confidential · 2020-06-09 · herpes zoster (hz) vaccine (gsk 1437173a). etrack study number and...

CONFIDENTIAL

05-MAY-2017 1

Clinical Study ProtocolSponsor:

GlaxoSmithKline Biologicals

Rue de l’Institut 89, 1330Rixensart, Belgium

Primary Study vaccine and number

GlaxoSmithKline (GSK) Biologicals’ lyophilized Herpes Zoster (HZ) vaccine (GSK 1437173A).

eTrack study number and Abbreviated Title

201198 (ZOSTER-048)

Investigational New Drug (IND) number

BB-IND 13879

Date of protocol Final Version 1: 24 February 2014

Date of protocol amendment Amendment 1 Final: 01 June 2015

Date of administrative change Administrative Change 1 Final: 05 May 2017

Title Immunogenicity and safety study of GSK Biologicals’ Herpes Zoster vaccine GSK1437173A in adults ≥ 65 years of age with and without Zostavax® vaccination at least 5 years earlier.

Detailed Title A phase III, open label, multicenter study of GSK Biological’ herpes zoster HZ/su candidate vaccine (GSK1437173A) administered intramuscularly on a 0 and 2 month schedule evaluating the immunogenicity, safety and reactogenicity in adults ≥ 65 years of age with a previous Zostavax®

vaccination ≥ 5 years earlier, compared to group-matched adults not previously vaccinated with Zostavax®.

Co-ordinating author(Amended 05 May 2017)

, Scientific Writer

CONFIDENTIAL201198 (ZOSTER-048)

Protocol Administrative Change 1 Final

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201198 (ZOSTER-048)

Investigational New Drug (IND) number

BB-IND 13879

Detailed Title A phase III, open label, multicenter study of GSK Biological’ herpes zoster HZ/su candidate vaccine (GSK1437173A) administered intramuscularly on a 0 and 2 month schedule evaluating the immunogenicity, safety and reactogenicity in adults ≥ 65 years of age with a previous Zostavax®


Contributing authors(Amended 05 May 2017)

, Clinical Research and Development Lead

, Clinical Research and Development Lead, Vaccine Discovery and Development

, Lead Statistician

, Project Statistician

, Study Delivery Lead

, Study Delivery Lead

, Global Regulatory Affairs

, Global Regulatory Affairs (USA)

, Safety Physician

, Clinical Laboratory Sciences (CLS) Project Manager

, Project Data Manager

, Portfolio Data Manager

, Global Patent

, Director, Clinical and Epidemiology Project Leader (CEPL), Belgian RDC

GSK Biologicals’ Protocol DS v14.1.1Copyright 2014-2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.




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Protocol Administrative Change 1 Sponsor Signatory Approval


201198 (ZOSTER-048)

IND number BB-IND 13879


Detailed Title A phase III, open label, multicenter study of GSK Biologicals’ herpes zoster HZ/su candidate vaccine (GSK1437173A) administered intramuscularly on a 0 and 2 month schedule evaluating the immunogenicity, safety and reactogenicity in adults ≥ 65 years of age with a previous Zostavax®


Sponsor signatory Lidia Oostvogels, Director, Clinical and Epidemiology Project Leader (CEPL), Belgian RDC

Signature

Date




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Protocol Administrative Change 1 Rationale

Administrative Change number:

Administrative Change 1

Rationale/background for changes:

The back-up study contact telephone number for reporting SAEs and pIMDs in the US was deleted in Section 8.3.2, since that telephone number, which was originally provided to the sites as a courtesy, has been inactivated.

The names of the co-ordinating author, contributing authors and sponsor have been updated on the title pages.






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Protocol Administrative Change 1 Investigator Agreement

I agree:

To conduct the study in compliance with this protocol, any future protocol amendments or protocol administrative changes, with the terms of the clinical trial agreement and with any other study conduct procedures and/or study conduct documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about the GSK Biologicals’ investigational vaccine and other study-related duties and functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required by local regulations, obtain the laboratory’s current certification or Quality Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or elsewhere without the approval of GSK Biologicals and the express written informed consent of the subject and/or the subject’s legally acceptable representative.

To perform no other biological assays on the clinical samples except those described in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to obtain and supply, as necessary, details about the investigator’s ownership interest in the sponsor or the investigational vaccine, and more generally about his/her financial ties with the sponsor. GSK Biologicals will use and disclose the information solely for the purpose of complying with regulatory requirements.

Hence I:

Agree to supply GSK Biologicals with any necessary information regarding ownership interest and financial ties (including those of my spouse and dependent children).

Agree to promptly update this information if any relevant changes occur during the course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other documents required by regulatory agencies for this study.






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eTrack study number and Abbreviated Title(s)

201198 (ZOSTER-048)





Investigator name

Signature

Date




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Sponsor Information

1. Sponsor

GlaxoSmithKline BiologicalsRue de l’Institut, 89, 1330 Rixensart, Belgium

2. Sponsor Medical Expert for the Study

Refer to the local study contact information document.

3. Sponsor Study Monitor

Refer to the local study contact information document.

4. Sponsor Study Contact for Reporting of a Serious Adverse Event

GSK Biologicals Central Safety Physician and Back-up Phone contact for Reporting SAEs: refer to protocol Section 8.3.2.






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SYNOPSIS



Indication Prevention of Herpes Zoster (HZ) and related complications in adults ≥ 50 years of age and immunocompromised adults ≥ 18 years of age.

Rationale for the study and study design

Rationale for the study

Varicella-zoster Virus (VZV) causes two distinct diseases. Varicella (chickenpox) occurs shortly after primary VZV infection and is characterized by systemic illness and a widely disseminated rash. HZ (shingles) occurs when VZV reactivates from latency and typically manifests as a localized, dermatomal rash.

The typical HZ rash lasts about 2 to 4 weeks and is usually accompanied by pain and pruritus. The most common complication of HZ is postherpetic neuralgia (PHN), defined as pain that persists after the resolution of the HZ rash. Declining VZV-specific immune responses with older age are a clear risk factor for developing shingles and PHN. In fact, age is the most common risk factor for developing HZ. 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. As the population ages, more and more people are expected to live until they are 80 with a 1 out of 2 risk of developing HZ if they live to be 85 YOA.

An observational short-term persistence study in Zostavax, recipients demonstrated waning efficacy after about 5 years. Consequently, people ≥ 60 YOA vaccinated with Zostavaxmay not be well protected from developing HZ 5 years or more after vaccination, at an age where the incidence of HZ is increasing. Furthermore, studies evaluating two doses of Zostavax found that a second dose of Zostavax at 1-2 month intervals did not enhance VZV-specific immunity beyond that induced by the single dose in subjects ≥ 60 YOA and in






05-MAY-2017 9

subjects ≥ 70 YOA. The relevance of this finding in terms of providing protection against HZ is unclear, but it seems likely that the duration of HZ protection would not be enhanced by adding another dose of Zostavax to the initial vaccination regimen.

GSK Biologicals’ candidate vaccine for the prevention of HZ is a recombinant subunit (su) vaccine consisting of VZV glycoprotein E (gE) antigen and an adjuvant system (AS01B). The VZV gE was chosen as the subunit vaccine antigen because of both its prominence as a target for host immune responses and its functional significance during viral infection. A recent analysis of the primary endpoint in the pivotal phase III study ZOSTER-006 showed that HZ/su reduced the risk of shingles by 97.16% (95% Confidence Interval (CI); Lower Limit (LL):93.72% - Upper Limit (UL):98.97%) compared to placebo in subjects ≥ 50 YOA.

Although no immunological correlate for protection against HZ has been identified, current knowledge suggests that VZV-specific Cell-Mediated Immunity (CMI) is of primary importance in preventing HZ. The role of humoral immune responses in preventing HZ is less clear. However, VZV-specific antibodies (Abs) may help control viral dissemination in immunocompromised persons and may thereby help limiting the severity of HZ.

Rationale for the study design

Since it has been observed that efficacy following Zostavaxvaccination wanes over time, it is likely that an additional vaccination will be required to ensure sustained protection against HZ. Thus the goal of this study is to generate immunogenicity, safety and reactogenicity data that will support the vaccination of previous Zostavax recipients with GSK Biologicals HZ/su vaccine. The study is a phase III, open-label, multi-center study conducted in the US. The study will evaluate two parallel groups of 200 adults ≥ 65 YOA; one group (Prev-Zvax) with a previous Zostavax vaccination at least 5 years earlier, versus the other group without a previous Zostavax vaccination (No prev-Zvax). At least 5 years post-Zostavax vaccination was chosen for the Prev-Zvax group as the waning of Zostavax efficacy was observed after about 5 years in the short-term persistence follow-up study.

Rationale for the use of placebo

No placebo will be used in this study.






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Objectives Co-Primary

To compare humoral immune responses at 1 month after dose 2 of HZ/su (Month 3) in subjects ≥ 65 years of age who received Zostavax ≥ 5 years earlier (Prev-Zvax) as compared to subjects who have never received Zostavax(No prev-Zvax).

Criterion:

Non-inferiority will be demonstrated if the upper limit of the two-sided 95% confidence interval of the adjusted geometric mean concentration (GMC) ratio (No prev-Zvax over Prev-Zvax) 1 month post-dose 2 is below 1.5 in terms of anti-gE antibodies.

To evaluate safety and reactogenicity up to 1 month after dose 2 of HZ/su in subjects ≥ 65 years of age who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax (No prev-Zvax).

Criterion:

This analysis is descriptive; no criterion has been defined.

Secondary

To assess humoral immune responses to HZ/su at Day 0, 1 month post-dose 1, and 1 and 12 months post-dose 2 in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax(No prev-Zvax).

To assess CMI responses to HZ/su at Day 0, 1 month post-dose 1, and 1 and 12 months post-dose 2 in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax (No prev-Zvax).

To evaluate the safety following administration of HZ/su during the post-dose 2 follow-up period (from 1 month post-dose 2 through 12 months post-dose 2) in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax No prev-Zvax).

Study design Experimental design: Phase III, open-label, group-matched, multi-center, single-country study with two parallel groups.






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Duration of the study: Approximately 20 months. Each subject will be enrolled during a screening visit approximately 6 months prior to Visit 1. Each subject receiving HZ/su vaccine (at Visit 1) will be followed after the second vaccine dose (at Visit 3) for approximately 12 months.

Epoch 001: Primary starting at the screening visit and ending at Visit 5 (Month 14).

Study groups:

Synopsis Table 1 Study groups and epochs foreseen in the study

Study groupsNumber of subjects

Age (Min/Max)Epochs

Epoch 001

Prev-Zvax 200 ≥ 65 years xNo prev-Zvax 200 ≥ 65 years x

Synopsis Table 2 Study groups and treatment foreseen in the study

Treatment nameVaccine/Product

nameStudy Groups

Prev-Zvax No prev-Zvax

HZ/suVZV gE x xAS01B x x

Control: not applicable.

Vaccination schedule: Two groups of subjects ≥ 65 YOA (Prev-Zvax and No prev-Zvax; 200 subjects per group) will receive two doses of the HZ/su vaccine (first dose given at Month 0 and second dose given 2 months later).

Treatment allocation: Subjects will be enrolled into either the Prev-Zvax or No prev-Zvax study groupdepending on Zostavax history.

Blinding:

Synopsis Table 3 Blinding of study epochs

Study Epochs BlindingEpoch 001 open






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Sampling schedule:

Blood samples (approximately 5 and 20 mL per visit) to assess humoral immunogenicity and CMI, respectively, will be collected from all subjects at Visits 1, 2, 4 and 5.

Clinical specimens of HZ lesions will be collected from subjects clinically diagnosed as having a suspected case of HZ.

Type of study: self-contained

Data collection: Electronic Case Report Form (eCRF).

Safety Monitoring: An internal GSK Safety Review Team (SRT) will oversee the safety of the study on a regular basis.

Number of subjects 400 with 200 subjects per group.

Endpoints Primary

Anti-gE humoral immunogenicity.

Anti-gE antibody concentrations, as determined by ELISA, at Month 3.

Occurrence of solicited local and general symptoms.

Occurrence, intensity, and duration of each solicitedlocal symptom within 7 days (Days 0-6) after each dose.

Occurrence, intensity, duration, and relationship to vaccination of each solicited general symptom within 7 days (Days 0-6) after each dose.

Occurrence of unsolicited symptoms (AEs).

Occurrence, intensity, and relationship to vaccination of each unsolicited symptom (AE) within 30 days (Days 0-29) after each dose, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.

Occurrence of serious adverse events (SAEs).

Occurrence and relationship to vaccination of all SAEs from Month 0 (dose 1) up to Month 3 (30 days post-dose 2).






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Occurrence of AEs of specific interest (potential immune-mediated diseases [pIMDs]).

Occurrence of any pIMDs from Month 0 (dose 1) up toMonth 3 (30 days post-dose 2).

Secondary


Anti-gE antibody concentrations, as determined by ELISA, at Months 0, 1, 3 and 14.

gE-specific CD4+ T-cell mediated immunogenicity.

– Frequencies of gE-specific CD4+ T-cells, expressing at least two activation markers (from among interferon gamma [IFN-γ], interleukin-2 [IL-2], tumor necrosis factor alpha [TNF-α] and CD40L), as determined by in vitro Intracellular cytokine staining (ICS), at Months 0, 1, 3 and 14.

Occurrence of Serious Adverse Events (SAEs).

Occurrence and relationship to vaccination of all SAEs from Month 3 (30 days post-vaccination 2) up to Month 14 (12 months post-vaccination 2).

Occurrence of AEs of specific interest (pIMDs).

Occurrence of any pIMDs from Month 3 (30 days post-vaccination 2) up to Month 14 (12 months post-vaccination 2).






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TABLE OF CONTENTS

PAGE

SPONSOR INFORMATION ............................................................................................7

SYNOPSIS......................................................................................................................8

LIST OF ABBREVIATIONS...........................................................................................21

GLOSSARY OF TERMS ...............................................................................................24

TRADEMARKS .............................................................................................................27

1. INTRODUCTION....................................................................................................281.1. Background ................................................................................................281.2. Rationale for the study and study design ....................................................29

1.2.1. Rationale for the study.................................................................291.2.2. Rationale for the study design......................................................301.2.3. Rationale for the use of placebo ..................................................30

1.3. Benefit : Risk Assessment ..........................................................................311.3.1. Risk Assessment .........................................................................311.3.2. Benefit Assessment .....................................................................321.3.3. Overall Benefit : Risk Conclusion.................................................32

2. OBJECTIVES.........................................................................................................322.1. Co-Primary objectives.................................................................................322.2. Secondary objectives..................................................................................32

3. STUDY DESIGN OVERVIEW ................................................................................34

4. STUDY COHORT...................................................................................................364.1. Number of subjects.....................................................................................364.2. Inclusion criteria for enrolment ....................................................................364.3. Exclusion criteria for enrolment...................................................................37

5. CONDUCT OF THE STUDY ..................................................................................385.1. Regulatory and ethical considerations, including the informed

consent process..........................................................................................385.2. Subject identification and randomization of treatment .................................39

5.2.1. Subject identification....................................................................395.2.1.1. Treatment allocation to the subject .............................39

5.2.1.1.1. Study group and treatment number allocation ...................................39

5.2.1.1.2. Treatment number allocation for subsequent doses ..................................40

5.3. Method of blinding ......................................................................................405.4. General study aspects ................................................................................405.5. Suspected HZ cases...................................................................................40

5.5.1. Evaluation and confirmation of suspected HZ cases....................415.5.2. Collection of HZ case information ................................................42






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5.6. Outline of study procedures ........................................................................435.7. Detailed description of study procedures ....................................................46

5.7.1. Procedures during the screening visit ..........................................465.7.1.1. Informed consent........................................................465.7.1.2. Check inclusion and exclusion criteria ........................475.7.1.3. Record demographic data ..........................................475.7.1.4. Record previous Zostavax history...............................475.7.1.5. Medical history ...........................................................475.7.1.6. Recording of medical condition...................................475.7.1.7. Training of subjects on self-reporting of the

signs and symptoms of typical HZ ..............................475.7.2. Procedures prior to the first vaccination .......................................485.7.3. Check contraindications, warnings and precautions to

vaccination...................................................................................485.7.4. History directed physical examination ..........................................485.7.5. Assess pre-vaccination body temperature ...................................485.7.6. Study group and treatment number allocation..............................485.7.7. Sampling......................................................................................49

5.7.7.1. Blood sampling for safety or immune response assessments ..............................................................49

5.7.8. Study Vaccine administration.......................................................495.7.9. Check and record concomitant medication/vaccination and

intercurrent medical conditions (IMC) including HZ ......................495.7.10. Recording of AEs, SAEs and pIMDs ............................................505.7.11. Study conclusion..........................................................................50

5.8. Biological sample handling and analysis.....................................................505.8.1. Use of specified study materials ..................................................515.8.2. Biological samples .......................................................................515.8.3. Laboratory assays .......................................................................525.8.4. Biological samples evaluation ......................................................53

5.8.4.1. Immunological read-outs ............................................535.8.5. Immunological correlates of protection.........................................53

6. STUDY VACCINES AND ADMINISTRATION ........................................................546.1. Description of study vaccine .......................................................................546.2. Storage and handling of study vaccine .......................................................546.3. Dosage and administration of study vaccine ...............................................556.4. Replacement of unusable vaccine doses....................................................556.5. Contraindications to subsequent vaccination ..............................................556.6. Concomitant medication/product and concomitant vaccination ...................56

6.6.1. Recording of concomitant medications/products and concomitant vaccination...............................................................57

6.6.2. Concomitant medications/products/vaccines that may lead to the elimination of a subject from ATP analyses........................57

6.7. Intercurrent medical conditions (IMCs) that may lead to elimination of a subject from ATP analyses ..................................................................58

7. HEALTH ECONOMICS ..........................................................................................59

8. SAFETY.................................................................................................................598.1. Safety definitions ........................................................................................59

8.1.1. Definition of an adverse event......................................................59






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8.1.2. Definition of a serious adverse event ...........................................608.1.3. Solicited adverse events ..............................................................61

8.1.3.1. Solicited local (injection-site) adverse events..............618.1.3.2. Solicited general adverse events ................................61

8.1.4. Clinical laboratory parameters and other abnormal assessments qualifying as adverse events or serious adverse events ............................................................................61

8.1.5. Adverse events of specific interest...............................................628.1.5.1. Potential immune-mediated diseases .........................62

8.2. Detecting and recording adverse events and serious adverse events.........................................................................................................648.2.1. Time period for detecting and recording adverse events

and serious adverse events .........................................................648.2.2. Post-Study adverse events and serious adverse events ..............678.2.3. Evaluation of adverse events and serious adverse events...........67

8.2.3.1. Active questioning to detect adverse events and serious adverse events........................................67

8.2.3.2. Assessment of adverse events...................................688.2.3.2.1. Assessment of intensity ..........................688.2.3.2.2. Assessment of causality .........................69

8.2.3.3. Assessment of outcomes............................................708.2.3.4. Medically attended visits.............................................71

8.3. Reporting of serious adverse events and other events...............................718.3.1. Prompt reporting of serious adverse events, and other

events to GSK Biologicals............................................................718.3.2. Contact information for reporting serious adverse events

and pIMDs ...................................................................................728.3.3. Completion and transmission of SAE reports to GSK

Biologicals ...................................................................................728.3.3.1. Back-up system in case the electronic SAE

reporting system does not work ..................................728.3.4. Reporting of pIMDs to GSK Biologicals........................................738.3.5. Updating of SAE and pIMD information after removal of

write access to the subject’s eCRF ..............................................738.3.6. Regulatory reporting requirements for serious adverse

events..........................................................................................738.4. Follow-up of adverse events and serious adverse events ...........................74

8.4.1. Follow-up of adverse events and serious adverse events ............748.4.1.1. Follow-up during the study..........................................748.4.1.2. Follow-up after the subject is discharged from

the study.....................................................................748.5. Treatment of adverse events ......................................................................748.6. Subject card................................................................................................748.7. Safety Monitoring........................................................................................75

9. SUBJECT COMPLETION AND WITHDRAWAL.....................................................759.1. Subject completion .....................................................................................759.2. Subject withdrawal......................................................................................75

9.2.1. Subject withdrawal from the study ...............................................759.2.2. Subject withdrawal from investigational vaccine...........................76

9.3. Screen failures............................................................................................76






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10. STATISTICAL METHODS......................................................................................7710.1. Primary endpoints.......................................................................................7710.2. Secondary endpoints ..................................................................................7710.3. Strategy for group matching between groups..............................................78

10.3.1. Contingency plan for the group matching strategy .......................7910.4. Determination of sample size......................................................................8010.5. Cohorts for Analysis....................................................................................81

10.5.1. Total vaccinated cohort................................................................8110.5.2. According To Protocol cohort for analysis of safety for the

active phase ................................................................................8210.5.3. According To Protocol cohort for analysis of

immunogenicity............................................................................8210.5.4. According To Protocol cohort for analysis of antibody

persistence ..................................................................................8210.6. Derived and transformed data.....................................................................82

10.6.1. Handling of missing data..............................................................8210.6.2. Humoral immune response..........................................................8310.6.3. Cell-mediated immune response .................................................83

10.7. Analysis of demographics ...........................................................................8410.8. Analysis of immunogenicity.........................................................................84

10.8.1. Within groups assessment...........................................................8410.8.1.1. Humoral immune response.........................................8410.8.1.2. Cell-mediated immune response ................................85

10.8.2. Between groups assessment .......................................................8510.9. Analysis of safety........................................................................................85

10.9.1. Within groups assessment...........................................................8510.9.2. Between groups assessment .......................................................86

10.10. Interpretation of analyses............................................................................8610.11. Conduct of analyses ...................................................................................86

10.11.1. Sequence of analyses..................................................................8610.11.2. Statistical considerations for interim analyses..............................87

11. ADMINISTRATIVE MATTERS ...............................................................................8711.1. electronic Case Report Form instructions ...................................................8711.2. Study Monitoring by GSK Biologicals..........................................................8711.3. Record retention .........................................................................................8811.4. Quality assurance.......................................................................................8911.5. Posting of information on publicly available clinical trial registers and

publication policy ........................................................................................8911.6. Provision of study results to investigators ...................................................89

12. COUNTRY SPECIFIC REQUIREMENTS...............................................................89

13. REFERENCES.......................................................................................................90






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LIST OF TABLES

PAGE

Table 1 Study groups and epochs foreseen in the study.....................................35

Table 2 Study groups and treatment foreseen in the study .................................35

Table 3 Blinding of study epochs ........................................................................35

Table 4 List of study procedures .........................................................................43

Table 5 Intervals between study visits.................................................................46

Table 6 Biological samples .................................................................................52

Table 7 Humoral Immunity (Antibody determination)...........................................52

Table 8 Cell-Mediated Immunity (CMI)................................................................52

Table 9 Molecular Biology (PCR tests)................................................................53

Table 10 Immunological read-outs ........................................................................53

Table 11 Study vaccine.........................................................................................54

Table 12 Dosage and administration.....................................................................55

Table 13 Solicited local adverse events ................................................................61

Table 14 Solicited general adverse events............................................................61

Table 15 List of potential immune-mediated diseases...........................................63

Table 16 Reporting periods for collecting safety information .................................66

Table 17 Intensity scales for solicited symptoms in adults.....................................68

Table 18 Timeframes for submitting serious adverse event and other events reports to GSK Biologicals ..........................................................71

Table 19 Power to show that the 95%CI for the GMC ratio between groups (No prev-Zvax over Prev-Zvax) for anti-gE is below a predefined limit of 1.5...............................................................................................80

Table 20 Exact 95% CI for proportion with 200 subjects and probability to detect 5%, 10% increase in the Prev-Zvax group as compared to the Non-Prev-Zvax group .......................................................................81

Table 21 The intervals allowed for the inclusion in the ATP cohort for analysis of immunogenicity ....................................................................82






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Table 22 GSK Biologicals’ laboratories .................................................................94

Table 23 Outsourced laboratories .........................................................................94






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LIST OF APPENDICES

PAGE

APPENDIX A LABORATORY ASSAYS .......................................................................92

APPENDIX B CLINICAL LABORATORIES ..................................................................94

APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE PROTOCOL...........................................................................................95






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LIST OF ABBREVIATIONS

Ab: Antibody

ACIP: Advisory Committee on Immunization Practices

AE: Adverse event

ANCA: Anti-Neutrophil Cytoplasmic Antibodies

AS01B: MPL, QS21, liposome based Adjuvant System (50 μg MPL and 50 μg QS21)

ATP: According-To-Protocol

CBER: Center for Biologics Evaluation and Research

CD4+: Helper T-cells expressing on their surface the co-receptor molecules designated Cluster of differentiation 4

CD-ROM: Compact disc read-only optical memory

CEVAC: Center for Vaccinology, Ghent, Belgium

CI: Confidence Interval

CMI: Cell-Mediated Immunity

CREST: Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia (syndrome)

D: Deltoid

DNA: Deoxyribonucleic Acid

eCRF: electronic Case Report Form

eTDF: electronic temperature excursion decision form

CSA: Clinical Study Associate

CSR: Clinical Study Report

ELISA: Enzyme Linked Immunosorbent Assay

FDA: Food and Drug Administration, United States

gE: VZV glycoprotein E

GCP: Good Clinical Practice

GM: Geometric Mean

GMC: Geometric Mean Concentration

GSK: GlaxoSmithKline

GVCL: Global Vaccines Clinical Laboratories






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HIV: Human Immunodeficiency Virus

HZ: Herpes Zoster

HZAC: HZ Ascertainment Committee

HZ/su: Herpes Zoster subunit vaccine

ICF: Informed Consent Form

ICH: International Conference on Harmonization

ICS: Intracellular cytokine staining

IEC: Independent Ethics Committee

IFN-γ: Interferon-gamma

IgG: Immunoglobulin class G

IL-2: Interleukin 2

IM: Intramuscular

IMC: Intercurrent Medical Conditions

IMP: Investigational Medicinal Products

IND: Investigational New Drug

IRB: Institutional Review Board

LL: Lower Limit

LLL: Lower Limit of Linearity

MedDRA: Medical Dictionary for Regulatory Activities

MPL: 3-O-desacyl-4’-monophosphoryl lipid A

N-D: Non-dominant

No prev-Zvax: No previous Zostavax immunization (Group)

PBMC: Peripheral Blood Mononuclear Cells

PCR: Polymerase Chain Reaction

PHN: Postherpetic Neuralgia

PI: Product Information

pIMD: Potential Immune-Mediated Disease

Prev-Zvax: Previous Zostavax immunization ≥ 5 years ago (Group)

PT: Preferred term

qPCR: quantitative Polymerase Chain Reaction






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QS21: Quillaja saponaria Molina, fraction 21 (purified saponin extract from the South American tree)

SAE: Serious Adverse Event

SAP: Statistical Analysis Plan

SAS: Statistical Analysis System

SBIR: Randomization System on Internet

SD: Standard deviation

SDV: Source Document Verification

SFU: Safety follow-up

SPC: Summary of Product Characteristics

SPM: Study Procedures Manual

SRT: Safety Review Team

STD: Standard Deviation

su: subunit

TNF-α: Tumor Necrosis Factor-alpha

TVC: Total Vaccinated cohort

UL: Upper Limit

US/USA: United States (of America)

Vacc: Vaccination

VE: Vaccine Efficacy

VZV: Varicella-Zoster Virus

YOA: Years of age






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GLOSSARY OF TERMS

Adverse event: Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Blinding: A procedure in which one or more parties to the trial are kept unaware of the treatment assignment in order to reduce the risk of biased study outcomes. The level of blinding is maintained throughout the conduct of the trial, and only when the data are cleaned to an acceptable level of quality will appropriate personnel be unblinded or when required in case of a serious adverse event.

