Observational Study to Assess Frailty of Subjects During ZOSTER-006 and ZOSTER-022 and HZ Efficacy, Immunogenicity and Safety of HZ/su by Frailty Status
Conditions: Herpes Zoster
Sponsor: GlaxoSmithKline

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Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut 89, 1330 Rixensart, Belgium
eTrack study number and 
Abbreviated Title
204878 (ZOSTER-064)
Investigational New Drug 
(IND) number
BB-IND-13857
Date of protocol
Final: 29 January 2018
Date of protocol 
amendment
Amendment 1 Final: 17 October 2018
Date of protocol 
administrative change
Administrative Change 1 Final 27 March 2018
Administrative Change 2 Final: 13 November 2018
Administrative Change 3 Final 11 February 2019
Title
Observational study to assess frailty of subjects during 
ZOSTER-006 and ZOSTER-022.
Detailed Title
Observational study to assess frailty of subjects during 
ZOSTER-006 and ZOSTER-022 and HZ efficacy, 
immunogenicity and safety of HZ/su by frailty status.
Co-ordinating author(s)
!
, Lead Scientific Writer
!
, Senior Scientific Writer
!
, Scientific Writer, XPE Pharma 
& Science for GSK Biologicals
!
, Scientific Writer, XPE Pharma 
& Science for GSK Biologicals (Administrative 
Change 3, 11 Feb 2019)
Contributing authors
!
, Clinical Research and 
Development Lead
!
, Study Delivery Lead
!
, Lead Statistician
!
, Lead Statistician
!
, Oversight Data Management

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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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eTrack study number and 
Abbreviated Title
204878 (ZOSTER-064)
Investigational New Drug 
(IND) number
BB-IND-13857
Detailed Title
Observational study to assess frailty of subjects during 
ZOSTER-006 and ZOSTER-022 and HZ efficacy, 
immunogenicity and safety of HZ/su by frailty status.
Contributing authors
(cont.)
!
, Director Value Evidence
!
, Health Economics Biostatistician
!
, Global Regulatory Affairs
(Administrative Change 3, 11 Feb 2019)
!
, Clinical and Epidemiology Project 
Lead (CEPL) for Zoster, US RDC
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 15.0
© 2018 - 2019 GSK group of companies or its licensor.

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PPD
PPD
PPD
PPD

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Protocol Administrative Change 3 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
204878 (ZOSTER-064)
IND number
BB-IND-13857
Date of protocol 
administrative change
Administrative Change 3 Final: 11 February 2019
Detailed Title 
Observational study to assess frailty of subjects 
during ZOSTER-006 and ZOSTER-022 and HZ 
efficacy, immunogenicity and safety of HZ/su by 
frailty status.
Sponsor signatory
Anne Schuind, Clinical and Epidemiology Project 
Lead for Zoster, GlaxoSmithKline Biologicals, US 
RDC
Signature
Date
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For internal use only
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Protocol Administrative Change 3 Rationale
Amendment number:
Administrative Change 3
Rationale/background for changes: 

The Japan Vaccine Company will no longer be in operation as of 01 April 2019.
Therefore, the reference to “Japan Vaccine Co., Ltd.” has been changed to “GSK
Japan”.
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Protocol Administrative Change 3 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) 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 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
204878 (ZOSTER-064)
IND number
BB-IND-13857
Date of protocol 
administrative change
Administrative Change 3 Final: 11 February 2019
Detailed Title
Observational study to assess frailty of subjects 
during ZOSTER-006 and ZOSTER-022 and HZ 
efficacy, immunogenicity and safety of HZ/su by 
frailty status.
Investigator name
Signature
Date
Leiter der klinischen 
Prüfung name, function and 
title
Signature
Date
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eTrack study number and 
Abbreviated Title
204878 (ZOSTER-064)
IND number
BB-IND-13857
Date of protocol 
administrative change
Administrative Change 3 Final: 11 February 2019
Detailed Title
Observational study to assess frailty of subjects 
during ZOSTER-006 and ZOSTER-022 and HZ 
efficacy, immunogenicity and safety of HZ/su by 
frailty status.
GSK Japan* study 
representative name, 
function and title
Signature
Date
*(Administrative Change 3, 11 February 2019)
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Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
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SYNOPSIS
Detailed Title
Observational study to assess frailty of subjects during 
ZOSTER-006 and ZOSTER-022 and HZ efficacy, 
immunogenicity and safety of HZ/su by frailty status.
Objective(s)
Primary

To assess the baseline frailty of subjects enrolled in 
ZOSTER-006 and ZOSTER-022.
Secondary

To present the distribution of SF-36 and EQ-5D scores in 
subjects included in ZOSTER-006 and ZOSTER-022 at 
b!aseline by country to allow comparison with normative 
values for those questionnaires in the general population 
of the countries participating in the study.

To assess vaccine efficacy against HZ by frailty status.

To assess HZ burden of illness (BOI) by frailty status.

To identify predictive factors for individuals developing 
HZ.

To describe safety per frailty status.

To assess humoral immunogenicity by frailty status.
Tertiary 

To describe CMI by frailty status of subjects enrolled in 
ZOSTER-006 only.
Rationale for the 
study
In the course of ZOSTER-006 and ZOSTER-022, QoL 
questionnaires were encoded into the respective trial database 
only for subjects who developed a suspected HZ episode 
during the study. This was done to assess the QoL of subjects 
who developed suspected cases of HZ between the vaccine 
group and the placebo group. The remaining subjects who did 
not develop suspected cases of HZ completed the 
questionnaires; however, these questionnaires were never 
encoded or analysed as part of ZOSTER-006 and ZOSTER-
022. The purpose of this study is to allow for the encoding 
and analysis of all questionnaires for subjects enrolled in 
ZOSTER-006 and ZOSTER-022. The aim is to assess the 
baseline frailty of subjects enrolled in ZOSTER-006 and 
ZOSTER-022 and to investigate the representativeness of the 
study population to the general population. Additionally, 
analysis of efficacy, safety and immunogenicity will be 
performed by frailty status. The study will also explore if 
quality of life data and subject characteristics reported by the 
subjects before the onset of HZ would be predictive of HZ. 
 
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This should help confirm previously hypothesized predictive 
factors such as age, stress or functional status, and also to 
assess other potential risk factors such as frailty, fatigue or 
emotional and mental health.
Study design

A multi-country, observational, retrospective study.

Study population: All subjects enrolled in ZOSTER-006 
and ZOSTER-022.

Type of study: Data to be analysed in this study have 
been collected in the ZOSTER-006 (eTrack 110390) and 
ZOSTER-022 (eTrack 113077) and will be combined for 
assessment of primary, secondary and tertiary objectives.

Data collection: QoL questionnaires and the year of birth
of subjects enrolled in ZOSTER-006 and ZOSTER-022.

QoL questionnaires: The SF-36 is a multi-purpose 
health survey with 36 questions. The EQ-5D is a 
questionnaire with 5 questions designed as a generic 
measure of health status that provides a simple 
descriptive profile and a single index value. The EQ-
5D defines health in terms of mobility, self-care, 
usual activities, pain/discomfort and 
anxiety/depression.

Method: Frailty scores for study subjects in ZOSTER-006 
and ZOSTER-022 will be calculated by incorporating the 
subject’s medical history and items from the SF-36 and 
EQ-5D questionnaires.
Discussion of study 
design
This is a retrospective, observational study of subjects 
previously enrolled in ZOSTER-006 and ZOSTER-022, 
therefore no new subjects will be enrolled in this study and no 
new ICF will be required from study subjects. 
Number of subjects
Approximately 30,000 subjects who were enrolled in 
ZOSTER-006 and ZOSTER-022 
Endpoints
Primary

Baseline Frailty Status:

Frailty Status pre-vaccination dose 1 as defined by 
responses to components of the SF-36 and EQ-5D
questionnaire at vaccination day 0 and the subjects 
coded medical history.
 
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Secondary

SF-36 and EQ-5D scale scores:

At months 0, 14, 26 and 38.

Confirmed HZ cases: 

Incidence of HZ cases during ZOSTER-006 and 
ZOSTER-022 for subjects in the modified Total 
Vaccinated Cohort (mTVC).

HZ Burden of Illness:

HZ Burden of Illness score for subjects in both 
ZOSTER-006 and ZOSTER-022 as calculated from
the Zoster Brief Pain Inventory (ZBPI).

Solicited local and general symptoms from ZOSTER-006 
and ZOSTER-022:

Occurrence, intensity of each solicited local 
symptom within 7 days (Days 0-6) after each 
vaccination, in subjects included in the 7-day diary 
card subset;

Occurrence, intensity and relationship to vaccination 
of each solicited general symptom within 7 days 
(Days 0-6) after each vaccination, in subjects 
included in the 7-day diary card subset.

Unsolicited adverse events (AEs) from ZOSTER-006 and 
ZOSTER-022:

Occurrence, intensity and relationship to vaccination 
of unsolicited AEs during 30 days (Days 0 - 29) after 
each vaccination, according to the Medical 
Dictionary for Regulatory Activities (MedDRA) 
classification in all subjects.

Serious Adverse Events (SAEs) from ZOSTER-006 and 
ZOSTER-022.

Occurrence and relationship to vaccination of all 
SAEs from Month 0 to Month 14 in all subjects;

Occurrence of SAEs related to study participation or 
to a concurrent GSK medication/vaccine during the 
entire study period in all subjects;

Occurrence of any fatal SAEs during the entire study 
period in all subjects.
 
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
Occurrence of pre-defined AEs

Occurrence and relationship to vaccination of any 
pIMDs during the entire study period in all subjects.

Humoral Immunogenicity of the study vaccine in subset 
of subjects from ZOSTER-006 and ZOSTER-022.

