
Recording of SAEs related to study participation
● 
Study conclusion* 3
●
 
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Table 3 Intervals between study visits/contacts/observations
Interval
Optimal length of interval 1
Allowed interval 2
Last Havrix dose vaccination date 
Visit 1 Epoch 001 (Year 8 Survey)
≥ 2920 days to < 3285 days (8.0-
8.9 years)
≥ 2555 days to < 3285 days
(7.0-8.9 years)
Last Havrix dose vaccination date 
Visit 1’ Epoch 002 (Year 10 Survey)
≥ 3650 days to < 4015 days (10.0-
10.9 years)
≥ 3285 days to < 4015 days 
(9.0-10.9 years)
1. Whenever possible the investigator should arrange study visits/contacts within this interval
2. Subjects will not be eligible for inclusion in the ATP cohort for analysis of each survey if they make the study 
visit outside this interval
Section 6.5.7 Record medical history including hepatitis A disease or vaccination 
history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to participation in the study in the eCRF. Record any previous history of 
hepatitis A disease or vaccination. The investigator will also record if the subject received 
1 dose or 2 doses of Havrix previously along with the vaccination dates, in order to 
assign the subject to the appropriate study group.
Section 6.6.3 Laboratory assays
Serological assays for the determination of antibodies against HAV will be performed by
ELISA using standardised and validated procedures at GSK Biologicals’ laboratory or in 
a laboratory designated by GSK Biologicalsa local laboratory. Subjects will be defined 
as being seropositive if their anti-HAV antibody concentration is 15 mIU/mL.
Table 5 Humoral immunity (antibody determination)
System
Component
Method
Kit / Manufacturer
Cut-off
Unit
Laboratory*
SER
Hepatitis A Virus 
Antibodies
ELI
Enzygnost (Siemens 
Healthcare)
15
mIU/mL
GSK Biologicals**
SER = Serum
ELI = Enzyme-linked immunosorbent assay
*Refer to APPENDIX B for the laboratory addresses
**GSK Biologicals laboratory refers to the Clinical Laboratories Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium.Global Vaccines Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium.
Section 6.6.4.1 Immunological read-outs
If subjects have anti-HAV levels below the seropositivity cut-off of 15 mIU/ml If 
subjects have a suboptimal response to anti-HAV (anti-HAV antibody concentration is < 
15 mIU/mL), the investigator will refer them to the appropriate point of care to assess if 
an extra dose of the Havrix vaccine needs be administered.
Section 7 Safety
All SAEs related to the study procedure (blood sample collection) will be collected from 
the time of sample collection up to study conclusion. Each subject will be monitored for a 
period of 30 minutes after blood sample collection.
 
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Synopsis and Section 8.1 Endpoints
Primary

Anti-HAV seropositivity status at approximately 8 years and 10 years after 
administration with the last received dose of Havrix.
Secondary

Anti-HAV concentrations (GMC) at approximately 8 years and 10 years after 
administration with the last received dose of Havrix.

Anti-HAV seropositivity status at approximately 8 years and 10 years after 
administration with the last received dose of Havrix.
Section 8.2 Determination of sample size
The primary objective of this study is to evaluate the persistence of anti-HAV antibodies, 
approximately 8 years and 10 years post vaccination with the last vaccination of the 
complete series of Havrix (2 doses) and the partial series (1 dose). Around 300 subjects 
will be enrolled in each group at Year 8 and Year 10 visits. Considering that 10-15% of 
the subjects will be non-evaluable or will not have any available immunogenicity result, 
it will be assumed that around 260 subjects per group will be included in the ATP cohort 
of persistence at Year 8 and at Year 10 for the analysis of the primary endpoint.
In terms of seropositivity rates: To explore the non-inferiority of the 1-dose of Havrix
when compared to 2-doses in terms of the percentage of subjects with anti-HAV antibody 
concentrations ≥ 15 mIU/mL, approximately 8 years and 10 years after the last 
vaccination dose.
Section 8.3.3 According-to-Protocol (ATP) cohort for persistence at Years 8 or 10
The ATP cohort for persistence at Year 8 or at Year 10 will include all enrolled subjects:

who have a valid ICF

who were born between 1st January 2005 2006 and 31st December 2009 2007. (i.e., 
6 to 9 years of age at Year 8 visit and 8 to 11 years of age at Year 10 visit)

who received either 1 or two doses of Havrix at selected health centres of Panama in 
2007-2008

who have ≥ 7 years and < 9 years between last dose and Persistence Visit 1 (Year 
8) and children ≥ 9 years and < 11 years between last dose and Persistence Visit 1’
(Year 10)
Section 8.6 Analysis of primary and secondary objectives
The analysis for persistence at Year 8 and at Year 10 serosurveys will be based on the 
ATP cohort. If the percentage of enrolled subjects with available serological results 
excluded from this ATP cohort is more than 5%, a second analysis based on the Total 
effective cohort will be performed to support the ATP analysis.
 