In an open-label study, no blind is used. Both the investigator and the subject know the identity of the treatment assigned. In a single-blind study, the investigator and/or his staff are aware of the treatment assignment but the subject is not.

Eligible: Qualified for enrolment into the study based upon strict adherence to inclusion/exclusion criteria.

Epoch: An epoch is a self-contained set of consecutive timepoints or a single timepoint from a single protocol. Self-contained means that data collected for all subjects at all timepoints within that epoch allows to draw a complete conclusion to define or precise the targeted label of the product. Typical examples of epochs are primary vaccinations, boosters, yearly immunogenicity follow-ups, and surveillance periods for efficacy or safety.

eTrack: GSK’s tracking tool for clinical trials.

Evaluable: Meeting all eligibility criteria, complying with the procedures defined in the protocol, and, therefore, included in the according-to-protocol (ATP) analysis (see Sections 6.6.2 and 10.5 for details on criteria for






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evaluability).

Immunological correlate of protection:

The defined humoral antibody response above which there is a high likelihood of protection in the absence of any host factors that might increase susceptibility to the infectious agent.

Intercurrent Medical Condition:

Any medical condition incurred by a study subject that has the capability of confounding their immune response to the study vaccine or its interpretation.

Investigational vaccine/product:

(Synonym of Investigational Medicinal Product)

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Potential Immune-Mediated Disease:

Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology.

Primary completion date:

The date that the final subject was examined or received an intervention for the purpose of final collection of data for the primary outcome, whether the clinical trial concluded according to the pre-specified protocol or was terminated.

Protocol amendment: The International Conference on Harmonization (ICH) defines a protocol amendment as: ‘A written description of a change(s) to or formal clarification of a protocol.’ GSK Biologicals further details this to include a change to an approved protocol that affects the safety of subjects, scope of the investigation, study design, or scientific integrity of the study.

Protocol administrative change:

A protocol administrative change addresses changes to only logistical or administrative aspects of the study.

Note: Any change that falls under the definition of a protocol amendment (e.g., a change that affects the safety of subjects, scope of the investigation, study design, or scientific integrity of the study) MUST be prepared as an amendment to the protocol.

Randomization: Process of random attribution of treatment to subjects in order to reduce bias of selection.






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Self-contained study: Study with objectives not linked to the data of another study.

Site Monitor: An individual assigned by the sponsor who is responsible for assuring proper conduct of clinical studies at one or more investigational sites.

Solicited adverse event: AEs to be recorded as endpoints in the clinical study. The presence/occurrence/intensity of these events is actively solicited from the subject or an observer during a specified post-vaccination follow-up period.

Subject: Term used throughout the protocol to denote an individual who has been contacted in order to participate or participates in the clinical study, either as a recipient of the vaccine(s)/product(s) or as a control.

Subject number: A unique number identifying a subject, assigned to each subject consenting to participate in the study.

Treatment: Term used throughout the clinical study to denote a set of investigational product(s) or marketed product(s) or placebo intended to be administered to a subject, identified by a unique number, according to the study randomization or treatment allocation.

Treatment number: A number identifying a treatment to a subject, according to the study randomization or treatment allocation.

Unsolicited adverse event:

Any AE reported in addition to those solicited during the clinical study. Also any ‘solicited’ symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event.






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TRADEMARKS

The following trademarks are used in the present protocol.

Note: In the body of the protocol (including the synopsis), the names of the vaccines/products and/or medications will be written without the superscript symbol ™ or ® and in italics.

Trademarks of the GlaxoSmithKline group of companies

Generic description

Zostavax® (Merck & Co., Inc.) Herpes zoster vaccine consisting of high-titer live attenuated varicella-zoster virus (Oka strain)






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1. INTRODUCTION

1.1. Background

Varicella-zoster Virus (VZV) causes two distinct diseases. Varicella (chickenpox) occurs shortly after primary VZV infection and is characterized by systemic illness and a widelydisseminated rash. HZ (shingles) occurs when VZV reactivates from latency and typically manifests as a localized, dermatomal rash.

The typical HZ rash lasts about 2 to 4 weeks and is usually accompanied by pain and pruritus. The most common complication of HZ is postherpetic neuralgia (PHN), defined as pain that persists after the resolution of the HZ rash. Declining VZV-specific immune responses with older age are a clear risk factor for developing shingles and PHN [NNii, 2008; Dworkin, 2007]. In fact, age is the most common risk factor for developing HZ. 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; Oxman, 2005]. As the population ages, more and more people are expected to live until they are 80 with a 1 out of 2 risk of developing HZ if they live to be 85 YOA [CDC, 2008].

Since HZ is caused by the reactivation of VZV, a vaccine that helps restore immunity to VZV may prevent HZ. A live attenuated VZV vaccine, Zostavax® (Merck & Co.), is licensed in multiple countries to prevent HZ in persons ≥ 50 YOA [Zostavax Prescribing Information, 2013; Zostavax Summary of Product Characteristics, 2012]. The potential of vaccination to protect against HZ was evaluated in a large efficacy study in which a single subcutaneous dose of Zostavax (a live attenuated HZ vaccine that is a high titerpreparation of the same virus strain used in the varicella vaccine, Varivax® [both manufactured by Merck & Co.]) partially protected immunocompetent older adults against HZ [Oxman, 2005]. In the overall study population (≥ 60 YOA), Zostavaxreduced the incidence of HZ by 51.3% (p-value < 0.001), although its efficacy decreased with the age of the vaccinee. The vaccine efficacy (VE) was only 37.6% among persons in the oldest age group ( 70 YOA) [Oxman, 2005]. Based on the data from this study, Zostavax was licensed in the United States (US) and other countries. In the US, Zostavaxis recommended for prevention of HZ in individuals ≥ 60 YOA and older [ACIP, 2013]. Zostavax is contraindicated in persons with immunodeficiency due to malignancy, human immunodeficiency virus (HIV) infection or immunosuppressive medical therapy [Kroger, 2011].

GSK Biologicals’ candidate vaccine for the prevention of HZ is a recombinant subunit (su) vaccine consisting of VZV glycoprotein E (gE) antigen and an adjuvant system (AS01B). The VZV gE was chosen as the subunit vaccine antigen because of both its prominence as a target for host immune responses and its functional significance during viral infection [Cohen, 2007]. Adjuvant System AS01B used in combination with the gE antigen was developed at GSK Biologicals, and contains the immunostimulants MPL (3-O-desacyl-4’-monophosphoryl lipid A) and QS21 (Quillaja saponaria Molina, fraction 21; (Antigenics Inc., a subsidiary of Agenus Inc., Lexington, MA, USA)






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formulated in combination with liposomes. MPL is a chemically detoxified form of the parent lipopolysaccharide from the gram negative bacterium Salmonella Minnesota andQS21 is a natural saponin molecule (triterpene glycoside) obtained from the tree bark of Quillaja saponaria Molina.

Different gE antigen doses (25, 50 or 100 μg) combined with the AS01 Adjuvant System have been evaluated in over a thousand adults in completed studies and administered to over 19,000 subjects (as of 28 November 2014) at the 50 µg gE antigen dose in ongoing trials. In the analyzed studies the candidate vaccine was shown to elicit strong cellular and humoral immune responses with an acceptable profile of safety and reactogenicity. Based on phase II data from the antigen dose-ranging study, ZOSTER-003, and the adjuvant dose comparison study, ZOSTER-010, a gE antigen dose of 50 g and the Adjuvant System AS01B were selected as the final vaccine formulation (henceforth, the final vaccine formulation of GSK Biologicals’ candidate HZ vaccine will be referred to as HZ/su). A recent analysis of the primary endpoint in the pivotal phase III study ZOSTER-006 showed that HZ/su vaccine reduced the risk of shingles by 97.16% (95% Confidence Interval (CI); Lower Limit (LL):93.72% - Upper Limit (UL):98.97%) compared to placebo in subjects 50 YOA and older [Lal, 2015].

Although no immunological correlate for protection against HZ has been identified current knowledge suggests that VZV-specific Cell-Mediated Immunity (CMI) is of primary importance in preventing HZ [CDC, 2008]. The role of humoral immune responses in preventing HZ is less clear. However, VZV-specific antibodies (Abs) may help control viral dissemination in immunocompromised persons and may thereby help limiting the severity of HZ [Onozawa, 2006].

Please refer to the current Investigator Brochure for information regarding the pre-clinical and clinical studies, and the potential risks and benefits of GSK Biologicals’ candidate HZ/su vaccine.

1.2. Rationale for the study and study design

1.2.1. Rationale for the study

An observational short-term persistence study in Zostavax, recipients demonstrated waning efficacy after about 5 years [Morrison, 2015; Schmader, 2012]. Consequently, people ≥ 60 YOA vaccinated with Zostavax may not be well protected from developing HZ 5 years or more after vaccination, at an age where the incidence of HZ is increasing. Furthermore, studies evaluating two doses of Zostavax found that a second dose of Zostavax at 1-2 month intervals did not enhance VZV-specific immunity beyond that induced by the single dose in subjects ≥ 60 YOA [Vermeulen, 2012] and in subjects 70 YOA [Vesikari, 2013]. The relevance of this finding in terms of providing protection against HZ is unclear, but it seems likely that the duration of HZ protection would not be enhanced by adding a second dose to the initial Zostavax vaccination regimen.






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1.2.2. Rationale for the study design

Since it has been observed that efficacy following Zostavax vaccination wanes over time, it is likely that an additional vaccination will be required to ensure sustained protection against HZ. Thus the goal of this study is to generate immunogenicity, safety and reactogenicity data that will support the vaccination of previous Zostavax recipients with GSK Biologicals HZ/su vaccine. The study is a phase III, open-label, multi-center study conducted in the US. The study will evaluate two parallel groups of 200 adults ≥ 65 YOA; one group (Prev-Zvax) with a previous Zostavax vaccination ≥ 5 yearsearlier, versus another group without a previous Zostavax vaccination (No prev-Zvax).At least 5 years post-Zostavax vaccination was chosen for the Prev-Zvax group as the waning of Zostavax efficacy was observed after about 5 years in the short-term persistence follow-up study [Zostavax Summary of Product Characteristics, 2012].

1.2.3. Rationale for the use of placebo

No placebo will be used in this study.






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1.3. Benefit : Risk Assessment

Please refer to the current Investigator Brochure for the summary of potential risks and benefits of HZ/su vaccine.

The following section outlines the risk assessment and mitigation strategy for this study protocol:

1.3.1. Risk Assessment

Important Potential/Identified Risk

Data/Rationale for Risk Mitigation Strategy

Investigational HZ/su vaccine

Theoretical risk of acquiring a vaccine induced autoimmune disease after vaccination.

No confirmed signals related to this potential risk have been identified during the clinical program. Available clinical data do not highlight any concern.

Close monitoring of pIMDs as per study protocol.

The potential risk of events of possible autoimmune aetiology to occur is mentioned in the ICF. In addition, the ICF advises subjects to contact the study doctor or the study staff immediately, should they get any symptoms that they feel maybe serious.

Study Procedures

Risk from blood sampling. Blood sampling associated risk of discomfort, syncope, dizziness, infection at the site after or during venipuncture.

Blood samples will be obtained by a trained professional and medical assistance will be available.

The potential risk of feeling faint, or experiencing mild local pain, bruising, irritation or redness at the site where blood was taken, is mentioned in the ICF. The amount of blood to be taken for sampling will not be harmful to the subject’s health.

Risk from lesion sampling. Swab/ needle sampling of lesions/crusts associated risk of secondary infection, and discomfort related to the procedure.

Lesion samples will be obtained by a trained professional and anti-bacterial ointment may be applied to minimize the potential for secondary infection.

The potential risk of some temporary discomfort during the sampling procedure and the precautionary use of an anti-bacterial ointment to reduce the risk of infection are mentioned in the ICF.






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1.3.2. Benefit Assessment

Benefits include:

Potential benefit of receiving the study vaccine that may provide a clinical benefit.

Medical evaluations/assessments associated with study procedures [e.g., physical examination].

1.3.3. Overall Benefit : Risk Conclusion

Taking into account the measures to minimize risk to subjects participating in this study, the potential or recognized risks identified in association with the investigational HZ/su vaccine and study procedures are offset by the potential benefits (prevention of HZ and related complications) that may be afforded to the subject(s).

2. OBJECTIVES

2.1. Co-Primary objectives

To compare humoral immune responses at 1 month after dose 2 of HZ/su (Month 3) in subjects ≥ 65 years of age who received Zostavax ≥ 5 years earlier (Prev-Zvax) as compared to subjects who have never received Zostavax (No prev-Zvax).

Criterion:

Non-inferiority will be demonstrated if the upper limit of the two-sided 95% confidence interval of the adjusted geometric mean concentration (GMC) ratio (No prev- Zvax over Prev-Zvax) 1 month post-dose 2 is below 1.5 in terms of anti-gE antibodies.

To evaluate safety and reactogenicity up to 1 month after dose 2 of HZ/su in subjects ≥ 65 years of age who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax (No prev-Zvax).

Criterion:

This analysis is descriptive; no criterion has been defined.

Refer to Section 10.1 for the definition of the primary endpoints.

2.2. Secondary objectives

To assess humoral immune responses to HZ/su at Day 0, 1 month post-dose 1, and 1 and 12 months post-dose 2 in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax (No prev-Zvax).

To assess CMI responses to HZ/su at Day 0, 1 month post-dose 1, and 1 and 12 months post-dose 2 in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax (No prev-Zvax).






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To evaluate the safety following administration of HZ/su during the post-dose 2 follow-up period (from 1 month post-dose 2 through 12 months post-dose 2) in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax No prev-Zvax).

Refer to Section 10.2 for the definition of the secondary endpoints.






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3. STUDY DESIGN OVERVIEW

Prev-Zvax : No prev-Zvax = 1:1

Prev-Zvax (N = 200)

No prev-Zvax (N = 200)

ScreeningVisit*

Monthly Screening Contacts**

Visit 1Month 0

Visit 2Month 1

Visit 3Month 2

Visit 4Month 3

Monthly Contacts***

Visit 5Month 14

Checking for eligibility, recording previous

Zostavax history and collecting variables for

matching

Safety

Blood sample(Immunogenicity)

Vaccination 1Safety


Safety

Vaccination 2Safety


SafetySafety


SafetyStudy conclusion

Epoch 001

* Refer to Table 4 for all procedures that occur at the screening visit.** Monthly screening contacts beginning approximately 1 month after the screening visit and ending approximately 1 month before Visit 1 will remind subjects about HZ and ask if

they have experienced any signs or symptoms of HZ and serious adverse events (SAE)s. The number of these monthly screening contacts will depend on the amount of time between the screening visit and Visit 1 for each subject.

*** Monthly contacts beginning approximately 1 month after the Visit 4 and ending approximately 1 month before the Visit 5 Study conclusion visit (between Months 3 and 14) to remind subjects about HZ and ask if they have experienced any signs or symptoms of HZ or had any SAEs. During these contacts study site personal will also ask subjects additional safety information such as if they had any intercurrent medical conditions (IMCs), concomitant medications/vaccinations and/or experienced any symptoms of potential immune-mediated diseases (pIMDs) (see Table 4).






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Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the outline of study procedures (Section 5.6), are essential and required for study conduct.

Experimental design: Phase III, open-label, group-matched, multi-center, single-country study with two parallel groups.

Duration of the study: Approximately 20 months. Each subject will be enrolled during a screening visit approximately 6 months prior to Visit 1. Each subject receiving HZ/su vaccine (at Visit 1) will be followed after the second vaccine dose (at Visit 3) for approximately 12 months.

Epoch 001: Primary starting at the screening visit and ending at Visit 5 (Month 14).

Study groups:

Table 1 Study groups and epochs foreseen in the study

Study groupsNumber of subjects

Age (Min/Max)Epochs

Epoch 001

Prev-Zvax 200 ≥ 65 years xNo prev-Zvax 200 ≥ 65 years x

Table 2 Study groups and treatment foreseen in the study

Treatment nameVaccine/Product

nameStudy Groups

Prev-Zvax No prev-Zvax

HZ/suVZV gE x xAS01B x x

Control: not applicable.

Vaccination schedule: Two groups of subjects ≥ 65 YOA (Prev-Zvax and No prev-Zvax; 200 subjects per group) will receive two doses of the HZ/su vaccine (first dose given at Month 0 and second dose given 2 months later).

Treatment allocation: Subjects will be enrolled into either the Prev-Zvax or No prev-Zvax study group depending on Zostavax history.

Blinding:

Table 3 Blinding of study epochs

Study Epochs BlindingEpoch 001 open

Sampling schedule:

Blood samples (approximately 5 and 20 mL per visit) to assess humoral immunogenicity and CMI, respectively, will be collected from all subjects at Visits 1, 2, 4 and 5.






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Type of study: self-contained.

Data collection: Electronic Case Report Form (eCRF).

4. STUDY COHORT

4.1. Number of subjects

Target enrolment will be approximately 400 eligible subjects (200 per group). Refer to Sections 4.2 and 4.3 for eligibility criteria and to Section 10.4 for details regarding the determination of sample size.

Overview of the recruitment plan:

The study is planned to be conducted at multiple sites in the US.

Recruitment of subjects in No prev-Zvax study group will be made based on the distribution of matching variables in the Prev-Zvax study group. Refer to Sections 5.2.1.1.1 and 10.3 for more details.

The recruitment rate will be monitored using a study-specific central Randomization System on Internet (SBIR).

4.2. Inclusion criteria for enrolment

Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

All subjects must satisfy ALL the following criteria at study entry:

Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).

A male or female ≥ 65 years of age at the time of the first vaccination.

Written informed consent obtained from the subject prior to performing any study specific procedure.

For the No prev-Zvax group only:

No previous vaccination with Zostavax.

For the Prev-Zvax group only:

Previous vaccination with Zostavax ≥ 5 calendar years earlier.

Documentation indicating the date of previous Zostavax vaccination will be required(see Section 5.7.1.4).






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4.3. Exclusion criteria for enrolment

Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

The following criteria should be checked at the time of study entry. If ANY exclusion criterion applies, the subject must not be included in the study:

Previous vaccination with Zostavax < 5 calendar years earlier and/or anyone that ever received more than a single dose of Zostavax.

Previous vaccination against VZV, administration of HZ/su vaccine or any other investigational or non-registered HZ vaccine (except Zostavax for the Prev-Zvax group).

Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine during the period starting 30 days before the first dose of study vaccine, or planned use during the study period.

Chronic administration (defined as > 14 consecutive days) of immunosuppressants or other immune-modifying drugs in the period starting 180 days prior to the first dose of vaccine. (For corticosteroids, a prednisone dose of < 20 mg/day, or equivalent, is allowed.) Inhaled, topical and intra-articular corticosteroids are allowed.

Administration of long-acting immune-modifying drugs (e.g., infliximab) in the period starting 180 days prior to the first vaccine dose or expected administration at any time during the study period.

Administration or planned administration of a live vaccine in the period starting 30 days before the first dose of study vaccine and ending 30 days after the last dose of study vaccine, or, administration or planned administration of a non-replicating vaccine* in the period starting 8 days prior to and ending 14 days after either dose of study vaccine.

*E.g., inactivated and subunit vaccines, including inactivated and subunit influenza vaccines and pneumococcal conjugate vaccines.

Current participation in or planned concurrent participation in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).

Planned administration of an HZ vaccine (including an investigational or non-registered vaccine) other than the study vaccine during the entire study.

History of HZ or any suspected HZ between the screening visit and Visit 1.

History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine/product.

Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease (e.g., malignancy, human immunodeficiency virus [HIV]






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infection) or immunosuppressive/cytotoxic therapy (e.g., medications used during cancer chemotherapy, organ transplantation or to treat autoimmune disorders).

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature ≥ 37.5°C (99.5°F) by oral route, axillary or tympanic setting, or 38.0°C/100.4°F on rectal setting. The recommended route for recording temperature in this study will be oral.

Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator.

Administration of immunoglobulins and/or any blood products in the period starting 90 days preceding the first dose of study vaccine or planned administration during the study period.

Significant underlying illness that, in the opinion of the investigator, would be expected to prevent completion of the study.

Any other condition that, in the opinion of the investigator, might interfere with the evaluations required by the study.

Any condition which, in the judgment of the investigator, would make intramuscular (IM) injection unsafe.

5. CONDUCT OF THE STUDY

5.1. Regulatory and ethical considerations, including the informed consent process

The study will be conducted in accordance with all applicable regulatory requirements.

The study will be conducted in accordance with the ICH Guideline for Good Clinical Practice (GCP), all applicable subject privacy requirements and the guiding principles of the Declaration of Helsinki.

GSK will obtain favorable opinion/approval to conduct the study from the appropriate regulatory agency, in accordance with applicable regulatory requirements, prior to a site initiating the study in that country.

Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and favorable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements as stated in the protocol.

GSK will provide full details of the above procedures to the investigator, either verbally, in writing, or both.






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Freely given and written informed consent must be obtained from each subject, as appropriate, prior to participation in the study.

GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody the ICH GCP and GSK Biologicals required elements. While it is strongly recommended that this model ICF is to be followed as closely as possible, the informed consent requirements given in this document are not intended to pre-empt any local regulations which require additional information to be disclosed for informed consent to be legally effective. Clinical judgment, local regulations and requirements should guide the final structure and content of the local version of the ICF.

The investigator has the final responsibility for the final presentation of the ICF, respecting the mandatory requirements of local regulations. The ICF generated by the investigator with the assistance of the sponsor’s representative must be acceptable to GSK Biologicals and be approved (along with the protocol, and any other necessary documentation) by the IRB/IEC.

5.2. Subject identification and randomization of treatment

5.2.1. Subject identification

Subject identification numbers will be assigned sequentially to the subjects who have consented to participate in the study, according to the range of subject identification numbers allocated to each study center.

5.2.1.1. Treatment allocation to the subject

The treatment allocation will be performed using SBIR. The treatment numbers will be allocated by dose.

5.2.1.1.1. Study group and treatment number allocation

The target will be to enroll approximately 400 eligible subjects who will be assigned to two study groups based on Zostavax vaccination history in a 1:1 ratio (approximately 200 subjects in each group).

Subjects in the No prev-Zvax will be matched to those enrolled in the Prev-Zvax group according to a defined list of variables. The variables chosen to be matched between groups for analyses are: age (65-69, 70-79, ≥80), gender (F/M), race (Caucasian, African American, Hispanic and Other) and medical condition.

Medical conditions: any one of the following medical conditions will be used for matching: immune mediated diseases, diabetes, depression (on current medication), pulmonary and heart conditions.

Refer to Section 10.3 for the strategy used for matching.






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At the screening visit, after obtaining the signed and dated ICF from the subject and having checked the subject’s eligibility, the site staff will access SBIR. The status of the subject’s previous Zostavax vaccination, age category, gender, race and their medical condition(s) will be entered into SBIR to register the subjects. The subjects will be entered as “Planned” in SBIR. It is anticipated that up to approximately 800 subjects will need to be entered into the system as Planned at the screening visit to ensure adequate matching of the subjects. However, in case this number is insufficient, there will be the potential for enrolment of additional subjects. A matching tool will subsequently match subjects in pairs, between the Prev-Zvax and No prev-Zvax study groups. The subjects matched in pairs by the algorithm will then be identified in SBIR allowing the investigator to contact the subjects to be present for Visit 1 (Day 0, Month 0). SBIR will manage: enrolment during the screening phase, identification of matched pairs of subjects (Prev-Zvax and No prev Zvax) and treatment allocation. Refer to the Study Procedures Manual (SPM) for details.

When SBIR is not available, please refer to the SBIR user guide or the SPM for specific instructions.

The number of each administered treatment must be recorded in the eCRF on the Vaccine Administration screen.

5.2.1.1.2. Treatment number allocation for subsequent doses

For the treatment number allocation for Dose 2 (Day 60, Month 2, Visit 3), the study staff in charge of the vaccine administration will access SBIR, provide the subject identification number, and the system will provide a treatment number consistent with the allocated study group.


5.3. Method of blinding

This study is an open-label study.

5.4. General study aspects

Supplementary study conduct information, not mandated to be present in this protocol, is provided in the accompanying SPM. The SPM provides the investigator and the site personnel with administrative and detailed technical information that does not impact the safety of the subjects.

5.5. Suspected HZ cases

Suspected HZ is defined as a new rash characteristic of HZ (i.e., unilateral, dermatomal and accompanied by pain broadly defined to include allodynia, pruritus or other sensations). A diagnosis of suspected HZ will be based upon the investigator’s clincal






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judgment. Complications of HZ include, but are not limited to, PHN, HZ vasculitis, disseminated disease, ophthalmic disease, neurologic disease, and visceral disease.

Starting at the screening visit, all subjects will be informed of the signs and symptoms of typical HZ and provided an HZ information card. At each subsequent visit and contact until study end at Visit 5, subjects will be reminded of the signs and symptoms of typical HZ. Subjects will be instructed to contact their study site immediately if they develop any symptoms suggestive of HZ. The subject will be asked to visit the study site and should be seen by the investigator as soon as possible for evaluation of the suspected case of HZ. If a case is clinically diagnosed as suspected HZ, the investigator should progress further with evaluation of the case. Refer to Section 5.5.1.

The occurrence of HZ is an intercurrent medical condition (IMC) (see Section 6.7). HZ, HZ complications and all other IMCs should be reported following the first vaccination visit (Month 0) until study end (Month 14) for all subjects and will be recorded in AE/SAE screens as appropriate. Refer to Section 5.5.2.

5.5.1. Evaluation and confirmation of suspected HZ cases

The following will take place to evaluate ALL suspected cases of HZ:

1. The study staff/investigator will record concomitant medication/vaccination, including concomitant medication the subject has already received and/or will receive for HZ treatment or any HZ-related complications. The study staff/investigator will check if the subject received any medical attention [hospitalization, emergency room visit, or a visit to or from medical personnel (medical doctor)] for HZ or any HZ-related complication.

In addition to bullet point 1. above, the following will take place to evaluate the suspected case of HZ following the first vaccination visit (Month 0) until study end (Month 14):

2. The rash will be documented by digital photography. At the discretion of the investigator, additional photographs of HZ rash may be taken at any time to help note the progression of the rash. This may occur at unscheduled visits.

3. Rash lesion samples will be collected from subjects clinically diagnosed as having a suspected case of HZ for subsequent quantitative polymerase chain reaction (qPCR) testing. Three replicate rash lesion samples (see Table 6) should be collected on the same day. If during clinical evaluation the investigator/study staff determines that adequate rash lesion samples cannot be collected (i.e., less than three lesions present, or if only papules are present), the subject should be asked to return to the study site for collection of additional samples if there is rash progression (i.e., appearance of new/additional lesions if originally less than three lesions present, or appearance of vesicles if originally only papules present) at an unscheduled visit within 7 days. When the subject returns to repeat sample collection, if possible three samples from separate lesions should be collected. See the SPM for further details on sample collection.






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4. If needed, suspected HZ cases may be referred to the HZ Ascertainment Committee (HZAC). The HZAC will classify all referred cases as either “HZ” or “not HZ”. However, the HZAC classification will serve as the final case definition only when the case cannot be confirmed or excluded by PCR results obtained by GSK Biologicals or a validated laboratory designated by GSK Biologicals, e.g., when all samples from a given subject are inadequate (as when both VZV and β-actin PCR results are negative), or when no samples are available for a given subject (including when suspected HZ occurs in the absence of a characteristic HZ or VZV rash).