Anti-gE and anti-VZV Ab concentrations as 
determined by Enzyme-linked Immunosorbent Assay 
(ELISA), in a subset of subjects at Months 0, 3, 14, 
26 and 38.
Tertiary

Cell-mediated immunogenicity (CMI) of the study 
vaccine in subsets of subjects from ZOSTER-006 only.

CMI in terms of frequencies of antigen-specific CD4 
T cells at Months 0, 3, 14, 26 and 38

Frequencies of CD4 T cells with antigen-specific 
Interferon gamma (IFN-γ) and/or Interleukin-2 (IL-
2) and/or Tumour Necrosis Factor alpha (TNF-α)
and/or CD40 Ligand (CD40L) secretion/expression 
to glycoprotein E (gE) and VZV as determined by 
intracellular cytokine staining (ICS) in a subset of 
subjects at Months 0, 3, 14, 26 and 38.
 
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TABLE OF CONTENTS
PAGE
SYNOPSIS......................................................................................................................9
LIST OF ABBREVIATIONS...........................................................................................18
GLOSSARY OF TERMS ...............................................................................................19
1.
INTRODUCTION....................................................................................................21
1.1.
Background ................................................................................................21
1.1.1.
Risk factors for herpes zoster ......................................................21
1.1.2
ZOSTER-006 and ZOSTER-022.................................................22
1.2.
Rationale for the study................................................................................22
2.
BENEFIT: RISK ASSESSMENT.............................................................................23
3.
OBJECTIVES.........................................................................................................23
3.1.
Primary Objective .......................................................................................23
3.2.
Secondary Objectives.................................................................................23
3.3.
Tertiary Objectives......................................................................................23
4.
STUDY DESIGN OVERVIEW ................................................................................24
4.1.
Discussion of study design .........................................................................24
5.
HZ CASE DEFINITION...........................................................................................24
6.
STUDY POPULATION...........................................................................................25
6.1.
Number of subjects/ centres .......................................................................25
6.2.
Inclusion criteria for the study .....................................................................25
6.2.1.
Inclusion criteria for the study data encoding ...............................25
6.3.
Exclusion criteria for the study ....................................................................26
6.3.1.
Exclusion criteria for data encoding .............................................26
7.
CONDUCT OF THE STUDY ..................................................................................26
7.1.
Regulatory and ethical considerations ........................................................26
7.2.
Informed consent........................................................................................26
8.
DETAILED STUDY PROCEDURES.......................................................................27
8.1.
Subject identification...................................................................................27
8.2.
Outline of study procedures ........................................................................28
8.3.
Detailed description of study procedures ....................................................28
8.3.1.
Check inclusion and exclusion criteria .........................................28
8.3.2.
Encoding of data in the ZOSTER-064 eCRF................................28
8.3.2.1.
Demographic characteristics ......................................28
8.3.3.
Encoding of QoL questionnaires..................................................29
8.3.4.
Study conclusion..........................................................................29
8.4.
Biological sample handling and analysis.....................................................29
9.
SAFETY.................................................................................................................29
10. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES...............29
 
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10.1.
Primary endpoint.........................................................................................29
10.2.
Secondary endpoints ..................................................................................29
10.3.
Tertiary endpoints.......................................................................................30
10.4.
Determination of sample size......................................................................31
10.4.1.
Number of subjects in the CMI subset .........................................31
10.4.2.
Number of subjects in the Humoral subset...................................31
10.5.
Cohorts for Analysis....................................................................................31
10.5.1.
Total Vaccinated cohort ...............................................................31
10.5.2.
modified Total Vaccinated Cohort................................................32
10.5.3.
According to Protocol cohort for analysis of 
immunogenicity .........................................................................32
10.6.
Derived and transformed data.....................................................................33
10.6.1.
Handling of missing data..............................................................33
10.6.2.
Humoral and CMI immune response............................................34
10.7.
Statistical methods......................................................................................34
10.7.1.
Quality of Life Questionnaires......................................................34
10.7.2.
SF-36 questionnaire ....................................................................34
10.7.3.
EQ-5D questionnaire ...................................................................35
10.7.4.
Definition of Frailty.......................................................................35
10.7.5.
HZ burden-of-illness score...........................................................37
10.7.6.
Analysis of Frailty.........................................................................37
10.7.6.1.
Analysis of primary objective ......................................37
10.7.6.2.
Analysis of secondary objectives................................37
10.7.6.2.1.
Vaccine efficacy against HZ by 
frailty status ............................................37
10.7.6.2.2.
Vaccine efficacy against HZ BOI 
by frailty status........................................38
10.7.6.3.
Predictive factors for individuals developing HZ..........38
10.7.6.4.
Analysis of safety by frailty status...............................39
10.7.7.
Analysis of immunogenicity..........................................................39
10.7.7.1.
Humoral immune response.........................................39
10.7.7.2.
Cell-mediated immune response ................................39
10.8.
Interpretation of analyses............................................................................40
10.9.
Conduct of analyses ...................................................................................40
10.9.1.
Sequence of analyses..................................................................40
10.9.2.
Statistical considerations for interim analyses..............................40
11. ADMINISTRATIVE MATTERS ...............................................................................41
11.1.
Electronic Case Report Form instructions...................................................41
11.2.
Study monitoring by GSK Biologicals..........................................................41
11.3.
Record retention .........................................................................................42
11.4.
Quality assurance.......................................................................................43
11.5.
Posting of information on publicly available registers and publication 
policy ..........................................................................................................43
11.6.
Provision of study results to investigators ...................................................43
12. COUNTRY SPECIFIC REQUIREMENTS...............................................................44
12.1.
Requirements for Japan..............................................................................44
12.1.1.
Regulatory and Ethical Considerations ........................................44
12.1.2.
Study period ................................................................................44
12.1.3.
Study administrative structure......................................................44
 
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13. REFERENCES.......................................................................................................45
 
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LIST OF TABLES
PAGE
Table 1
List of study procedures .........................................................................28
Table 2
Construction of the eight scales generated from the SF-36....................35
Table 3
Detail of frailty components ....................................................................35
 
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LIST OF ABBREVIATIONS
ATP
According to protocol
BOI
Burden of illness
EQ-5D
EuroQol 5D questionnaire 
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HZ
Herpes Zoster
HZ/su
Herpes Zoster Subunit Vaccine (50µg gE/AS01B)
HZAC
Herpes Zoster Ascertainment Committee
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
mTVC
modified Total Vaccinated Cohort
PCR
Polymerase Chain Reaction
PHN
Postherpetic Neuralgia
QoL
Quality of Life
SDV
Source Document Verification
SF-36
Short Form 36 Questionnaire 
TTO
Time-Trade-Off
TVC
Total Vaccinated Cohort
VZV
Varicella-Zoster Virus
YOA
Years of Age
ZBPI
Zoster Brief Pain Inventory
 
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GLOSSARY OF TERMS
According to Protocol 
(ATP)
In ZOSTER-006 and ZOSTER-022, the ATP cohort 
included all evaluable subjects meeting all eligibility 
criteria, complying with the procedures and intervals 
allowed for the analysis, with no elimination criteria during 
the study.
Case-control study:
A form of epidemiological study where the study population 
is selected on the basis of whether the subjects do (cases) or 
do not (controls) have the particular outcome (disease) 
under study. The groups are then compared with respect to 
exposure/ characteristic of interest.
Coded:
Data from which personal identifier information has been 
removed and replaced by a key. These data are not 
anonymised since a decode listing exists and it is therefore 
possible to identify the patient under certain circumstances 
by an authorised or legally appointed third party data 
custodian, or by the original holder of the data.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
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 timepoints 
or a single timepoint from a single protocol. Self-contained 
means that data collected for all subjects at all-timepoints 
within that epoch allows to draw a complete conclusion. 
Typical examples of epochs are retrospective data 
collection and prospective data collection, etc.
eTrack:
GSK Biologicals’ tracking tool for clinical/ epidemiological 
trials.
modified Total 
Vaccinated cohort 
(mTVC)
The mTVC will include only subjects from centres that 
participate in ZOSTER-064, which will exclude subjects in 
the TVC who were not administered the second vaccination 
or who developed a confirmed case of HZ prior to 1 month 
after the second vaccination (i.e. these subjects that were 
included in the mTVC of ZOSTER-006 and ZOSTER-022.
 
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Non-interventional 
(observational) 
Human Subject 
Research:
Studies where medicinal products, should they be 
administered, are prescribed in normal (routine) medical 
practice. No medical care or medical/scientific procedures 
as required in a research protocol are administered to 
participants except as part of routine medical care.
Quality of Life (QoL)
Quality of life is measured, using two questionnaires (EQ-
5D and SF-36) that were completed by the subject. EQ-5D
and SF-36 provide multi-dimensional evaluation of the 
health status.
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.
Retrospective study:
A study that looks backward in time (e.g., at events that 
occurred in the past; outcomes and exposure can no longer 
be influenced), usually using medical records, databases or 
interviews in order to address one or more study objectives. 
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.
Total Vaccinated 
cohort (TVC)
The TVC will include all subjects from centres that 
participate in ZOSTER-064 and all subjects who had a HZ 
suspected case in either the ZOSTER-006 or ZOSTER-022 
studies. Subjects enrolled in ZOSTER-064 need to have 
been part of the TVC in ZOSTER-006 or ZOSTER-022. 
 
