A Phase III Randomized, Placebo-Controlled, Clinical Trial to Study the Safety and Efficacy of V212 in Adult Patients With Solid Tumor or Hematologic Malignancy
Phase: PHASE3
Conditions: Herpes Zoster
Sponsor: Merck Sharp & Dohme LLC

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase III Randomized, Placebo-Controlled, Clinical Trial to 
Study the Safety and Efficacy of V212 in Adult Patients with Solid 
Tumor or Hematologic Malignancy 
NCT number: 
NCT01254630 
Document Date: 
30-Jun-2015 

Product:  V212
Page 1
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION 
RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY 
OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., 
INC., WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as 
the SPONSOR or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Administrative 
Binder.
TITLE:
A Phase III Randomized, Placebo-Controlled, Clinical Trial to Study the Safety and 
Efficacy of V212 in Adult Patients with Solid Tumor or Hematologic Malignancy
INVESTIGATOR:
PRIMARY:
CLINICAL PHASE: III
US IND NUMBER:
13752
SITE:
INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:

Product:  V212
Page 2
Protocol/Amendment No.: 011-04
Confidential
Table of Contents
SUMMARY OF CHANGES...............................................................................................6
Primary Reason for This Amendment: ................................................................................6
Additional Changes for This Amendment:........................................................................10
1. SUMMARY.................................................................................................................11
1.1
TITLE ....................................................................................................................11
1.2
INDICATION........................................................................................................11
1.3
SUMMARY OF RATIONALE.............................................................................11
1.4
SUMMARY OF STUDY DESIGN ......................................................................13
1.5
SAMPLE ...............................................................................................................15
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN.........................15
1.7
STUDY FLOW CHART.......................................................................................16
1.8
STUDY FLOW CHART FOR PATIENTS WITH SUSPECTED HZ.................19
2. CORE PROTOCOL.....................................................................................................21
2.1
OBJECTIVES AND HYPOTHESES ...................................................................21
2.1.1
Primary Objectives .........................................................................................21
2.1.2
Primary Hypotheses........................................................................................21
2.1.3
Secondary Objectives .....................................................................................21
2.1.4
Exploratory Objectives...................................................................................21
2.2
PATIENT INCLUSION CRITERIA.....................................................................22
2.3
PATIENT EXCLUSION CRITERIA....................................................................24
2.3.1
Deferment Criteria (Prior to Vaccination of Doses 2 through 4) ...................24
2.3.2
Continuation in the Study under Special Circumstances ...............................25
2.4
STUDY DESIGN AND DURATION...................................................................25
2.4.1
Summary of Study Design..............................................................................25
2.4.2
Vaccination Plan.............................................................................................29
2.5
LIST OF EFFICACY/IMMUNOGENICITY MEASUREMENTS......................30
2.5.1
HZ Case Determination..................................................................................30
2.5.2
Secondary Efficacy Measurements ................................................................32
2.5.3
Immunogenicity Measurements .....................................................................32
2.6
LIST OF SAFETY MEASUREMENTS...............................................................33
2.7
STATISTICAL ANALYSIS PLAN SUMMARY................................................34
2.7.1
Efficacy...........................................................................................................34
2.7.2
Immunogenicity..............................................................................................35
2.7.3
Safety..............................................................................................................35
2.7.4
Power and Sample Size ..................................................................................36
2.7.5
Interim Analysis .............................................................................................37
3. PROTOCOL DETAILS...............................................................................................38
3.1
RATIONALE ........................................................................................................38
3.1.1
General Background.......................................................................................38
3.1.1.1
Epidemiology of HZ in Patients with HM..............................................39

Product:  V212
Page 3
Protocol/Amendment No.: 011-04
Confidential
3.1.1.2
Epidemiology of HZ in Patients with STM ............................................40
3.1.2
Rationale for This Study.................................................................................40
3.1.2.1
Rationale for Choice of Vaccine Inactivation Method ...........................42
3.1.2.2
Rationale for Dose Regimen...................................................................43
3.1.2.3
Rationale for Selection of Efficacy Endpoint Measures.........................45
3.1.2.4
Rationale for the Immunogenicity Endpoint Measures ..........................45
3.2
STUDY PROCEDURES.......................................................................................46
3.2.1
Visit Windows................................................................................................46
3.2.2
Informed Consent ...........................................................................................46
3.2.3
Assignment of Baseline Number....................................................................47
3.2.4
Non-Randomized Patients..............................................................................47
3.2.5
Study Participation Patient Identification Card..............................................47
3.2.6
Physical Examination.....................................................................................47
3.2.7
Medical History/Conditions ...........................................................................47
3.2.8
History of Varicella-Zoster Virus Infection ...................................................48
3.2.9
Concomitant Medication(s)/Treatment(s) ......................................................48
3.2.10 Contraception .................................................................................................49
3.2.11 Pregnancy Testing ..........................................................................................50
3.2.12 Stratification/Randomization/Allocation........................................................50
3.2.13 Blood Collection for Immunoassays ..............................................................51
3.2.14 Vaccination.....................................................................................................51
3.2.14.1 Dosage and Administration.....................................................................52
3.2.14.2 General Precautions for Administration .................................................52
3.2.14.3 Preparation of the Vaccine......................................................................52
3.2.14.4 Administration of the Study Vaccine......................................................53
3.2.14.5 Replacement Vials ..................................................................................53
3.2.15 Clinical follow-up for safety ..........................................................................53
3.2.16 Exposure Survey.............................................................................................53
3.2.17 Follow-up of Suspected HZ Cases .................................................................54
3.2.17.1 Definition of a Suspected Case of HZ ....................................................54
3.2.17.2 Identification of Suspected HZ Cases.....................................................54
3.2.17.3 Suspected HZ Case Follow-Up (Cases With HZ and HZ-like 
Rash) .......................................................................................................55
3.2.17.4 Suspected HZ Case Follow-Up (Cases Without HZ/HZ-like 
Rash) .......................................................................................................58
3.2.17.5 Treatment of HZ in Study Patients .........................................................59
3.2.18 Blinding/Unblinding.......................................................................................60
3.2.19 Study Completion Procedures ........................................................................60
3.2.20 Discontinuation/Withdrawal from Study .......................................................61
3.2.20.1 Discontinuation/Withdrawal Criteria......................................................61
3.2.21 Committees.....................................................................................................61
3.2.21.1 Clinical Adjudication Committee ...........................................................61
3.2.21.2 Scientific Advisory Committee...............................................................61
3.2.21.3 Data Monitoring Committee...................................................................61
3.2.21.4 Steering Committee.................................................................................62