The HZAC will consist of physicians with HZ expertise. HZAC members, participating as investigator in this study, will not evaluate cases from their own study site. HZAC members will be blinded to group assignments. For every such case, each reviewing HZAC member will be asked to make a clinical determination of whether the case is HZ, based on review of the available clinical and laboratory information from the study site (e.g., summary of the rash and pain evaluations, digital photographs of the subject's rash, clinical progress notes and site laboratory information).

5.5.2. Collection of HZ case information

All HZ cases that occur during the study period until the end of the study will be documented. The exclusion criteria will be reconfirmed at Visit 1 (see Table 4) and subjects with suspected HZ between the screening visit and Visit 1 will be excluded from the study (see Section 4.3). Specific clinical information about each HZ case, following the first vaccination visit (Month 0) until study end (Month 14), will be entered into theeCRF. Please refer to the SPM for information about recording the details of HZ cases.






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5.6. Outline of study procedures

The list of study procedures is presented in Table 4.

Table 4 List of study procedures

Epoch Primary

Type of contactScreening

VisitMonthly

Screening Contacts 1 Visit 1 Visit 2 Visit 3 Visit 4 Monthly Contacts Visit 5

Timepoint(s)Between Screening Visit and Month 0

Month 0 Month 1 Month 2 Month 3Between Month 3

and Month 14Month 14

Sampling timepoint(s) Pre-Vacc Post-Vacc I Post-Vacc II Post-Vacc II

Informed consent ● O 2

Check inclusion / exclusion criteria ● ● 3

Record demographic data ● ●

Record previous Zostavax history ● ●

Medical history ● ●

Record of medical condition (Refer to Section 10.3) ● ● 4 ●

Training of subjects on self-reporting of the signs and symptoms of typical HZ (Refer to Section 5.5)

O O O O O O O

Screening conclusion (Investigator sign-off) ●

Check contraindications ● ● 5

History directed physical examination (Refer to Section 5.7.4) O

Pre-vaccination body temperature 6 ● ●

Assignment/recording of treatment number ● ●

Blood sampling for Ab determination from all subjects (~5 ml) ● ● ● ●

Blood sampling for CMI response from all subjects (~20 ml) ● ● ● ●

Vaccination ● ● 5

Training on completion of diary cards O O

Distribution of diary cards O O






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Epoch Primary


VisitMonthly





Sampling timepoint(s) Pre-Vacc Post-Vacc I Post-Vacc II Post-Vacc II

Daily post-vaccination recording of solicited AEs (Days 0–6) by subjects on diary card 7 O O

Daily post-vaccination recording of unsolicited AEs and concomitant medication/vaccination (Days 0-29) by subjects on diary card 7

O O

Return of diary cards O O

Diary card transcription by investigator/ designee ● ●

Recording of solicited adverse events within 7 days (Days 0-6) post-vaccination, by investigator/site staff

● ●

Recording of non-serious adverse events within 30 days (Days 0-29) post-vaccination, by investigator/site staff

● ●

Record any concomitant medication/vaccination (Refer to Section 6.6)

● ● ● ● ● ●

Record any Intercurrent Medical Conditions (IMC) including HZ (Refer to Section 6.7)

● ● ● ● ● ●

Recording of serious adverse events (SAEs) by investigator(Refer to Section 8.3) 8

● ● ● ● ● ● ●

Recording of potential immune-mediated diseases (pIMDs)(Refer to Table 15)

● ● ● ● ● ●

Follow-up of HZ ● 9 ● ● ● ● ● ●

Investigator sign-off before analysis ●

Study conclusion ●

Note: The double-line border following Month 3 indicates the analyses which may be performed on all data (i.e., data that are as clean as possible) obtained up to Visit 4.● is used to indicate a study procedure that requires documentation in the individual eCRF.O is used to indicate a study procedure that does not require documentation in the individual eCRF. However, items with this designation should be noted in the subject’s source documentation.Vacc = Vaccination; Ab = Antibody; CMI = Cell-Mediated Immunity; HZ = Herpes Zoster.1 The number of these monthly screening contacts will depend on the amount of time between the screening visit and Visit 1 for each subject.






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2 Informed consent given at the screening visit, will be reconfirmed at Visit 1. Refer to the SPM for details regarding the process for reconfirmation.3 Enrolment occurs at the screening visit within approximately 6 months prior to Visit 1, with potentially more time as required to ensure adequate matching of the subjects by Visit

1, as per the defined matching rules. Inclusion and exclusion criteria are checked at the screening visit. A check for any changes compared to the screening visit will be performed at Visit 1. In case the subject is no longer eligible, or interested at Visit 1, the subject will be withdrawn from the study (Refer to Section 10.3).

4 The medical condition must be updated in the eCRF during the monthly screening contacts and any updates should also be done in SBIR in parallel.5 Any subject with a clinically diagnosed HZ episode between Visit 1 and Visit 3 should not receive the second dose.6 Pre-vaccination temperatures should always be recorded orally at study sites. In rare situations when there is no other alternative, the temperature may be recorded by other

route. If the temperature is taken by another route (axillary, rectal or tympanic), the route should be documented.7 The recommended route for recording temperature in this study is oral. When there is no other alternative, the temperature may be recorded by other route. If the temperature is

taken by another route (axillary, rectal or tympanic), the route should be documented.8 SAEs related to study participation or GSK concomitant medication/vaccine are to be recorded from the time the subject consents to participate in the study. All other SAEs are to

be reported after administration of the first dose of vaccine (Refer to Table 16).9 The evaluation of suspected HZ cases between the Screening Visit and Visit 1 will not include lesion sampling or photography (Refer to Sections 5.5 and 5.5.1).






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Time intervals between study visits/contact related to study procedures performed insubjects participating in the study are presented in Table 5

Table 5 Intervals between study visits

Interval Optimal length of interval 1 Allowed interval

Screening visit Visit 1 (Month 0) 2 6 months 1 - 9 months

Monthly screening contacts

between Screening visit and Visit 1 31 month each 25-35 days for each interval 4

Visit 1 (Month 0) Visit 2 (Month 1) 1 month 28 - 48 days

Visit 1 (Month 0) Visit 3 (Month 2) 2 months 49 - 83 days 5

Visit 3 (Month 2) Visit 4 (Month 3) 1 month 28 - 48 days 5

Monthly contacts between Visit 4 (Month 3) and Visit 5 (Month 14)

1 month each 25-35 days for each interval 4

Visit 3 (Month 2) Visit 5 (Month 14) 12 months 335 - 395 days

1 Whenever possible the investigator should arrange study visits within this interval.2 The timing interval between the screening visit and Visit 1 is flexible and will depend on the adequate matching of the

subjects at Visit 1 as per the defined matching rules. Visits outside of this interval will not necessarily result in exclusion from the ATP cohort. Approximately 6 months represents an expected length for this interval, with as little as 1 month and potentially more time required (up to approximately 9 months), to ensure adequate matching of the subjects by Visit 1, as per the defined matching rules.

3 The number of these monthly screening contacts will depend on the amount of time between the screening visit and Visit 1 for each subject.

4 The monthly phone contacts are to be as evenly spaced throughout time as possible. Phone contacts which are not at the intervals as specified in this table will not necessarily result in elimination from the ATP cohort.

5 Subjects may not be eligible for inclusion in the ATP cohort for analysis if they make the study visit outside this interval (see Section 10.5.3 and Table 21).

5.7. Detailed description of study procedures

5.7.1. Procedures during the screening visit

Enrolment occurs at the screening visit. The screening visit should take place within approximately 6 months before Visit 1. Since it is unpredictable how long it will exactly take to complete the matching, timing from screening visit to Visit 1 could be prolonged.

5.7.1.1. Informed consent

The signed informed consent of the subject must be obtained before study participation. Refer to Section 5.1 for the requirements on how to obtain informed consent. Informed consent given at the screening visit, will be reconfirmed at Visit 1. Refer to the SPM for details regarding the process for reconfirmation.






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5.7.1.2. Check inclusion and exclusion criteria

Check all applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3before enrolment. A check for any changes compared to the screening visit will be performed at Visit 1 and recorded appropriately.

5.7.1.3. Record demographic data

Record demographic data such as date of birth, gender, geographic ancestry and ethnicity in the subject’s eCRF. A check for any changes compared to the screening visit will be performed at Visit 1 and recorded appropriately.

5.7.1.4. Record previous Zostavax history

Verify and record the date of the previous Zostavax vaccination from documented vaccination history, such as the date in the subject’s immunization card or equivalent.

5.7.1.5. Medical history

Obtain the subject’s medical history by interview and /or review of the subject’s medical records and record any pre-existing conditions or signs and/or symptoms present in a subject prior to the first study vaccination in the eCRF. A check for any changes compared to the screening visit will be performed at Visit 1 and recorded appropriately.

5.7.1.6. Recording of medical condition

Record any medical condition in the subject’s eCRF.

a. Immune Mediated Diseases

b. Diabetes Mellitus

c. Depression (current) must be on current medication

d. Pulmonary Conditions

e. Heart Conditions

f. None of the above

The medical condition must be updated in the eCRF during the monthly screening contacts and any updates made should also be done in SBIR in parallel (see Table 4). Refer to Section 10.3 and the SPM for the application of the medical condition and additional details on the matching strategy.

5.7.1.7. Training of subjects on self-reporting of the signs and symptoms of typical HZ

Starting at the screening visit, all subjects will be informed of the signs and symptoms of typical HZ and provided an HZ information card (see Section 5.5).






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5.7.2. Procedures prior to the first vaccination

Note that informed consent given at the screening visit, will be reconfirmed at Visit 1 (see Section 5.7.1.1 and Table 4). Refer to the SPM for more information.

Inclusion and exclusion criteria are initially checked at the screening visit (see Section 5.7.1.2 and Table 4). A check for any changes compared to the screening visit will be performed at Visit 1. In case the subject is no longer eligible or interested at Visit 1, the subject will be withdrawn from the study. Refer to Sections 9.3 and 10.3. Subjects withdrawn following vaccination will not be replaced (Section 9.2.).

Any changes in demographic data, previous Zostavax vaccination history, medical history and/or medical condition, between the screening visit and Visit 1, must be recorded in the eCRF.

5.7.3. Check contraindications, warnings and precautions to vaccination

Contraindications to vaccination must be checked at the beginning of each vaccination visit. Refer to Section 6.5 for more details.

5.7.4. History directed physical examination

Perform a history directed physical examination. If the investigator determines that the subject’s health on the day of vaccination temporarily precludes vaccination, the visit will be rescheduled.

Treatment of any abnormality observed during this examination has to be performed according to local medical practice outside this study or by referral to an appropriate health care provider.

5.7.5. Assess pre-vaccination body temperature

The body temperature of all subjects needs to be measured prior to any study vaccine administration. Pre-vaccination temperatures should always be recorded orally. In rare situations when there is no other alternative, the temperature may be recorded by other route. If the temperature is taken by another route (axillary, rectal or tympanic), the route should be documented and justified. If the subject has fever (fever is defined as temperature 37.5°C/99.5°F by oral route, axillary or tympanic setting, or ≥ 38.0°C/100.4°F on rectal setting) on the day of vaccination, the vaccination visit will be rescheduled within the allowed interval for this visit (see Table 5).

5.7.6. Study group and treatment number allocation

Study group and treatment number allocation will be performed as described in Section5.2.1.1. The number of each administered treatment must be recorded in the eCRF.






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5.7.7. Sampling

Refer to the Quest Laboratory Manual for detailed instructions for the collection, handling and processing of the samples.

5.7.7.1. Blood sampling for safety or immune response assessments

Blood samples will be taken during certain study visits as specified in Section 5.6 List of Study Procedures.

A volume of approximately 5 mL of whole blood should be drawn from all subjects for each analysis of humoral immune response at each pre-defined timepoint (seeTable 4). After centrifugation, serum samples should be kept at –20°C/ –4°F or below until shipment. Refer to the Quest Laboratory Manual for more details on sample storage conditions.

A volume of approximately 20 mL of whole blood should be drawn from all subjects for analysis of CMI response at each pre-defined timepoint (see Table 4). Until the samples are picked up for shipment, the blood should be maintained at room temperature at the investigator’s site and it must not be centrifuged. Samples will be shipped at room temperature (15 to 25°C/68 to 77°F) to the designated laboratory for cell separation to be performed within 24 hours. Refer to the Quest Laboratory Manual for more details on sample handling.

5.7.8. Study Vaccine administration

After completing all prerequisite procedures prior to vaccination, the dose(s) of HZ/su vaccine will be administered IM in the deltoid region of the non-dominant arm according to the administration schedule (refer to Section 6.3 for detailed description of the vaccines administration procedure). If the investigator or delegate determines that the subject’s health on the day of administration temporarily precludes vaccine(s) administration, the visit will be rescheduled within the allowed interval for this visit (refer to Table 5).

The subjects will be observed closely for at least 30 minutes following the administration of the vaccine(s), with appropriate medical treatment readily available in case of anaphylaxis.

Any subjects with an event of HZ between Visit Day 0 and any dose of HZ/suvaccine should not receive the upcoming dose(s) of the HZ/su vaccine.

5.7.9. Check and record concomitant medication/vaccination and intercurrent medical conditions (IMC) including HZ

Concomitant medication/vaccination must be checked and recorded in the eCRF as described in Section 6.6.

IMCs must be checked and recorded in the eCRF as described in Section 6.7.






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5.7.10. Recording of AEs, SAEs and pIMDs

Refer to Section 8.2 for procedures for the investigator to record AEs, SAEs and pIMDs. Refer to Section 8.3 for guidelines and how to report SAE and pIMD reports to GSK Biologicals.

The subjects will be instructed to contact the investigator immediately should theymanifest any signs or symptoms they perceive as serious.

At each vaccination visit, and for each vaccine administered, diary cards will be provided to the subject. The subject will record body (oral) temperature and any solicited local/general AEs (i.e., on the day of vaccination and during the next 6 days) or any unsolicited AEs (i.e., on the day of vaccination and during the next 29 days occurring after vaccination). If the temperature is taken by another route (axillary, rectal or tympanic), the route should be documented with an explanation for why it was different from the oral route. The subject will be instructed to return the completed diary cards.

Collection and verification of completed diary cards will occur during discussion with the subject at the visit following each vaccination visit.

Any unreturned diary cards will be sought from the subject through any convenient procedure. The investigator and/or delegate will transcribe the collected information into the eCRF in English.

5.7.11. Study conclusion

The investigator will:

Review data collected to ensure accuracy and completeness,

Complete the Study Conclusion screen in the eCRF.

5.8. Biological sample handling and analysis

Please refer to the Quest Laboratory Manual for details on biospecimen management (handling, storage and shipment).

Samples will not be labeled with information that directly identifies the subject but will be coded with the identification number for the subject (subject number). The personnel, within GSK Biologicals or a validated laboratory designated by GSK Biologicalsperforming immunogenicity assessments, will be blinded to the study group.

Collected samples will be used for protocol mandated research and purposes related to the improvement, development and quality assurance of the laboratory testsdescribed in this protocol. This may include the management of the quality of these tests, the maintenance or improvement of these tests, the development of new test methods, as well as making sure that new tests are comparable to previous methods and work reliably.






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It is also possible that future findings may make it desirable to use the samples acquired in this study for future research, not described in this protocol. Therefore, all subjects will be asked to give a specific consent to allow GSK or a contracted partner to use the samples for future research. Future research will be subject to the laws and regulations in the US and will only be performed once an IEC or IRB has approved this research. This is also applicable for the local regulations in countries where the subjects’ samples may reside, and data derived from them, are analyzed. (see APPENDIX B).

Information on further investigations and their rationale can be obtained from GSK Biologicals.

Any sample testing will be done in line with the consent of the individual subject.

Refer also to the Protocol Investigator Agreement, where it is noted that the investigator cannot perform any other biological assays except those described in the protocol or its amendment(s).

Collected samples will be stored for a maximum of 20 years (counting from when the last subject performed the last study visit), unless local rules, regulations or guidelines require different timeframes or different procedures, which will then be in line with the subject consent. These extra requirements need to be communicated formally to and discussed and agreed with GSK Biologicals.

5.8.1. Use of specified study materials

When materials are provided by GSK Biologicals, it is MANDATORY that all clinical samples (including serum samples) be collected and stored exclusively using those materials in the appropriate manner. The use of other materials could result in the exclusion of the subject from the ATP analysis (See Section 10.5 for the definition of study cohorts/ data sets to be analyzed). The investigator must ensure that his/her personnel and the laboratory(ies) under his/her supervision comply with this requirement. However, when GSK Biologicals does not provide material for collecting and storing clinical samples, appropriate materials from the investigator’s site must be used. Refer to the Module on Clinical Trial Supplies in the SPM.

5.8.2. Biological samples

The different biological samples collected in the study, the quantity needed, the unit and the time points are described in Table 6.






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Table 6 Biological samples

Sample typeQuantity (approximate vol.)

Unit TimepointNumber of Subjects

Blood (Humoral immunity)

5 mL Visit 1, 2, 4 and 5 All subjects

Cell-mediated immunity)

20 mL Visit 1, 2, 4 and 5 All subjects

Clinical specimens of HZ lesions

3 samples, taken on the same day, of the highest priority lesion type available (1) vesicle fluid; 2) crust; 3) crust swab; 4) papule swab) †

NAIn case of suspected HZ for diagnosis

Subjects clinically diagnosed as having a suspected case of HZ

mL = Milliliter; HZ = Herpes Zoster; NA = Not applicable.† If during clinical evaluation for suspected HZ, the investigator determines that adequate rash lesion samples cannot

be collected (i.e., less than three lesions present, or if only papules are present), the subject should be asked to return to the study site for collection of additional samples within 7 days. When the subject returns to repeat sample collection, if possible, 3 samples from separate lesions should be collected.

5.8.3. Laboratory assays

Please refer to APPENDIX A for a detailed description of the assays performed in the study. Please refer to APPENDIX B for the address of the clinical laboratories used for sample analysis.

Laboratory assays, which will be used in this study, are summarized in Table 7 (Humoral Immunity), Table 8 (CMI) and Table 9 (Molecular Biology), respectively. Assays for the determination of anti-gE antibodies will be performed by Enzyme-linked Immunosorbent Assay (ELISA) at a GSK Biologicals’ laboratory. The CMI testing will be conducted in a laboratory designated by GSK Biologicals using standardized and validated procedures.

Table 7 Humoral Immunity (Antibody determination)

System Component Method Kit / Manufacturer Unit Cut-off LaboratorySerum VZV.gE Ab.IgG ELISA NA mIU/ml 97 GSK Biologicals*

*GSK Biologicals laboratory refers to the Global Vaccines Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium.VZV = Varicella Zoster Virus; gE = Glycoprotein E; Ab = Antibody; IgG = Immunoglobulin class G; ELISA = Enzyme-linked Immunosorbent Assay; NA = Not applicable; ml = milliliter; mIU = milli international unit.

Table 8 Cell-Mediated Immunity (CMI)

System Component Challenge Method Unit LaboratoryPBMC CD4.polypositives

CD40L+IL-2+TNFα+IFNγ *gE ICS Events CEVAC +

PBMC = Peripheral Blood Mononuclear Cells; IL-2 = Interleukin 2; TNFα = Tumor Necrosis Factor-alpha; IFNγ = Interferon-gamma; gE = Glycoprotein E; ICS = Intracellular cytokine staining.

* CD4.polypositives CD40L+IL2+TNFα+IFNγ = CD4+ T-cells expressing at least 2 activation markers (from among IFN-γ, IL-2, TNF-α and CD40L).

+ CEVAC refers to the Center for Vaccinology, Ghent University, Building A - 1st floor, De Pintelaan 185, 9000 Ghent, Belgium.






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Table 9 Molecular Biology (PCR tests)

System Component Method Unit LaboratoryHZ lesion sample Varicella Zoster Virus DNA PCR No unit GSK Biologicals*HZ lesion sample Actin Gene DNA PCR No unit GSK Biologicals*

HZ = Herpes Zoster; DNA = Deoxyribonucleic Acid; PCR = Polymerase Chain Reaction.* GSK Biologicals laboratory refers to the Global Vaccines Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium.

The GSK Biologicals’ clinical laboratories have established a Quality System supported by procedures. The activities of GSK Biologicals’ clinical laboratories are audited regularly for quality assessment by an internal (sponsor-dependent) but laboratory-independent Quality Department.

5.8.4. Biological samples evaluation

5.8.4.1. Immunological read-outs

The samples will be analyzed according to Table 10.

Table 10 Immunological read-outs

Blood sampling timepointNo. subjects ComponentType of contact and

timepointSampling timepoint

Visit 1 (Month 0) Pre-Vacc

All VZV gE Ab.IgG ELISAVisit 2 (Month 1) Post-Vacc IVisit 4 (Month 3) Post-Vacc II

Visit 5 (Month 14) Post-Vacc IIVisit 1 (Month 0) Pre-Vacc

All CD4.polypositives CD40L+IL-2+TNFα+IFNγVisit 2 (Month 1) Post-Vacc IVisit 4 (Month 3) Post-Vacc II

Visit 5 (Month 14) Post-Vacc IIVacc = Vaccination; VZV = Varicella Zoster Virus; gE = Glycoprotein E; Ab = Antibody; IgG = Immunoglobulin class G; ELISA = Enzyme-linked Immunosorbent Assay; IL-2 = Interleukin 2; TNFα = Tumor Necrosis Factor-alpha; IFNγ = Interferon-gamma.

Additional testing may be performed if deemed appropriate by GSK Biologicals should any findings in the present study, or in other studies, indicate that further investigation of the immunogenicity of the vaccine is warranted.

5.8.5. Immunological correlates of protection

No generally accepted immunological correlate of protection against HZ has been demonstrated for the gE antigen used in the HZ/su candidate vaccine.






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6. STUDY VACCINES AND ADMINISTRATION

6.1. Description of study vaccine

The candidate vaccine to be used has been developed and manufactured by GSK Biologicals.

The Quality Control Standards and Requirements for the candidate vaccine are described in separate Quality Assurance documents (e.g., release protocols, certificate of analysis) and the required approvals have been obtained.

The vaccine is labeled and packed according to applicable regulatory requirements.

The characteristics of the study vaccine are detailed in Table 11.

Table 11 Study vaccine

Treatment name

Vaccine name

Formulation PresentationVolume to be administered

Number of doses

HZ/su

VZV gEgE=50µg per 0.5 mL of reconstituted vaccine

Lyophilized pellet in a monodose vial

0.5 mL 2

AS01BMPL=50µg; QS21=50µg; Liposomes per 0.5 mL of reconstituted vaccine

Liquid in a monodose vial

VZV = Varicella Zoster Virus, gE = recombinant purified Glycoprotein E; AS01B = Adjuvant System AS01B; MPL = 3-O-desacyl-4’-monophosphoryl lipid A; QS21 = Quillaja saponaria Molina, fraction 21 (purified saponin extract from the South American tree).

6.2. Storage and handling of study vaccine

The study vaccine must be stored at the respective label storage temperature conditions in a safe and locked place. Access to the storage space should be limited to authorized study personnel. The storage conditions will be assessed during pre-study activities under the responsibility of the sponsor study contact. The storage temperature should be continuously monitored with calibrated (if not validated) temperature monitoring device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for more details on storage of the study vaccine.

Temperature excursions must be reported in degree Celsius.

Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to +46°F label storage condition) impacting investigational medicinal products (IMPs) must be reported in the appropriate (electronic) temperature excursion decision form ([e]TDF). The impacted IMPs must not be used and must be stored in quarantine at label temperature conditions until usage approval has been obtained from the sponsor.

In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to +8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still






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be administered, but the site should avoid re-occurrence of such temperature excursion.Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to take.

Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on the temperature excursion reporting and usage decision process, packaging and accountability of the study vaccine.

6.3. Dosage and administration of study vaccine

Refer to the SPM for details regarding the reconstitution of the HZ/su study vaccine.

After removal of the vaccine components from the temperature monitored refrigerator, the vaccine should be reconstituted and administered within 6 hours, and should be kept at room temperature (between 2°C/36°F and 30°C/86°F).

Table 12 Dosage and administration

Type of contact and time pointVolume to be administered

Study GroupsTreatment

nameRoute 1 Site Side

Visit 1 (Month 0), Visit 3 (Month 2) 0.5 mLPrev-Zvax

HZ/su IM DeltoidNon-

dominantNo prev-Zvax1 Intramuscular (IM)

6.4. Replacement of unusable vaccine doses

In addition to the vaccine doses provided for the planned number of subjects (including over-randomization when applicable), at least 5% additional vaccine doses will be supplied to replace those that are unusable.

6.5. Contraindications to subsequent vaccination

The following events constitute absolute contraindications to further administration ofHZ/su vaccine. If any of these events occur during the study, the subject must not receive additional doses of vaccine but may continue other study procedures at the discretion of the investigator (see Section 8.4).

Anaphylaxis following the administration of vaccine.

If the subject experiences an SAE judged to be vaccine-related by the investigator/ delegate.

If the subject experiences an event of HZ between the first and the second dose of HZ/su vaccine.

Any confirmed or suspected immunosuppressive or immunodeficient condition, including HIV infection.

Any condition that in the judgment of the investigator would make intramuscular injection unsafe.






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Other events that constitute contraindications to administration of HZ/su vaccine:

Any medical condition including the occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the opinion of the investigator, exposes the subject to unacceptable risk from subsequent vaccination. In such cases, investigators should use their clinical judgment prior to administering the second dose of the study product. Refer to Section 8.1.5.1 for the definition of pIMD.

The following events constitute contraindications to administration of the HZ/su vaccineat that point in time; if any of these events occur at the time scheduled for vaccination, the subject may be vaccinated at a later date, within the time window specified in the protocol (see Section 5.6), or the subject may be withdrawn at the discretion of the investigator (see Section 9.2).

Acute disease and/or fever at the time of vaccination.

Fever is defined as temperature 37.5°C/99.5°F by oral route, axillary or tympanic setting, or 38.0°C/100.4°F on rectal setting. The recommended route for recording temperature in this study will be oral.

Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever can be administered all vaccines/products.

Refer to Table 4 for instruction that any subject with an event of HZ between Visit 1 and Visit 3 should not receive the second dose.

6.6. Concomitant medication/product and concomitant vaccination

At each study visit, the investigator should question the subject about any medication/product taken and vaccination received by the subject.






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6.6.1. Recording of concomitant medications/products and concomitant vaccination

The following concomitant medications/products/vaccines must be recorded in the eCRF or SAE report if administered during the indicated recording period:

All concomitant medications/products, except vitamins and dietary supplements, administered during the period starting 30 days before and for 30 days following each dose of study vaccine.

Any concomitant vaccination administered in the period starting 30 days before the first dose of study vaccine and ending at the last study visit.

Prophylactic medication (i.e., medication administered in the absence of ANY symptom and in anticipation of a reaction to the vaccination).

E.g., an anti-pyretic is considered to be prophylactic when it is given in the absence of fever and any other symptom, to prevent fever from occurring [fever is defined as temperature 37.5°C/99.5°F by oral route, axillary or tympanic setting, or 38.0°C/100.4°F on rectal setting. The preferred route for recording temperature in this study will be oral].

Any concomitant medications/products/vaccines listed in Section 6.6.2.

Any concomitant medications/products/vaccines relevant to a SAE/pIMD to be reported as per protocol or administered at any time during the study period for the treatment of a SAE/pIMD need to be recorded on the expedited Adverse Event report.

Any concomitant medication/product administered for the treatment of HZ and complications during the study period.

6.6.2. Concomitant medications/products/vaccines that may lead to the elimination of a subject from ATP analyses

The use of the following concomitant medications/products/vaccines will not require withdrawal of the subject from the study but may determine a subject’s evaluability in the ATP analysis. See Section 10.5 for study cohorts/ data sets to be analyzed.