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1.
INTRODUCTION
1.1.
Background
Varicella-Zoster Virus (VZV) causes two distinct diseases. Varicella (chickenpox) 
shortly occurs after primary VZV infection and is characterised by systemic illness and a 
widely disseminated rash. Herpes Zoster (HZ, shingles) occurs when VZV reactivates 
from latency and typically manifests as a localised, dermatomal rash. The typical HZ rash 
usually lasts 2 to 4 weeks and is usually accompanied by pain; that is often described as 
burning, shooting, or stabbing, and pruritus, which can also be severe, may be as 
common as pain. In some patients, even touching the affected area lightly may cause
severe pain, a phenomenon known as allodynia. The most common complication of HZ is 
postherpetic neuralgia (PHN), defined as pain that persists after the resolution of the HZ 
rash. Patients affected by PHN typically report constant burning, throbbing, intermittent 
sharp or electric shock-like pain, or allodynia. PHN tends to improve over a period of 
months and about 70-80% of cases resolve within 1 year. However, in some persons PHN 
persists for many years [Dworkin, 2007].
Inclusion of subjects in clinical trials may be biased for various reasons, e.g. 
inclusion/exclusion criteria, selection of patients by investigators, self-selection of 
patients. As such, the aim of this study is to explore if the subjects in the ZOSTER-006 
and ZOSTER-022 studies were representative of an older adult population. This will be 
done by exploring the baseline frailty status and quality of life scores of subjects within 
the studies. 
Several studies have demonstrated that the incidence and severity of HZ increases with 
age [CDC, 2008]. It is also likely that the incidence and severity of HZ is higher in frail 
subjects. However, as with age vaccine efficacy may somewhat lower in frail subjects. 
This study will therefore allow a synthesis of the benefit of vaccination in frail subjects, 
i.e. in terms of increased incidence, vaccine efficacy, safety and immunogenicity.
1.1.1.
Risk factors for herpes zoster
Several risk factors for developing HZ have previously been identified, amongst which 
the age of the individual is the most common. The incidence of HZ is relatively constant 
at 2-3 cases per 1000 persons per year until age 40, and then increases progressively with 
age: At 50-59 years of age (YOA) the incidence is about 5 cases per 1000 persons per 
year, and it increases to 10 cases per 1000 persons per year in people ≥ 60 YOA [CDC, 
2008]. Half of all HZ cases occur in subjects over the age of 60, and individuals who 
reach 85 years old have a 50% chance of having HZ during their lifetime [Oxman, 2005]. 
Age has also been demonstrated to be a risk factor for the development of PHN amongst 
patients with HZ [Oxman, 2005; Scott, 2006; Kanbayashi, 2012; Kawai, 2015].
 
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A second factor that has been consistently related to HZ development is the presence of 
immunosuppressive conditions [Cohen, 2007; Buchbinder, 1992; Langan, 2013]. Other 
factors have been suggested to be associated with an increase of HZ incidence, including 
female gender [Fleming, 2004; Jung, 2004; Liu, 2015], race [Fleming, 2004; Schmader, 
1998], psychological symptoms such as stress and depression [Irwin, 1998; Schmader, 
1998; Lasserre, 2012], or impaired functional status [Wolfe, 2006; Liu, 2015].
Some factors have also been associated with greater incidence of PHN among patients 
with HZ: psychological symptoms [Clark, 2000; Volpi, 2008], impaired physical and 
social functional status [Katz, 2005; Drolet, 2010, Kawai, 2015] and severity of the HZ 
rash and associated pain [Whitley, 1999; Jung, 2004; Opstelten, 2007; Drolet, 2010; 
Kanbayashi, 2012].
1.1.2
ZOSTER-006 and ZOSTER-022
Two GSK-sponsored Phase III studies investigated the effect of GSK’s candidate HZ/su
vaccine on the incidence of the disease in subjects 50 YOA and older (ZOSTER-006, 
eTrack number 110390, NCT01165177, started in 2010) [Lal, 2015] and in subjects 70 
YOA and older (ZOSTER-022, eTrack number 113077, NCT01165229, started in 2010), 
respectively [Cunningham, 2016].
An indication in adults ≥ 50 YOA was filed for registration. HZ/su (trade name Shingrix) 
was first approved in Canada and the United States in October 2017.
As part of the study procedures, each subject enrolled in one of these two studies was 
asked to complete two quality of life (QoL) questionnaires named respectively SF-36 and 
EQ-5D at predefined timepoints. These questionnaires were to be completed 
independently from the fact that subjects had HZ or not and provide relevant information 
about the QoL (functional status, ability to socialize, mental health, etc.) of subjects 
before they develop HZ (see APPENDIX A and APPENDIX B for samples of the SF-36
and EQ-5D questionnaires).
1.2.
Rationale for the study
In the course of ZOSTER-006 and ZOSTER-022, Quality of Life questionnaires (QoL), 
EQ-5D and SF-36, were completed by all study subjects at baseline. Extracting some 
elements of these questionnaires and combining them with other medical history data
allows attributing of frailty scores.
As these questionnaires were encoded into the respective trial databases only for subjects 
who developed a suspected Herpes Zoster (HZ) episode during the studies, as per the 
original study protocols, the purpose of ZOSTER-064 is to allow for the encoding of 
remaining questionnaires of the subjects and analysis of all questionnaires together. This 
will allow classification in different levels of frailty and therefore will allow baseline 
frailty assessment of subjects that took part in the ZOSTER-006 and ZOSTER-022 
studies. This will inform the representativeness of the study sample to the general 
population in older adults, i.e. in terms of the proportion of subjects who are pre-frail and 
frail. In addition, a comparison of the SF-36 and EQ-5D scores in subjects at baseline 
 
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with normative values for those questionnaires in the general population of the countries 
participating in the study (where these values are available) will also provide further 
insight in the study population and allow to better understand the study population 
compared to the overall target population for the vaccine.
Analyses pertaining to efficacy, safety and immunogenicity as per frailty score might 
then also be performed according to the methodology used in the ZOSTER-006 and 
ZOSTER-022 studies. 
Additionally, the data collected can be used to assess if some physical, physiological 
and/or psychological characteristics reported by the subjects before the onset of HZ 
would be predictive of HZ. This will help understand the previously hypothesized 
predictive factors such as stress or functional status, and also to assess other potential risk 
factors such as frailty, fatigue or emotional and mental health.
2.
BENEFIT: RISK ASSESSMENT
ZOSTER-064 study will use data collected as part of the SF-36 and EQ-5D QoL 
questionnaires completed by subjects in ZOSTER-006 and ZOSTER-022 studies. There 
are no risks or benefits to subjects in this study because this is a retrospective 
observational study. 
3.
OBJECTIVES
3.1.
Primary Objective

To assess the baseline frailty of subjects enrolled in ZOSTER-006 and ZOSTER-
022.
3.2.
Secondary Objectives

To present the distribution of SF-36 and EQ-5D scores in subjects included in
ZOSTER-006 and ZOSTER-022 at baseline by country to allow comparison with 
normative values for those questionnaires in the general population of the countries 
participating in the study.

To assess vaccine efficacy against HZ by frailty status.

To assess HZ burden of illness (BOI) by frailty status.

To identify predictive factors for individuals developing HZ.

To describe safety per frailty status.

To assess humoral immunogenicity by frailty status.
3.3.
Tertiary Objectives

To describe CMI by frailty status of subjects enrolled in ZOSTER-006 only.
 
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4.
STUDY DESIGN OVERVIEW
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the outline of study procedures (Section 8), are 
essential and required for study conduct. 

Type of design: Observational, retrospective study.

Study population: Adults aged ≥50 years of age who participated in either ZOSTER-
006 or ZOSTER-022.

Type of study: to be combined with other protocols for analysis: data to be analysed 
in this study have been collected in ZOSTER-006 (eTrack 110390) and ZOSTER-
022 (eTrack 113077).

Data collection: CRF/eCRF

Duration of the study: The time between the first and the last information to be 
encoded will be approximately 8 months.
4.1.
Discussion of study design
This is a retrospective, observational study, therefore no new subjects will be enrolled in 
this study and no new ICF will be required from study subjects (see Section 7.2). In
ZOSTER-006 and ZOSTER-022, encoding of QoL questionnaires (SF-36, EQ-5D) was 
only performed for subjects who developed a suspected HZ episode during the study.
This was done to assess the QoL of subjects who developed suspected cases of HZ 
between the vaccine group and the placebo group. The remaining study subjects who did 
not develop suspected cases of HZ completed the questionnaires; however, these 
questionnaires were never encoded or analysed as part of ZOSTER-006 and ZOSTER-
022. The purpose of ZOSTER-064 is to allow for the encoding of the remaining 
questionnaires to assess the baseline frailty of all the subjects in ZOSTER-006 and 
ZOSTER-022.
5.
HZ CASE DEFINITION
Classification as a HZ confirmed case was done during ZOSTER-006 and ZOSTER-022, 
after confirmation of all suspected HZ cases by either of the two following ways:

Polymerase Chain Reaction (PCR): 
Rash lesion samples were collected from subjects clinically diagnosed as having a 
suspected case of HZ. The samples were transferred to GSK Biologicals or a 
validated laboratory designated by GSK Biologicals using standardised and validated 
procedures for laboratory diagnosis of HZ by PCR. For more information, please 
refer to Appendix B of the ZOSTER-006 protocol.