Product:  V212
Page 4
Protocol/Amendment No.: 011-04
Confidential
3.3
EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC. 
MEASUREMENTS...............................................................................................62
3.3.1
HZ Case Determination..................................................................................62
3.3.1.1
Clinical Adjudication..............................................................................62
3.3.1.2
Final Case Determination........................................................................63
3.3.2
PCR Assay for Lesion Samples......................................................................63
3.3.3
PCR Assay for Whole Blood Samples...........................................................64
3.3.4
VZV Antibody gpELISA ...............................................................................64
3.3.5
VZV IFN-γ ELISPOT ....................................................................................65
3.4
SAFETY MEASUREMENTS ..............................................................................66
3.4.1
Clinical Measurements for Safety/Vaccination Report Card .........................66
3.4.1.1
Safety Follow-up During the Vaccination Period...................................66
3.4.1.2
Post-Vaccination Safety Follow-up ........................................................67
3.4.1.3
Adverse Experience Toxicity Grading....................................................67
3.4.1.4
PCR testing for Miscellaneous Samples in Patients with 
Serious Adverse Experiences..................................................................68
3.4.2
Recording Adverse Experiences.....................................................................68
3.4.3
Definition of an Overdose for This Protocol..................................................69
3.4.3.1
Reporting of Overdose to SPONSOR.....................................................69
3.4.4
Reporting of Pregnancy to SPONSOR...........................................................69
3.4.5
Immediate Reporting of Adverse Experiences to the SPONSOR..................69
3.4.5.1
Serious Adverse Experiences..................................................................69
3.4.6
Evaluating Adverse Experiences....................................................................70
3.4.7
SPONSOR Responsibility for Reporting Adverse Experiences ....................73
3.5
STATISTICAL ANALYSIS PLAN......................................................................73
3.5.1
Responsibility for Analyses............................................................................73
3.5.2
Hypotheses .....................................................................................................74
3.5.3
Analysis Endpoints.........................................................................................74
3.5.3.1
Efficacy...................................................................................................74
3.5.3.2
Immunogenicity ......................................................................................76
3.5.3.3
Safety ......................................................................................................76
3.5.4
Analysis Populations ......................................................................................77
3.5.4.1
Efficacy Analysis Populations ................................................................77
3.5.4.2
Immunogenicity Analysis Populations ...................................................78
3.5.4.3
Safety Analysis Populations....................................................................78
3.5.5
Statistical Methods .........................................................................................78
3.5.5.1
Analysis of Vaccine Efficacy..................................................................78
3.5.5.1.1
Analysis of Vaccine Efficacy on Incidence of HZ Cases ...............80
3.5.5.1.2
Analysis of Vaccine Efficacy on Secondary Efficacy 
Endpoints.........................................................................................80
3.5.5.1.3
Analysis of Vaccine Efficacy on Exploratory Endpoints................82
3.5.5.1.4
Analysis on the Durability of Vaccine Efficacy..............................82
3.5.5.1.5
Additional Evaluation of Vaccine Efficacy.....................................83
3.5.5.2
Analysis of Vaccine Immunogenicity.....................................................83
3.5.5.3
Analysis of Vaccine Safety.....................................................................84
3.5.6
Multiplicity.....................................................................................................86

Product:  V212
Page 5
Protocol/Amendment No.: 011-04
Confidential
3.5.7
Sample Size and Power ..................................................................................87
3.5.7.1
Efficacy Analysis ....................................................................................87
3.5.7.2
Safety Analysis .......................................................................................88
3.5.7.3
Immunogenicity Analysis .......................................................................89
3.5.8
Interim Analysis .............................................................................................89
3.5.8.1
Interim Analyses of Futility/ Efficacy for Potential Early 
Study Termination...................................................................................89
3.5.8.2
Interim Monitoring of Safety by Data Monitoring Committee...............89
3.5.8.3
Interim Monitoring Guidelines for the Data Monitoring 
Committee...............................................................................................90
3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND 
RETURN OF CLINICAL SUPPLIES...................................................................90
3.6.1
Product Description........................................................................................90
3.6.2
Packaging Information ...................................................................................90
3.6.3
Clinical Supplies Disclosure...........................................................................90
3.6.4
Storage and Handling Requirements..............................................................91
3.6.5
Standard Policies / Return of Clinical Supplies .............................................92
3.6.6
Distributing to Sites and Dispensing to Patients ............................................92
3.7
DATA MANAGEMENT ......................................................................................92
3.8
BIOLOGICAL SPECIMENS................................................................................93
4. ADMINISTRATIVE AND REGULATORY DETAILS............................................94
4.1
CONFIDENTIALITY ...........................................................................................94
4.1.1
Confidentiality of Data...................................................................................94
4.1.2
Confidentiality of Subject/Patient Records ....................................................94
4.1.3
Confidentiality of Investigator Information ...................................................95
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT.............................95
4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE 
REQUIREMENTS ................................................................................................97
4.4
QUALITY CONTROL AND QUALITY ASSURANCE ....................................97
4.5
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL 
TRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS ................97
4.6
PUBLICATIONS ..................................................................................................98
5. LIST OF REFERENCES.............................................................................................99
6. APPENDICES ...........................................................................................................104
6.1
IMMUNOSUPPRESSION CATEGORIES: HEMATOLOGIC 
MALIGNANCY..................................................................................................104
6.2
ADVERSE EXPERIENCE TOXICITY GRADING SCALE ............................108
6.3
INTERIM ANALYSIS PLAN STRATEGY ......................................................110
7. ATTACHMENTS......................................................................................................120
8. SIGNATURES...........................................................................................................123
8.1
SPONSOR’S REPRESENTATIVE ....................................................................123
8.2
INVESTIGATOR................................................................................................123