Any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) used during the study period.

Immunosuppressants or other immune-modifying drugs administered chronically(defined as > 14 consecutive days) during the study period. For corticosteroids, this will mean prednisone 20 mg/day, or equivalent. A prednisone dose of < 20 mg/day is allowed. Inhaled, topical and intra-articular corticosteroids are allowed.

Long-acting immune-modifying drugs administered at any time during the study period (e.g., infliximab).

Administration of a live vaccine in the period starting 30 days before the first dose of study vaccine and ending 30 days after the last dose of study vaccine, or,






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administration of a non-replicating vaccine* within 8 days prior to or within 14 days after either dose of study vaccine. *E.g. inactivated and subunit vaccines, including inactivated and subunit influenza vaccines and pneumococcal conjugate vaccines.

In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a pandemic) is organized by the public health authorities, outside the routine immunization program, the time period described above can be reduced if necessary for that vaccine provided it is licensed and used according to its (Summary of Product Characteristics) SPC or (Product Information) PI and according to the local governmental recommendations and provided a written approval of the Sponsor is obtained.

Immunoglobulins and/or any blood products administered during the study period.

Receipt of a vaccine against HZ other than the study vaccine during the study period.

6.7. Intercurrent medical conditions (IMCs) that may lead to elimination of a subject from ATP analyses

At each study visit subsequent to the first vaccination visit, until Month 14 it must be verified if the subject has experienced or is experiencing any IMC. If it is the case, the condition(s) must be recorded in the eCRF. IMCs will be recorded in AE/SAE screens as appropriate.

IMCs are clinical events during the course of the study which might alter or confound the interpretation of the immunologic (not safety) assessments of the protocol. In regards to humoral gE assessments, this includes any clinical event that might increase or decrease the measurement of anti-gE antibodies, such as protein losing conditions in which the loss of gammaglobulin or total proteins might underestimate the subject’s gE response (e.g., protein losing enteropathy, proteinuria, or cachexia). Additional examples would be conditions that would cause the administration of exogenous gE antibodies, resulting in an overestimate of the subject’s anti-gE antibody response to HZ/su vaccination, such as conditions requiring the use of intravenous immunoglobulin or blood products.

With regard to measuring cellular immunity, IMCs will be active viral infections that may alter CD4+ T cell counts and/or responses. Examples, not exhaustive, of such acute viral infections would include acute Hepatitis A, acute Hepatitis B, new onset HIV, and potentially acute cytomegalovirus and/or Epstein–Barr virus infections.

The occurrence of HZ is an IMC, since the anti-gE antibody or cellular immune response formed as a result of active shingles cannot be distinguished from the anti-gE antibody or cellular immune response resulting from HZ/su vaccination.

All IMCs including HZ should be reported until Month 14 for all subjects.

Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, they incur a condition that has the capability of confounding their immune response to the study vaccine or its interpretation (e.g., cases of HZ up to study end).






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7. HEALTH ECONOMICS

Not applicable.

8. SAFETY

The investigator or site staff is/are responsible for the detection, documentation and reporting of events meeting the criteria and definition of an adverse event (AE) or serious adverse event (SAE) as provided in this protocol.

Each subject will be instructed to contact the investigator immediately should they/the subject manifest any signs or symptoms they perceive as serious.

8.1. Safety definitions

8.1.1. Definition of an adverse event

An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Examples of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational vaccine(s)/product(s) administration even though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational vaccine(s)/product(s) or a concurrent medication (overdose per se should not be reported as an AE/SAE).

Signs, symptoms temporally associated with vaccine administration.

Pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen).

AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other AEs will be recorded as UNSOLICITED AEs.






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Examples of an AE DO NOT include:

Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g., social and/or convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

Pre-existing conditions or signs and/or symptoms present in a subject prior to the first study vaccination. These events will be recorded in the medical history section of the eCRF.

8.1.2. Definition of a serious adverse event

A SAE is any untoward medical occurrence that:

a. Results in death,

b. Is life-threatening,

Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, had it been more severe.

c. Requires hospitalization or prolongation of existing hospitalization,

Note: In general, hospitalization signifies that the subject has been admitted at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or in an out-patient setting. Complications that occur during hospitalization are also considered AEs. If a complication prolongs hospitalization or fulfils any other serious criteria, the event will also be considered serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition (known or diagnosed prior to informed consent signature) that did not worsen from baseline is NOT considered an AE.

d. Results in disability/incapacity, OR

Note: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza like illness, and accidental trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e. Is a congenital anomaly/birth defect in the offspring of a study subject.

Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be






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immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization.

8.1.3. Solicited adverse events

8.1.3.1. Solicited local (injection-site) adverse events

The following local (injection-site) AEs will be solicited:

Table 13 Solicited local adverse events

Pain at injection siteRedness at injection siteSwelling at injection site

8.1.3.2. Solicited general adverse events

The following general AEs will be solicited:

Table 14 Solicited general adverse events

FatigueFever

Gastrointestinal symptoms †

HeadacheMyalgia

Shivering†Gastrointestinal symptoms include nausea, vomiting, diarrhea and/or abdominal pain.

Note: Temperature (oral) will be recorded in the evening. Should additional temperature measurements be performed at other times of day, the highest temperature will be recorded in the eCRF.

8.1.4. Clinical laboratory parameters and other abnormal assessments qualifying as adverse events or serious adverse events

In absence of diagnosis, abnormal laboratory findings (e.g., clinical chemistry, haematology, urinalysis) or other abnormal assessments that are judged by the investigator to be clinically significant will be recorded as AE or SAE if they meet the definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically significant abnormal laboratory findings or other abnormal assessments that are present at baseline and significantly worsen following the start of the study will also be reported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.






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8.1.5. Adverse events of specific interest

8.1.5.1. Potential immune-mediated diseases

Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. AEs that need to be recorded and reported as pIMDs include those listed in Table 15.

However, the investigator will exercise his/her medical and scientific judgment in deciding whether other diseases have an autoimmune origin (i.e., pathophysiology involving systemic or organ-specific pathogenic autoantibodies) and should also be recorded as a pIMD.






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Table 15 List of potential immune-mediated diseases

Neuroinflammatory disorders Musculoskeletal disorders Skin disorders

Cranial nerve disorders, including paralyses/paresis (e.g. Bell’s palsy)

Optic neuritis Multiple sclerosis Transverse myelitis Guillain-Barré syndrome, including

Miller Fisher syndrome and other variants

Acute disseminated encephalomyelitis, including site specific variants: e.g. non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculoneuritis

Myasthenia gravis, including Lambert-Eaton myasthenic syndrome

Immune-mediated peripheral neuropathies and plexopathies, (including chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and polyneuropathies associated with monoclonal gammopathy).

Narcolepsy

Systemic lupus erythematosus and associated conditions

Systematic Scleroderma (Systematic sclerosis), including diffuse systemic form and CREST syndrome

Idiophatic inflammatory myopathies, including Dermatomyositis, Polymyositis

Antisynthetase syndrome Rheumatoid arthritis and

associated conditions, including Juvenile chronic arthritis and Still’s disease

Polymyalgia rheumatic Spondyloarthritis, including

ankylosing spondylitis, reactive arthritis (Reiter's Syndrome) and undifferentiated spondyloarthritis

Psoriatic arthropathy Relapsing polychondritis

Mixed connective tissue disorder

Psoriasis Vitiligo Erythema nodosum Autoimmune bullous

skin diseases (including pemphigus, pemphigoid and dermatitis herpetiformis)

Cutaneous lupus erythematosus

Alopecia areata Lichen planus Sweet’s syndrome

Localised Scleroderma (Morphoea)

Vasculitides Blood disorders Others

Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and temporal arteritis.

Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's granulomatosis, Churg–Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease (thromboangiitis obliterans), necrotizing vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet's syndrome, leukocytoclastic vasculitis.

Autoimmune hemolytic anemia

Autoimmune thrombocytopenia

Antiphospholipid syndrome

Pernicious anemia Autoimmune aplastic

anemia Autoimmune

neutropenia Autoimmune

pancytopenia

Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and mesangioproliferative glomerulonephritis)

Ocular autoimmune diseases (including autoimmune uveitis and autoimmune retinopathy

Autoimmune myocarditis/cardiomyopathy

Sarcoidosis Stevens-Johnson syndrome Sjögren’s syndrome Idiopathic pulmonary fibrosis Goodpasture syndrome Raynaud’s phenomenon






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Liver disorders Gastrointestinal disorders Endocrine disorders

Autoimmune hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Autoimmune cholangitis

Inflammatory Bowel disease, including Crohn’s disease, ulcerative colitis, microscopic colitis, ulcerative proctitis

Celiac disease Autoimmune pancreatitis

Autoimmune thyroiditis (including Hashimoto thyroiditis)

Grave's or Basedow’s disease Diabetes mellitus type I Addison’s disease Polyglandular autoimmune syndrome Autoimmune hypophysitis

CREST = Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia (syndrome)

When there is enough evidence to make any of the above diagnoses, the AE must be reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the final or definitive diagnosis has been determined, and alternative diagnoses have been eliminated or shown to be less likely.

In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above diagnoses will be available to investigators at study start.

8.2. Detecting and recording adverse events and serious adverse events

8.2.1. Time period for detecting and recording adverse events and serious adverse events

All AEs starting within 30 days following administration of each dose of study vaccine must be recorded into the appropriate section of the eCRF, irrespective of intensity or whether or not they are considered vaccination-related.

The time period for collecting and recording SAEs will begin at the first receipt of study vaccine and will end approximately 12 months following administration of the last dose of study vaccine for each subject. See Section 8.3 for instructions on reporting of SAEs.

All AEs/SAEs leading to withdrawal from the study will be collected and recorded from the time of the first receipt of study vaccine.

In addition to the above-mentioned reporting requirements and in order to fulfillinternational reporting obligations, SAEs that are related to study participation (i.e., protocol-mandated procedures, invasive tests, a change from existing therapy) or are related to a concurrent GSK medication/vaccine will be collected and recorded from the time the subject consents to participate in the study until she/he is discharged from the study.

The time period for collecting and recording of pIMDs will begin at the first receipt of study vaccine and will end approximately 12 months following administration of the last dose of study vaccine at Visit 5 (last study visit). See section 8.3.4 for instructions on reporting of pIMDs.






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IMCs other than HZ (see Section 6.7) will be recorded from Visit 1 until Visit 5 (last study visit) and will be recorded in AE/SAE screens as appropriate.

The occurrence of HZ will constitute an AE/SAE as appropriate. The reporting period for cases of HZ will be from the Screening Visit to Visit 5 (last study visit). Refer to Table 16 and Sections 5.5 and 5.5.1.

An overview of the protocol-required reporting periods for AEs, SAEs, pIMDs and IMCs is given in Table 16.






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Table 16 Reporting periods for collecting safety information

Study activity C Vacc 1 Vacc 2 Study conclusion

Visit Screening visit Visit 1 Visit 3 Visit 5

Timing of reporting Month 0

7 da

ys

Pos

t-V

acc

30 d

ays

Pos

t-V

acc

Month 2

7 da

ys

Pos

t-V

acc

30 d

ays

Pos

t-V

acc

Month 14

Solicited local and general AEs

Unsolicited AEs

All SAEs including SAEs related to the investigational vaccine/product

SAEs related to study participation or concurrent GSK medication/vaccine

pIMDs

IMCs including HZ (see Section 6.7) 1

C = Consent; Vacc = vaccination; AE = Adverse Event; SAE = Serious Adverse Event; pIMDs = potential Immune Mediated Diseases; IMC = Intercurrent Medical Conditions; HZ = Herpes Zoster.

1 All IMCs including HZ should be reported from Visit 1 (Month 0) until Visit 5 (Month 14) for all subjects. For the evaluation of suspected HZ cases between the Screening Visit and Visit 1, refer to Sections 5.5 and 5.5.1.






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8.2.2. Post-Study adverse events and serious adverse events

A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE reporting period defined in Table 16. Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the investigator learns of any SAE at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the investigational vaccine/product, the investigator will promptly notify the Study Contact for Reporting SAEs.

8.2.3. Evaluation of adverse events and serious adverse events

8.2.3.1. Active questioning to detect adverse events and serious adverse events

As a consistent method of collecting AEs, the subject should be asked a non-leading question such as:

‘Have you felt different in any way since receiving the vaccine or since the previous visit?’

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory and diagnostics reports) relative to the event. The investigator will then record all relevant information regarding an AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the subject’s medical records to GSK Biologicals instead of appropriately completing the eCRF. However, there may be instances when copies of medical records for certain cases are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded on the copies of the medical records prior to submission to GSK Biologicals.

The investigator will attempt to establish a diagnosis pertaining to the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the individual signs/symptoms.






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8.2.3.2. Assessment of adverse events

8.2.3.2.1. Assessment of intensity

The intensity of the following solicited AEs will be assessed as described in Table 17.

Table 17 Intensity scales for solicited symptoms in adults

Adverse Event Intensity grade ParameterPain at injection site 0 None

1 Mild: Any pain neither interfering with nor preventing normal every day activities.

2 Moderate: Painful when limb is moved and interferes with every day activities.

3 Severe: Significant pain at rest. Prevents normal every day activities.

Redness at injection site Record greatest surface diameter in mmSwelling at injection site Record greatest surface diameter in mmFever* Record temperature in °C/°F

Headache 0 Normal1 Mild: Headache that is easily tolerated2 Moderate: Headache that interferes with normal activity3 Severe: Headache that prevents normal activity

Fatigue 0 Normal1 Mild: Fatigue that is easily tolerated2 Moderate: Fatigue that interferes with normal activity3 Severe: Fatigue that prevents normal activity

Gastrointestinal symptoms 0 Normal(nausea, vomiting, diarrhea and/or abdominal pain)

1 Mild: Gastrointestinal symptoms that are easily tolerated

2 Moderate: Gastrointestinal symptoms that interfere with normal activity

3 Severe: Gastrointestinal symptoms that prevent normal activity

Myalgia 0 Normal1 Mild: Myalgia that is easily tolerated2 Moderate: Myalgia that interferes with normal activity3 Severe: Myalgia that prevents normal activity

Shivering 0 None1 Shivering that is easily tolerated2 Shivering that interferes with normal activity3 Shivering that prevents normal activity

* The preferred route for recording temperature in this study is oral. When there is no other alternative, the temperature may be recorded by other route. If the temperature is taken by another route (axillary, rectal or tympanic), the route should be documented.






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The maximum intensity of local injection site redness/swelling will be scored at GSK Biologicals as follows using GSK Biologicals’ standard grading scale based on the USFood and Drug Administration (FDA) guidelines for Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers enrolled in Preventive Vaccine Clinical Trials [FDA, 2007]:

0 : < 20 mm diameter1 : 20 mm to 50 mm diameter2 : > 50 mm to 100 mm diameter3 : > 100 mm diameter

The investigator will assess the maximum intensity that occurred over the duration of the event for all unsolicited AEs (including SAEs) recorded during the study. The assessment will be based on the investigator’s clinical judgment.

The intensity should be assigned to one of the following categories:

1 (mild) = An AE which is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

2 (moderate) = An AE which is sufficiently discomforting to interfere with normal everyday activities.

3 (severe) = An AE which prevents normal, everyday activities (such an AE would, for example, prevent attendance at work/school and would necessitate the administration of corrective therapy.)

An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 3 is a category used for rating the intensity of an event; and both AEs and SAEs can be assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 8.1.2.

8.2.3.2.2. Assessment of causality

The investigator is obligated to assess the relationship between investigational vaccine/product and the occurrence of each AE/SAE. The investigator will use clinical judgment to determine the relationship. Alternative plausible causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the investigational vaccine/product will be considered and investigated. The investigator will also consult the IB to determine his/her assessment.

There may be situations when a SAE has occurred and the investigator has minimal information to include in the initial report to GSK Biologicals. However, it is very important that the investigator always makes an assessment of causality for every event prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The investigator may change his/her opinion of causality in light of follow-up information and






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update the SAE information accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

In case of concomitant administration of multiple vaccines, it may not be possible to determine the causal relationship of general AEs to the individual vaccines administered. The investigator should, therefore, assess whether the AE could be causally related to vaccination rather than to the individual vaccines.

All solicited local (injection site) reactions will be considered causally related to vaccination. Causality of all other AEs should be assessed by the investigator using the following question:

Is there a reasonable possibility that the AE may have been caused by the investigational vaccine/product?

YES : There is a reasonable possibility that the vaccine(s) contributed to the AE.

NO : There is no reasonable possibility that the AE is causally related to the administration of the study vaccine(s). There are other, more likely causes and administration of the study vaccine(s) is not suspected to have contributed to the AE.

If an event meets the criteria to be determined as ‘serious’ (see Section 8.1.2), additional examinations/tests will be performed by the investigator in order to determine ALL possible contributing factors for each SAE.

Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).

8.2.3.3. Assessment of outcomes

The investigator will assess the outcome of all unsolicited AEs (including SAEs) recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.






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Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).

8.2.3.4. Medically attended visits

For each solicited and unsolicited symptom the subject experiences, the subject will be asked if he/she received medical attention defined as hospitalization, or an otherwise unscheduled visit to or from medical personnel for any reason, including emergency room visits. This information will be recorded in the eCRF.

8.3. Reporting of serious adverse events and other events

8.3.1. Prompt reporting of serious adverse events, and other events to GSK Biologicals

SAEs that occur in the time period defined in Section 8.2 will be reported promptly to GSK within the timeframes described in Table 18, once the investigator determines that the event meets the protocol definition of a SAE.

pIMDs that occur in the time period defined in Section 8.2 will be reported promptly to GSK within the timeframes described in Table 18, once the investigator determines that the event meets the protocol definition of a pIMD.

Table 18 Timeframes for submitting serious adverse event and other events reports to GSK Biologicals

Type of EventInitial Reports

Follow-up of Relevant Information on a Previous Report

Timeframe Documents Timeframe DocumentsSAEs 24 hours*‡ electronic Expedited Adverse

Events Report24 hours* electronic Expedited Adverse

Events ReportpIMDs 24 hours**‡ electronic Expedited Adverse

Events Report24 hours* electronic Expedited Adverse

Events Report* Timeframe allowed after receipt or awareness of the information.** Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD.‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the

electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD.






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8.3.2. Contact information for reporting serious adverse events and pIMDs

Study Contact for Reporting SAEs and pIMDsRefer to the local study contact information document.

Back-up Study Contact for Reporting SAEs and pIMDs

24/24 hour and 7/7 day availability:

GSK Biologicals Clinical Safety & Pharmacovigilance

Back-up Study Contact for USA for Reporting SAEsUS Safety CSAFax: (Amended 05 May 2017)

SAE = Serious Adverse Event; pIMD = potential Immune Mediated Diseases; USA = United States (of America); CSA = Clinical Study Associate.

8.3.3. Completion and transmission of SAE reports to GSK Biologicals

Once an investigator becomes aware that a SAE has occurred in a study subject, the investigator (or designate) must complete the information in the electronic Expedited Adverse Events Report WITHIN 24 HOURS. The report will always be completed as thoroughly as possible with all available details of the event. Even if the investigator does not have all information regarding a SAE, the report should still be completed within 24 hours. Once additional relevant information is received, the report should be updated WITHIN 24 HOURS.

The investigator will always provide an assessment of causality at the time of the initial report. The investigator will be required to confirm the review of the SAE causality by ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of submission of the SAE.

8.3.3.1. Back-up system in case the electronic SAE reporting system does not work

If the electronic SAE reporting system does not work, the investigator (or designate) must complete, then date and sign a paper Expedited Adverse Events Report and fax it to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or to the GSK Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.

This back-up system should only be used if the electronic reporting system is not working and NOT if the system is slow. As soon as the electronic reporting system is working again, the investigator (or designate) must complete the electronic Expedited Adverse Events Report within 24 hours. The final valid information for regulatory reporting will be the information reported through the electronic SAE reporting system.




PPD



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8.3.4. Reporting of pIMDs to GSK Biologicals

Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or designate) must complete the information in the electronic Expedited Adverse Events Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. The report allows to specify that the event is a pIMD and whether it is serious or non serious. The report will always be completed as thoroughly as possible with all available details of the event, in accordance with the pIMD standard questionnaire provided. Even if the investigator does not have all information regarding a pIMD, the report should still be completed within 24 hours. Once additional relevant information is received, the report should be updated WITHIN 24 HOURS.

The investigator will always provide an assessment of causality at the time of the initial report. The investigator will be required to confirm the review of the pIMD causality by ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of submission of the pIMD.

Refer to Section 8.3.3.1 for back-up system in case the electronic SAE reporting system does not work.

8.3.5. Updating of SAE and pIMD information after removal of writeaccess to the subject’s eCRF

When additional SAE or pIMD information is received after removal of the write access to the subject’s eCRF, new or updated information should be recorded on the appropriatepaper report, with all changes signed and dated by the investigator. The updated report should be faxed to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance department within the designated reporting time frames specified in Table 18.

8.3.6. Regulatory reporting requirements for serious adverse events

The investigator will promptly report all SAEs to GSK in accordance with the procedures detailed in Section 8.3.1. GSK Biologicals has a legal responsibility to promptly notify, as appropriate, both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. Prompt notification of SAEs by the investigator to the Study Contact for Reporting SAEs is essential so that legal obligations and ethical responsibilities towards the safety of other subjects are met.

Investigator safety reports are prepared according to the current GSK policy and are forwarded to investigators as necessary. An investigator safety report is prepared for a SAE(s) that is both attributable to the investigational vaccine/product and unexpected. The purpose of the report is to fulfill specific regulatory and GCP requirements, regarding the product under investigation.






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8.4. Follow-up of adverse events and serious adverse events

8.4.1. Follow-up of adverse events and serious adverse events

8.4.1.1. Follow-up during the study

After the initial AE/SAE report, the investigator is required to proactively follow each subject and provide additional relevant information on the subject’s condition to GSK Biologicals (within 24 hours for SAEs; refer to Table 18).

All SAEs and pIMDs (serious or non-serious) documented at a previous visit/contact and designated as not recovered/not resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the end of the study.

All AEs documented at a previous visit/contact and designated as not recovered/not resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 days after the last vaccination.

8.4.1.2. Follow-up after the subject is discharged from the study

The investigator will follow subjects:

with SAEs, pIMDs (serious or non-serious), or subjects withdrawn from the study as a result of an AE, until the event has resolved, subsided, stabilized, disappeared, or until the event is otherwise explained, or the subject is lost to follow-up.

If the investigator receives additional relevant information on a previously reported SAE, he/she will provide this information to GSK Biologicals using an electronic Expedited Adverse Events Report as applicable.

GSK Biologicals may request that the investigator performs or arranges the conduct of additional clinical examinations/tests and/or evaluations to elucidate as fully as possible the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a subject dies during participation in the study or during a recognized follow-up period, GSK Biologicals will be provided with any available post-mortem findings, including histopathology.

8.5. Treatment of adverse events

Treatment of any AE is at the sole discretion of the investigator and according to current good medical practice. Any medication administered for the treatment of an AE should be recorded in the subject’s eCRF (refer to Section 6.6).

8.6. Subject card

Study subjects must be provided with the address and telephone number of the main contact for information about the clinical study.






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The investigator (or designate) must therefore provide a “subject card” to each subject. In an emergency situation this card serves to inform the responsible attending physician that the subject is in a clinical study and that relevant information may be obtained by contacting the investigator.

Subjects must be instructed to keep subject cards in their possession at all times.

8.7. Safety Monitoring

An internal GSK Safety Review Team (SRT) will oversee the safety of the ZOSTER-048 study on a regular basis. SAEs and AEs including pIMDs will be reviewed by the SRT at regular intervals together with data from other ongoing ZOSTER vaccine studies. Any potential safety concern related to conduct of the study will be escalated to higher governing bodies as per internal GSK process.

9. SUBJECT COMPLETION AND WITHDRAWAL

9.1. Subject completion

A subject who returns for the concluding visit/is available for the concluding contact foreseen in the protocol is considered to have completed the study.

9.2. Subject withdrawal

Subjects withdrawn following vaccination will not be replaced.

9.2.1. Subject withdrawal from the study

From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did not come back for the concluding visit/was not available for the concluding contact foreseen in the protocol.

All data collected until the date of withdrawal/last contact of the subject will be used for the analysis.

A subject is considered a ‘withdrawal’ from the study when no study procedure has occurred, no follow-up has been performed and no further information has been collected for this subject from the date of withdrawal/last contact.

Investigators will make an attempt to contact those subjects who do not return for scheduled visits or follow-up.

Information relative to the withdrawal will be documented in the eCRF. The investigator will document whether the decision to withdraw a subject from the study was made by the subject himself/herself, or by the investigator, as well as which of the following possible reasons was responsible for withdrawal:






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Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).

*In case a subject is withdrawn from the study because he/she has withdrawn consent, the investigator will document the reason for withdrawal of consent, if specified by the subject, in the eCRF.

Subjects who are withdrawn from the study because of SAEs/AEs must be clearly distinguished from subjects who are withdrawn for other reasons. Investigators will follow subjects who are withdrawn from the study as result of a SAE/AE until resolution of the event (see Section 8.4.1.2).

9.2.2. Subject withdrawal from investigational vaccine

A ‘withdrawal’ from the investigational vaccine refers to any subject who does not receive the complete treatment, i.e., when no further planned dose is administered from the date of withdrawal. A subject withdrawn from the investigational vaccine may not necessarily be withdrawn from the study as further study procedures or follow-up may be performed (safety or immunogenicity) if planned in the study protocol.

Information relative to premature discontinuation of the investigational vaccine will be documented on the Vaccine Administration page/screen of the eCRF. The investigator will document whether the decision to discontinue further vaccination/treatment was made by the subject himself/herself, or by the investigator, as well as which of the following possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Other (specify).

9.3. Screen failures

Subjects enrolled at the screening visit will sign the ICF, have inclusion and exclusion criteria checked, have demographic data, date of any previous Zostavax vaccination and their medical history including any medical condition(s) recorded (Section 5.7.1 and Table 4). As indicated in Section 10.3, only a minimum of 400 subjects will be invited for Visit 1 (i.e., first vaccination visit), from the subjects enrolled during the screening visit. Certain subjects may not be matched, and will therefore not proceed with the rest of






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the study. In addition, subjects may no longer be eligible, may lose interest or may experience a change in medical condition rendering them unable to be matched by Visit 1. The ineligible subjects and the un-matched subjects will be informed by the investigator about their status, and they will be withdrawn from the study.

10. STATISTICAL METHODS

10.1. Primary endpoints


Anti-gE antibody concentrations, as determined by ELISA, at Month 3.

Occurrence of solicited local and general symptoms.

Occurrence, intensity, and duration of each solicited local symptom within 7 days (Days 0-6) after each dose.

Occurrence, intensity, duration, and relationship to vaccination of each solicited general symptom within 7 days (Days 0-6) after each dose.

Occurrence of unsolicited symptoms (AEs).

Occurrence, intensity, and relationship to vaccination of each unsolicited symptom (AE) within 30 days (Days 0-29) after each dose, according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.

Occurrence of serious adverse events (SAEs).

Occurrence and relationship to vaccination of all SAEs from Month 0 (dose 1) up to Month 3 (30 days post-dose 2).

Occurrence of AEs of specific interest (potential immune-mediated diseases [pIMDs]).

Occurrence of any pIMDs from Month 0 (dose 1) up to Month 3 (30 days post-dose 2).

10.2. Secondary endpoints


Anti-gE antibody concentrations, as determined by ELISA, at Months 0, 1, 3 and 14.

gE-specific CD4+ T-cell mediated immunogenicity.