The HZ Ascertainment Committee:
 
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All suspected HZ cases were referred to the HZ Adjudication Committee (HZAC). 
The HZAC classified all referred cases as either “HZ”, “not HZ”, or “not able to 
decide”. However, the HZAC classification was to serve as the final case definition 
only when the case could not be confirmed or excluded by PCR, e.g., when all 
samples from a given subject were inadequate (as when both VZV and β-actin PCR 
results were negative), or when no samples were available for a given subject. If the 
case could not be confirmed or excluded by PCR and the HZAC final outcome was 
‘not able to decide’, the overall final outcome was “No possible classification”; for 
analysis the categories “not HZ” and “No possible classification” were considered as 
“not HZ”.
6.
STUDY POPULATION
6.1.
Number of subjects/ centres
Approximately 30,000 subjects enrolled in ZOSTER-006 and ZOSTER-022 
There will be no new subjects enrolled in the ZOSTER-064 study. The protocol is 
developed to allow for the encoding into the eCRF of all QoL questionnaires of subjects 
enrolled in ZOSTER-006 and ZOSTER-022 and analysing frailty status.
6.2.
Inclusion criteria for the study
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study. Therefore, adherence to the criteria as specified in the 
protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

All subjects enrolled in ZOSTER-006 and ZOSTER-022 (See Section 7.2 and 8.3.1)
6.2.1.
Inclusion criteria for the study data encoding

All subjects enrolled in ZOSTER-006 and ZOSTER-022 (See Section 7.2 and 8.3.1)

Subjects who died or were lost to follow-up during ZOSTER-006 and ZOSTER-022 
will be considered for enrolment in ZOSTER-064 and their data/questionnaires up to 
that point will be used.
See Section 8.1 for site specific subject lists. 
 
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6.3.
Exclusion criteria for the study
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study. 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 the exclusion 
criterion applies, the subject must not be included in the study:

Subjects who were excluded from all analyses from ZOSTER-006 and ZOSTER-
022. This will include any subject eliminated following deviations from GCP 
compliance.
6.3.1.
Exclusion criteria for data encoding

Subjects who developed a suspected HZ case during ZOSTER-006 and ZOSTER-
022 (since their QoL questionnaires were encoded in the eCRF for ZOSTER-006 and 
ZOSTER-022).
7.
CONDUCT OF THE STUDY
7.1.
Regulatory and ethical considerations
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki.
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.

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.
7.2.
Informed consent
ZOSTER-064 is a study related to ZOSTER-006 and ZOSTER-022 that allows for 
encoding and analysis of questionnaires already completed by the subjects who were part 
of those earlier studies. Not all of the previously completed questionnaires have been 
encoded and analysed yet. As such, ZOSTER-064 will provide an opportunity to assess 
the frailty index of all subjects enrolled in ZOSTER-006 and ZOSTER-022.
Every subject considered for inclusion in this study has previously signed an ICF from 
the investigational sites of ZOSTER-006 or ZOSTER-022. The ICF signed by the 
patients in ZOSTER-006 and ZOSTER-022 allows for the use of all collected 
information in new studies. In these ICFs, it was specified that:
 
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“The coded information collected by the study doctor will be sent to GSK, who may:
!
Keep it and analyse it by computer to find out what this study is telling us.
!
Share it with agencies that approve new vaccines / products / medicines, or with 
groups that check that research is done properly.
!
Write up the study results for medical journals (this will not include any information 
that directly identifies you).
!
Share it with other companies or universities to better understand the disease / or 
develop this vaccine. If the information is sent to another country, GSK will apply 
the same level of protection to your information, to the extent permitted by local law.
!
Use it to plan new studies, other types of research or other medical purposes.
Information regarding the study and coded results will be publicly available on the 
internet. Information from this study may also be combined with the data from other 
studies in future.”
Since consent has been obtained in the prior studies (ZOSTER-006 and ZOSTER-022), it 
is the Sponsor’s request to obtain a waiver of informed consent from subjects to be 
enrolled in ZOSTER-064.
8.
DETAILED STUDY PROCEDURES
8.1.
Subject identification
Subjects will be identified by the same subject identification number as in ZOSTER-006 
and ZOSTER-022,
 
 
 This will prevent from the possibility of having two 
subjects enrolled in two different studies with the same identification number.
Sites will be provided with a list of subjects for whom questionnaires and data should be 
encoded. To help the investigator/delegate identify subjects for which data and QoL 
questionnaires are to be encoded, the list will include (but may not be limited to) the 
following information for each subject:
!
Subject identification number in ZOSTER-006 or ZOSTER-022 
!
New subject identification number to be used in ZOSTER-064 
!
Site number
!
Date of birth (year)
!
Date of subject’s consent withdrawal, when applicable
!
Occurrence of suspected HZ episode in ZOSTER-006 and ZOSTER-022

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8.2.
Outline of study procedures
Table 1
List of study procedures
Activity
Epoch-001
Check inclusion/exclusion criteria*
○
Encoding of subject's year of birth**
●
Encoding of QoL questionnaires **
●
Study conclusion (Investigator’s signature)**
●
QoL: quality of life
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure performed by GSK and not documented in the eCRF.
* To be performed by GSK.
** Procedure to be performed for subjects with no suspected HZ episode during ZOSTER-006 and ZOSTER-022. 
Refer to Section 8.3 for details about the study procedures.
8.3.
Detailed description of study procedures
8.3.1.
Check inclusion and exclusion criteria
Check all applicable inclusion and exclusion criteria as described in Sections 6.2 and 6.3, 
respectively, before encoding of subject data.
Checking of the eligibility criteria will be performed centrally. Sites will receive a list of 
subjects for which data and QoL questionnaires should be encoded (see Section 8.1).
8.3.2.
Encoding of data in the ZOSTER-064 eCRF
A new eCRF database (using the Inform system) will be created for ZOSTER-064.
8.3.2.1.
Demographic characteristics
The list of subjects for which demographic characteristics need to be encoded in the 
ZOSTER-064 eCRF will be provided to the sites (see Section 8.1).
Demographic characteristics to be encoded in the ZOSTER-064 eCRF include:

the subject identification number to be used in ZOSTER-064

the site number,

the date of birth (year).
These data will be provided in the list of subjects that will be sent to the sites.
To note: Additional subject’s information related to (but not limited to) medical history, 
development of an immune-compromising condition or taking immune-suppressive 
treatments will be used to perform the analysis. These data do not need to be encoded on 
the ZOSTER-064 eCRF, but will be retrieved centrally from the ZOSTER-006 and 
ZOSTER-022 databases and linked to perform the required analyses.
 
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8.3.3.
Encoding of QoL questionnaires
The list of subjects for which QoL questionnaires (SF-36 and EQ-5D) need to be encoded 
in the ZOSTER-064 eCRF will be provided to the sites (see Section 8.1).
Reminder: Eligible subject for this study, for which QoL questionnaires and the year of 
birth should be encoded, were those enrolled in ZOSTER-006 and ZOSTER-022. This 
includes any subjects that completed the study, data collected up to withdraw of consent 
for subjects who withdrew from the study, or data collected up to date of death for 
subjects who died (as documented in the database for ZOSTER-006 and ZOSTER-022), 
and whose questionnaires were not previously encoded into the eCRF during these 
studies (subjects who did not have suspected HZ).
8.3.4.
Study conclusion
The investigator/delegate will:

review all the data encoded in eCRF to ensure accuracy and completeness,

sign the eCRF.
8.4.
Biological sample handling and analysis
No samples will be collected as part of this study.
9.
SAFETY
Not applicable.
10.
DATA EVALUATION: CRITERIA FOR EVALUATION OF
OBJECTIVES 
10.1.
Primary endpoint

Baseline Frailty Status:

Frailty Status pre-vaccination dose 1 as defined by responses to components of 
the SF-36 and EQ-5D questionnaire at vaccination day 0 and the subjects coded 
medical history.
10.2.
Secondary endpoints

SF-36 and EQ-5D scale scores:

At months 0, 14, 26 and 38.

Confirmed HZ cases:

Incidence of HZ cases during the ZOSTER-006 and ZOSTER-022 studies for 
subjects in the mTVC.
 
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
HZ Burden of Illness

HZ Burden of Illness score for subjects in both the ZOSTER-006 and -022 
studies as calculated from the ZBPI.

Solicited local and general symptoms from ZOSTER-006 and ZOSTER-022:

Occurrence, intensity of each solicited local symptom within 7 days (Days 0-6) 
after each vaccination, in subjects included in the 7-day diary card subset;

Occurrence, intensity and relationship to vaccination of each solicited general 
symptom within 7 days (Days 0-6) after each vaccination, in subjects included 
in the 7-day diary card subset.

Unsolicited adverse events (AEs) from ZOSTER-006 and ZOSTER-022:

Occurrence, intensity and relationship to vaccination of unsolicited AEs during 
30 days (Days 0 - 29) after each vaccination, according to the Medical 
Dictionary for Regulatory Activities (MedDRA) classification in all subjects.

Serious Adverse Events (SAEs) from ZOSTER-006 and ZOSTER-022.

Occurrence and relationship to vaccination of all SAEs from Month 0 to Month 
14 in all subjects;

Occurrence of SAEs related to study participation or to a concurrent GSK 
medication/vaccine during the entire study period in all subjects;

Occurrence of any fatal SAEs during the entire study period in all subjects.

Occurrence of pre-defined AEs

Occurrence and relationship to vaccination of any pIMDs during the entire study 
period in all subjects.

Humoral Immunogenicity of the study vaccine in subset of subjects from ZOSTER-
006 and ZOSTER-022.

Anti-gE and anti-VZV Ab concentrations as determined by Enzyme-linked 
Immunosorbent Assay (ELISA), in a subset of subjects at Months 0, 3, 14, 26 
and 38.
10.3.
Tertiary endpoints

Cell-mediated immunogenicity (CMI) of the study vaccine in subsets of subjects 
from ZOSTER-006 only.

CMI in terms of frequencies of antigen-specific CD4 T cells at Months 0, 3, 14, 
26 and 38;

Frequencies of CD4 T cells with antigen-specific Interferon gamma (IFN-γ)
and/or Interleukin-2 (IL-2) and/or Tumour Necrosis Factor alpha (TNF-α) 
and/or CD40 Ligand (CD40L) secretion/expression to glycoprotein E (gE) and 
VZV as determined by intracellular cytokine staining (ICS) in a subset of 
subjects at Months 0, 3, 14, 26 and 38.
 