Product:  V212
Page 6
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section 
Numbers
Section Titles
Description of Changes
Rationale
1.2
Indication 
Removed hematologic 
malignancy (HM) 
population.
All changes in this 
table were made 
based upon the 
projected case accrual 
rate in the STM arm 
and/or the outcome of 
the first interim 
analysis which 
demonstrated clear 
evidence of futility in 
the HM population.
An interim analysis 
for futility was 
conducted for both 
the HM and STM 
populations on 29-
Oct-2014. This 
analysis demonstrated 
clear evidence of 
futility in the HM 
arm.  On 04-Nov-
2014, enrollment and 
vaccination in the HM 
arm was stopped.  
Close-out procedures 
began in the HM 
population on 19-
Nov-2014.
1.3
Summary of 
Rationale
Clarification that there will 
be no further interim 
analysis for the solid tumor 
malignancy (STM)
population.
1.4
Summary of Study 
Design
Added description of 
outcome of interim analysis 
for futility.  Updated the 
target herpes zoster (HZ)
case accrual to 90 from 210
for the STM population and 
removed the second interim 
analysis. Clarified study 
duration time frame.
1.7
Study Flow Chart
Removed gpELISA blood 
sample text related to STM 
enrichment following first 
interim analysis in footnote
marked with ††.
2.1.2
Primary 
Hypotheses
As only one primary 
hypothesis will be tested for 
the STM population, testing 
alpha level was changed to 
0.0125 (from 0.0115).
2.1.3
Secondary 
Objectives
Removed testing lower 
bound of VE=10% for a 
single population.  
2.1.3
Secondary 
Objectives
Edited to test secondary 
objectives for HM and STM 

Product:  V212
Page 7
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
separately.
.
2.1.4
Exploratory 
Objectives
All objectives in HM 
population were changed to 
exploratory and, when 
applicable, exploratory 
objectives will be tested 
separately in the HM and 
STM populations.
2.4.1
Summary of Study 
Design
Modified text to reflect 
outcome of interim analysis 
for futility.  Edited to reflect 
that study is continuing with 
STM population only and 
second interim analysis will 
not be performed. 
2.5.3
Immunogenicity 
Measurements
Removed mention of sample 
size enrichment.
2.7.1
Efficacy
Updated the hypothesis and 
endpoints and statistical 
analysis method for 
primary/secondary efficacy 
analyses. With only one 
study population and no 
enrichment, there are no 
statistical concerns 
regarding type I error rate 
inflation and biased VE 
estimate. To be aligned with 
V212-001, Cox proportional 
hazards regression model 
will be used.
2.7.4
Power and Sample
Size
Updated target case accrual 
for STM population and 
power statement and revised
the feasibility assessment 
language.
2.7.5
Interim Analysis
Placed text describing plan 
for interim analysis which 
already occurred in 
Appendix 6.3.  Removed the 

Product:  V212
Page 8
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
second interim analysis and 
population enrichment.
3.1.2
Rationale for this 
Study
Added text describing 
outcome of interim analysis.
3.5.1
Responsibility for 
Analyses
Removed second interim 
efficacy analysis.
3.5.3.1
Efficacy
Updated secondary 
endpoints and edited to test 
secondary/exploratory 
objectives for HM and STM 
separately for each 
population.
3.5.5.1
Analysis of 
Vaccine Efficacy
Updated Table 3.2.
3.5.5.1.1
Analysis of 
Vaccine Efficacy 
on Incidence of 
HZ Cases
Updated the hypothesis and 
endpoints and statistical 
analysis method for primary 
analysis.  Added statement 
that Efron’s method will be 
used to handle ties in event 
times.
3.5.5.1.2
Analysis of 
Vaccine Efficacy 
on Secondary
Efficacy Endpoints
Updated the endpoints and 
statistical analysis method.
3.5.5.1.3
Analysis of 
Vaccine Efficacy 
on Exploratory 
Endpoints
Edited to test exploratory 
endpoints separately for 
each population.
3.5.5.1.4
Analysis on the 
Durability of 
Vaccine Efficacy
Edited to evaluate durability 
separately for each 
population.
3.5.5.2
Analysis of 
Vaccine 
Immunogenicity
Removed the mention of
population enrichment.
3.5.6
Multiplicity
Updated the testing alpha 

Product:  V212
Page 9
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
level and removed 
multiplicity adjustment for 
interim efficacy.
3.5.7.1
Efficacy Analysis
Updated target case accrual 
for STM population and
power statement and revised
the feasibility assessment 
language.
3.5.8
Interim Analysis
Removed second interim 
efficacy analysis and 
mention of enrichment.
3.5.8.1
Interim Analyses 
of Futility/ 
Efficacy for 
Potential Early 
Study Termination
Modified text to reflect 
outcome of interim analysis.  
Removed second interim 
efficacy analysis and 
mention of enrichment.

Product:  V212
Page 10
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
ADDITIONAL CHANGES FOR THIS AMENDMENT:
Section 
Numbers
Section Titles
Description of Changes
Rationale
1.7
Study Flow Chart
Updated footnote marked by 
(§) to reflect that one arm of 
the study may enter close-out 
based on DMC 
recommendation.
Clarity.
3.1.2.4
Rationale for the 
Immunogenicity 
Endpoint Measures
Applicable text revised
Revised to reflect 
change in central 
laboratory.
3.3.2
PCR Assay for 
Lesion Samples
Applicable text revised
3.3.3
PCR Assay for 
Whole Blood 
Samples
Applicable text revised
3.3.4
VZV Antibody 
gpELISA
Applicable text revised
3
Protocol Details 
Tables renumbered 
sequentially throughout 
Section 3.
Due to the deletion and 
addition of tables based 
on changes detailed in 
Summary of Changes. 
6.2
Adverse 
Experience 
Toxicity Grading 
Scale
Added Note to Table 6-6
‘Systemic AE Toxicity 
Grading Scale’ stating events 
determined to be life-
threatening or resulting in 
death are also assigned a 
Toxicity Grade = 4.
Updated for 
consistency with Data 
Entry Guidelines.