Frequencies of gE-specific CD4+ T-cells, expressing at least two activation markers (from among interferon gamma [IFN-γ], interleukin-2 [IL-2], tumor necrosis factor alpha [TNF-α] and CD40L), as determined by in vitro Intracellular cytokine staining (ICS), at Months 0, 1, 3 and 14.

Occurrence of Serious Adverse Events (SAEs).






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Occurrence and relationship to vaccination of all SAEs from Month 3 (30 days post-vaccination 2) up to Month 14 (12 months post-vaccination 2).

Occurrence of AEs of specific interest (pIMDs).

Occurrence of any pIMDs from Month 3 (30 days post-vaccination 2) up to Month 14 (12 months post-vaccination 2).

10.3. Strategy for group matching between groups

The following four variables have been chosen to be matched between groups. However, in case the matching is not feasible, some categories within a variable may be merged or no longer be considered for matching:

Age,

65-69 70-79 ≥80

Gender,

Male (M) Female (F)

Race,

Caucasian African American Hispanic Other

Medical condition.

Only one medical condition cited below will be used for the matching in a hierarchical manner, with a. being the condition to match subjects on first, then down the list until f.





e. Heart Conditions


The strategy used for matching of groups will utilize a specific matching algorithm, integrated in SBIR to manage the variables and match subjects between the groups starting at the screening visit.

Enrolment starts at the screening visit where up to approximately 800 subjects will be entered into SBIR as “Planned” (for the study);






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The status of the subjects’ Zostavax vaccination will be recorded;

Matching variables such as age category, gender, race and medical condition(s) will be entered into SBIR to register the subjects;

A matching algorithm will match subjects to be included in the No prev-Zvax group with subjects from the Prev-Zvax group;

Not all subjects identified as Planned during the screening visit will be able to participate in the study. Certain subjects may not be matched, and will therefore not proceed with the rest of the study. From the Planned subjects identified during the screening visit, only a minimum of 400 subjects will be invited for Visit 1 (i.e., first vaccination visit), and the remaining un-matched subjects will be withdrawn from the study once a target of 400 enrolled subjects has been met. These withdrawn subjects will be informed by the investigator when recruitment at their site is completed.

In case a subject is no longer eligible, or in case a change in medical condition makes the subject unable to be matched, the subject will be withdrawn from the study.

Refer to the SPM for further details on the matching strategy.

10.3.1. Contingency plan for the group matching strategy

Continuous in stream evaluation of the matching strategy during screening will determine if a particular combination of variables is unlikely to be matched. If the matching of subjects is not feasible because the target number for some matching variable(s)/categoryis limiting, the following two-step contingency plan will be implemented:

1. The categories within the limiting variables (race or medical condition) will first be merged. The categories in the variable age will never be merged. Merging the variable gender will not be done as a first step (since merging gender will result in removing of the variable). The categories that could be merged will depend on which variable is a barrier to matching, between race and medical condition.

2. If the matching of subjects continues to be blocked after the merging of categories within either race or medical condition, the variable could be removed. If after removing the first variable there are still difficulties in completing enrolment into the No prev-Zvax group, then the remaining variables will be considered for removal. For example, if race becomes a limiting factor, it will no longer be taken into consideration for matching. The variable for age will never be removed.

The timing for merging categories or removing a matching variable cannot be predicted in advance as it depends on enrolment. The decision to merge categories or remove a matching variable will be established by the central GSK study team. Additional details on the matching strategy may be found in the SPM.






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10.4. Determination of sample size

Non-inferiority in term of anti-gE GMC

Non-inferiority will be demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) for the adjusted GMC group ratio (No prev-Zvax over Prev-Zvax) of anti-gE antibodies is below 1.5.

For non-inferiority of GMCs, the following assumptions were made to assess the sample-size:

Type I error: 0.025 (One-sided).

Based on the GSK HZ/su candidate vaccine studies ZOSTER-003 (108494) and ZOSTER-010 (112077), a standard deviation of the log10-transformed concentrations of 0.35 was assumed.

Null-hypothesis: The GMC of the No prev-Zvax group is at least 1.5-fold higher than the GMC of the Prev-Zvax group.

H0: GMTNo-prevZos / GMTPrevZos > .

Table 19 presents the power to reach the non-inferiority, assuming the enrolment is 200 subjects per group and non-evaluable rate is either 5% or 10%.

Table 19 Power to show that the 95%CI for the GMC ratio between groups (No prev-Zvax over Prev-Zvax) for anti-gE is below a predefined limit of 1.5

Antigens Endpoints Reference values* Clinically acceptable limit

Power(N=190 vs. 190)**

Power(N=180 vs. 180)**

gE GMC post-dose 2 STD of log10 concentrations of 0.35

1.5 fold 99.8% 99.7%

gE = VZV Glycoprotein E; GMC = Geometric Mean Concentration; STD = Standard Deviation.* Reference for the variability of anti-gE GMCs: ZOSTER 003 AND ZOSTER 010.** Pass 2005, one-sided equivalence of means (non-inferiority), alpha = 2.5%, assuming the same GMC in both groups.

Descriptive analysis for safety and reactogenicity

In this study, descriptive safety assessment is a co-primary objective.

The 95% CIs for a given percentage of subjects reporting a symptom after vaccination, assuming a sample size of 200 subjects per group is presented in Table 20. However, no formal comparison between groups has been foreseen. Therefore, overlapping between groups of the 95%CIs should be interpreted with caution because the sample size does not allow to detect a significant difference. In addition, no adjustment of type I error for multiple comparisons and no clinical criteria of a difference have been considered. The table illustrates the probability to detect a 5% and 10% increase in the Prev-Zvax group as compared to the Non-prev-Zvax group with no adjustment for multiplicity.






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Table 20 Exact 95% CI for proportion with 200 subjects and probability to detect 5%, 10% increase in the Prev-Zvax group as compared to the Non-Prev-Zvax group

% of subjects with a symptom in the no-prev Zvax group (N=200)

95% ConfidenceProbability to detect 5% increase in the Prev-Zvax group (N=200)*

Probability to detect 10% increase in the Prev-Zvax group (N=200)*

Interval (CI)

LowerLimit

UpperLimit

1% 0.10% 3.60% 68.91% 98.16%

5% 2.40% 9.00% 40.03% 88.95%

10% 6.20% 15.00% 27.39% 76.04%

15% 10.40% 20.70% 21.85% 66.21%

20% 14.70% 26.20% 18.84% 59.31%

25% 19.20% 31.60% 17.01% 54.53%

30% 23.70% 36.90% 15.85% 51.27%

35% 28.40% 42.00% 15.11% 49.17%

40% 33.20% 47.10% 14.66% 47.98%

45% 38.00% 52.20% 14.45% 47.60%

50% 42.90% 57.10% 14.45% 47.98%

55% 47.80% 62.00% 14.66% 49.17%

60% 52.90% 66.80% 15.11% 51.27%

65% 58.00% 71.60% 15.85% 54.53%

70% 63.10% 76.30% 17.01% 59.31%

75% 68.40% 80.80% 18.84% 66.21%

80% 73.80% 85.30% 21.85% 76.04%

85% 79.30% 89.60% 27.39% 88.95%

90% 85.00% 93.80% 40.03% 99.31%

95% 91.00% 97.60% 82.50% 82.50%

*Pass 2005, 1-sided Fisher’s Exact test for two proportions, alpha = 2.5%

10.5. Cohorts for Analysis

10.5.1. Total vaccinated cohort

The Total vaccinated cohort (TVC) will include all subjects with at least one vaccine administration documented:

A reactogenicity analysis based on the TVC will include all subjects with at least one vaccine administration documented;

The TVC for analysis of safety will include all subjects with at least one vaccine dose administered;

An immunogenicity analysis based on the TVC will include all vaccinated subjects for whom immunogenicity data are available;






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The TVC analysis will be performed per actual group to which the subject belongs as based on previous Zostavax vaccination status.

10.5.2. According To Protocol cohort for analysis of safety for the active phase

The ATP cohort for analysis of safety will include all subjects:

Who have received at least one dose of study vaccine;

For whom administration site of study vaccine is known/correct;

Who have not received other vaccine forbidden in the protocol;

For the Prev-Zvax group, a previous vaccination with Zostavax ≥ 5 calendar years earlier.

10.5.3. According To Protocol cohort for analysis of immunogenicity

The ATP cohort for analysis of immunogenicity will include all evaluable subjects (i.e., those meeting all eligibility criteria, complying with the procedures and intervals allowed for the analysis (see Table 21), with no elimination criteria during the study) for whom data concerning immunogenicity endpoint measures are available.

Table 21 The intervals allowed for the inclusion in the ATP cohort for analysis of immunogenicity

Interval Allowed interval for ATP cohort analysis of immunogenicity

Interval between vaccinations HZ/su (Dose 1, Day 0) –HZ/su (Dose 2, Month 2)

49-83 Days

Interval between vaccination and blood sample taken

HZ/su (Dose 2, Month 2) –Visit Month 3 for BS for anti-gEAb

28-48 days

ATP = According To Protocol; HZ/su = Herpes Zoster subunit vaccine; BS= Blood Sample; gE = VZV glycoprotein E; Ab = Antibody.

10.5.4. According To Protocol cohort for analysis of antibody persistence

The ATP cohort for analysis of Ab persistence will include all subjects in the ATP cohort for analysis of immunogenicity for whom immunogenicity data are available at 12 months post-dose 2 (Month 14).

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. The missing endpoint and censoring are supposed to occur






05-MAY-2017 83

independently, and the pattern of the missing value(s) being either Missing Completely At Random or Missing At Random 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/pIMDs/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 the analysis of immunogenicity, missing or non-evaluable measurements will not be replaced. Therefore, a subject will be excluded from an analysis if all measurements are missing or non-evaluable.

10.6.2. Humoral immune response

A seronegative subject is a subject whose Ab concentration is below the cut-off value.

A seropositive subject is a subject whose Ab concentration is greater than or equal to the cut-off value.

The seropositivity rate is defined as the percentage of seropositive subjects.

The GMC calculations are performed by taking the anti-log of the mean of the log concentration transformations. Ab concentrations below the cut-off of the assay will be given an arbitrary value equal to half the cut-off for the purpose of GMC calculation.

10.6.3. Cell-mediated immune response

For the descriptive analyses, the frequency of CD4[2+] T-cells upon in vitro stimulation with the gE-antigen (induction condition) is calculated by dividing the number of activated CD4[2+] T-cells (numerator) over the total number of CD4 T-cells involved (denominator). The same calculation will be performed for the frequency computation for any kinds of cells and for each individual activation marker as appropriate.

The frequency of gE-specific CD4 T-cells for each individual subject is calculated as the difference between the frequency of CD4[2+] T-cells, upon in vitro stimulation with the gE antigen (induction condition) minus the frequency of CD4[2+] T-cells upon in vitro stimulation in medium only (background condition). The differences

)(inductionassay in theinvolvedcellsTCD4ofnumber Total

antigenwith theinduction after markersactivation2least at secretingcellsTCD4ofnumber 4

2

4

224

CD

Induction

CDInduction

InductionCDInduction

N

n

N

nFreq






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less or equal to one are imputed to one gE-specific CD4[2+] T-cell per 106 CD4+ T-cells. The same calculation will be performed for the frequency computation for any kind of cells and for each individual activation marker as appropriate.

The Geometric Mean frequency calculations are performed by taking the anti-log of the mean of the log frequency transformations.

10.7. Analysis of demographics

Demographic characteristics (age, gender and ethnicity) as well as the matched variables characteristic at Visit 1 will be tabulated per group.

The mean age (plus range and standard deviation [SD]) of the vaccinated subjects, as a whole, and per group will be calculated.

The distribution of subjects vaccinated among the study sites will be tabulated as a whole and per group.

The same tabulations might be performed by age category if deemed necessary.

10.8. Analysis of immunogenicity

The primary analysis will be based on the ATP cohort for analysis of immunogenicity. If in any group the percentage of enrolled subjects excluded from this ATP cohort is more than 5%, a second analysis based on the TVC will be performed to complement the ATP analysis.

10.8.1. Within groups assessment

10.8.1.1. Humoral immune response

The following parameters will be tabulated by vaccine group at each time point when a blood sample result is available:

Seropositivity rate with exact 95% CI;

GMC with 95% CI.

) backgroundof(inductionassay in theinvolvedcells-TCD4ofnumber Total

conditionsmediumin themarkersactivation2least at secretingcells-T CD4ofnumber

antigen -gE with theinduction after markersactivation2least at secretingcells-T CD4ofnumber

1 1

1

4

2

2

4

2

4

224

4

2

4

2

4

2

4

224

N

n

n

CD

Background

Induction

CDBackground

Background

CDInduction

InductionCDSpecific

CDBackground

Background

CDInduction

InductionCDBackground

Background

CDInduction

InductionCDSpecific

N

n

N

nifFreq

N

n

N

nif

N

n

N

nFreq






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10.8.1.2. Cell-mediated immune response

Descriptive statistics (N, mean, SD, min, Q1, median, Q3, max) of the following parameters will be tabulated by group at all timepoints:

10.8.2. Between groups assessment

A General Linear Model will be used to compare the GMC between No prev-Zvax and Prev-Zvax groups at month 2.

The log-transformed antibody concentration will be modeled. The group-matching variable used will be included in the model. Adjusted means and difference of means between No prev-Zvax and Prev-Zvax groups will be calculated together with 2-sided CIs and back-transformed to the original units to provide GMCs and GM ratios.

The non-inferiority is demonstrated if the upper limit of the two-sided 95% CI of the adjusted GMC ratio (No prev-Zvax over Prev-Zvax) 1-month post-dose 2 is below 1.5 in terms of anti-gE antibodies.

10.9. Analysis of safety

The primary analysis for safety will be based on the TVC. If in any group, the percentage of enrolled subjects excluded from this ATP cohort is more than 5%, a second analysis based on the ATP cohort will be performed to complement the TVC analysis.

10.9.1. Within groups assessment

Safety analyses might be performed overall and by age stratum (65-69, 70-79 and ≥ 80 YOA).

When appropriate, tabulations will be presented overall and by time of occurrence relative to last vaccination (e.g., using windows such as Days 0-6, Days 0-29 and more than 30 days post-vaccination).

The results for the analysis of safety will be tabulated as follows:

The number and percentage of subjects with at least one local solicited AE, with at least one general solicited AE and with any solicited AE during the 7-day follow-up period with exact 95% CIs after each vaccine dose and overall by group will be provided. The same tabulation will be performed for grade 3 solicited AE.

The percentage of subjects reporting each individual solicited local and general AE during the solicited 7-day follow-up period will be tabulated with exact 95% CI. The same tabulation will be performed for grade 3 solicited AEs and for solicited general AEs with relationship to vaccination;

Number of days with each individual solicited local and general AE during the solicited 7-day follow-up period;






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The proportion of subjects with at least one report of unsolicited AE classified by the MedDRA PT and reported up to 30 days after each vaccination will be tabulated with exact 95% CI;

The same tabulation will be performed for grade 3 unsolicited AEs and for unsolicited AEs with a relationship to vaccination. The proportion of AEs resulting in a medically attended visit will also be tabulated;

Total number/percentages of doses (per dose and overall) followed by AEs will be tabulated;

Number of subjects with pIMDs will be tabulated;

SAEs and withdrawal due to AE(s) will be described in detail.

10.9.2. Between groups assessment

Not applicable.

10.10. Interpretation of analyses

Except for the analysis on the immunogenicity objective with a pre-defined success criterion and a one-sided type I error of 2.5%, analyses will be descriptive with the aim to characterize safety/reactogenicity/immunogenicity of subjects having previously received Zostavax. These descriptive analyses should not be interpreted.

10.11. 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.

10.11.1. Sequence of analyses

Two analyses are planned: one analysis for data up to 1 month post-dose 2 (Month 3) may occur if needed, and one for data up to 12 months post-dose 2 of the study (Month 14).

Month 3 analysis:

If performed, the analysis at Month 3 will be performed on data collected through Visit 4 post-dose 2) which are as clean as possible (data are cleaned but the possibility of post-analysis data changes exists afterwards because data collection and data entry may continue through Month 14). At this point, the GSK central clinical team will have access to the lab data.

End of study - Month 14 analysis:

The analysis at Month 14 will be performed on data collected through Visit 5 (12 months post-dose 2) which have been cleaned.

Final individual listings will only be provided at this stage.






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Note that in case data changes have been made after the Month 3 analysis has been done, the impact of these changes on the endpoints will be evaluated and the Month 3 statistical report analysis will be updated consequently. The details of the procedure will be described in the SAP.

A clinical study report (CSR) will be written at the conclusion of the study, presenting all data up to and including Month 14.

10.11.2. Statistical considerations for interim analyses

No interim analysis is planned.

11. ADMINISTRATIVE MATTERS

To comply with ICH GCP administrative obligations relating to data collection, monitoring, archiving data, audits, confidentiality and publications must be fulfilled.

11.1. electronic Case Report Form instructions

A validated GSK defined electronic data collection tool, will be used as the method for data collection.

In all cases, subject initials will not be collected nor transmitted to GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures.

While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study site, omissions or inconsistencies detected by subsequent eCRF review may necessitate clarification or correction of omissions or inconsistencies with documentation and approval by the investigator or appropriately qualified designee. In all cases, the investigator remains accountable for the study data.

The investigator will be provided with a CD-ROM of the final version of the data generated at the investigational site once the database is archived and the study report is complete and approved by all parties.

11.2. Study Monitoring by GSK Biologicals

GSK will monitor the study to verify that, amongst others, the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other study agreements, GCP and all applicable regulatory requirements.






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The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents.

The investigator must ensure provision of reasonable time, space and qualified personnel for monitoring visits.

Direct access to all study-site related and source data is mandatory for the purpose of monitoring review. The monitor will perform an eCRF review and a Source Document Verification (SDV). By SDV we understand verifying eCRF entries by comparing them with the source data that will be made available by the investigator for this purpose.

The Source Documentation Agreement Form describes the source data for the different data in 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 eCRF will serve as the source must be identified, agreed and documented in the source documentation agreement form.

For eCRF, the monitor freezes completed and approved screens at each visit.

Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, and GSK procedures.

11.3. Record retention

Following closure of the study, the investigator must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible, when needed (e.g., audit or inspection), and must be available for review in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by applicable laws/regulations or institutional policy, some or all of these records can be maintained in a validated format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for making these reproductions.

GSK will inform the investigator/institution of the time period for retaining these records to comply with all applicable regulatory requirements. However, the investigator/institution should seek the written approval of the sponsor before proceeding with the disposal of these records. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any institutional requirements, applicable laws or regulations, or GSK standards/procedures.

The investigator/institution must notify GSK of any changes in the archival arrangements, including, but not limited to archival at an off-site facility, transfer of ownership of the records in the event the investigator leaves the site.






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11.4. Quality assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.

11.5. Posting of information on publicly available clinical trial registers and publication policy

Study information from this protocol will be posted on publicly available clinical trial registers before enrolment of subjects begins.

Summaries of the results of GSK interventional studies (phase I-IV) are posted on publicly available results registers within 12 months of the primary completion date for studies of authorized vaccines and 18 months for studies of non-authorized vaccines.

GSK also aims to publish the results of these studies in the searchable, peer reviewed scientific literature. Manuscripts are submitted for publication within 24 months of the last subject’s last visit. At the time of publication, this protocol will be fully disclosed.

11.6. Provision of study results to investigators

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK Biologicals will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

12. COUNTRY SPECIFIC REQUIREMENTS

Not applicable.






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13. REFERENCES

ACIP Zoster Working Group 2013. http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-jun-2013/01-Herpes-Zoster-Duchin.pdf. Accessed 16 October 2013.

Centers for Disease Control and Prevention (CDC). Prevention of Herpes Zoster: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Early Release 2008; 57: 1-30. http://www.cdc.gov/mmwr/pdf/rr/rr57e0515.pdf. Accessed 24 October 2013.

Cohen JI, Straus SE, Arvin AM. Varicella zoster virus and its replication. 2007. p. 2774-2818. In D. M. Knipe and P. M. Howley (ed.), Fields virology, 5th ed. Lippincott/The Williams & Wilkins Co., Philadelphia, PA.

Dworkin RH, Johnson RW, Breuer J, et al., Recommendations for the management of herpes zoster. Clin Infect Dis. 2007; 44 Suppl 1: S1-26.

FDA, U.S. Department of Health and Human Services, Center for Biologics Evaluation and Research. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Version of September 2007.

Kroger AT, Sumaya CV, Pickering LK, Atkinson WL. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011; 60:1-61.

Lal H, Cunningham AL, Godeaux O, et al., Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults. N Engl J Med. 2015: DOI: 10.1056/NEJMoa1501184.

Morrison VA, Johnson GR, Schmader KE, et al., Long-Term Persistence of Zoster Vaccine Efficacy. Clin Infect Dis. 2015; 60(6): 900-9.

National Network for Immunization Information (NNii). Herpes Zoster. Updated: April 2008. http://www.immunizationinfo.org/vaccines/shingles-herpes-zoster. Accessed 24 October 2013.

Onozawa M, Hashino S, Takahata M et al., Relationship between pre-existing anti-varicella-zoster virus (VZV) antibody and clinical VZV reactivation in hematopoietic stem cell transplantation recipients. J Clin Microbiol. 2006; 44(12): 4441-3.

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: 2271-84.

Schmader KE, Oxman MN, Levin MJ, et al., Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis. 2012; 55(10): 1320-8.






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Vermeulen JN, Lange JM, Tyring SK, et al., Safety, tolerability, and immunogenicity after 1 and 2 doses of zoster vaccine in healthy adults ≥60 years of age. Vaccine. 2012; 30(5): 904-10.

Vesikari T, Hardt R, Rümke HC, et al., Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax(®)) in individuals aged ≥ 70 years: A randomized study of a single dose vs. two different two-dose schedules. Hum Vaccin Immunother. 2013; 9(4): 858-64.

Zostavax [shingles (herpes zoster) vaccine (live)] Summary of Product Characteristics; December 2012.http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/MMR_20/WC500136263.pdf. Accessed 15 October 2013.

Zostavax [shingles (herpes zoster) vaccine (live)] Prescribing Information. June 2013. http://www.merck.com/product/usa/pi_circulars/z/zostavax/zostavax_pi2.pdf. Accessed15 October 2013.






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APPENDIX A LABORATORY ASSAYS

Specific Ab (anti-gE) measurements:

Anti-gE ELISA: Anti-gE Ab concentrations will be measured using an anti-gE ELISA. Diluted blood serum samples of study subjects will be added to microtitre wells pre-coated with gE antigen. Secondary peroxidase-conjugated anti-human Abs will be added, which bind to the primary human anti-gE Abs. After incubation of the microtitre wells with a chromogen substrate solution, the enzymatic reaction will be stopped. Optical densities will be recorded and anti-gE Ab concentrations are calculated from a standard curve. The assay cut-off is 97 mIU/mL.

Intracellular cytokine staining (ICS):

CMI responses will be performed by GSK Biologicals (or designated laboratory) on thawed Peripheral Blood Mononuclear Cells (PBMCs) by ICS. The assay will be performed on samples collected during the course of the study. This assay provides information on the frequency of CD4 T cells responding to culture medium or antigens (gE peptide pool or VZV lysate) by secreting cytokine molecules involved in immunity such as IFN-, IL-2, TNF-, and CD40L.

Briefly, PBMC collected from the subjects are stimulated for two hours using culture medium (for evaluation of the non-specific response), a pool of overlapping peptides covering the entire sequence of the vaccine antigen gE or a VZV lysate. Then, an intracellular block (brefeldin A) is added to inhibit cytokine secretion for a subsequent overnight incubation. Cells are then harvested, stained for surface markers (CD3, CD4 and CD8) and fixed. The fixed cells are then permeabilised and stained with anti-cytokine Abs, washed and analyzed by cytofluorometry.

The results of ICS assays are expressed as the frequency of specific CD4 T cells per million total CD4 T cells.

PCR assay for confirmation of suspected case of HZ:

HZ cases will be confirmed by a Polymerase Chain Reaction (PCR) based algorithm that assesses the presence of VZV Deoxyribonucleic Acid (DNA) in samples, and the adequacy of the samples (by assessing the presence of β-actin DNA).

VZVand β-actin DNA in HZ clinical specimens will be assessed using real-time PCR detection by the 5’ nuclease assay based on the Taqman probe technology. If the VZV PCR is negative, β-actin PCR will be performed to assess adequacy of the sample and if a specimen is found to be VZV–PCR negative and β-actin–PCR negative, it is considered to be inadequate.

In the Taqman-based PCR experiments, the formation of a PCR product is monitored in real-time during amplification by means of fluorogenic probes that bind specifically to the amplified product. The reporter fluorophore is at the 5’ end of the Taqman probe and the quencher is at the 3’ end. As long as the probe is intact, no fluorescence is produced by the fluorophore. During the PCR polymerization step, the Taq DNA polymerase displaces the Taqman probe by 3-4 nucleotides, and the 5’ nuclease activity of the DNA






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polymerase separates the fluorophore from the quencher, and a measurable fluorescent signal proportional to the DNA copy number is produced.

As mentioned above, the 5' nuclease-based PCR assay allows the determination of the DNA copy number within samples, but in the present study the VZV and β-actin DNA PCR data on samples from suspected HZ lesions (swabs of vesicles, papules and crusts, and crusts themselves) will be used qualitatively only according to the above mentioned approach.






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APPENDIX B CLINICAL LABORATORIES

Table 22 GSK Biologicals’ laboratories

Laboratory AddressGSK Biologicals Global Vaccine Clinical Laboratory, Rixensart

Biospecimen Reception - B7/44Rue de l'Institut, 89 - B-1330 Rixensart - Belgium

GSK Biologicals Global Vaccine Clinical Laboratory, Wavre-Nord Noir Epine

Avenue Fleming, 20 - B-1300 Wavre - Belgium

Table 23 Outsourced laboratories

Laboratory AddressCEVAC - University of Ghent Building A - 1st floor, De Pintelaan 185, 9000

Ghent, BelgiumCEVAC = Centre for Vaccination






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APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE PROTOCOL


Clinical Research & Development

Protocol Amendment 1eTrack study number and Abbreviated Title

201198 (ZOSTER-048)


Amendment number: Amendment 1

Amendment date: 01 June 2015

Co-ordinating author: , Scientific writer, XPE Pharma & Science, Contractor for GSK Biologicals


Contributing authors have been updated (Title page and Sponsor signature page).

The Document Standard template version was promoted from v14.0 to v14.1.1. To this end the Section on Benefit : Risk Assessment was added (Section 1.3) and revisions made to biological specimens (Section 5.8) and safety reporting (Section 8.3).

A statement about the recent primary analysis of the pivotal phase III ZOSTER-006 study has been added to the (Synopsis, Rationale for the study and Section 1.1).

The cell-mediated immunity (CMI) assay will be conducted on all study subjects instead of a sub-cohort of subjects so the sub-cohort Section has been removed (formerly Section 4.2 and Table 4). The CMI testing on all subjects has been indicated and any mention of a sub-cohort removed from the Synopsis, secondary objectives and secondary endpoints, glossary of terms, Sections 3 and 4, Table 4 of Section 5.6, and Section 5.7.11.1 and details of the CMI assay have been updated (Section 5.8.3 Table 8).

The temperature for fever as ≥ 37.5°C (99.5°F) by oral route, axillary or tympanic setting, or ≥ 38.0°C/100.4°F on rectal setting (Sections 4.3, 5.7.5, 6.5 and 6.6.1).