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10.4.
Determination of sample size
Approximately 30,000 subjects were enrolled in ZOSTER-006 and ZOSTER-022. Out of 
these, approximately 1000 subjects will have developed suspected HZ cases over the 
course of the studies and their QoL questionnaires were encoded in the eCRF for 
ZOSTER-006 and ZOSTER-022, according to the protocols of those studies, 
respectively. Therefore approximately 29,000 subjects whose QoL questionnaires were 
completed and collected but not encoded in the earlier studies, will be encoded in the 
ZOSTER-064 study. Data encoded as part of the 064 study will be combined with data 
from the ZOSTER-006 and ZOSTER-022 studies to ensure that subjects data are 
available for analysis, as appropriate taking into account inclusion/exclusion criteria (see 
section 6) and cohorts for analysis (see section 10.5).
10.4.1.
Number of subjects in the CMI subset
The CMI analyses was performed for ZOSTER-006 only in the Immunogenicity subset in 
three countries (Czech Republic, Japan and United States) at designated sites that had 
access to a PBMC processing facility within the acceptable time window from sample 
collection to PBMC processing. The CMI subset contained approximately 350 subjects. 
As a consequence, analysis of CMI by frailty status is expected to be limited.
10.4.2.
Number of subjects in the Humoral subset
The analysis of humoral immunogenicity was performed in both the ZOSTER-006 and 
ZOSTER-022 studies. The Humoral subset contained approximately 2800 subjects in 
total between ZOSTER-006 and ZOSTER-022.
10.5.
Cohorts for Analysis
10.5.1.
Total Vaccinated cohort
The primary analysis of EQ-5D and SF-36 questionnaires will be performed on the TVC. 
The TVC will include all subjects from centres that participated in ZOSTER-064 and all 
subjects who had a HZ suspected event in either the ZOSTER-006 or ZOSTER-022 
studies.
Subjects enrolled in ZOSTER-064 need to have been part of the TVC in ZOSTER-006 or 
ZOSTER-022. Refer to the glossary of terms for the definition of TVC.
The TVC for analysis of safety will include all subjects with at least one vaccine 
administration documented.
 
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10.5.2.
modified Total Vaccinated Cohort
The mTVC will include only subjects from centres that participate in ZOSTER-064 (i.e. 
these subjects that were included in the mTVC of ZOSTER-006 and ZOSTER-022), 
which will exclude subjects in the TVC who were not administered the second 
vaccination or who developed a confirmed case of HZ prior to 1 month after the second 
vaccination.
10.5.3.
According to Protocol cohort for analysis of immunogenicity 
The analysis of the immunogenicity data from the ZOSTER-064 (i.e. combined
immunogenicity data from ZOSTER-006 and ZOSTER-022) will be performed on the 
ATP cohort for analysis of immunogenicity
In ZOSTER-006 and ZOSTER-022, the ATP cohort for analysis of immunogenicity 
included all evaluable subjects from the ATP cohort for analysis of safety (i.e., those 
meeting all eligibility criteria, complying with the procedures and intervals allowed for 
the analysis, with no elimination criteria during the study) for whom data concerning 
immunogenicity endpoint measures were available.
For the immunogenicity tables where different timepoints were presented, the concept of 
“Adapted ATP cohort for immunogenicity” was used to denote that for each timepoint, 
the corresponding ATP cohort for immunogenicity was used.
More specifically,

The analyses on the timepoints Month 0 and Month 3 were based on the ATP cohort 
for immunogenicity Month 3;

The analysis on the timepoint Month 14 was based on the ATP cohort for 
immunogenicity Month 14;

The analysis on the timepoint Month 26 was based on the ATP cohort for 
immunogenicity Month 26;

The analysis on the timepoint Month 38 was based on the ATP cohort for 
immunogenicity Month 38;
The goal was to include all evaluable subjects in the statistical analysis at a specific 
timepoint, i.e., by including all the subjects not impacted by the elimination code for a 
specific Adapted ATP cohort for immunogenicity. For the criterion impacted only a 
specified timepoint (specified blood sampling interval), the subject was excluded from 
the analysis at that timepoint. For the criteria impacting a specified timepoint and the 
subsequent ones (e.g., medication forbidden by the protocol), the subject was excluded 
from the analyses performed at that timepoint onwards. For the criteria impacting all 
timepoints (e.g., not received two doses), the subject was excluded from the analyses at 
all-timepoints.
For the analysis of humoral immunogenicity, ATP cohort was further defined as ATP 
cohort for immunogenicity – Humoral.
 
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For CMI the analysis will be performed on all the samples available (TVC) due to low 
number of samples.
Compared to the criteria applicable for the ATP cohort for analysis of safety, additional 
criteria for the ATP cohort for immunogenicity were the following:

Administration of any medication forbidden by the protocol

Underlying medical condition forbidden by the protocol

Concomitant infection related to the disease under study (VZV) which might have 
influenced immune response

Concomitant infection not related to the disease under study (VZV) which might 
have influenced immune response

Vaccination done but not compliant with Dose 1- Dose 2 vaccination schedules 
(dates of vaccination not corresponding to protocol intervals or unknown vaccination
dates)

Blood sample taken but not compliant with blood sampling schedules (dates of BS 
not corresponding to adapted protocol intervals or unknown BS/vaccination dates)

Serological results not available for antigens POST vaccination (including lost 
samples, not done, unable to test, absence of parallelism)

Subject did not belong to the specified Immunogenicity subset

The subject did not receive two doses
10.6.
Derived and transformed data
10.6.1.
Handling of missing data
For a given subject and a given measurement, missing or non-evaluable measurements 
will not be imputed for the analysis. The missing endpoint and censoring are supposed to 
occur independently, and the pattern of the missingness being either Completely At 
Random (MCAR) or Missing At Random (MAR) only.
For the analysis of solicited symptoms, missing or non-evaluable measurements will not 
be replaced. Therefore, the analysis of the solicited symptoms based on the TVC will 
include only subjects/doses with documented safety data (i.e., symptom screen/sheet 
completed). 
For the analysis of unsolicited AEs/SAEs/concomitant medication, all vaccinated subjects 
will be considered and subjects who did not report an event will be considered as subjects 
without an event.
For a given subject and a given immunogenicity measurement, missing or non-evaluable 
measurements will not be replaced. Therefore, an analysis will exclude subjects with 
missing or non-evaluable measurements.
 
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10.6.2.
Humoral and CMI immune response
The derivation of data transformed variables for humoral immunogenicity and CMI will 
be consistent with the derivation provided in the Zoster-006 and Zoster-022 protocols, 
and the details will be included in the statistical analysis plan.
10.7.
Statistical methods
Age in years will be computed as the difference between the date of completion of the 
QoL questionnaire collected at Month 0 and the date of birth. 
As this is an exploratory analysis, no adjustment will be done for multiple comparisons 
(i.e. a 2-sided significance level of 0.05 will be used).
Spearman correlations coefficients will be presented to display the relationships between 
pairs of variables. In addition, particularly for the QoL variables, the variance inflation 
factor and the condition indices for testing multicollinearity will be estimated.
A bootstrap analysis will be carried out to evaluate the robustness of the results with 
respect to the selection of variables in the final multivariate model.
All analyses will be carried out using SAS Version 9.1.3 or later. 
GSK vaccines will be responsible for performing the statistical analysis.
10.7.1.
Quality of Life Questionnaires
The EQ-5D and SF-36 QoL questionnaires have been completed by subjects enrolled in 
ZOSTER-006 and ZOSTER-022. Questionnaires were completed by all subjects to assess 
the frailty of subjects enrolled in ZOSTER-006 and ZOSTER-022 and also the existence 
of predictive factors for the development of HZ. Both the EQ-5D and SF-36
questionnaires are international standards and have been appropriately validated.
10.7.2.
SF-36 questionnaire
The SF-36 is a multi-purpose health survey with 36 questions underlying the construction 
of 8 scales [Ware, 2001]. All but one of the 36 items (self-reported health transition) are 
used to score the eight SF-36 scales (see Table 2). Each item is used in scoring only one 
scale. Scale scores are to be constructed following the summated ratings and standardized 
SF-36 scoring algorithms. See APPENDIX A for a sample of SF-36 questionnaire.
 