Product:  V212
Page 11
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
1. SUMMARY
1.1
TITLE
A Phase III Randomized, Placebo-Controlled, Clinical Trial to Study the Safety and 
Efficacy of V212 in Adult Patients with Solid Tumor or Hematologic Malignancy
1.2
INDICATION
The proposed indication for V212/inactivated varicella-zoster virus (VZV) vaccine is the 
prevention of herpes zoster (HZ) and HZ-related complications in immunocompromised 
patients with solid tumor malignancy (STM).
1.3
SUMMARY OF RATIONALE
HZ, known also as shingles, is a manifestation of reactivation of VZV1, which, as a 
primary infection, produces chickenpox (varicella).  Following initial infection, the virus 
remains latent in the spinal dorsal root or cranial sensory ganglia until it reactivates and 
replicates, producing HZ.  ZOSTAVAX™ is the only currently-licensed intervention that 
can reduce the risk of developing HZ, postherpetic neuralgia (PHN), and the acute and 
chronic pain associated with HZ.  ZOSTAVAX™ was developed by Merck Research 
Laboratories (MRL) for the prevention of HZ and its complications, especially HZ-
related pain.  However ZOSTAVAX™, a live attenuated vaccine, is contraindicated in 
immunocompromised patients.
The incidence of HZ in immunocompetent older adults (i.e., ≥ 60 years of age) is 7 to 11 
per 1000 person-years [1]. Immunocompromised individuals have a higher incidence of 
HZ, and are at increased risk for developing severe and life-threatening complications [2-
12]. Based on a MRL-sponsored epidemiology study conducted at Kaiser Permanente 
Northern California (KPNC) for HM and STM populations, the incidence rate of HZ is 
approximately 19 per 1000 for STM and ranges from 23 to 56 per 1000 person-years for 
HM [13]. Prevention of HZ disease in immunocompromised individuals, including those 
with HM or those with STM receiving chemotherapy, represents an area of significant 
medical need, since these immunocompromised individuals cannot receive the live 
attenuated zoster vaccine.
                                                
1 Abbreviations frequently used in this protocol: CAC: Clinical Adjudication Committee; DMC: Data 
Monitoring Committee; HCT: hematopoietic cell transplant; HM: hematologic malignancy; HZ: herpes 
zoster; IC: immunocompromise; PHN: post-herpetic neuralgia; SAE: serious adverse event; STM: solid 
tumor malignancy; VRC: Vaccination Report Card; VZV: varicella-zoster virus.

Product:  V212
Page 12
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Two proof-of-concept (POC) studies in hematopoietic cell transplant (HCT) recipients 
using heat-inactivated Oka/Merck varicella vaccine demonstrated: 1) reduced morbidity 
(i.e., extent and severity of HZ) following a 3-dose vaccine regimen and, 2) a decreased 
incidence of disease due to VZV reactivation, following a 4-dose vaccine regimen [14, 
15].  The heat-treated VZV vaccine appeared generally safe. Overall, these two studies 
demonstrated that inactivated VZV vaccine given to recipients of HCT had a significant 
impact on the development of HZ.
Subsequently, Protocol 002, a randomized, double-blind, multicenter, immunogenicity 
and safety Phase I clinical study of V212 inactivated by heat-treatment was conducted in 
4 distinct immunocompromised populations: recipients of HCT (allogeneic and 
autologous), patients infected with human immunodeficiency virus (HIV) with CD4 
counts <200 cells/mm3, patients with HM and patients with STM receiving 
chemotherapy.  The study demonstrated promising immunogenicity following a 4-dose 
regimen in the autologous-HCT, STM and HM populations, less robust responses in the 
HIV population, and poor responses in the allogeneic-HCT study population.  No safety 
signals were identified in any of the immunocompromised populations studied [16].
Inactivation of the vaccine via the heat-treatment targets a reduction of VZV infectious 
particles to <10 plaque-forming units (PFU) per dose. Inactivation by gamma irradiation 
further reduces residual infectivity to <0.1 PFU per dose.  Protocol 004, a randomized, 
double-blind, multicenter Phase I study to evaluate the safety, tolerability, and 
immunogenicity of V212 inactivated by gamma-irradiation and V212 inactivated by heat-
treatment in healthy adults 50 to 59 years old, demonstrated that V212 inactivated by 
gamma-irradiation elicited acceptable immunogenicity and had an acceptable safety 
profile when administered to healthy individuals [17].
Protocol 011 is a Phase III study to assess the efficacy, safety, and immunogenicity of 
V212 inactivated by gamma irradiation in a larger population of adults with HM or STM 
receiving chemotherapy. The study will be conducted using a 4-dose regimen 
administered ~30 days apart, consistent with the vaccine regimen used in the Phase I 
study, Protocol 002 (rationale for the 4-dose regimen is provided in Section 3.1.2.2).  The 
study will expand upon the experience of the earlier studies, including the POC studies 
and P002, which suggested that inactivated VZV vaccine administered as a 4-dose 
regimen is well-tolerated and immunogenic, and could provide substantial reduction in 
HZ incidence in HM and STM patients [14-16].
V212-011 is an adaptively designed study which included a planned interim analysis for 
futility when 50% of the targeted cases of HZ had accrued in each population.  At this 
interim analysis, conducted 29-Oct-2014, clear evidence of futility was demonstrated for 
the primary endpoint in the HM arm.  Thus, the HM arm is being closed and with this 
amendment, there will be no further interim analysis in the STM arm and the final 
analysis will be conducted on cases accrued in the STM arm only.  

Product:  V212
Page 13
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
1.4
SUMMARY OF STUDY DESIGN
Approximately 5264 patients (~2568 HM patients; ~2696 STM patients), 18 years of age 
or older will be equally randomized to receive a 4-dose regimen of either V212 or 
placebo. (Note: In India only, enrollment is restricted to patients 18 to 65 years of 
age.) Patient allocation will be double-blinded, with in-house blinding procedures. 
Enrollment for this study is expected to be completed in approximately 36 months.  Study 
duration is anticipated to be approximately 5 years from the date the first patient is 
enrolled.
This is an event-driven study based upon the occurrence of confirmed HZ cases.  HZ 
rates will be monitored on an ongoing basis using the blinded database. The primary 
efficacy analysis will be conducted after at least 90 confirmed HZ cases have been 
accrued in the STM population.  Patients will remain in the study from the time of 
enrollment until accrual of the targeted number (~90) of confirmed HZ cases. This study 
uses an adaptive design based on pre-specified criteria, using an independent, external 
Data Monitoring Committee (DMC) to monitor safety and efficacy. The study will be 
conducted based on 2 key efficacy milestones as listed below:

When at least 50% of the required confirmed HZ cases have accrued for each 
population, HM and STM, interim futility analysis will be conducted for each 
group (completed 29-Oct-2014).