The blood sampling volume to assess humoral immunogenicity has changed from approximately 8 mL to approximately 5 mL per visit (Synopsis, Section 3, Section 5.6 Table 4, Section 5.7.7.1 and Section 5.8.2 Table 6).

A screening visit has been added to enroll subjects and interview them about their medical conditions to register the subjects’ variables for the matching strategy. In addition, two series of monthly contacts have been added to the study. The first series begins approximately 1 month after the screening visit and ends approximately 1 month before Visit 1 (monthly screening contacts). The other




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series of monthly contacts begins approximately 1 month after the Visit 4 blood sample and ends approximately 1 month before the Visit 5 Study conclusion visit (between Months 3 and 14). Both these monthly contacts have been added to remind subjects about herpes zoster (HZ) and ask if they have experienced any signs or symptoms of HZ or serious adverse events (SAEs). These contacts will also ask subjects additional safety information such as if they had any intercurrent medical conditions (IMCs), concomitant medications/vaccinations and/or experienced any symptoms of potential immune-mediated diseases (pIMDs). Both these monthly phone contacts are now indicated in the Study Design Overview figure (Section 3), the List of study procedures Table 4 and intervals between study visits Table 5 (Section 5.6). The screening visit has also been indicated in Table 16 of Section 8.2.1.

In response to feedback from the Center for Biologics Evaluation and Research (CBER) a statement about a Safety Review Team (SRT) that will oversee the safety of the study on a regular basis has been added (Synopsis and Section 8.7).

An updated reference citation and its corresponding reference were added (Sections 1.2.1 and 13, respectively).

In response to CBER feedback the requirement for documentation of the date of previous Zostavax vaccination has been added (Sections 4.2 and 5.7.1.4).

An inclusion criterion has been added for the No prev Zvax group only specifying that these subjects must have no previous vaccination with Zostavax (Sections 4.2)

Two exclusion criteria were added for any subject with a previous Zostavaxvaccination < 5 calendar years earlier or a previous vaccination against VZV, administration of HZ/su vaccine or any other investigational or non-registered HZ vaccine (except Zostavax for the Prev-Zvax group) (Section 4.3).

Clarified that for subject matching, the medical condition for depression will be limited to those on current medication (Sections 5.2.1.1.1 and 10.3).

Evaluation and confirmation of suspected HZ cases is now described in a new subsection 5.5.1. Additional detail was added on suspected HZ cases including a new subsection 5.5.2 about the collection of HZ case information (Section 5.5).Subjects clinically diagnosed as having a suspected case of HZ will have specimens of HZ lesions sampled as described in Table 6 for polymerase chain reaction (PCR) testing as described in Table 9 (Sections 5.8.2 and 5.8.3, respectively).

In response to CBER feedback a statement has been added indicating that personnel within GSK Biologicals or a validated laboratory designated by GSK Biologicals, performing immunogenicity assessments will be blinded to the study group (Section 5.8).

The criterion for elimination from the ATP analyses by administration of a live vaccine in the period starting 30 days before the first dose of study vaccine and ending 30 days after the last dose of study vaccine (Section 6.6.2), has been aligned with the corresponding exclusion criterion in Section 4.3.






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More detail about what constitutes an Intercurrent Medical Condition has been added (Section 6.7).

Updated the Table 15 List of potential immune-mediated diseases (Section 8.1.5.1).

A section has been added describing that any screen failures will be withdrawn from the study by the investigator (Section 9.3).

A contingency plan has been added to the strategy for group matching between groups (Section 10.3.1).

The power to reach non-inferiority assuming the enrolment is 200 subjects per group and non-evaluable rate is about 10% has been added (Section 10.4, Table 19).

The descriptive analysis for safety and reactogenicity has been revised so that the exact 95% confidence interval for proportion with 200 subjects has been updated to include the probability to detect 5%, 10% increase in the Prev-Zvax group as compared to the Non-Prev-Zvax group in Section 10.4 Table 19.

Added the intervals for inclusion in the ATP cohort for analysis of immunogenicity (Section 10.5.3 Table 21) and aligned the Month 0 to Month 1 and Month 2 to Month 3 intervals to a minimum of 28 days instead of 30 days in Table 5 (Section 5.6).

Revisions were made to the derived and transformed data Section 10.6 for humoral immune response and cell-mediated immune response in Sections 10.6.2 and 10.6.3, respectively.

Revisions were made to the within groups assessment Section 10.8.1 for humoral immune response and cell-mediated immune response in Sections 10.8.1.1 and 10.8.1.2, respectively.

Revisions were made to clarify the analysis of immunogenicity between groups assessment and the analysis of safety within groups assessment (Sections 10.8.3 and 10.9.1, respectively).

Clarification that a clinical study report will be written at the conclusion of the study (Section 10.11.1).

The Laboratory Assay methodology has been updated to include intracellular cytokine staining (ICS) and the PCR Assay (APPENDIX B).

The GSK Biologicals’ laboratories and outsourced laboratories have been updated (APPENDIX B Table 22 and Table 23, respectively).

Typos were corrected and minor modifications made throughout for clarification.

Amended text has been included in bold italics and deleted text in strikethrough in the following sections:






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Title page Co-ordinating author and Contributing authors

Co-ordinating author , Scientific Writer, XPE Pharma & Science, out-cContractor for GSK Biologicals

Contributing authors , Clinical Research and Development Lead, Vaccine Discovery and Development

, Study Delivery Lead , Global Regulatory Affairs

(USA) , Safety Physician , Global Vaccine Clinical

Laboratories Team Lead , Project Data Manager , ProjectPortfolio Data

Manager , Vaccine Supply Coordinator,

Aprova, Contractor for GSK Biologicals , Director, Portfolio Clinical

Research and Development Lead, Vaccine Discovery and Development

Sponsor Signature page sponsor signatory

Sponsor signatory , Lead Clinical Development Manager, Director, Global Vaccine Development

, Director, Portfolio Clinical Research and Development Lead, Vaccine Discovery and Development

Synopsis

Furthermore, recent studies evaluating two doses of Zostavax found that a second dose of Zostavax at 1-2 month intervals did not enhance VZV-specific immunity beyond that induced by the single dose in subjects ≥ 60 YOA and in subjects ≥ 70 YOA. The relevance of this finding in terms of providing protection against HZ is unclear, but it seems likely that the duration of HZ protection would not be enhanced by adding another dose of Zostavax to the initial vaccination regimen.

A recent analysis of the primary endpoint in the pivotal phase III study ZOSTER-006 showed that HZ/su reduced the risk of shingles by 97.16% (95% 95% Confidence Interval (CI); Lower Limit (LL):93.72% - Upper Limit (UL):98.97%) compared to placebo in subjects ≥ 50 YOA [Lal, 2015].




PPD

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PPD

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Primary Objectives


Criterion:

Non-inferiority will be demonstrated if the upper limit of the two-sided 95% confidence interval of the adjusted geometric mean concentration (GMC) ratio (No prev-Zvax over Prev-Zvax) 1 month post-dose is equal or below 1.5 in terms of anti-gE antibodies.

Secondary Objectives

To assess CMI responses to HZ/su at Day 0, 1 month post-dose 1, and 1 and 12 months post-dose 2 in a sub-cohort of subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax (No prev-Zvax).

To evaluate the safety and reactogenicity following administration of HZ/su during the post-dose 2 follow-up period (from 1 month post-dose 2 through 12 months post-dose 2) in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax No prev-Zvax).

Synopsis (continued)

Experimental design: Phase III, open-label, group-matched, multi-centeric, single-country study with two parallel groups.

Duration of the study: Approximately 1420 months. Each subject will be enrolled during a screening visit approximately 6 months prior to Visit 1. Each subject receiving HZ/su vaccine (at Visit 1) will be followed after the second vaccine dose (at Visit 3)for safety follow-up for approximately 12 months.

Epoch 001: Primary starting at Visit 1 (Day 0) approximately 6 months prior to Visit 1 and ending at Visit 5 (Month 14).

Sampling schedule:

Blood samples (approximately 5 and 20 mL per visit) to assess humoral immunogenicity and CMI, respectively, (approximately 8mL per visit) will be collected from all subjects at Visits 1, 2, 4 and 5. In addition, blood samples to assess CMI (approximately 20 mL per visit) will be collected from a sub-cohort of subjects at Visits 1, 2, 4 and 5.


Safety Monitoring: An internal GSK Safety Review Team (SRT) will oversee the safety of the study on a regular basis.






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Primary Endpoints


Anti-gE antibody concentrations, as determined by ELISA, at Months 0, 1 and 3.

Secondary Endpoints

gE-specific CD4+ T-cell mediated immunogenicity, in the CMI sub-cohort.

LIST OF ABBREVIATIONS

ANCA: Anti-Neutrophil Cytoplasmic Antibodies

ANOVA: Analysis of Variance

CBER: Center for Biologics Evaluation and Research

CREST: Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia (syndrome)

DNA: Deoxyribonucleic Acid

HZAC: HZ Ascertainment Committee

IL-2: Interleukin 2

LL: Lower Limit

MATEX: MATerial EXcellence

PBMC: Peripheral Blood Mononuclear Cells

PCR: Polymerase Chain Reaction

qPCR: quantitative Polymerase Chain Reaction

RDE: Remote Data Entry

SAP: Statistical Analysis Plan

SRT: Safety Review Team

UL: Upper Limit

GLOSSARY OF TERMS

Sub-cohort: A group of subjects for whom specific study procedures are planned as compared to other subjects






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Section 1.1 Background

Different gE antigen doses (25, 50 or 100 μg) combined with the AS01 Adjuvant System have been evaluated in over a thousand adults in completed studies and administered to over 15,000 19,000 subjects (as of 28 November 2014)predominantly at the 50 µg gE antigen dose in ongoing trials not yet analyzed. In the analyzed studies the candidate vaccine was shown to elicit strong cellular and humoral immune responses with an acceptable profile of safety and reactogenicity. Based on phase II data from the antigen dose-ranging study, ZOSTER-003, and the adjuvant dose comparison study, ZOSTER-010, a gE antigen dose of 50 g and the Adjuvant System AS01B were selected as the final vaccine formulation (henceforth, the final vaccine formulation of GSK Biologicals’ candidate HZ vaccine will be referred to as HZ/su). A recent analysis of the primary endpoint in the pivotal phase III study ZOSTER-006 showed that HZ/su vaccine reduced the risk of shingles by 97.16% (95% 95% Confidence Interval (CI); Lower Limit (LL):93.72% - Upper Limit (UL):98.97%) compared to placebo in subjects 50 YOA and older.

However, VZV-specific antibodies (Abs) may help control viral dissemination in immunocompromised persons and may thereby help limiting the severity of HZ[Onozawa, 2006].

Please refer to the Prescribing Information for information regarding the potential risks and benefits of Zostavax [Zostavax Prescribing Information, 2013].

Section 1.2.1 Rationale for the study

An observational short-term persistence study in Zostavax, recipients demonstrated waning efficacy after about 5 years [Morrison, 2015; Schmader, 2012].

Furthermore, recent studies evaluating two doses of Zostavax found that a second dose of Zostavax at 1-2 month intervals did not enhance VZV-specific immunity beyond that induced by the single dose in subjects ≥ 60 YOA [Vermeulen, 2012] and in subjects ≥ 70 YOA [Vesikari, 2013]. The relevance of this finding in terms of providing protection against HZ is unclear, but it seems likely that the duration of HZ protection would not be enhanced by adding a 2-second dose scheduleto the initial Zostavax vaccination regimen.

Section 1.2.2 Rationale for the study design

The study is a phase III, open-label, multi-center study conducted in the US. The study will evaluate two parallel groups of 200 adults ≥ 65 YOA; one group (Prev-Zvax) with aprevious Zostavax vaccination at least≥ 5 years earlier, versus another group without a previous Zostavax vaccination (No prev-Zvax).






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Section 1.3. Benefit : Risk Assessment

Please refer to the current Investigator Brochure for the summary of potential risks and benefits of HZ/su vaccine.

The following section outlines the risk assessment and mitigation strategy for this study protocol:

Section 1.3.1. Risk Assessment

Important Potential/Identified Risk

Data/Rationale for Risk Mitigation Strategy

Investigational HZ/su vaccine

Theoretical risk of acquiring a vaccine induced autoimmune disease after vaccination.

No confirmed signals related to this potential risk have been identified during the clinical program. Available clinical data do not highlight any concern.

Close monitoring of pIMDs as per study protocol.

The potential risk of events of possible autoimmune aetiology to occur is mentioned in the ICF. In addition, the ICF advises subjects to contact the study doctor or the study staff immediately, should they get any symptoms that they feel maybe serious.

Study Procedures

Risk from blood sampling.

Blood sampling associated risk of discomfort, syncope, dizziness, infection at the site after or during venipuncture.

Blood samples will be obtained by a trained professional and medical assistance will be available.

The potential risk of feeling faint, or experiencing mild local pain, bruising, irritation or redness at the site where blood was taken, is mentioned in the ICF. The amount of blood to be taken for sampling will not be harmful to the subject’s health.

Risk from lesion sampling.

Swab/ needle sampling of lesions/crusts associated risk of secondary infection, and discomfort related to the procedure.

Lesion samples will be obtained by a trained professional and anti-bacterial ointment may be applied to minimize the potential for secondary infection.

The potential risk of some temporary discomfort during the sampling procedure and the precautionary use of an anti-bacterial ointment to reduce the risk of infection are mentioned in the ICF.






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Section 1.3.2. Benefit Assessment

Benefits include:

Potential benefit of receiving the primary study vaccine that may provide a clinical benefit.

Medical evaluations/assessments associated with study procedures [e.g., physical examination].

Section 1.3.3. Overall Benefit : Risk Conclusion

Taking into account the measures to minimize risk to subjects participating in this study, the potential or recognized risks identified in association with the investigational HZ/su vaccine and study procedures are offset by the potential benefits (prevention of HZ and related complications) that may be afforded to the subject(s).

Section 2.1 Primary Objectives


Criterion:

Non-inferiority will be demonstrated if the upper limit of the two-sided 95% confidence interval of the adjusted geometric mean concentration (GMC) ratio (No prev-Zvax over Prev-Zvax) 1 month post-dose is equal or below 1.5 in terms of anti-gE antibodies.

Section 2.2 Secondary Objectives

To assess CMI responses to HZ/su at Day 0, 1 month post-dose 1, and 1 and 12 months post-dose 2 in a sub-cohort of subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax (No prev-Zvax).

To evaluate the safety and reactogenicity following administration of HZ/su during the post-dose 2 follow-up period (from 1 month post-dose 2 through 12 months post-dose 2) in subjects who received Zostavax ≥ 5 years earlier (Prev-Zvax) and in subjects who have never received Zostavax No prev-Zvax).






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Section 3. STUDY DESIGN OVERVIEW

(Previous Figure)


Prev-Zvax (N = 200)


Visit 1Month 0

Visit 2Month 1

Visit 3Month 2

Visit 4Month 3

Visit 5Month 14


Vaccination 1Safety


Safety

Vaccination 2Safety


Safety



Epoch 001






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(New Figure)


Prev-Zvax (N = 200)


ScreeningVisit*

MonthlyScreening Contacts**

Visit 1Month 0

Visit 2Month 1

Visit 3Month 2

Visit 4Month 3

MonthlyContacts***

Visit 5Month 14

Checking for eligibility, recordingprevious Zostavax

history and collecting variables for matching

Safety


Vaccination 1Safety


Safety

Vaccination 2Safety


SafetySafety



Epoch 001* Refer to Table 4 for all procedures that occur at the screening visit.** Monthly screening contacts beginning approximately 1 month after the screening visit and ending approximately 1 month before Visit 1 will remind subjects about HZ

and ask if they have experienced any signs or symptoms of HZ and serious adverse events (SAE)s. The number of these monthly screening contacts will depend on the amount of time between the screening visit and Visit 1 for each subject.

*** Monthly contacts beginning approximately 1 month after the Visit 4 and ending approximately 1 month before the Visit 5 Study conclusion visit (between Months 3 and 14) to remind subjects about HZ and ask if they have experienced any signs or symptoms of HZ or had any SAEs. During these contacts study site personal willalso ask subjects additional safety information such as if they had any intercurrent medical conditions (IMCs), concomitant medications/vaccinations and/or experienced any symptoms of potential immune-mediated diseases (pIMDs) (see Table 4).






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Experimental design: Phase III, open-label, group-matched, multi-centeric, single-country study with two parallel groups.

Duration of the study: Approximately 1420 months. Each subject will be enrolled during a screening visit approximately 6 months prior to Visit 1. Each subject receiving HZ/su vaccine (at Visit 1) will be followed after the second vaccine dose (at Visit 3)for safety follow-up for approximately 12 months.

Epoch 001: Primary starting at Visit 1 (Day 0) approximately 6 months prior to Visit 1 and ending at Visit 5 (Month 14).

Sampling schedule:

Blood samples (approximately 5 and 20 mL per visit) to assess humoral immunogenicity and CMI, respectively, (approximately 8mL per visit) will be collected from all subjects at Visits 1, 2, 4 and 5. In addition, blood samples to assess CMI (approximately 20 mL per visit) will be collected from a sub-cohort of subjects at Visits 1, 2, 4 and 5.


Section 4. STUDY COHORT

4.2 Sub-cohort

The sub-cohort foreseen for CMI analyses is described in Table 4. At the designated sites, subjects will be assigned to the CMI sub-cohort as they enroll until the estimated subject number is reached.

Table 4 Sub-cohorts

Sub-cohort name DescriptionEstimated number of subjects

(50 per group)

Section 4.1 Inclusion criteria for enrolment (formerly Section 4.2)

Overview of the recruitment plan:

The study is planned to be conducted at multiple sites in the US.

Staggered recruitment: rRecruitment of subjects in No prev-Zvax study group will be made based on the distribution of matching variables in the Prev-Zvax study group. Refer to Sections 5.2.1.1.1 and 10.3 for more details.






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Section 4.2 Inclusion criteria for enrolment (formerly Section 4.3)

Written informed consent obtained from the subject prior to performing any study specific procedure

For the No prev-Zvax group only:

No previous vaccination with Zostavax.

For the Prev-Zvax group only:

Previous vaccination with Zostavax ≥ 5 calendar years earlier.

Oral history is acceptable, dDocumentation indicating the date of previous Zostavax vaccination will be required for ambiguous cases (see Section 5.7.1.4).

Section 4.3. Exclusion criteria for enrolment (formerly Section 4.4)

Previous vaccination with Zostavax < 5 calendar years earlier and/or anyone thatever received more than a single dose of Zostavax.

Previous vaccination against VZV, administration of HZ/su vaccine or any other investigational or non-registered HZ vaccine (except Zostavax for the Prev-Zvax group).

Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine withinduring the period starting 30 days precedingbefore the first dose of study vaccine, or planned use during the study period.

Administration or planned administration of a live vaccine including FluMist®in the period starting 30 days before the first dose of study vaccine and ending 30 days after the last dose of study vaccine, or, administration or planned administration of a non-replicating vaccine* in the period starting 8 days prior to and ending 14 days after either dose of study vaccine.

Current participation in or planned Cconcurrently participatingparticipation in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).

History of HZ or any suspected HZ between the screening visit and Visit 1.

Acute disease and/or fever at the time of enrolment.

Fever is defined as temperature ≥ 37.5°C (99.5°F) by oral route, axillary or tympanic setting, or 38.0°C/100.4°F on rectal setting. The recommended route for recording temperature in this study will be oral.






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Section 5.2.1.1.1. Study group and treatment number allocation

Medical conditions: any one of the following medical conditions will be used for matching: immune mediated diseases, diabetes, depression (on current medication), pulmonary and heart and lung disorderconditions and immune mediated diseases.

Refer to Section 10.3 for the strategy used for matching..

Allocation of the subject to a study group at the investigator site will be performed using SBIR. When SBIR is not available, please refer to the SBIR user guide or the Study Procedures Manual (SPM) for specific instructions.

After obtaining the signed and dated ICF from the subject and having checked the eligibility of the subject, the site staff in charge of the vaccine administration will access SBIR. Upon providing the age category, the gender, the race and the medical condition as well as the previous Zostavax status and the subject identification number, the randomization system will determine the study group and will provide the treatment number(s) to be used at Day 0 (Month 0, Visit 1).


At the screening visit, after obtaining the signed and dated ICF from the subject and having checked the subject’s eligibility, the site staff will access SBIR. The status of the subject’s previous Zostavax vaccination, age category, gender, race and their medical condition(s) will be entered into SBIR to register the subjects. The subjects will be entered as “Planned” in SBIR. It is anticipated that up to approximately 800 subjects will need to be entered into the system as Planned at the screening visit to ensure adequate matching of the subjects. However, in case this number is insufficient, there will be the potential for enrolment of additional subjects. A matching tool will subsequently match subjects in pairs, between the Prev-Zvax and No prev-Zvax study groups. The subjects matched in pairs by the algorithm will then be identified in SBIR allowing the investigator to contact the subjects to be present for Visit 1 (Day 0, Month 0). SBIR will manage: enrolment during the screening phase, identification of matched pairs of subjects (Prev-Zvax and No prev Zvax) and treatment allocation. Refer to the Study Procedures Manual (SPM) for details.

When SBIR is not available, please refer to the SBIR user guide or the Study Procedures Manual (SPM) for specific instructions.

Section 5.2.1.1.2. Treatment number allocation for subsequent doses

For the treatment number allocation for dDose 2 subsequent to the first dose at (Day 60,(Month 2, Visit 3), the study staff in charge of the vaccine administration will access SBIR, provide the subject identification number, and the system will provide a treatment number consistent with the allocated study group.






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Section 5.5 Suspected HZ cases

Suspected HZ is defined as a new rash characteristic of HZ (i.e., unilateral, dermatomal and accompanied by pain broadly defined to include allodynia, pruritus or other sensations). A diagnosis of suspected HZ will be based upon the investigator’sdiscretionclincal judgment. Complications of HZ include, but are not limited to, PHN, HZ vasculitis, disseminated disease, ophthalmic disease, neurologic disease, and visceral disease.

Starting at the screening visit, all subjects will be informed of the signs and symptoms of typical HZ and provided an HZ information card. At each subsequent visit and contact until study end at Visit 5, subjects will be reminded of the signs and symptoms of typical HZ. Subjects will be instructed to contact their study site immediately if they develop any symptoms suggestive of HZ. The subject will be asked to visit the study site and should be seen by the investigator as soon as possible for evaluation of the suspected case of HZ. If a case is not clinically diagnosed as suspected HZ, the investigator should not progress further with evaluation of the case. Refer to Section 5.5.1.

The occurrence of HZ is an intercurrent medical condition (IMC) (see Section 6.7). BothHZ, HZ complications and all other IMCs should be reported following the first vaccination visit (Month 0) until study end (Month 14) for all subjects and will be recorded in AE/SAE screens as appropriate. Refer to Section 5.5.2.

The standard reporting period as specified in Section 8.3.1 for AE/SAE should be used for HZ complications.

At Visit Day 0, all subjects will be informed of the signs and symptoms of typical HZ.

Section 5.5.1. Evaluation and confirmation of suspected HZ cases

The following will take place to evaluate ALL suspected cases of HZ:

1. The study staff/investigator will record concomitant medication/vaccination, including concomitant medication the subject has already received and/or will receive for HZ treatment or any HZ-related complications. The study staff/investigator will check if the subject received any medical attention [hospitalization, emergency room visit, or a visit to or from medical personnel (medical doctor)] for HZ or any HZ-related complication.

In addition to bullet point 1. above, the following will take place to evaluate the suspected case of HZ following the first vaccination visit (Month 0) until study end (Month 14):

2. The rash will be documented by digital photography. At the discretion of the investigator, additional photographs of HZ rash may be taken at any time to help note the progression of the rash. This may occur at unscheduled visits.






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3. Rash lesion samples will be collected from subjects clinically diagnosed as having a suspected case of HZ for subsequent quantitative polymerase chain reaction (qPCR) testing. Three replicate rash lesion samples (see Table 6) should be collected on the same day. If during clinical evaluation the investigator/study staff determines that adequate rash lesion samples cannot be collected (i.e., less than three lesions present, or if only papules are present), the subject should be asked to return to the study site for collection of additional samples if there is rash progression (i.e., appearance of new/additional lesions if originally less than three lesions present, or appearance of vesicles if originally only papules present) at an unscheduled visit within 7 days. When the subject returns to repeat sample collection, if possible three samples from separate lesions should be collected. See the SPM for further details on sample collection.

4. If needed, suspected HZ cases may be referred to the HZ Ascertainment Committee (HZAC). The HZAC will classify all referred cases as either “HZ” or “not HZ”. However, the HZAC classification will serve as the final case definition only when the case cannot be confirmed or excluded by PCR results obtained by GSK Biologicals or a validated laboratory designated by GSK Biologicals, e.g., when all samples from a given subject are inadequate (as when both VZV and β-actin PCR results are negative), or when no samples are available for a given subject (including when suspected HZ occurs in the absence of a characteristic HZ or VZV rash).

The HZAC will consist of physicians with HZ expertise. HZAC members, participating as investigator in this study, will not evaluate cases from their own study site. HZAC members will be blinded to group assignments. For every such case, each reviewing HZAC member will be asked to make a clinical determination of whether the case is HZ, based on review of the available clinical and laboratory information from the study site (e.g., summary of the rash and pain evaluations, digital photographs of the subject's rash, clinical progress notes and site laboratory information).

Section 5.5.2. Collection of HZ case information

All HZ cases that occur during the study period until the end of the study will be documented. The exclusion criteria will be reconfirmed at Visit 1 (see Table 4) and Subjects with suspected HZ between the screening visit and Visit 1 will be excluded from the study (see Section 4.3). Specific clinical information about each HZ case, following the first vaccination visit (Month 0) until study end (Month 14), will be entered into the eCRF. Please refer to the SPM for information about recording the details of HZ cases.






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Section 5.6. Outline of study procedures

The lists of study procedures areis presented in Table 54.

Table 4 List of study procedures (Formerly Table 5)

Epoch Epoch 001Primary


VisitMonthly





Sampling timepoint(s) Pre-VaccPost-Vacc I PostVacc I Post-Vacc II Post-Vacc II

Informed consent ● O 2

Check inclusion / exclusion criteria ● ● 3

Record demographic data ● ●

Record previous Zostavax history ● ●

Medical history ● ●

Record of medical condition (Refer to Section 10.3 ● ● 4 ●

Training of n self-reporting by subjects on self-reporting of the signs and symptoms of typical HZ (Refer to Section 5.5)

O O O O O O O

Screening conclusion (Investigator sign-off) ●

Check contraindications ● ● 5

History directed physical examination (Refer to Section 5.7.4)

O

Pre-vaccination body temperature 6 ● ●

Assignment/recording of treatment number ● ●

Blood sampling for Ab determination from all subjects (~5 ml) ● ● ● ●

Blood sampling for CMI response from all subjects (~20 ml) ● ● ● ●

Vaccination ● ● 5

Training on completion of diary cards O O






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Epoch Epoch 001Primary


VisitMonthly





Sampling timepoint(s) Pre-VaccPost-Vacc I PostVacc I Post-Vacc II Post-Vacc II

Distribution of diary cards O O

Inform subjects of the signs and symptoms of typical HZ O

Daily post-vaccination recording of solicited AEs (Days 0–6) by subjects on diary card 7 O O

Daily post-vaccination recording of unsolicited AEs and concomitant medication/vaccination (Days 0-29) by subjects on diary card 7

O O

Return of diary cards O O

Diary card transcription by investigator/ designee ● ●

Recording of solicited adverse events within 7 days (Days 0-6) post-vaccination, by investigator/site staff

● ●

Recording of non-serious adverse events within 30 days (Days 0-29) post-vaccination, by investigator/site staff

● ●

Record any concomitant medication/vaccination (Refer to Section 6.6.26.6)

● ● ● ● ● ●

Record any Intercurrent Medical Conditions (IMC) including HZ (Refer to Section 6.7)

● ● ● ● ● ●

Recording of serious adverse events (SAEs) by investigator(Refer to Section 8.3) 8

● ● ● ● ● ● ●

Recording o f potential immune-mediated diseases (pIMDs) (Refer to Table 15)

● ● ● ● ● ●

Follow-up of HZ ● 9 ● ● ● ● ● ●

Investigator sign-off before analysis ●

Study conclusion ●

Note: The double-line border following Month 3 indicates the analyses which will may be performed on all data (i.e., data that are as clean as possible) obtained up to Visit 4.1 Subjects will be instructed to contact their study site immediately if they manifest any symptoms they perceive as serious.2 If any abnormalities is detected during the physical exam it should be reported in the eCRF as appropriate.