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Table 2
Construction of the eight scales generated from the SF-36
Scale
Items
Response Categories Per Item
Physical Functioning (PF)
3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j
3
Role Physical (RP)  
4a, 4b, 4c, 4d
5
Bodily Pain (BP) 
7*, 8*
6, 5
General Health (GH) 
1*, 11a, 11b*, 11c, 11d*
5
Vitality (VT)
9a*, 9e*, 9g, 9i
5
Social functioning (SF)
6*, 10
5
Role Emotional (RE)
5a, 5b, 5c
5
Mental Health (MH) 
9b, 9c, 9d*, 9f, 9h*
5
* Item Reversed
10.7.3.
EQ-5D questionnaire
The EQ-5D questionnaire is a generic measure of health status that provides a simple 
descriptive profile and a single index value [Kind, 1996]. The EQ-5D defines health in 
terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 
5 items are combined to generate health profiles, i.e. a respondent who responds 1 (no 
problem\no symptom) to all 5 items has a profile “11111” and similarly a subject who 
responds with the highest level of difficulty or symptom to all items has a profile 
“33333”. These profiles are subsequently converted to a continuous single index utility 
score using a one to one matching, e.g. “11111”=1.00, “22222”=0.52 and “33333”= -
0.59, using value sets (i.e. matching profiles to single index utility scores). As suggested 
by the developers, for international studies, the United Kingdom Time-Trade-Off (TTO) 
value set is to be used for the main analysis. Note: higher scores represent a better QoL. 
See APPENDIX B for a sample of EQ-5D questionnaire.
10.7.4.
Definition of Frailty
Frailty status will be measured in relation to the accumulation of deficits using a frailty 
index (FI) adapted from the model proposed by Mitnitski et al. [Mitnitski, 2001]. The 
different aspects of frailty composing the FI will be assessed through the medical history 
and SF-36 and EQ-5D questionnaires recorded pre-vaccination dose 1. The frailty index 
will be a score between 0 and 41 as detailed in Table 3.
Table 3
Detail of frailty components
Item
Scoring method based on response 
to question
Max Contribution to 
Frailty Index
SF-36 Q1
Poor=1, 
Fair=0.5
Good=0,
Very good=0
Excellent=0
1
SF-36 Q11A-11D
Q11A, Q11C
Definitely true=1
Mostly true=0.5
Don’t know=0
Mostly false=0
Definitely false=0
4
 
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Item
Scoring method based on response 
to question
Max Contribution to 
Frailty Index
Q11B, Q11D
Definitely true=0
Mostly true=0
Don’t know=0
Mostly false=0.5
Definitely false=1
SF-36 Q3I - Q3J 
Limited a lot=1
Limited a little=0.5
Not limited at all=0
10
SF-36 Q9A - Q9I
Q9A, Q9D, Q9E, Q9H:
All of the Time=0
Most of the time=0
Some of the time=0
A little of the time=0.5
None of the time=1
Q9B, Q9C, Q9F, Q9G, Q9I :
All of the Time=1
Most of the time=0.5
Some of the time=0
A little of the time=0
None of the time=0
9
SF-36 Q2 Compared to one week before, 
how did the subject rate his / her health 
in general?
Much worse=1,
Somewhat worse=0.5,
Same=0
Somewhat better=0
Better=0
1
EQ-5D Mobility
No Problems=0
Some Problems=0.5
Confined to bed=1
1
EQ-5D Anxiety
No Anxiety=0
Moderate Anxiety=0.5
Extreme Anxiety=1
1
EQ-5D Self care
No Problems=0
Some Problems=0.5
Inability to wash or dress himself 
/herself=1
1
EQ-5D Usual activities
No Problems=0
Some Problems=0.5
Inability to perform usual activities=1
1
Medical history
Cancer
1
Diabetes Mellitus
1
High Blood Pressure
1
Heart Attack
1
Congestive Heart Failure
1
Cerebrovascular Disease
1
Arthritis
1
Chronic Lung Disease
1
Stomach or Intestinal Ulcers
1
Migraine
1
Cataract
1
Glaucoma
1
Total
41
 
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The medical history is divided into 12 categories; each category will contribute a score of 
0 or 1 to the frailty index. The coded medical history database will be searched and 
subjects with the relevant preferred terms will be assigned to 1 or more of the above 
categories. A frailty index will be defined by combining all 41 items into a score from 0 
to 1 whereby: frailty index = (accumulation of deficits) / (number of items).
Each subject will then be assigned to one of three categories, Non-Frail, Pre-Frail and 
Frail.
If the frailty index is less than or equal to 0.08 then the subject is classified as Non-Frail. 
If the score is greater than 0.08 but less than or equal to 0.25 then the subject is classified 
as pre-frail. If the score is greater than 0.25 then the subject is classified as Frail.
Further details of the calculation of the frailty index will be provided in the statistical 
analysis plan (SAP).
10.7.5.
HZ burden-of-illness score
For each confirmed case of HZ in ZOSTER-006 and ZOSTER-022, responses to the 
“worst pain” question in the ZBPI were used to calculate a “HZ burden-of-illness” score, 
defined as the area under the curve (AUC) of HZ-associated pain plotted against time 
during the 182-day period after the onset of the case. Subjects who developed HZ 
presented “burden-of-illness” scores ranging from 0 up to, theoretically, 1820. A score of 
0 is recorded for subjects in whom HZ did not develop during the study period.
10.7.6.
Analysis of Frailty 
10.7.6.1.
Analysis of primary objective
The number and percentage of subjects in each of the frailty status categories (non-frail, 
pre-frail and frail) pre-vaccination dose 1 will be presented by vaccination group, overall 
by age and the following age strata: 50-59, 60-69, 70-79 and 80 YOA. 
10.7.6.2.
Analysis of secondary objectives
Descriptive statistics of the 8 derived scales of the SF-36 and the EQ-5D Utility is
presented at vaccination day 0 and post-vaccination months 14, 26 and 38.
The analyses will also be presented by country to allow comparison with normative 
values for those questionnaires in the general population of the countries participating in 
the study.
10.7.6.2.1. Vaccine efficacy against HZ by frailty status
The primary efficacy endpoint in ZOSTER-006 and ZOSTER-022, vaccine efficacy 
against HZ, will be summarised by baseline frailty status (non-frail, pre-frail, frail) for 
subjects in the modified Total Vaccinated cohort.
 
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10.7.6.2.2. Vaccine efficacy against HZ BOI by frailty status
Vaccine efficacy against HZ BOI will be analysed by frailty status (non-frail, pre-frail, 
frail) for subjects in the modified Total Vaccinated cohort.
10.7.6.3.
Predictive factors for individuals developing HZ
Only subjects in the placebo vaccination group will be included in the analysis of 
potential predictive factors. A Cox proportional hazards regression model allowing for 
time-dependent covariates will be fitted to identify which factors are predictive of 
developing HZ. The model will include time to HZ as the outcome variable and as 
potential predictors: demographic and clinical characteristics, SF-36 variables and EQ-5D
variables. Subjects who did not develop HZ will be censored at the time of their last 
study visit. The proportional hazards regression model will be used for both minimally 
adjusted analyses and multivariate analyses. All factors will initially be examined in an 
age- and sex-adjusted model with stratification for the clinical trial (i.e. ZOSTER-006 
and ZOSTER-022). Factors will be included in the multivariate model if they are 
associated (P < 0.05 using a two-sided test) with HZ in the minimally adjusted model. 
The multivariate model will also include age and gender with stratification for the clinical 
trial (i.e. ZOSTER-006 and ZOSTER-022). A step-down (backward) variable selection 
procedure will be used to fit the final multivariate model. This model will be fitted using 
the PHREG procedure of the SAS/STAT package. 
Spearman correlations coefficients will be presented to display the relationships between 
pairs of variables. In addition, particularly for the quality of life variables, the variance 
inflation factor and the condition indices for testing multicollinearity will be estimated.
In the analysis, the impact of excluding “suspected but not confirmed cases” of HZ will 
be explored. Three analyses will be performed whereby it will be assumed that 
“suspected but not confirmed cases” are (1) “Not in at risk group” (2) “In at risk group” 
and event=0, (3) “In at risk group” and event=1.
Due to the multiple measurements of the EQ-5D and SF-36 over time, repartition in the 
HZ positive or HZ negative will be dynamic. Subjects who did not develop a confirmed 
HZ before one-timepoint (Day 0, Month 14, Month 26 and Month 38) will be considered 
HZ negative at that timepoint, and the characteristics and QoL scores reported for this 
subject at the previous timepoint will be considered as not leading to HZ.
Subjects who developed a confirmed HZ during the interval between two timepoints will 
be considered HZ+ at the later timepoint. Characteristics and QoL scores reported for this 
subject at the last timepoint before onset of HZ will be considered leading to HZ.
Example: A subject developed a confirmed HZ episode on Month 22:

Subject’s characteristics and QoL scores reported at Day 0 will be considered as not 
leading to HZ.

Subject’s characteristics and QoL scores reported at Month 14 will be considered as 
leading to HZ.
 
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
Subject’s characteristics and QoL scores reported at timepoints posterior to onset of 
HZ (Month 26 and Month 38) will be censored.
Further, details regarding the analysis will be provided in the statistical analysis plan.
10.7.6.4.
Analysis of safety by frailty status
This analysis of the safety data from the ZOSTER-064 population will be based on the 
Total Vaccinated cohort for safety. Solicited, unsolicited and serious adverse events will 
be analysed by baseline frailty status.
Incidences of SAEs during the 30-day (Days 0 29) follow-up period after each 
vaccination, up to 8 months and during any time during the study classified according to 
the MedDRA System Organ Class and Preferred Terms will be tabulated by frailty status.
10.7.7.
Analysis of immunogenicity 
The analysis will be based on the immunogenicity data from the ZOSTER-064 
population for subjects in the adapted ATP for analysis of humoral immunogenicity, and 
for subjects in the TVC for analysis of CMI, respectively (Section 10.5.3). 
10.7.7.1.
Humoral immune response
Humoral immune response will be assessed and analysed by frailty status in the Humoral 
Immunogenicity subset.
Descriptive statistics:
If the data allows the following parameters will be tabulated by vaccination group and 
frailty status at Month 0, Month 3, Month 14, Month 26 and Month 38:

Geometric mean concentrations (GMCs) of anti-gE/anti-VZV Ab with 95% CIs;

Humoral seropositivity rates with exact 95% CIs;

Vaccine response rates with 95% CIs.
10.7.7.2.
Cell-mediated immune response
CMI response will only be assessed and analysed in the CMI component of the 
Immunogenicity subset for subjects in the ZOSTER-006 study.
Descriptive statistics:
For CMI response; provided the data allows, the following parameters will be tabulated 
by vaccination group and frailty status at Months 0, 3, 14, 26 and 38:

descriptive statistics of the frequency of CD4 T cell secreting at least two different 
cytokines (IFN-, IL-2, TNF-,CD40L) to both VZV and gE antigens;
 
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
descriptive statistics of the frequency of CD4 T cell secreting at least IFN-and 
another cytokine (IL-2, TNF-,CD40L) to both VZV and gE antigens;

descriptive statistics of the frequency of CD4 T cell secreting at least IL-2 and 
another cytokine (IFN-, TNF-,CD40L) to both VZV and gE antigens;

descriptive statistics of the frequency of CD4 T cell secreting at least TNF-and 
another cytokine (IFN-, IL-2, CD40L) to both VZV and gE antigens;

descriptive statistics of the frequency of CD4 T cell secreting at least CD40L and 
another cytokine (IFN-, IL-2, TNF-) to both VZV and gE antigens;

proportion of responders with exact 95% CI.
10.8.
Interpretation of analyses
Comparative analyses will be descriptive with the aim to characterise the difference 
between groups in the endpoint related to the objective. These descriptive analyses 
should be interpreted with caution. 
10.9.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
10.9.1.
Sequence of analyses
There will be one analysis (final analysis) after completion of the data encoding.
10.9.2.
Statistical considerations for interim analyses
All analyses will be conducted on final data and therefore no statistical adjustment for 
interim analyses is required.
 