When 90 confirmed HZ cases have accrued in the STM population, the database 
will be unblinded and the final efficacy analysis will be conducted. Of note, if the 
observed HZ case accrual rate indicates that more than 5 years of patient follow-
up will be necessary to accrue the targeted number of confirmed cases, then the 
SPONSOR will consider it beyond the adjustment cap and terminate the study
after approximately 5 years of patient follow-up have occurred (from the date the 
first patient is enrolled).
During the interim analysis, a futility analysis was conducted to assess whether efficacy 
met a pre-specified level. The analysis was conducted separately for each patient 
population (HM and STM) when at least 50% of required HZ cases had accrued in the 
corresponding population (29-Oct-2014). Analysis results were evaluated by the DMC
with the following outcome:
HM population: solid statistical evidence of futility for the primary endpoint.  Thus, 
enrollment and vaccination was stopped on 04-Nov-2014 and study close-out procedures 
in this population began on 19-Nov-2014.
STM population: no significant safety concerns nor a reason to stop the study due to 
futility. 

Product:  V212
Page 14
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
The DMC recommended that the study in the STM population should proceed.  A final 
case count of 90 will be targeted in this population which will provide adequate power 
for the primary endpoint without the need for enrollment of additional subjects.
Based on this adaptive design, the study may end in the following situations: 
1) When the required number of confirmed HZ cases has accrued; or
2) If the decision is made to end the study early following a recommendation made 
by the DMC based on safety concerns; or
3) The HZ event rates will be monitored on an ongoing basis using the blinded 
database. If the observed HZ case accrual rate indicates that more than 5 years of 
patient follow-up will be necessary to accrue the targeted number of confirmed 
cases, then the SPONSOR will declare the trial infeasible and terminate the study 
after approximately 5 years of patient follow-up have occurred.
In any of these events, the study will begin to enter the close-out phase and no additional 
suspected cases of HZ will be accrued.
Safety information will be collected for all patients for the entire duration of the study as 
described in Section 2.6.  In the event the study ends sooner than 1 year after the last 
vaccine dose is administered, the study will continue to follow all patients for safety and 
efficacy for a minimum duration of 1 year following the last dose of study vaccine.
Exploratory immunogenicity measurements will be conducted on a subset of patients, as 
described in Section 2.5, to assess the immunogenicity of the vaccine and attempt to 
investigate correlation of immune responses to the vaccine with clinical efficacy.

Product:  V212
Page 15
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
1.5
SAMPLE
This study will enroll men and women with a life expectancy of at least 12 months, who 
are varicella-history (or VZV-antibody) positive or based on regional epidemiology have 
a high likelihood of latent VZV infection, are not likely to undergo hematopoietic cell 
transplant (HCT) and

are 18 years of age or older and receiving chemotherapy for STM or HM. 
OR

are 50 years of age or older* and have HM, not in remission, regardless of 
whether or not they are receiving chemotherapy.
*Note: In India only, enrollment is restricted to patients 18 to 65 years of age.
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN
All patients enrolled in the study will be randomized 1:1 to receive either V212 or 
placebo given as a 4-dose regimen. Placebo will be the vaccine stabilizer for the VZV 
vaccine with no virus antigen.
Dose 1 of V212 or placebo regimen will be administered at the time of enrollment (Day 
1).  Doses 2 through 4 will be administered approximately 30 days following each 
previous dose, in those patients who are not receiving chemotherapy or in those who are 
on a daily chemotherapy regimen.  In those patients receiving cyclic chemotherapy, Dose 
1 of V212 or placebo regimen should be administered approximately 5 days before the 
onset of any chemotherapy dose in the cycle.  Doses 2 through 4 are to be administered 
approximately 20 to 40 days following the previous dose of study vaccine or placebo, 
with the condition that V212 or placebo be administered approximately 5 days prior to 
the upcoming dose of chemotherapy.  See Sections 1.7 and 1.8 for all permitted visit 
windows.
Each dose of V212 or placebo will be administered as a 0.5-mL subcutaneous injection 
preferably in the deltoid region of the arm, alternating arms for each study vaccine or 
placebo dose, if possible.

Product:  V212
Page 16
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
1.7
STUDY FLOW CHART
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Periodic 
Efficacy  
Contact†
Periodic 
Safety 
Contact 
(SAE) ‡
Study Close-
out Visit§
Prior to 
Study
Procedures
Dose 1
Dose 2║
Dose 3║
Dose 4║
28 days 
Postdose 4║
Monthly
Every 3 
months
Visit window permitted (day)║
N/A
Day 1
20 to 40 
days post-
dose 1
20 to 40  
days post-
dose 2
20 to 40  
days post-
dose 3
28 to 60 
days post-
dose 4#
7/+14 days
+/-30 days
N/A
Obtain Informed Consent
X
Provide and Review Patient 
Identification Card
X
Perform Physical Exam, including 
weight
X
Collect Medical History
X
Review Inclusion/Exclusion criteria 
X
Review Deferment Criteria
X
X
X
Perform Pregnancy Test¶
X
X
X
X
Assign Study Vaccine or Placebo using 
IVRS#
X
X
X
X
Collect blood for gpELISA testing on all 
patients in the STM study group††
X
X
Collect blood for IFN γ ELISPOT testing 
in ELISPOT substudy patients only‡‡
X
X
Administer Vaccine/Placebo
X
X
X
X

Product:  V212
Page 17
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Periodic 
Efficacy 
Contact†
Periodic 
Safety 
Contact 
(SAE)‡
Study Close-
out Visit§
Prior to 
Study
Procedures
Dose 1
Dose 2║
Dose 3║
Dose 4║
28 days 
Postdose 4║
Monthly 
Every 3 
Months
Visit window permitted (day)║
N/A
Day 1
20 to 40 
days post-
dose 1
20 to 40 
days post-
dose 2
20 to 40 
days post-
dose 3
28 to 60 
days post-
dose 4║
7/+14 days
+/-30 days
N/A
Educate patients on signs and symptoms 
of HZ
X
X
X
X
X
X
Assess for occurrence of unreported 
symptoms of suspected HZ
X
X
X
X
X
X
X
Provide VRC and review instructions 
with patient§§
X
X
X
X
Collect and review completed VRC with 
patient and collect information on 
adverse experiences║║
X
X
X
X
Ascertainment of Serious Adverse 
Experience Reporting
X
X
X
X
X
X
X
Assess for exposure to varicella or HZ¶¶
X
X
X
X
End of Study Questionnaire
X