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1 The number of these monthly screening contacts will depend on the amount of time between the screening visit and Visit 1 for each subject.2 Informed consent given at the screening visit, will be reconfirmed at Visit 1. Refer to the SPM for details regarding the process for reconfirmation.3 Enrolment occurs at the screening visit within approximately 6 months prior to Visit 1, with potentially more time as required to ensure adequate matching of the

subjects by Visit 1, as per the defined matching rules. Inclusion and exclusion criteria are checked at the screening visit. A check for any changes compared to thescreening visit will be performed at Visit 1. In case the subject is no longer eligible, or interested at Visit 1, the subject will be withdrawn from the study (Refer to Section 10.3).

4 The medical condition must be updated in the eCRF during the monthly screening contacts and any updates should also be done in SBIR in parallel.4 5 Any subject with a clinically diagnosed HZ episode between Visit 1 and Visit 3 should not receive the second dose.3 6 Pre-vaccination temperatures should always be recorded orally at study sites. In rare situations when there is no other alternative, the temperature may be recorded by other

route. If the temperature is taken by another route (axillary, rectal or tympanic), the route should be documented.5 7The recommended route for recording temperature in this study is oral. When there is no other alternative, the temperature may be recorded by other route. If the temperature is

taken by another route (axillary, rectal or tympanic), the route should be documented.6 Occurrence of HZ is an IMC which should be reported until study end (Month 14).7 8 SAEs related to study participation or GSK concomitant medication/vaccine are to be recorded from the time the subject consents to participate in the study. All other SAEs are

to be reported after administration of the first dose of vaccine. (Refer to Table 16).9 The evaluation of suspected HZ cases between the Screening Visit and Visit 1 will not include lesion sampling or photography (Refer to Sections 5.5 and 5.5.1).






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Time intervals between study visits/contact related to study procedures performed insubjects participating in the study are presented in Table 65.

Table 5 Intervals between study visits (Formerly Table 6)

Interval Optimal length of interval 1 Allowed interval 2

Screening visit Visit 1 (Month 0) 2 6 months 1 - 9 months

Monthly screening contacts

between Screening visit and Visit 1 3 1 month each 25-35 days for each interval 4

Visit 1 (Month 0) Visit 2 (Month 1) 1 month 3028 - 48 days

Visit 1 (Month 0) Visit 3 (Month 2) 2 months 49 - 83 days 5

Visit 3 (Month 2) Visit 4 (Month 3) 1 month 3028 - 48 days 5

Monthly contacts between Visit 4 (Month 3) and Visit 5 (Month 14)

1 month each 25-35 days for each interval 4

Visit 3 (Month 2) Visit 5 (Month 14) 12 months 335 - 395 days2 Subjects may not be eligible for inclusion in the ATP cohort for analysis if they make the study visit outside this

interval (see Section 10.5).2 The timing interval between the screening visit and Visit 1 is flexible and will depend on the adequate

matching of the subjects at Visit 1 as per the defined matching rules. Visits outside of this interval will not necessarily result in exclusion from the ATP cohort. Approximately 6 months represents an expected length for this interval, with as little as 1 month and potentially more time required (up to approximately 9 months),to ensure adequate matching of the subjects by Visit 1, as per the defined matching rules.

3 The number of these monthly screening contacts will depend on the amount of time between the screening visit and Visit 1 for each subject.

4 The monthly phone contacts are to be as evenly spaced throughout time as possible. Phone contacts which are not at the intervals as specified in this table will not necessarily result in elimination from the ATP cohort.

5 Subjects may not be eligible for inclusion in the ATP cohort for analysis if they make the study visit outside this interval (see Section 10.5.3 and Table 21).

Section 5.7. Detailed description of study procedures

Section 5.7.1. Procedures during the screening visit

Enrolment occurs at the screening visit. The screening visit should take place within approximately 6 months before Visit 1. Since it is unpredictable how long it will exactly take to complete the matching, timing from screening visit to Visit 1 could be prolonged.

Section 5.7.1.1. Informed consent

The signed informed consent of the subject must be obtained before study participation. Refer to Section 5.1 for the requirements on how to obtain informed consent. Informed consent given at the screening visit, will be reconfirmed at Visit 1. Refer to the SPM for details regarding the process for reconfirmation.






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Section 5.7.1.2. Check inclusion and exclusion criteria

Check all applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before enrolment. A check for any changes compared to the screening visit will be performed at Visit 1 and recorded appropriately.

Section 5.7.1.3. CollectRecord demographic data

Record demographic data such as date of birth, gender, geographic ancestry and ethnicity in the subject’s eCRF. A check for any changes compared to the screening visit will be performed at Visit 1 and recorded appropriately.

Section 5.7.1.4. Record Pprevious Zostavax history

Verify and record the date of the previous Zostavax vaccination from documented vaccination history, such as the date in the subject’s immunization card or equivalent.

Section 5.7.1.5. Medical history

Obtain the subject’s medical history by interview and /or review of the subject’s medical records and record any pre-existing conditions or signs and/or symptoms present in a subject prior to the first study vaccination in the eCRF. A check for any changes compared to the screening visit will be performed at Visit 1 and recorded appropriately.

Section 5.7.1.6. Recording of medical condition






e. Heart Conditions

f. Other

gf. None of the above

The medical condition must be updated in the eCRF during the monthly screening contacts and any updates made should also be done in SBIR in parallel (see Table 4). Refer to Section 10.3 and the SPM for the application of the medical condition and additional details on the matching strategy.






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Section 5.7.1.6. Training of subjects on self-reporting of the signs and symptoms of typical HZ

Starting at the screening visit, all subjects will be informed of the signs and symptoms of typical HZ and provided an HZ information card (see Section 5.5).

Section 5.7.1. Informed consent

The signed/witnessed informed consent of the subject must be obtained before study participation. Refer to Section 5.1 for the requirements on how to obtain informed consent.

Section 5.7.2. Check inclusion and exclusion criteria

Check all inclusion and exclusion criteria as described in Sections 4.3 and 4.4 before enrolment.

Section 5.7.2. Procedures prior to the first vaccination

Note that informed consent given at the screening visit, will be reconfirmed at Visit 1 (see Section 5.7.1.1 and Table 4). Refer to the SPM for more information.

Inclusion and exclusion criteria are initially checked at the screening visit (see Section 5.7.1.2 and Table 4). A check for any changes compared to the screening visit will beperformed at Visit 1. In case the subject is no longer eligible or interested at Visit 1, the subject will be withdrawn from the study. Refer to Sections 9.3 and 10.3. Subjects withdrawn following vaccination will not be replaced (Section 9.2).

Any changes in demographic data, previous Zostavax vaccination history, medical history and/or medical condition, between the screening visit and Visit 1, must be recorded in the eCRF.

Section 5.7.3. Collect demographic data

Record demographic data such as date of birth, gender, geographic ancestry and ethnicity in the subject’s eCRF.

Section 5.7.4. Previous Zostavax history

Record the date of the previous Zostavax vaccination (if known).






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Section 5.7.5. Recording of medical condition






e. Heart Conditions

f. Other

g. None of the above

Section 5.7.6. Medical history

Obtain the subject’s medical history by interview and /or review of the subject’s medical records and record any pre-existing conditions or signs and/or symptoms present in a subject prior to the first study vaccination in the eCRF.

Section 5.7.5. Assess pre-vaccination body temperature

If the subject has fever (fever is defined as temperature 37.5°C/99.5°F by oral route, axillary or tympanic setting, or ≥ 38.0°C/100.4°F on rectal setting) on the day of vaccination, the vaccination visit will be rescheduled within the allowed interval for this visit (see Table 5).

Section 5.7.7.1. Blood sampling for safety or immune response assessments

A volume of approximately 8 5 mL of whole blood should be drawn from all subjects for each analysis of humoral immune response at each pre-defined timepoint(see Table 54). After centrifugation, serum samples should be kept at –20°C/ –4°F or below until shipment. Refer to the Quest Laboratory Manual for more details on sample storage conditions.

A volume of approximately 20 mL of whole blood should be drawn from all subjects included in the immunogenicity sub-cohort for analysis of cell-mediated immune (CMI) response at each pre-defined timepoint (see Table 4 and Table 54). Until the samples are picked up for shipment, Tthe blood should be maintained at room temperature at the investigator’s site and it must not be centrifuged. Samples will be shipped at room temperature (15 to 25°C/68 to 77°F) to the designated laboratory for cell separation to be performed within 24 hours. Refer to the Quest Laboratory Manual for more details on sample handling.






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Section 5.7.8. Study Vaccine administration

After completing all prerequisite procedures prior to vaccination, the dose(s) of HZ/su vaccine(s) will be administered IM in the arms’ deltoid(s) region of the non-dominant arm according to the administration schedule (refer to Section 6.3 for detailed description of the vaccines administration procedure). If the investigator or delegate determines that the subject’s health on the day of administration temporarily precludes vaccine(s) administration, the visit will be rescheduled within the allowed interval for this visit (refer to Table 65).

The subjects will be observed closely for at least 30 minutes following the administration of the vaccine(s), with appropriate medical treatment readily available in case of anaphylaxis.

appropriate medical treatment readily available in case of anaphylaxis.

Section 5.7.9. Check and record concomitant medication/vaccination and intercurrent medical conditions (IMC) including HZ

Section 5.7.10. Recording of AEs, SAEs and pIMDs

Refer to Section 8.2 for procedures for the investigator to record AEs, SAEs and pIMDs. Refer to Section 8.3 for guidelines onand how to submitreport SAE and pIMD reports to GSK Biologicals.

Any unreturned diary cards will be sought from the subject through any convenient procedure. The investigator and/or delegate will transcribe the collected information into the eCRF in English.

Section 5.8. Biological sample handling and analysis

Please refer to the SPMQuest Laboratory Manual for details on biospecimen management (handling, storage and shipment).

Samples will not be labeled with information that directly identifies the subject but will be coded with the identification number for the subject (subject number). The personnel, within GSK Biologicals or a validated laboratory designated by GSK Biologicalsperforming immunogenicity assessments, will be blinded to the study group.

Under the following circumstances, additional testing on the samples may be performed by GSK Biologicals outside the scope of this protocol:

Collected samples may be used in other assays, for test improvement or development of analytical methods related to the study vaccine(s) and its constituents or the disease under study.

Collected samples may be used for purposes related to the quality assurance of data generated linked to the study vaccine(s) or the disease(s) under study, such as for maintenance of assays described in this protocol and comparison between analytical methods and/or laboratories.






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Collected samples will be used for protocol mandated research and purposes related to the improvement, development and quality assurance of the laboratory tests described in this protocol. This may include the management of the quality of these tests, the maintenance or improvement of these tests, the development of new test methods, as well as making sure that new tests are comparable to previousmethods and work reliably.

It is also possible that future findings may make it desirable to use the samples acquired in this study for future research, not described in this protocol. Therefore, all subjects will be asked to give a specific consent to allow GSK or a contracted partner to use the samples for future research. Future research will be subject to the laws and regulations in the US and will only be performed once an IEC or IRB has approved this research. This is also applicable for the local regulations in countries where the subjects’ samples may reside, and data derived from them, are analyzed. (see APPENDIX B).

Section 5.8.2. Biological samples

Table 6 Biological samples (Formerly Table 7)

Sample type(Amended 19 November 2012)

Quantity (approximate vol.)

Unit TimepointSub-cohort Name*Number of Subjects

Blood (Humoral immunity)

8 5 mL Visit 1, 2, 4 and 5 All subjects

Blood (Cell-mediated immunity)

20 mL Visit 1, 2, 4 and 5CMI sub-cohortAll subjects

Clinical specimens of HZ lesions

3 samples, taken on the same day, of the highest priority lesion type available (1) vesicle fluid; 2) crust; 3) crust swab; 4) papule swab) †

NAIn case of suspected HZ for diagnosis

Subjects clinically diagnosed as having a suspected case of HZ

* Refer to Section 4.2 for sub-cohort descriptionmL = Milliliter; HZ = Herpes Zoster; NA = Not applicable.† If during clinical evaluation for suspected HZ, the investigator determines that adequate rash lesion samples

cannot be collected (i.e., less than three lesions present, or if only papules are present), the subject should be asked to return to the study site for collection of additional samples within 7 days. When the subject returns to repeat sample collection, if possible, 3 samples from separate lesions should be collected.

Section 5.8.3. Laboratory Assays

Laboratory assays, which will be used in this study, are summarized in Table 7 (Humoral Immunity), and Table 8 (CMI) and Table 9 (Molecular Biology), respectively. Assays for the determination of anti-gE antibodies will be performed by Enzyme-linked Immunosorbent Assay (ELISA) at a GSK Biologicals’ laboratory. The CMI testing will be conducted in a laboratory designated by GSK Biologicals using standardized and validated procedures.






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Table 7 Humoral Immunity (Antibody determination)

System Component Method Kit / Manufacturer Unit Cut-off LaboratoryVZV.gE Ab.IgG ELISA NA mIU/ml 97 GSK Biologicals*

*GSK Biologicals laboratory refers to the Global Vaccines Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium; Laval, Canada.

Table 8 Cell-Mediated Immunity (CMI) (Formerly Table 9)

System Component Challenge Method Unit LaboratoryPBMCPeripheral Blood Mononuclear Cells

Cells CD4.CD40L(+)+Interleukin-2(-)+Tumor Necrosis Factor alpha(-)+Interferon gamma(-) Background ReducedCD4.polypositives CD40L+IL2+TNFα+IFNγ

gE ICS Events/10E6 CEVAC*+

PBMC = Peripheral Blood Mononuclear Cells; IL-2 = Interleukin 2; TNFα = Tumor Necrosis Factor-alpha; IFNγ = Interferon-gamma; gE = Glycoprotein E; ICS = Intracellular cytokine staining.

* CD4.polypositives CD40L+IL2+TNFα+IFNγ = CD4+ T-cells expressing at least 2 activation markers (from among IFN-γ, IL-2, TNF-α and CD40L)

+ CEVAC refers to the Center for Vaccinology, Ghent University, Building A - 1st floor, De Pintelaan 185, 9000 Ghent, Belgium.

Table 9 Molecular Biology (PCR tests) (New Table)

System Component Method Unit LaboratoryHZ lesion sample Varicella Zoster Virus.DNA PCR No unit GSK Biologicals*HZ lesion sample Actin Gene.DNA PCR No unit GSK Biologicals*

HZ = Herpes Zoster; DNA = Deoxyribonucleic Acid; PCR = Polymerase Chain Reaction.* GSK Biologicals laboratory refers to the Global Vaccines Clinical Laboratories (GVCL) in Rixensart, Belgium;

Wavre, Belgium.

Section 5.8.4.1. Immunological read-outs

In case of insufficient blood sample volume to perform assays for all antibodies, tThe samples will be analyzed according to Table 10.

Table 10 Immunological read-outs

Blood sampling timepointNo. subjects ComponentType of contact and

timepointSampling timepoint

Visit 1 (Month 0) Pre-Vacc

All VZV gE Ab.IgG ELISAVisit 2 (Month 1) Post-Vacc IVisit 4 (Month 3) Post-Vacc II

Visit 5 (Month 14) Post-Vacc IIVisit 1 (Month 0) Pre-Vacc

CMI sub-cohort

All

Cells CD4.All double CD40 Ligand or Interleukin-2 or Tumor Necrosis Factor alpha

or Interferon gammaCD4.polypositives CD40L+IL-2+TNFα+IFNγ

Visit 2 (Month 1) Post-Vacc IVisit 4 (Month 3) Post-Vacc II

Visit 5 (Month 14) Post-Vacc IIVacc = Vaccination; VZV = Varaicella Zoster Virus; CMI = Cell-Mediated Immunity; IL-2 = Interleukin 2; TNFα =

Tumor Necrosis Factor-alpha; IFNγ = Interferon-gamma.






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Section 6.5. Contraindications to subsequent vaccination

Any condition that in the judgment of the investigator would make intramuscular injection unsafe.

Acute disease and/or fever at the time of vaccination.

The following events constitute contraindications to administration of the HZ/su vaccineat that point in time; if any of these events occur at the time scheduled for vaccination, the subject may be vaccinated at a later date, within the time window specified in the protocol (see Section 5.6), or the subject may be withdrawn at the discretion of the investigator (see Section 8.49.2).

Fever is defined as temperature 37.5°C/99.5°F by oral route, axillary or tympanic setting, or 38.0°C/100.4°F on rectal setting. The recommended route for recording temperature in this study will be oral.

Section 6.6.1. Recording of concomitant medications/products and concomitant vaccination

All concomitant medications/products, except vitamins and dietary supplements, administered induring the period starting 30 days before and for 30 days followingeach dose of study vaccine.

E.g., an anti-pyretic is considered to be prophylactic when it is given in the absence of fever and any other symptom, to prevent fever from occurring [fever is defined as temperature 37.5°C/99.5°F by oral route, axillary or tympanic setting, or 38.0°C/100.4°F on rectal setting. The preferred route for recording temperature in this study will be oral].

Any concomitant medications/products/vaccines relevant to a SAE*/pIMD to be reported as per protocol or administered at any time during the study period for the treatment of a SAE*/pIMD need to be recorded on the expedited Adverse Event report.* SAEs that are required to be reported per protocol.

Concomitant medication administered for the treatment of pIMDs at any time during the study.

Any concomitant medication/product administered for the treatment of HZ and complications during the study period.

Section 6.6.2. Concomitant medications/products/vaccines that may lead to the elimination of a subject from ATP analyses

Administration of a live vaccine in the period starting 30 days before the first dose of study vaccine and ending at the last blood sampling30 days after the last dose of study vaccine, or, administration of a non-replicating vaccine* within 8 days prior to or within 14 days after either dose of study vaccine. *E.g. inactivated and subunit vaccines,






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including inactivated and subunit influenza vaccines and pneumococcal conjugate vaccines.

Section 6.7. Intercurrent medical conditions (IMCs) that may lead to elimination of a subject from ATP analyses

At each study visit subsequent to the first vaccination visit, until Month 14 it must be verified if the subject has experienced or is experiencing any IMC. If it is the case, the condition(s) must be recorded in the eCRF. IMCs will be recorded in AE/SAE screens as appropriate.

IMCs are clinical events during the course of the study which might alter or confound the interpretation of the immunologic (not safety) assessments of the protocol. In regards to humoral gE assessments, this includes any clinical event that might increase or decrease the measurement of anti-gE antibodies, such as protein losing conditions in which the loss of gammaglobulin or total proteins might underestimate the subject’s gE response (e.g., protein losing enteropathy, proteinuria, or cachexia). Additional examples would be conditions that would cause the administration of exogenous gE antibodies, resulting in an overestimate of the subject’s anti-gE antibody response to HZ/su vaccination, such as conditions requiring the use of intravenous immunoglobulin or blood products.

With regard to measuring cellular immunity, IMCs will be active viral infections that may alter CD4+ T cell counts and/or responses. Examples, not exhaustive, of such acute viral infections would include acute Hepatitis A, acute Hepatitis B, new onset HIV, and potentially acute cytomegalovirus and/or Epstein–Barr virus infections.

The occurrence of HZ is an IMC, since the anti-gE antibody or cellular immune response formed as a result of active shingles cannot be distinguished from the anti-gE antibody or cellular immune response resulting from HZ/su vaccination.

All IMCs including HZ should be reported until Month 14 for all subjects.

Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, they incur a condition that has the capability of confounding their immune response to the study vaccine or its interpretation (e.g., cases of HZ up to study end).

Section 8.1.3.2. Solicited general adverse events

Note: Temperature (oral) will be recorded in the evening. Should additional temperature measurements be performed at other times of day, the highest temperature will be recorded in the eCRF.

Section 8.1.2. Potential immune-mediated diseases

A serious adverse eventSAE is any untoward medical occurrence that:






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Section 8.1.5.1. Potential immune-mediated diseases

Table 15 List of potential immune-mediated diseases

Neuroinflammatory disorders Musculoskeletal disorders Skin disorders

Cranial nerve disorders, including paralyses/paresis (e.g. Bell’s palsy)

Optic neuritis Multiple sclerosis Transverse myelitis Guillain-Barré syndrome, including

Miller Fisher syndrome and other variants

Acute disseminated encephalomyelitis, including site specific variants: e.g. non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitismyeloradiculon euritis

Myasthenia gravis, including Lambert-Eaton myasthenic syndrome

Immune-mediated peripheral neuropathies and plexopathies, (including chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and polyneuropathies associated with monoclonal gammopathy).

Narcolepsy

Systemic lupus erythematosus and associated conditions

Systematic Scleroderma (Systematic sclerosis), including diffuse systemic form and CREST syndrome

Systemic sclerosis Idiophatic

inflammatory myopathies, including Dermatomyositis, Polymyositis

Polymyositis Antisynthetase

syndrome Rheumatoid arthritis,

and associated conditions, including Juvenile chronic arthritis and Still’s disease

Juvenile chronic arthritis, (including Still’s disease)

Polymyalgia rheumatic Spondyloarthritis,

including ankylosing spondylitis, reactive arthritis (Reiter's Syndrome) and undifferentiated spondyloarthritis

Psoriatic arthropathy Relapsing

polychondritis Mixed connective tissue

disorder

Psoriasis Vitiligo Erythema nodosum Autoimmune bullous skin

diseases (including pemphigus, pemphigoid and dermatitis herpetiformis)

Cutaneous lupus erythematosus Alopecia areata Lichen planus Sweet’s syndrome Localised Scleroderma

(Morphoea)






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Vasculitides Blood disorders Others

Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and temporal arteritis.

Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's granulomatosis, Churg–Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease (thromboangiitis obliterans), necrotizing vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet's syndrome, leukocytoclastic vasculitis.

Autoimmune hemolytic anemia

Autoimmune thrombocytopenia

Antiphospholipid syndrome

Pernicious anemia Autoimmune aplastic

anemia Autoimmune

neutropenia Autoimmune

pancytopenia

Autoimmune hemolytic anemia Autoimmune thrombocytopenia Antiphospholipid syndrome Pernicious anemia Autoimmune glomerulonephritis

(including IgA nephropathy, glomerulonephritis rapidly progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and mesangioproliferative glomerulonephritis)

Ocular autoimmune diseases (including autoimmune uveitis and autoimmune retinopathy

Uveitis Autoimmune

myocarditis/cardiomyopathy Sarcoidosis Stevens-jJohnson syndrome Sjögren’s syndrome Idiopathic pulmonary fibrosis Goodpasture syndrome Raynaud’s phenomenon

Liver disorders Gastrointestinal disorders Metabolic diseasesEndocrine disorders

Autoimmune hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Autoimmune cholangitis

Inflammatory Bowel disease, including Crohn’s disease,ulcerative colitis, microscopic colitis, ulcerative proctitis

Ulcerative colitis Ulcerative proctitis Celiac disease Autoimmune

pancreatitis

Autoimmune thyroiditis (including Hashimoto thyroiditis)

Grave's or Basedow’s disease Diabetes mellitus type I Addison’s disease Polyglandular autoimmune

syndrome Autoimmune hypophysitis

CREST = Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia (syndrome)

Section 8.2.1. Time period for detecting and recording adverse events and serious adverse events

The time period for collecting and recording of pIMDs will begin at the first receipt of study vaccine and will end approximately 12 months following administration of the last dose of study vaccine at Visit 5 (last study visit). See Section 8.3.4 for instructions on reporting of pIMDs.

IMCs other than HZ (see Section 6.7) will be recorded from Day 0Visit 1 until Month 14 for subjects Visit 5 (last study visit)and will be recorded in AE/SAE screens as appropriate.






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The occurrence of HZ will constitute an AE/SAE as appropriate. The reporting period for cases of HZ will be from Day 0the Screening Visit to Visit 5 (last study visit)end. Refer to Table 16 and Sections 5.5 and 5.5.1.






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Table 16 Reporting periods for adverse events, serious adverse events, potential immune-mediated diseases and intercurrent medical conditions collecting safety information

Study activity C Vacc 1 Vacc 2 Study conclusion

Visit Screening visit Visit 1 Visit 3 Visit 5

Timing of reporting Month 0

7 da

ys

Pos

t-V

acc

30 d

ays

Pos

t-V

acc

Month 2

7 da

ys

Pos

t-V

acc

30 d

ays

Pos

t-V

acc

Month 14

Solicited local and general AEs

Unsolicited AEs

All SAEs including SAEs related to the investigational vaccine/product

SAEs related to study participation or concurrent GSK medication/vaccine

pIMDs

IMCs including HZ (see Section 6.7) 1

1 All IMCs including HZ should be reported from Visit 1 (Month 0) until Visit 5 (Month 14) for all subjects. For the evaluation of suspected HZ cases between the Screening Visit and Visit 1, refer to Sections 5.5 and 5.5.1.






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Section 8.2.3.2.1. Assessment of intensity

Table 17 Intensity scales for solicited symptoms in adults

Adverse Event Intensity grade ParameterGastrointestinal symptoms 0 Gastrointestinal symptoms nNormal

Section 8.2.3.2.2 Assessment of causality

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory and diagnostics reports) relative to the event. The investigator will then record all relevant information regarding an AE/SAE on the Expedited Adverse Events Report in the eCRF. The investigator is not allowed to send photocopies of the subject’s medical records to GSK Biologicals instead of appropriately completing the Expedited Adverse Events Report as applicable in the eCRF. However, there may be instances when copies of medical records for certain cases are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded on the copies of the medical records prior to submission to GSK Biologicals.

Section 8.2.3.2.2. Assessment of causality

There may be situations when a SAE has occurred and the investigator has minimal information to include in the initial report to GSK Biologicals. However, it is very important that the investigator always makes an assessment of causality for every event prior to submission of the SAE reportExpedited Adverse Events Report to GSK Biologicals. The investigator may change his/her opinion of causality in light of follow-up information and update the SAE information accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

Section 8.3.1. Prompt reporting of serious adverse events, and other events to GSK Biologicals

pIMDs that occur in the time period defined in Section 8.2 will be reported promptly to GSK within the timeframes described in Table 18, once the investigator becomes aware of determines that the event meets the protocol definition of a pIMD.