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11.
ADMINISTRATIVE MATTERS
To comply with ICH GCP or other applicable guidelines, administrative obligations 
relating to data collection, monitoring, archiving data, audits, confidentiality, ownership 
and publications must be met.
11.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor, omissions or 
inconsistencies detected by subsequent eCRF (specifically the QoL questionnaires) 
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.
11.2.
Study monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data (QoL questionnaires) is mandatory 
for the purpose of monitoring review. The monitor will perform 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. 
 
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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.
11.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g., audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP or other applicable 
guidelines, any institutional requirements or applicable laws or regulations, or GSK 
standards/procedures. The source documents (QoL questionnaires) completed during 
ZOSTER-006 and ZOSTER-022 will be retained according to what was agreed for these 
studies.
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. 
 
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11.4.
Quality assurance
To ensure compliance with GCP or other applicable guidelines and all applicable 
regulatory requirements, GSK may conduct a quality assurance audit. Regulatory 
agencies may also conduct a regulatory inspection of this study. Such audits/inspections 
can occur at any time during or after completion of the study. If an audit or inspection 
occurs, the investigator and institution agree to allow the auditor/inspector direct access 
to all relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues.
11.5.
Posting of information on publicly available registers and 
publication policy
Results of research studies, utilizing data or biological samples from previous GSK 
clinical studies that do not evaluate GSK (or other) vaccines/products are progressed for 
publication in the scientific literature when the results provide important scientific or 
medical knowledge.
11.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK 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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12.
COUNTRY SPECIFIC REQUIREMENTS 
12.1.
Requirements for Japan
12.1.1.
Regulatory and Ethical Considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (Ministry of Health 
and Welfare [MHW] No.28 dated 27th March, 1997)” and Law for Ensuring the Quality, 
Efficacy, and Safety of Drugs and Medical Devices.
The statement “I acknowledge that I am responsible for the overall study conduct.” on the 
Investigator Protocol Agreement Page means the investigator’s responsibility as defined 
by Japanese GCP.
Study Monitoring
Direct access to essential documents by monitors, the scope of those documents, and 
collection of information on safety according to the Japanese local regulation for the 
post-marketing clinical study will be specified separately in the written procedures for 
monitoring prepared for this study.
12.1.2.
Study period
Study period is included in the Japanese specific exhibit document.
12.1.3.
Study administrative structure
Sponsor information and List of Medical Institutions and Investigators are included in the 
Japanese specific exhibit document.
 
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13.
REFERENCES
Buchbinder SP, Katz MH, Hessol NA, et al. Herpes zoster and human immunodeficiency 
virus infection. J Infect Dis. 1992;166:1153-1156.
CDC. Prevention of herpes zoster. Recommendations of the Advisory Committee on 
Immunization Practices (ACIP). MMWR. 2008;57:1–30.
Clark MR, Heinberg LJ, Haythornthwaite JA, et al. Psychiatric symptoms and distress 
differ between patients with postherpetic neuralgia and peripheral vestibular disease. J 
Psychosom Res. 2000;48:51-57.
Cohen JI, Straus SE, Arvin A. Varicella-zoster virus replication, pathogenesis and 
management. In Fields virology, Fields BN, Knipe DM, Howley PM, eds. 2007. 
(Philadelphia, Wolters Kluwer Health/Lippincott Williams and Wilkins)
Cunningham AL, Lal H, Kovac M et al. Efficacy of the Herpes Zoster subunit vaccine in 
adults 70 years of age and older. N Engl J Med, 2016;375:1019-32.
Drolet M, Brisson M, Schmader K, et al. Predictors of postherpetic neuralgia among 
patients with herpes zoster: a prospective study. J Pain. 2010;11:1211-1221.
Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of 
herpes zoster. Clin Infect Dis. 2007;44 Suppl 1:S1–26.
Fleming DM, Cross KW, Cobb WA, et al. Gender difference in the incidence of shingles. 
Epidemiol Infect. 2004;132:1-5.
Irwin M, Costlow C, Williams H, et al. Cellular immunity to varicella-zoster virus in 
patients with major depression. J Infect Dis. 1998;178 Suppl 1:S104-108.
Jung BF, Johnson RW, Griffin DR, et al. Risk factors for postherpetic neuralgia in 
patients with herpes zoster. Neurology. 2004;62:1545-1551.
Kanbayashi Y, Onishi K, Fukazawa K, et al. Predictive factors for postherpetic neuralgia 
using ordered logistic regression analysis. Clin J Pain. 2012;28:712-714.
Katz J, McDermott MP, Cooper EM, et al. Psychosocial risk factors for postherpetic 
neuralgia: a prospective study of patients with herpes zoster. J Pain. 2005;6:782-790.
Kawai K, Rampakakis E, Tsai TF, et al. Predictors of postherpetic neuralgia in patients 
with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin 
America and Asia. Int J Infect Dis. 2015;34:126-131.
Kind P. The EuroQL instrument: An index of health-related quality of life. in: Spilker B, 
editor. Quality of Life and Pharmacoeconomics in Clinical Trials. Second Edition. 
Philadelphia: Lippincott-Raven Publishers; 1996.
Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster 
subunit vaccine in older adults. N Engl J Med. 2015;372:2087-2096.
 
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Langan SM, Smeeth L, Margolis DJ, et al. Herpes zoster vaccine effectiveness against 
incident herpes zoster and post-herpetic neuralgia in an older US population: a cohort 
study. PLoS Med. 2013;10:e1001420.
Lasserre A, Blaizeau F, Gorwood P, et al. Herpes zoster: a family history and 
psychological stress-case control study. J Clin Virol. 2012;55:153-157.
Liu B, Heywood AE, Reekie J, et al. Risk factors for herpes zoster in a large cohort of 
unvaccinated older adults: a prospective cohort study. Epidemiol Infect. 2015;16:1-11.
Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure 
of aging. Sci World J. 2001; 1: 323-36.
Opstelten W, Zuithoff NP, Van Essen GA, et al. Predicting postherpetic neuralgia in 
elderly primary care patients with herpes zoster: Prospective prognostic study. Pain. 
2007;132 Suppl 1:S52-59.
Oxman MN, Levin MJ, Johnson GR, et al. Shingles Prevention Study Group. A vaccine 
to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 
2005;352:2271–2284.
Schmader K, George LK, Burchett BM, et al. Race and stress in the incidence of herpes 
zoster in older adults. J Am Geriatr Soc. 1998;46:973-977.
Scott F, Johnson R, Leedham-Green M, et al. The burden of herpes zoster: A prospective 
population based study. Vaccine. 2006; 24:1308–1314.
Volpi A, Gatti A, Pica F, et al. Clinical and psychosocial correlates of post-herpetic 
neuralgia. J Med Virol. 2008;80:1646-1652.
Ware JE, Kosinski M. Interpreting SF-36 summary health measures: a response. Qual 
Life Res. 2001;10:405-13; discussion 415-20.
Whitley RJ, Weiss HL, Soong SJ, et al. Herpes zoster: risk categories for persistent pain. 
J Infect Dis. 1999;179:9-15.
Wolfe F, Michaud K, Chakravarty EF. Rates and predictors of herpes zoster in patients 
with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. 
Rheumatology (Oxford). 2006;45:1370-1375.
 