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Analysis of persistence
For the subjects who had received either one dose or two doses of Havrix, at each 
serosurvey (approximately 8 years and 10 years after the last vaccine dose):
Exploratory between groups analysis:
An exploratory evaluation of the differences in the immune response approximately 8 
years and 10 years after the last vaccination dose with Havrix between the subjects who 
received only one dose of Havrix and subjects who received two doses of Havrix at each 
serosurvey (approximately 8 years and 10 years after the last received vaccine dose) will 
be performed in terms of:

Differences in anti-HAV antibody concentrations between the subjects who received 
only one dose of Havrix and subjects who received two doses of Havrix at each 
serosurvey.
Computation of the asymptotic standardised 2-sided 95% CIs for the difference in 
the percentage of subjects with anti-HAV antibody concentrations ≥ 15 mIU/mL at 
Year 8 or at Year 10 after the last received Havrix vaccination dose (1-dose group 
minus the 2-dose group): if the lower limit of the 2-sided 95% CI for the difference 
in the percentage of subjects with anti-HAV antibody concentrations ≥ 15 mIU/mL 
at Year 8 or at Year 10 serosurveys after the last received Havrix vaccination dose, 
(1-dose group minus the 2-dose group) is greater than or equal to the pre-defined 
clinical limit of -10%, the pre-defined criteria for the exploratory objective is 
considered met and the 1-dose group non-inferior to the 2-dose group in terms of 
seropositivity rate)
Section 8.7 Interpretation of analyses
There will be no comparison between the two serosurveys (Year 8 and Year 10) post 
vaccination with the last vaccine dose). It will be descriptive in nature.
Section 8.8.1 Sequence of analyses
All statistical analysis will be performed at the end of each cross-sectional survey (at 
Year 8 (Epoch 001) and Year 10 (Epoch 002)) after the last received Havrix vaccination 
dose) on clean data and carried out on the final dataset, following recruitment of the last 
subject of each serosurvey.
Section 11 References
WHO guidelines on drawing blood. Best practices in phlebotomy. 2010.URL: 
http://apps.who.int/iris/bitstream/10665/44294/1/9789241599221_eng.pdf. Last 
accessed: 05 April 2016.
 
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Appendix B Clinical Laboratories
Table 10 GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Global Vaccine Clinical Laboratory
Clinical Laboratory Sciences, Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium
GSK Biologicals Global Vaccine Clinical Laboratory
Clinical Laboratory Sciences, Wavre-Nord Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
 
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GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
201630 ((EPI-HAV-007 BOD PA)
Amendment number:
Amendment 2
Amendment date:
24 July 2017
Co-ordinating author:
, Freelance Scientific Writer for GSK 
Biologicals
Rationale/background for changes:
!
The date of birth requirement has been eliminated from the study as it is not 
necessary for the design or the objectives of the study and will ease the 
recruitment constraint observed in the study.
!
The post last dose interval will be updated due to low number of eligible subjects 
identified within the existing intervals which puts at risk achieving adequate 
sample size.
∀
For the Year 8 survey: The new post last dose time interval may include 
children with ≥ 7 years and < 10 years between last dose.
∀
For the Year 10 survey: The new post last dose time interval may include 
children with ≥ 10 years and < 13 years between last dose.
∀
This post last dose time criteria have been added to inclusion criteria section 
for clarification.

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Amended text has been included in bold italics and deleted text in strikethrough
throughout the protocol.
Title page- List of contributing authors has been updated.
!
,
, Study Delivery Leads
!
, 
, Project Statisticians
!
, 
, Lead Statisticians
Synopsis and Section 4 Study Design Overview
!
Study population comprises of children who had received Havrix at selected health 
centres of Panama in 2007-2009.
!
Definition of the cohorts foreseen in the study:
∀
Year 8 cohort: All subjects participating in the Year 8 cross-sectional survey 
(Visit 1 Epoch 001) - May include children with ≥ 7 years and < 9 10 years 
between last Havrix dose and Persistence Visit 1 (Year 8)
∀
Year 10 cohort: All subjects participating in the Year 10 cross-sectional survey 
(Visit 1’ Epoch 002) - May include children with ≥ 910 years and < 11 13 years 
between last Havrix dose and Persistence Visit 1’ (Year 10)
Synopsis and Section 5.1 Number of subjects
Approximately 600 subjects born between 1st January 2005 and 31st December 2007
(about 300 subjects vaccinated with one dose of Havrix and about 300 subjects 
vaccinated with two doses of Havrix) are planned to be enrolled at each cross-sectional 
survey time points (Year 8 and Year 10)
Section 5.2 Inclusion criteria for enrolment
!
Children born between 1st January 2005 and 31st December 2007.
!
Children with ≥ 7 years and < 9 10 years between last dose and Persistence Visit 1 
(Year 8) and children ≥ 910 years and < 11 13 years between last dose and 
Persistence Visit 1’ (Year 10)
Section 6.4 Outline of study procedures
Table 3 Intervals between study visits/contacts/observations
Interval
Allowed interval 1
Last Havrix dose vaccination date %
Visit 1 Epoch 001 (Year 8 Survey)
≥ 2555 days to <3285 3650
days (7.0-8.99.9 years)
Last Havrix dose vaccination date %
Visit 1’ Epoch 002 (Year 10 Survey)
≥3285 3650 days to < 4015
4745 days (9.010.0-10.912.9
years)
1Subjects will not be eligible for inclusion in the ATP cohort for analysis of each survey if they make the study visit 
outside this interval
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Section 8.3.3 According-to-Protocol (ATP) cohort for persistence at Years 8 or 10
The ATP cohort for persistence at Year 8 or at Year 10 will include all enrolled subjects:

who were born between 1st January 2005 and 31st December 2007.

who have ≥ 7 years and < 910 years between last dose and Persistence Visit 1 (Year 
8) and children ≥ 910 years and < 1113 years between last dose and Persistence Visit 
1’ (Year 10).
 
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