Product:  V212
Page 18
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
† Monthly efficacy contact by telephone, via the internet, or during a study visit will be required for each patient for the duration of the study to assess for occurrence of 
unreported symptoms of suspected HZ.  At Visit 5, site personnel will assist the patient with the first efficacy contact using the IVRS via the
internet or via phone.
‡ Beginning 3 months following Visit 5 and continuing every 3 months for the duration of the study, patients will be contacted by site personnel, and using a pre-defined 
script, patients will be queried as to whether all serious adverse experiences have been reported since last contact.  Concomitant medications administered as a result of any 
SAE for the duration of the study will also be collected.  Information obtained from this contact will facilitate accurate and timely reporting of SAEs
§ Study will continue until the required number of cases of herpes zoster (HZ) has accrued, or if the decision is made to terminate the study or one arm early following a 
recommendation made by the DMC based on safety concerns or futile efficacy results from the interim futility analysis or if the trial is declared infeasible. At that time, the 
study or arm will begin to enter the close-out phase and no additional suspected HZ cases will be accrued.  Patients already entered in suspected HZ case follow-up will 
complete their 6-month HZ assessment period.  In the event the study or arm is terminated sooner than 1 year after the last vaccine dose is administered in this study, the 
study will continue to allow all patients to complete a minimum of 1 year post-vaccination follow-up for safety and efficacy. All patients enrolled in the study will be 
contacted by telephone to complete the study close-out questions.
║The allowable window between each vaccine dose is 20 to 40 days.  All study procedures must be performed at the vaccination visit.  Visit window permitted for Visit 5 is 
28 to 60 days Postdose 4.  Every attempt should be made to schedule the patient’s Postdose 4 follow-up visit as close to day 28 Postdose 4 to assure for accurate and timely 
safety reporting.  Deviations from the permitted visit windows (i.e., the patient meets deferment criteria or the patient is not able to complete the visit as scheduled per 
protocol because of medical or logistical reasons) require consultation between the investigator and the SPONSOR and written documentation of the collaborative decision 
on patient management.
¶
Women of childbearing potential must have serum or urine pregnancy testing (sensitive to 25IU β-hCG) at enrollment and prior to subsequent vaccination doses. See 
Section 2.2 (inclusion criterion #7) for a definition of "woman of childbearing potential" under this Protocol.
# Study personnel will access IVRS to register patients visit at time of randomization and at subsequent visits.  IVRS will assign V212 or placebo to the patient at the time of 
randomization and at subsequent dosing visits.
†† Blood samples (5 mL) will be collected from all patients in the STM study group (based on the planned number of ~2696 patients) and used for testing via gpELISA
Sample collection procedures are provided in the Laboratory Manual.
‡‡ Blood samples (60 mL) will be collected from all patients enrolled in the ELISPOT substudy and tested via IFN-γ  ELISPOT. Sample collection procedures are provided in 
the Laboratory Manual.
§§ Patients will be instructed to record daily oral temperatures and injection-site and systemic adverse experiences on the VRC from the date of each vaccine dose through the 
day prior to the next dose, or for 28 days Postdose 4.  The VRC actively prompts for reporting injection-site adverse experiences for 5 days after each vaccination dose.
║║Collect information about adverse experiences.  Patients must complete safety follow-up after each vaccination dose and record adverse experiences on the VRC.  After each 
vaccination dose, a new safety follow-up should begin using a new VRC.
¶¶ Study personnel will obtain information detailing the patient’s exposure to varicella and/or HZ since last visit.  Exposure is defined as contact with an individual from 5 days 
prior to the onset of a chickenpox rash, or from the day of onset of an HZ rash, until crusting of lesions
IVRS = Interactive Voice Response System
IFN-γ ELISPOT = Interferon-gamma enzyme-linked immunospot assay                                      VRC = Vaccination Report Card
gpELISA = glycoprotein enzyme-linked immunosorbent assay                                                     PCR = polymerase chain reaction
Note: Patients who contact the site for rash or acute HZ symptom(s) evaluation should be seen by a medically qualified investigator as soon as possible, preferably within 24 to 
72 hours of rash or symptom(s) onset and if they have a suspected case of HZ, will be monitored for 6 months of HZ follow-up.  For additional information, see “Study Flow 
Chart for Patients with Suspected HZ” in Section 1.8.

Product:  V212
Page 19
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
1.8
STUDY FLOW CHART FOR PATIENTS WITH SUSPECTED HZ
Onset of 
rash or 
other 
symptoms 
of HZ
First 
Evaluation†
Every 3 to 5 
days until no 
new lesions 
appear/acute HZ 
symptom(s) 
improve
1 month post-
symptom onset
2 months post-
symptom onset
3 months post-
symptom onset
4 months post-
symptom onset
5 months  post-
symptom onset
6 months post-
symptom onset
Visit window permitted (days)‡
N/A
N/A
N/A
(+/5 days)
(+/5 days)
(+/5 days)
(+/5 days)
(+/5 days)
(+/5 days)
Patient calls site 
X
Perform assessment of HZ rash, 
acute HZ-related symptom(s) and 
HZ-related complications§
X
X
Collect lesion sample for PCR (for 
patients with an HZ-like RASH)║
X
Collect blood sample for PCR (for 
all patients with suspected HZ)¶
X
Assess for exposure to varicella or 
HZ#
X
Perform ZBPI assessment††
X
X
X
X
X
X
X
X
Perform EuroQol-EQ5D 
assessment‡‡
X
X
X
X
X
X
X
X
Perform HCU assessment§§
X
X
X
X
X
X
X
X
Perform WPQ assessment║║
X
X
X
X
X
X
X
X
† All patients who experience rash or other symptoms that could be due to a suspected case of HZ should be seen by a medically qualified investigator (defined as a physician, or in accordance with local 
regulations, a nurse practitioner or physician assistant) as soon as possible, preferably within 24 to 72 hours of rash onset. Antiviral therapy should be started and diagnostic procedures should be performed 
as soon as possible after HZ symptom onset.  Report all concomitant medications (i.e., antiviral treatment, pain medications) administered as a result of a suspected case of HZ for the duration of the study.
‡ Study procedures may be performed up to 5 days prior or 5 days following the scheduled visit day. Deviations from the permitted visit windows (i.e., if the patient will not be able to complete visit as 
scheduled per protocol because of medical or logistical reasons) require consultation between the investigator and the Sponsor and written documentation of the collaborative decision on patient 
management.
§ For suspected HZ cases with rash, patients should be monitored by a medically qualified investigator for rash evolution and the signs and symptoms of the development of HZ-associated complications 
every 3 to 5 days until no new skin lesions appear, and clinical findings and relevant laboratory results should be reported.  For suspected HZ cases without a rash, patients should be monitored by a 
physician for acute HZ progression and the signs and symptoms of the development of HZ-associated complications every 3 to 5 days until acute HZ symptoms are resolved, and clinical findings and 
relevant laboratory or radiologic results should be reported. 
║Skin lesion samples will be collected for analysis by PCR for patients with an HZ-like rash. If the patient develops a suspicious rash after the first evaluation for a suspected case of HZ, the skin lesion 
samples for PCR should be obtained when the rash is first observed.