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Table 18 Timeframes for submitting serious adverse event and other events reports to GSK Biological

Type of EventInitial Reports

Follow-up of Relevant Information on aPrevious Report

Timeframe Documents Timeframe DocumentsSAEs 24 hours*‡ electronic SAE

reportExpedited Adverse Events Report

24 hours* electronic SAE reportExpedited Adverse Events Report

pIMDs 24 hours**‡ electronic SAE reportExpedited Adverse Events Report

24 hours* electronic SAE reportExpedited Adverse Events Report

* Timeframe allowed after receipt or awareness of the information.** Timeframe allowed after the diagnosis is established and known to once the investigator determines that the event meets the protocol definition of a pIMD.‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in

the electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD

Section 8.3.2. Contact information for reporting serious adverse events and other events to GSK BiologicalspIMDs

Study Contact for Reporting SAEs and pIMDs24/24 hour and 7/7 day availability:

GSK Biologicals Clinical Safety & Pharmacovigilance

Back-up Study Contact for USA for Reporting SAEsUS Safety CSAFax: , Tel:

Section 8.3.3. Completion and transmission of SAE reports to GSK Biologicals

Once an investigator becomes aware that a SAE has occurred in a study subject, the investigator (or designate) must complete the information in the electronic SAE reportExpedited Adverse Events Report WITHIN 24 HOURS. The SAE report will always be completed as thoroughly as possible with all available details of the event. Even if the investigator does not have all information regarding a SAE, the report should still be completed within 24 hours. Once additional relevant information is received, the report should be updated WITHIN 24 HOURS.

The investigator will always provide an assessment of causality at the time of the initial report. The investigator will be required to confirm the review of the SAE causality by ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of submission of the SAE.




PPD PPD



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Section 8.3.3.1. Back-up system in case the electronic SAE reporting system does not work

If the electronic SAE reporting system does not work, the investigator (or designate) must complete, then date and sign a paper SAE reportExpedited Adverse Events Report and fax it to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or and fax it to the GSK Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.

This back-up system should only be used if the electronic SAE reporting system is not working and NOT if the system is slow. As soon as the electronic SAE reporting system is working again, the investigator (or designate) must complete the electronic SAE reportExpedited Adverse Events Report within 24 hours. The final valid information for regulatory reporting will be the information reported through the electronic SAE reporting system.

Section 8.3.4. Reporting of pIMDs to GSK Biologicals

Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or designate) must complete the information in the electronic SAE reportExpedited Adverse Events Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. A field on the SAE The report allows to specify that the event is a pIMD and whether it is serious or non serious. The SAE report will always be completed as thoroughly as possible with all available details of the event, in accordance with the pIMD standard questionnaire provided. Even if the investigator does not have all information regarding a pIMD, the report should still be completed within 24 hours. Once additional relevant information is received, the report should be updated WITHIN 24 HOURS.

The investigator will always provide an assessment of causality at the time of the initial report. The investigator will be required to confirm the review of the pIMD causality by ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of submission of the pIMD.

Section 8.3.5. Updating of SAE and pIMD information after freezingremoval of write access to the subject’s eCRF

When additional SAE or pIMD information is received after freezingremoval of the write access to the subject’s eCRF, new or updated information should be recorded on athe appropriate paper report, with all changes signed and dated by the investigator. The updated report should be faxed to the Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance department or to the Study Contact for Reporting SAEs (refer to the Sponsor Information Sheet) within the designated reporting time frames specified in Table 18.






05-MAY-2017 130

Section 8.7. Safety Monitoring

An internal GSK Safety Review Team (SRT) will oversee the safety of the ZOSTER-048 study on a regular basis. SAEs and AEs including pIMDs will be reviewed by the SRT at regular intervals together with data from other ongoing ZOSTER vaccine studies. Any potential safety concern related to conduct of the study will be escalated to higher governing bodies as per internal GSK process.

Section 9.2 Subject withdrawal

WithdrawalsSubjects withdrawn following vaccination will not be replaced.

Section 9.3. Screen failures

Subjects enrolled at the screening visit will sign the ICF, have inclusion and exclusion criteria checked, have demographic data, date of any previous Zostavax vaccination and their medical history including any medical condition(s) recorded (Section 5.7.1and Table 4). As indicated in Section 10.3, only a minimum of 400 subjects will be invited for Visit 1 (i.e., first vaccination visit), from the subjects enrolled during the screening visit. Certain subjects may not be matched, and will therefore not proceed with the rest of the study. In addition, subjects may no longer be eligible, may lose interest or may experience a change in medical condition rendering them unable to be matched by Visit 1. The ineligible subjects and the un-matched subjects will be informed by the investigator about their status, and they will be withdrawn from the study.

Section 10.1. Primary endpoints


Anti-gE antibody concentrations, as determined by ELISA, at Months 0, 1 and3.

Section 10.2. Secondary Endpoints

gE-specific CD4+ T-cell mediated immunogenicity, in the CMI sub-cohort.






05-MAY-2017 131

Section 10.3. Strategy for group matching between groups

The following four variables have been chosen to be matched between groups for analyses are,. However, in case the matching is not feasible, some categories within a variable may be merged or no longer be considered for matching:

Only one medical condition cited below will be used for the matching in a hierarchical manner, with a. being the condition to match subjects on first, then down the list until gf.





e. Heart Conditions

f. Other


The strategy used for matching of groups will utilize a specific matching algorithm, integrated in SBIR to manage the variables and match subjects between the groups starting at the screening visit.

Enrolment starts at the screening visit where up to approximately 800 subjects will be entered into SBIR as “Planned” (for the study);

The status of the subjects’ Zostavax vaccination will be recorded;

Matching variables such as age category, gender, race and medical condition(s) will be entered into SBIR to register the subjects;

A matching algorithm will match subjects to be included in the No prev-Zvax group with subjects from the Prev-Zvax group;

Not all subjects identified as Planned during the screening visit will be able to participate in the study. Certain subjects may not be matched, and will therefore not proceed with the rest of the study. From the Planned subjects identified during the screening visit, only a minimum of 400 subjects will be invited for Visit 1 (i.e., first vaccination visit), and the remaining un-matched subjects will be withdrawn from the study once a target of 400 enrolled subjects has been met. These withdrawn subjects will be informed by the investigator when recruitment at their site is completed.

In case a subject is no longer eligible, or in case a change in medical condition makes the subject unable to be matched, the subject will be withdrawn from the study.

Refer to the SPM for further details on the matching strategy.






05-MAY-2017 132

proceed in 3 Steps:

Step 1: Enroll initial Prev-Zvax subjects and determine their variable profile.

After enrolling approximately 50 subjects for the Prev-Zvax group (those who previously received Zostavax ≥ 5 years earlier), the distribution across 144 combinations of the matching variable will be analyzed. This will then be used to determine the number of subjects to enroll in each matched variable combination for the No prev-Zvax group.

Step 2: Enroll No prev-Zvax subjects according to the Prev-Zvax profile distribution determined at Step 1.

Step 3: Monitor for any profile changes and adapt matching enrolment criteria accordingly.

A monitoring of the distribution of subjects for each matching variable combination for the Prev-Zvax group will be performed regularly (e.g., approximately every 50 subjects enrolled). The criteria to enroll No prev-Zvax subjects will be adapted, should the distribution of matching variables change, compared to those initially determined in Step 1. Therefore, Step 1 and 2 will be repeated until the required number of subjects has been enrolled.

Section 10.3.1. Contingency plan for the group matching strategy

Continuous in stream evaluation of the matching strategy during screening will determine if a particular combination of variables is unlikely to be matched. If the matching of subjects is not feasible because the target number for some matching variable(s)/category is limiting, the following two-step contingency plan will be implemented:

1. The categories within the limiting variables (race or medical condition) will first be merged. The categories in the variable age will never be merged. Merging the variable gender will not be done as a first step (since merging gender will result in removing of the variable). The categories that could be merged will depend on which variable is a barrier to matching, between race and medical condition.

2. If the matching of subjects continues to be blocked after the merging of categories within either race or medical condition, the variable could be removed. If after removing the first variable there are still difficulties in completing enrolment into the No prev-Zvax group, then the remaining variables will be considered for removal. For example, if race becomes a limiting factor, it will no longer be taken into consideration for matching. The variable for age will never be removed.

The timing for merging categories or removing a matching variable cannot be predicted in advance as it depends on enrolment. The decision to merge categories or remove a matching variable will be established by the central GSK study team. Additional details on the matching strategy may be found in the SPM.






05-MAY-2017 133

Section 10.4. Determination of sample size

Non-inferiority in term of anti-gE GMC

Non-inferiority will be demonstrated if the upper limit of the 2-sided 95% confidence interval (CI) for the adjusted GMC group ratio (No prev-Zvax over Prev-Zvax) of anti-gE antibodies is equal to or below 1.5.

Table 19 presents the power to reach the non-inferiority, assuming the enrolment is 200 subjects per group and non-evaluable rate is abouteither 5% or 10%.

Table 19 Power to show that the 95%CI for the GMC ratio between groups (No prev-Zvax over Prev-Zvax) for anti-gE is below a predefined clinically-acceptable limit of 1.5

Antigens Endpoints Reference values* Clinically acceptable limit

Power(N=190 vs. 190)**

Power(N=180 vs. 180)**

gE GMC post-dose 2

STD of log10 concentrations of 0.35

1.5 fold 99.8% 99.7%

Descriptive analysis for safety and reactogenicity

In this study, descriptive safety assessment is a co-primary objective.

The 95% CIs for a given percentage of subjects reporting a symptom after vaccination, assuming a sample size of 200 subjects per vaccine group is presented in Table 20. However, no formal comparison between groups has been foreseen. Therefore, overlapping between groups of the 95%CIs should be interpreted with caution because the sample size does not allow to detect a significant difference. In addition, no adjustment of type I error for multiple comparisons and no clinical criteria of a difference have been considered. The table illustrates the probability to detect a 5% and 10% increase in the Prev-Zvax group as compared to the Non-prev-Zvax group with no adjustment for multiplicity.






05-MAY-2017 134

Table 20 Exact 95% confidence interval CI for proportion with 200 subjects and probability to detect 5%, 10% increase in the Prev-Zvax group as compared to the Non-Prev-Zvax group

(Deleted Table)

No. of subjects with a symptom

% of subjects with a symptom (N=200)

95% Confidence Interval (CI)

Lower Limit

Upper Limit

0 0.0 0.0 1.8

10 5.0 2.4 9.0

20 10.0 6.2 15.0

30 15.0 10.4 20.7

40 20.0 14.7 26.2

50 25.0 19.2 31.6

60 30.0 23.7 36.9

70 35.0 28.4 42.0

80 40.0 33.2 47.1

90 45.0 38.0 52.2

100 50.0 42.9 57.1

110 55.0 47.8 62.0

120 60.0 52.9 66.8

130 65.0 58.0 71.6

140 70.0 63.1 76.3

150 75.0 68.4 80.8

160 80.0 73.8 85.3

170 85.0 79.3 89.6

180 90.0 85.0 93.8

190 95.0 91.0 97.6






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(New Table 20)

% of subjects with a symptom in the no-prev Zvax group (N=200)

95% ConfidenceProbability to detect 5% increase in the Prev-Zvax group (N=200)*

Probability to detect 10% increase in the Prev-Zvax group (N=200)*

Interval (CI)

LowerLimit

UpperLimit

1% 0.10% 3.60% 68.91% 98.16%

5% 2.40% 9.00% 40.03% 88.95%

10% 6.20% 15.00% 27.39% 76.04%

15% 10.40% 20.70% 21.85% 66.21%

20% 14.70% 26.20% 18.84% 59.31%

25% 19.20% 31.60% 17.01% 54.53%

30% 23.70% 36.90% 15.85% 51.27%

35% 28.40% 42.00% 15.11% 49.17%

40% 33.20% 47.10% 14.66% 47.98%

45% 38.00% 52.20% 14.45% 47.60%

50% 42.90% 57.10% 14.45% 47.98%

55% 47.80% 62.00% 14.66% 49.17%

60% 52.90% 66.80% 15.11% 51.27%

65% 58.00% 71.60% 15.85% 54.53%

70% 63.10% 76.30% 17.01% 59.31%

75% 68.40% 80.80% 18.84% 66.21%

80% 73.80% 85.30% 21.85% 76.04%

85% 79.30% 89.60% 27.39% 88.95%

90% 85.00% 93.80% 40.03% 99.31%

95% 91.00% 97.60% 82.50% 82.50%

*Pass 2005, 1-sided Fisher’s Exact test for two proportions, alpha = 2.5%

Section 10.5. Study cCohorts for Analysis

Section 10.5.1. Total vaccinated cohort

The TVC analysis will be performed per treatment actuallyactual group administered (at Dose 1) to which the subject belongs as based on previous Zostavax vaccination status.

Section 10.5.3. According To Protocol cohort for analysis of immunogenicity

The ATP cohort for analysis of immunogenicity will include all evaluable subjects (i.e., those meeting all eligibility criteria, complying with the procedures and intervals defined in the protocolallowed for the analysis (see Table 20), with no elimination criteria during the study) for whom data concerning immunogenicity endpoint measures are available.






05-MAY-2017 136

Table 21 The intervals allowed for the inclusion in the ATP cohort for analysis of immunogenicity (New Table)

Interval Allowed interval for ATP cohort analysis of immunogenicity

Interval between vaccinations HZ/su (Dose 1, Day 0) –HZ/su (Dose 2, Month 2)

49-83 Days

Interval between vaccination and blood sample taken

HZ/su (Dose 2, Month 2) –Visit Month 3 for BS for anti-gE Ab

28-48 days

ATP = According To Protocol; HZ/su = Herpes Zoster subunit vaccine; BS= Blood Sample; gE = VZV glycoprotein E; Ab = Antibody.

Section 10.6.2. Humoral immune response

The GMC calculations are performed by taking the anti-log of the mean of the log concentration transformations. For descriptive statistics only, Ab concentrations below the cut-off of the assay will be given an arbitrary value equal to half the cut-off for the purpose of GMC calculation.

Section 10.6.3. Cell mediated immune response

The frequency of CD4 T-cells producing at least two activation markers (IFN-, IL-2, TNF- and/or CD40 Ligand, termed CD4[2+]) upon in vitro stimulation with the antigen (induction condition) is calculated by adding an offset of 0.5 to the number of activated CD4 T-cells (numerator) divided by the total number of CD4 T-cells involved (denominator). A similar calculation will be made for the frequency of CD4[2+] upon in vitro stimulation in medium only (background condition).

(Deleted Figure)

The frequency of gE-specific CD4 T-cells for each individual subject is calculated as the difference between the frequency of CD4[2+], upon in vitro stimulation with the gE antigen (induction condition) minus the frequency of (CD4[2+] upon in vitro stimulation in medium only (background condition). The differences less or equal to one are imputed to one gE-specific activation marker expressing CD4 T-cells per 106 CD4 T-cells. These transformations are mainly used for descriptive statistics purposes.






05-MAY-2017 137

(Deleted Figure)

The geometric mean frequency calculations are performed by taking the anti-log of the mean of the log frequency transformations.

For the descriptive analyses, the frequency of CD4[2+] T-cells upon in vitro stimulation with the gE-antigen (induction condition) is calculated by dividing the number of activated CD4[2+] T-cells (numerator) over the total number of CD4 T-cells involved (denominator). The same calculation will be performed for the frequency computation for any kinds of cells and for each individual activation marker as appropriate.

The frequency of gE-specific CD4 T-cells for each individual subject is calculated as the difference between the frequency of CD4[2+] T-cells, upon in vitro stimulation with the gE antigen (induction condition) minus the frequency of CD4[2+] T-cells upon in vitro stimulation in medium only (background condition). The differences less or equal to one are imputed to one gE-specific CD4[2+] T-cell per 106 CD4+ T-cells. The same calculation will be performed for the frequency computation for any kind of cells and for each individual activation marker as appropriate.

The Geometric Mean frequency calculations are performed by taking the anti-log of the mean of the log frequency transformations.

)(inductionassay in theinvolvedcellsTCD4ofnumber Total

antigenwith theinduction after markersactivation2least at secretingcellsTCD4ofnumber 4

2

4

224

CD

Induction

CDInduction

InductionCDInduction

N

n

N

nFreq

) backgroundof(inductionassay in theinvolvedcells-TCD4ofnumber Total

conditionsmediumin themarkersactivation2least at secretingcells-T CD4ofnumber

antigen -gE with theinduction after markersactivation2least at secretingcells-T CD4ofnumber

1 1

1

4

2

2

4

2

4

224

4

2

4

2

4

2

4

224

N

n

n

CD

Background

Induction

CDBackground

Background

CDInduction

InductionCDSpecific

CDBackground

Background

CDInduction

InductionCDBackground

Background

CDInduction

InductionCDSpecific

N

n

N

nifFreq

N

n

N

nif

N

n

N

nFreq






05-MAY-2017 138

Section 10.7. Analysis of demographics

Demographic characteristics (age, gender and ethnicity) as well as the matched variables characteristic at the time of enrolmentVisit 1 will be tabulated per treatment group.

The mean age (plus range and standard deviation [SD]) of the enrolledvaccinatedsubjects, as a whole, and per treatment group will be calculated.

The distribution of subjects enrolledvaccinated among the study sites will be tabulated as a whole and per treatment group.

Section 10.8.1.1. Humoral immune response

Descriptive statistics of the following parameters will be tabulated by vaccine group:

The following parameters will be tabulated by vaccine group at each time point when a blood sample result is available:

Section 10.8.1.2. Cell-mediated immune response

Descriptive statistics (N, mean, SD, min, Q1, median, Q3, max) of the following parameters will be tabulated by vaccine group at all timepoints:

Descriptive statistics of the frequency of CD4+ T-cells secreting at least two activation markers (from among IFN-, IL-2, TNF-,CD40L) for gE-specific stimulation.

Section 10.8.2. Between groups assessment

A General Linear Modeln ANOVA model will be used to compare the GMC assess the geometric mean (GM) fold increase between No prev-Zvax and Prev-Zvax groups at month 2.

The log-transformed antibody concentration will be modelled. The group effect and each categorical variable used for the group-matching variable used enrolment will be included in the model. Sensitivity analyses will be conducted to explore the effect of potential other covariables.

Geometric means of Month 2 post-vaccination antibody concentrations will be calculated

conditionally to the means of all adjusted variables calculated across the groups. Adjusted

means and difference of means between No prev-Zvax and Prev-Zvax groups will be

calculated together with 2-sided CIs and back-transformed to the original units to provide

GMCs and GM ratios.

The non-inferiority be is demonstrated if the upper limit of the two-sided 95% CI of the

adjusted GMC ratio (No prev-Zvax over Prev-Zvax) 1-month post-dose 2 is equal or

below 1.5 in terms of anti-gE antibodies.






05-MAY-2017 139

Section 10.9.1. Within groups assessment

Safety analyses might be performed overall and by age stratum (65-69, 70-79 and ≥ 780 YOA).

The results for the analysis of safety will be tabulated as follows:

The number and percentage of subjects with at least one local solicited AE, with at least one general solicited AE and with any solicited AE during the 7-day follow-up period with exact 95% CIs after each vaccine dose and overall by vaccination group will be provided. The same tabulation will be performed for grade 3 solicited AE.

The percentage of subjects reporting each individual solicited local and general AE during the solicited 7-day follow-up period will be tabulated with exact 95% CI;

For all solicited symptoms, t. The same tabulation will be performed for grade 3 solicited AEs and for solicited general AEs with relationship to vaccination;

Section 10.11.1. Sequence of analyses

Two analyses are planned: one analysis for data up to 1 month post-dose 2 (Month 3) may occur if needed, and one for data up to 12 months post-dose 2 of the study (Month 14).

Month 3 analysis:

TIf performed, the analysis at Month 3 will be performed on data collected through Visit 4 (Month 3; 1 month post-dose 2) which are as clean as possible (data are cleaned but the possibility of post-analysis data changes exists afterwards because data collection and data entry may continue through Month 14). At this point, the GSK central clinical team will be unblinded (i.e., will have access to the lab data).

This analysis will be presented in a Clinical Study Report (CSR). No individual listings will be provided at this stage.

End of study - Month 14 analysis:

The analysis at Month 14 will be performed on data collected through Visit 5 (Month 14; 12 months post-dose 2) which have been cleaned.

These analyses will be presented in a CSR. Final individual listings will only be provided at this stage.

Note that all the analysis previously done at Month 3 will be regenerated again to evaluate the impact of database changein case data changes have been made after the Month 3 analysis has been done, the impact of these changes on the endpoints will be evaluated and the Month 3 statistical report analysis will be updated consequently. The details of the procedure will be described in the SAP.

A clinical study report (CSR) will be written at the conclusion of the study, presenting all data up to and including Month 14.






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Section 11.1. Remote Data Entryelectronic Case Report Forminstructions

Remote Data Entry (RDE), aA validated computer applicationGSK defined electronic data collection tool, will be used as the method for data collection.

Section 11.2. Study Monitoring by GSK Biological

Direct access to all study-site related and source data is mandatory for the purpose of monitoring review. The monitor will perform an InFormeCRF review and a Source Document Verification (SDV). By SDV we understand verifying InFormeCRF entries by comparing them with the source data that will be made available by the investigator for this purpose.

The Source Documentation Agreement Form describes the source data for the different data in InFormeCRF. 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 InFormeCRF will serve as the source must be identified, agreed and documented in the source documentation agreement form.

For InFormeCRF, the monitor will markfreezes completed and approved screens at each visit.

Section 11.3. Record retention

The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any institutional requirements, applicable laws or regulations, or GSK standards/procedures; otherwise, the minimum retention period will default to 15 years.

Section 11.5. Posting of information on publicly available clinical trial registers and publication policy

GSK also aims to publish the results of these studies in the searchable, peer reviewed scientific literature. Manuscripts are submitted for publication within 24 months of the last subject’s last visit. At the time of publication, this protocol will be fully disclosed.

Section 13. REFERENCES

Lal H, Cunningham AL, Godeaux O, et al., Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults. N Engl J Med. 2015: DOI: 10.1056/NEJMoa1501184.

Morrison VA, Johnson GR, Schmader KE, et al., Long-Term Persistence of ZosterVaccine Efficacy. Clin Infect Dis. 2015; 60(6): 900-9.






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Onozawa M, Hashino S, Takahata M et al., Relationship between pre-existing anti-varicella-zoster virus (VZV) antibody and clinical VZV reactivation in hematopoietic stem cell transplantation recipients. J Clin Microbiol. 2006; 44(12): 4441-3.

APPENDIX A LABORATORY ASSAYS

Intracellular cytokine staining (ICS):

CMI responses will be performed by GSK Biologicals (or designated laboratory) on thawed Peripheral Blood Mononuclear Cells (PBMCs) by ICS. The assay will be performed on samples collected during the course of the study. This assay provides information on the frequency of CD4 T cells responding to culture medium or antigens (gE peptide pool or VZV lysate) by secreting cytokine molecules involved in immunity such as IFN-, IL-2, TNF-, and CD40L.

Briefly, PBMC collected from the subjects are stimulated for two hours using culture medium (for evaluation of the non-specific response), a pool of overlapping peptides covering the entire sequence of the vaccine antigen gE or a VZV lysate. Then, an intracellular block (brefeldin A) is added to inhibit cytokine secretion for a subsequent overnight incubation. Cells are then harvested, stained for surface markers (CD3, CD4 and CD8) and fixed. The fixed cells are then permeabilised and stained with anti-cytokine Abs, washed and analyzed by cytofluorometry.

The results of ICS assays are expressed as the frequency of specific CD4 T cells per million total CD4 T cells.

PCR assay for confirmation of suspected case of HZ:

HZ cases will be confirmed by a Polymerase Chain Reaction (PCR) based algorithm that assesses the presence of VZV Deoxyribonucleic Acid (DNA) in samples, and the adequacy of the samples (by assessing the presence of β-actin DNA).

VZVand β-actin DNA in HZ clinical specimens will be assessed using real-time PCR detection by the 5’ nuclease assay based on the Taqman probe technology. If the VZV PCR is negative, β-actin PCR will be performed to assess adequacy of the sample and if a specimen is found to be VZV–PCR negative and β-actin–PCR negative, it is considered to be inadequate.

In the Taqman-based PCR experiments, the formation of a PCR product is monitored in real-time during amplification by means of fluorogenic probes that bind specifically to the amplified product. The reporter fluorophore is at the 5’ end of the Taqman probe and the quencher is at the 3’ end. As long as the probe is intact, no fluorescence is produced by the fluorophore. During the PCR polymerization step, the Taq DNA polymerase displaces the Taqman probe by 3-4 nucleotides, and the 5’ nuclease activity of the DNA polymerase separates the fluorophore from the quencher, and a measurable fluorescent signal proportional to the DNA copy number is produced.

As mentioned above, the 5' nuclease-based PCR assay allows the determination of the DNA copy number within samples, but in the present study the VZV and β-actin DNA






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PCR data on samples from suspected HZ lesions (swabs of vesicles, papules and crusts, and crusts themselves) will be used qualitatively only according to the above mentioned approach.

APPENDIX B CLINICAL LABORATORIES

Table 22 GSK Biologicals’ laboratories (Formerly Table 21)

Laboratory AddressGSK Biologicals Global Vaccine Clinical Laboratory, Rixensart

Biospecimen Reception - B7/44Rue de l'Institut, 89 - B-1330 Rixensart - Belgium

GSK Biologicals Global Vaccine Clinical Laboratory, North America-Laval

Biospecimen Reception - Clinical Serology525 Cartier blvd West - Laval - Quebec - Canada -H7V 3S8

GSK Biologicals Global Vaccine Clinical Laboratory, Wavre-Nord Noir Epine

Avenue Fleming, 20 - B-1300 Wavre - Belgium

Table 23 Outsourced laboratories (Formerly Table 22)

Laboratory AddressQuest Diagnostics Clinical Trials (US)

27027 Tourney Road, Suite 2EValencia, CA 91355USA

CEVAC - University of Ghent Building A - 1st floor, De Pintelaan 185, 9000 Ghent, Belgium

CEVAC = Centre for Vaccination






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Clinical Research & Development

Protocol Administrative Change 1eTrack study number and Abbreviated Title

201198 (ZOSTER-048)


Administrative change number:

Administrative change 1

Administrative change date: 05 May 2017

Co-ordinating author: , Scientific writer


The back-up study contact telephone number for reporting SAEs and pIMDs in the US was deleted in Section 8.3.2, since that telephone number, which was originally provided to the sites as a courtesy, has been inactivated.

The names of the co-ordinating author, contributing authors and sponsor have been updated on the title pages.

Amended text has been included in bold italics and deleted text in strikethrough in the following sections:




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Title page Co-ordinating author and Contributing authors

Co-ordinating author , Scientific Writer, XPE Pharma & Science, Contractor for GSK Biologicals

Contributing authors , Clinical Research and Development Lead

, Director, Clinical Research and Development Lead, Vaccine Discovery and Development

, Study Delivery Lead , Study Delivery Lead , Study Delivery Lead , Study Delivery Lead , Global Regulatory Affairs (USA) , Global Regulatory Affairs

(USA) , Manager, Global Regulatory

Affairs , Safety Physician , Safety Physician , Safety Physician , Global Vaccine Clinical

Laboratories Team Lead Clinical LaboratorySciences (CLS) Project Manager

, Global Vaccine Clinical Laboratories Project Manager

, Project Data Manager , Project Data Manager , Vaccine Supply Coordinator,

Aprova, Contractor for GSK Biologicals , Vaccine Supply Coordinator,

consultant, Valesta for GSK Biologicals , Director, Portfolio Clinical

Research and Development Lead, Vaccine Discovery and DevelopmentClinical and Epidemiology Project Leader (CEPL), Belgian RDC

, Director, Portfolio Clinical Research and Development Lead, Global Late Clinical Development

Sponsor Signature page sponsor signatory

Sponsor signatory Lidia Oostvogels, Director, Portfolio Clinical Research and Development Lead, Vaccine Discovery and DevelopmentClinical and Epidemiology Project Leader (CEPL), Belgian




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RDC

Section 8.3.2. Contact information for reporting serious adverse events and pIMDs

Study Contact for Reporting SAEs and pIMDsBack-up Study Contact for USA for Reporting SAEsUS Safety CSAFax: , Tel:




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