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APPENDIX C
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Administrative Change 1
eTrack study number 
and Abbreviated Title
204878 (ZOSTER-064)
IND number
BB-IND-13857
Administrative change 
number:
Administrative change 1
Administrative change 
date:
27 March 2018
Co-ordinating author:
, Scientific Writer 
Rationale/background for changes: 
!
Trademark table updated to include Shingrix
!
Updated background text to include clinical indication
!
Updated study personnel
!
Additional spelling and grammar changes were made throughout for clarification. 
!
The Sample EQ-5D questionnaire in Appendix B of the protocol was missing the 
Visual Analogue Scale (VAS). Images of pages from a sample EQ-5D
questionnaire, including the VAS, are now provided to replace the EQ-5D
questionnaire text, to better represent the appearance of the EQ-5D questionnaire 
used in the study. 
!
To complement the images of an EQ-5D sample questionnaire in APPENDIX B, 
images of pages from a sample SF-36 questionnaire are now provided to replace 
the SF-36 questionnaire text in APPENDIX A, to better represent the appearance 
of the SF-36 questionnaire used in this study.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Synopsis
Secondary Endpoints 
!
Solicited local and general symptoms from ZOSTER-006 and ZOSTER-022:
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Tertiary Endpoints 

Frequencies of CD4 T cells with antigen-specific Interferon gamma (IFN-γ)
and/or Interleukin-2 (IL-2) and/or Tumour Necrosis Factor alpha (TNF-α) 
and/or CD40 Ligand (CD40L) secretion/expression to glycoprotein E (gE) and 
VZV as determined by intracellular cytokine staining (ICS) in a subset of 
subjects at Months 0, 3, 14, 26 and 38. 
Trademark Section 
Trademarks owned by the 
GlaxoSmithKline group of companies
Generic description
Shingrix
Herpes Zoster vaccine non-live recombinant 
AS01a adjuvanted 
An indication in adults ≥50 YOA was filed for registration. HZ/su (trade name 
Shingrix) was first approved in the United States and Canada in October 2017.
Secondary Endpoint (body of text)

Solicited local and general symptoms from ZOSTER-006 and ZOSTER-022:
Tertiary Endpoints (body of text)

Frequencies of CD4 T cells with antigen-specific Interferon gamma (IFN-γ) 
and/or Interleukin-2 (IL-2) and/or Tumour Necrosis Factor alpha (TNF-α)
and/or CD40 Ligand (CD40L) secretion/expression to glycoprotein E (gE) and 
VZV as determined by intracellular cytokine staining (ICS) in a subset of 
subjects at Months 0, 3, 14, 26 and 38.
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
204878 (ZOSTER-064)
IND number
BB-IND-13857
Amendment number:
Amendment 1
Amendment date:
17 October 2018
Co-ordinating author:
, Lead Scientific Writer 
Rationale/background for changes:
!
This protocol is amended to include the specific requirements of the Japanese 
Ministry of Health and Welfare, Labour Ministerial Ordinance on the Standards for 
Conduct of Clinical Trials of Medicinal Products, dated 27 March 1997. (country 
specific).
!
The list of medical conditions used to build the Frailty Index, which is based on the 
comorbidities terminology of Zoster 063 study, has been clarified.
!
Updates to the definition of Cohorts for Analysis.
!
Additional typographical changes were made throughout for clarification.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Title Page
Co-ordinating author(s)
!
, Lead Scientific Writer
!
Lead Scientific Writer
Contributing authors
!
 Clinical Research and 
Development Lead
!
Clinical Research and 
Development Lead
!
, Clinical Research and Development 
Lead
!
, Study Delivery Lead
!
Study Delivery Lead
!
, Study Delivery Lead
!
, Lead Statistician
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!
, Study Delivery Lead
!
 Lead Statistician
!
, Oversight Data Management
!
, Director Value Evidence
!
, Health Economics Biostatistician
!
, Global Regulatory Affairs
!
, Global Regulatory Affairs
!
Clinical and Epidemiology 
Project Lead (CEPL) for Zoster, Belgian US RDC
GLOSSARY OF TERMS
modified Total 
Vaccinated Cohort 
(mTVC)
In the The mTVC will include only subjects from centres 
that participate in ZOSTER-064-006 and ZOSTER-022 
studies, the mTVC was the primary population for 
efficacy analysis, which excludedwill exclude subjects in 
the TVC for efficacy analysis who were not 
administeredwith the second vaccination or who 
developed a confirmed case of HZ prior to 1 month after 
the second vaccination (i.e. these subjects that were 
included in the mTVC of ZOSTER-006 and ZOSTER-
022.
Total Vaccinated cohort 
(TVC)
In the ZOSTER-006 and ZOSTER-022 studies, the TVC 
included all subjects who received at least one dose of 
study product (vaccine or placebo) and were not 
withdrawn due to GCP issues. The TVC will include all 
subjects from centres that participate in ZOSTER-064 
and all subjects who had a HZ suspected case in either 
the ZOSTER-006 or ZOSTER-022 studies. Subjects 
enrolled in ZOSTER-064 need to have been part of the 
TVC in ZOSTER-006 or ZOSTER-022.
1.1.2 ZOSTER-006 and ZOSTER-022
An indication in adults ≥ 50 YOA was filed for registration. HZ/su (trade name Shingrix) 
was first approved in Canada and the United States and Canada in October 2017.
8.3.2 Encoding of data in the Zoster-064 eCRF
A new eCRF database study (using the Inform system) will be created for ZOSTER-064.
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10.5    Cohorts for Analysis
10.5.1 Total Vaccinated cohort - ZOSTER-006 and ZOSTER-022
The primary analysis of EQ-5D and SF-36 questionnaires will be performed on the TVC. 
The TVC will include all subjects analysed from centres that participated in ZOSTER-
064 and all subjects who had a HZ suspected event in either the ZOSTER-006 or 
ZOSTER-022 studies.
10.5.2 Modified Total Vaccinated Cohort 
The mTVC will be the population include only subjects from centres that participate in
ZOSTER-064 (i.e. these subjects that were included in the mTVC of ZOSTER-006 and 
ZOSTER-022), which will exclude subjects in the TVC who were not administered the 
second vaccination or who developed a confirmed case of HZ prior to 1 month after the 
second vaccination.
10.7.4 Definition of Frailty
Table 3    Detail of frailty components
Item
Scoring method based on response 
to question
Max Contribution to 
Frailty Index
Medical history
Cancer
1
Diabetes Mellitus
1
High Blood Pressure
1
Myocardial Infarction Heart Attack
1
CHF
1
Cerebrovascular Disease
1
Arthritis
1
Chronic Lung Disease
1
Stomach or Intestinal disorders Ulcers
1
Migraine
1
Cataract
1
Glaucoma
1
Total
41
If the frailty index is less than or equal to 0.08 then the subject is classified as Non-Frail. 
If the score is greater than 0.08 but less than or equal to 0.25 then the subject is classified 
as pre-frail. If the score is greater than or equal to 0.25 then the subject is classified as 
Frail.
10.7.7.2 Cell Mediated Response
If data allows, CMI response will only be assessed and analysed in the CMI component 
of the Immunogenicity subset for subjects in the ZOSTER-006 study. 
 
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12. COUNTRY SPECIFIC REQUIREMENTS
12.1 Requirements for Japan
12.1.1 Regulatory and Ethical Considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (Ministry of Health 
and Welfare [MHW] No.28 dated 27th March 1997)” and, Law for Ensuring the Quality, 
Efficacy, and Safety of Drugs and Medical Devices.
The statement “I acknowledge that I am responsible for the overall study conduct.” on the 
Investigator Protocol Agreement Page means the investigator’s responsibility as defined 
by Japanese GCP.
Study Monitoring
Direct access to essential documents by monitors, the scope of those documents, and 
collection of information on safety according to the Japanese local regulation for the 
post-marketing clinical study will be specified separately in the written procedures for 
monitoring prepared for this study.
12.1.2      Study period
Study period is included in the Exhibit.
12.1.3     Study administrative structure
Sponsor information and List of Medical Institutions and Investigators are included in
the Exhibit.
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Administrative Change 2
eTrack study number 
and Abbreviated Title
204878 (ZOSTER-064)
IND number
BB-IND-13857
Administrative change 
number:
Administrative change 2
Administrative change 
date:
13 November 2018
Co-ordinating author:
, Lead Scientific Writer 
Rationale/background for changes: 
!
Typographical errors corrected
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Synopsis
Endpoints
Secondary
!
SF-36 and EQ-5D scale scores:
∀
At months 0, 14, 26 and 38.
!
Confirmed HZ cases: 
∀
Incidence of HZ cases during ZOSTER-006 and ZOSTER-022 for subjects in 
the modified Total Vaccinated Cohort (mTVC).
!
Humoral Immunogenicity of the study vaccine in subset of subjects from 
ZOSTER-006 and ZOSTER-022.
∀
Anti-gE Ab and anti-VZV Ab concentrations as determined by Enzyme-linked 
Immunosorbent Assay (ELISA), in a subset of subjects at Months 0, 3, 14, 26 
and 38.
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Section 4: Study Design Overview

Type of study: to be combined with other protocols for analysis to be combined 
with other protocols for analysis to be combined with other protocols for analysis:
data to be analysed in this study have been collected in ZOSTER-006 (eTrack 
110390) and ZOSTER-022 (eTrack 113077).

Data collection: CRF/eCRF CRF/eCRF CRF/eCRF
Section 8.3.1: Check inclusion and exclusion criteria

Check all applicable inclusion and exclusion criteria as described in Sections 0 6.2
and 6.3, respectively, before encoding of subject data.

Checking of the eligibility criteria will be performed centrally. Sites will receive a 
list of subjects for which data and QoL questionnaires should be encoded (see 
Section 8.1).
Section 10.5.2 modified Total Vaccinated Cohort
 
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GlaxoSmithKline Biologicals SA
Vaccines R &D
Protocol Administrative Change 3
eTrack study number 
and Abbreviated Title
204878 (ZOSTER-064)
IND number
BB-IND-13857
Administrative change 
number:
Administrative Change 3
Administrative change 
date:
11 February 2019
Co-ordinating author:
, Scientific Writer, XPE Pharma & 
Science for GSK Biologicals 
Rationale/background for changes: 
!
The Japan Vaccine Company will no longer be in operation as of 01 April 2019. 
Therefore, the reference to “Japan Vaccine Co., Ltd.” has been changed to “GSK 
Japan”.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Added to authors:
!
, Scientific Writer, XPE Pharma & Science for GSK Biologicals
!
, Global Regulatory Affairs
On page 2 changed copyright date: © 2018 2019 GSK group of companies or its licensor.
On page 7 Signature page for Japan representative: GSK Japan JapanVaccine Co
representative name, function and title
Section 8.1 Subject Identification: Date of subject’s consent 
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