Product:  V212
Page 20
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
¶   All patients with suspected HZ will have two 10-mL whole blood samples collected for analysis by PCR at the initial evaluation only. Sample collection procedures are provided in the Laboratory Manual.
# Study personnel will obtain information detailing the patient’s exposure to varicella and/or HZ since vaccination.  Exposure is defined as contact with an individual from 5 days prior to the onset of a 
chickenpox rash, or from the day of onset of an HZ rash, until crusting of lesions.
†† Severity of pain and interference with activities of daily living (ADL) will be assessed using the Zoster Brief Pain Inventory (ZBPI) at each evaluation time point.
‡‡ Functional health status and quality of life will be assessed using the European Quality of Life (EuroQol-EQ5D) questionnaire.
§§ HZ-related non-protocol-mandated health care resource utilization will be assessed using the Health Care Utilization (HCU) questionnaire.
║║Work and productivity loss will be assessed using the Work Productivity Questionnaire (WPQ).
HZ = Herpes Zoster
PCR = polymerase chain reaction
IVRS = Interactive Voice Response System
Note: After no new lesions appear or when acute HZ symptom(s) improve all assessments will be obtained (by telephone or during a study visit) for 6 months from onset of suspected HZ.
Note: Patients with a suspected case of HZ who have pain persisting longer than 6 months should continue in HZ follow-up until the pain resolves or the study ends.
Note: Deviations from the 6-month suspected HZ case follow-up period as scheduled per protocol because of medical or logistical reasons require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision.

Product:  V212
Page 21
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
2. CORE PROTOCOL
2.1
OBJECTIVES AND HYPOTHESES
2.1.1
Primary Objectives
1. To assess the safety and tolerability of V212 when administered to adults with STM .
2. To assess the impact of V212 on the development of HZ in adults with STM.
2.1.2
Primary Hypotheses
Vaccination with V212 will reduce the incidence of HZ compared with placebo in adults 
with STM. The following hypothesis will be tested at the end of the study in the STM 
population.
1) The statistical criterion for success requires that the lower bound of the 97.5% 
(one-sided α=0.0125) confidence interval (CI) for the estimated vaccine efficacy 
in adults with STM be greater than 25%.
2.1.3
Secondary Objectives
1. To assess the impact of V212 on the development of moderate to severe HZ-
associated pain at any time from HZ onset through the end of the 6 month HZ follow-
up period. Moderate to severe HZ-associated pain is defined as 2 or more occurrences 
of a score of 3 or greater (0-to-10 scale) on the Zoster Brief Pain Inventory (ZBPI).
2. To assess the impact of V212 on the development of HZ complications defined as the 
occurrence of any of the following during the study:  hospitalization or prolongation 
of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or 
VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, or 
administration of intravenous acyclovir therapy for treatment of HZ.
3. To assess the impact of V212 on the development of PHN.  PHN is defined as a worst 
pain score (in the previous 24 hours) of 3 or greater (0-to-10 scale) on the ZBPI, that 
persists or appears greater than or equal to 90 days after the onset of HZ rash.
The above objectives will be evaluated for STM only.
2.1.4
Exploratory Objectives
     1. To assess the safety and tolerability of V212 when administered to adults with HM.
2. To assess the impact of V212 on the development of HZ in adults with HM. 
3. To assess the impact of V212 on the development of moderate to severe HZ-
associated pain at any time from HZ onset through the end of the 6 month HZ follow-
up period.  Moderate to severe HZ-associated pain is defined as 2 or more 
occurrences of a score of 3 or greater (0-to-10 scale) on the Zoster Brief Pain 
Inventory (ZBPI) in adults with HM.

Product:  V212
Page 22
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
4. To assess the impact of V212 on the development of HZ complications defined as 
the occurrence of any of the following during the study:  hospitalization or 
prolongation of hospitalization due to HZ, disseminated HZ (including disseminated 
HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due 
to HZ, or administration of intravenous acyclovir therapy for treatment of HZ in 
adults with HM.
5. To assess the impact of V212 on the development of PHN.  PHN is defined as a 
worst pain score (in the previous 24 hours) of 3 or greater (0-to-10 scale) on the 
ZBPI, that persists or appears greater than or equal to 90 days after the onset of HZ 
rash in adults with HM.
6. To assess the immunogenicity of V212 in adults with STM or HM.
7. To describe the impact of HZ on activities of daily living (ADL) and quality of life 
(QoL), and to assess the impact of V212 on interference with ADL and QoL in study 
patients who develop HZ.
8. To describe HZ-related non-protocol-mandated health care resource utilization 
(HCRU), and assess the impact of V212 on HZ-related non-protocol-mandated 
HCRU, and work and productivity loss (WPQ).
9. To assess the impact of V212 on the severity and duration of HZ-related pain.
10. To assess the impact of V212 on the severity of HZ rash including the extent of 
rash, number of skin lesions present, and number of dermatomes involved.
11. To assess the association of immunogenicity at postvaccination with the risk of 
HZ in adults with STM or HM.
The exploratory objectives (1)-(5) will be evaluated for HM only; objectives(6)-(10) will 
be evaluated for STM and HM separately and (11) will be evaluated in both combined 
STM and HM populations and individual subpopulation.
2.2
PATIENT INCLUSION CRITERIA
An individual will be eligible to participate in this study if all of the following criteria 
apply:
1. Patient has been diagnosed with a solid tumor or hematologic malignancy AND is not 
likely to undergo hematopoietic cell transplant (HCT) and meets one of the criteria 
specified below.

Is 18 years of age or older and is receiving a cytotoxic or immunosuppressive 
chemotherapy regimen. 
OR

Product:  V212
Page 23
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential

Is 50 years of age or older* with a hematologic malignancy, not in remission, 
regardless of whether the patient is or is not receiving chemotherapy.
* Note: In India only, enrollment is restricted to patients 18 to 65 years of age.
2. Life expectancy ≥ 12 months.
3. Signed an informed consent prior to any study procedures.
4. Patient has prior history of varicella, antibodies to VZV (documented prior to receipt 
of blood products), or residence (for ≥30 years) in a country with endemic VZV 
infection, or if participant is 30 years old, attended primary or secondary school in a 
country with endemic VZV infection (see Section 3.2.8 for more details).
5. All female patients of childbearing potential (as defined below under #7) must have a 
negative serum or urine pregnancy test (sensitive to 25IU β-hCG).
6. Able to understand and complete study questionnaires.
7. Patient is highly unlikely to conceive during the time period starting 2 weeks prior to 
enrollment through 6 months from last vaccination dose, as indicated by at least one 
“yes” answer to the following questions:

Patient is male.

Patient is female who agrees to remain abstinent or use (or have their partner use) 
adequate contraception during the time period starting 2 weeks prior to enrollment 
through 6 months from the last vaccination dose. Note that simultaneous use of 
two reliable forms of contraception is recommended.

Patient is a female who is not of reproductive potential. A female patient who is 
not of reproductive potential is defined as: one who has either (1) reached natural 
menopause (defined as 6 months of spontaneous amenorrhea with serum follicle 
stimulating hormone [FSH] levels in the postmenopausal range as determined by 
a laboratory, or 12 months of spontaneous amenorrhea), (2) post-surgical bilateral 
oophorectomy and/or hysterectomy, or (3) bilateral tubal ligation.
8. Patients with STM will be eligible for enrollment if they have not received (nor are 
expected to require receipt of) blood products within 3 months prior to enrollment 
through 28 days Postvaccination 4.

Product:  V212
Page 24
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
2.3
PATIENT EXCLUSION CRITERIA
An individual will not be eligible to participate in this study if any of the following 
criteria apply:
1. A history of allergic reaction to any vaccine component (including gelatin) or an 
anaphylactic/anaphylactoid reaction to neomycin (a history of contact dermatitis to 
neomycin is not a criterion for study exclusion).
2. Prior history of HZ within 1 year of enrollment.
3. Prior or expected receipt of any varicella or non-study zoster vaccine.
4. Patient is currently receiving or expected to receive long-term antiviral prophylaxis 
(greater than 4 weeks duration) with activity against herpes simplex virus (HSV), 
VZV or cytomegalovirus (CMV).
5. Patient is pregnant or breastfeeding or expecting to conceive within the period of 2 
weeks prior to enrollment throughout 6 months after last vaccination dose.
6. Any live virus vaccine administered or scheduled in the period from 4 weeks prior to 
Dose 1 through 28 days postvaccination dose 4.
7. Any inactivated vaccine administered or scheduled within the period from 7 days 
prior to, through 7 days following, any dose of study vaccine.
8. Unlikely to adhere to the study procedures or attend study visits.
9. Any other reason that in the opinion of the investigator might interfere with the 
evaluation required by the study.
10. Patients with STM will be excluded from study if they have received (or are expected 
to require receipt of) blood products within 3 months prior to enrollment through 28 
days Postvaccination 4.
2.3.1
Deferment Criteria (Prior to Vaccination of Doses 2 through 4)
NOTE:  SPONSOR must be notified of deferment.  At sites located in the United States, 
site personnel should contact one of the study personnel listed on the Sponsor Contact 
page in the Administrative Binder.  Internationally, the site should contact the local 
Merck subsidiary monitor.
1. The patient has an acute illness that requires active medical intervention or 
monitoring to avert serious danger to the participant's health or well-being and, in the 
opinion of the investigator, may interfere with the evaluation of the study objectives.  
(The maximum amount of time for which the vaccination should be deferred is 30 
additional days).

Product:  V212
Page 25
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
2. The patient has received an inactivated vaccine such as the influenza vaccine.  In that 
case, administration of the study vaccination should be deferred for 7 days following 
receipt of the inactivated vaccine.
The deferment criteria noted above must be reviewed prior to each vaccination for 
Doses 2 through 4, to ensure that patients do not meet the criteria specified.  If a 
participant meets any deferment criterion, this must be reported to the SPONSOR, and 
all study procedures with the exception of the administration of the vaccine/placebo 
should be conducted on the day the vaccination was deferred.
2.3.2
Continuation in the Study under Special Circumstances
A patient should not receive additional doses of vaccine or placebo but should remain in 
the study to be followed for safety, efficacy and immunogenicity if:

The patient develops a severe allergic reaction to a component of the vaccine (i.e., 
swelling of the mouth and throat, difficulty breathing, hypotension or shock) 
following administration of the prior vaccine dose.

The patient becomes pregnant.

The patient undergoes hematopoietic cell transplant (HCT).
2.4
STUDY DESIGN AND DURATION
2.4.1
Summary of Study Design
This is a randomized, double-blind (with in-house blinding procedures), placebo-
controlled, multicenter study to evaluate the efficacy, immunogenicity, safety and 
tolerability of V212 in adults with STM or HM.  The study will enroll patients who are 
18 years of age and older who have either STM or HM and are receiving chemotherapy. 
(Note: In India only, enrollment is restricted to patients 18 to 65 years of age.) In
addition, patients 50 years of age and older who have HM, not in remission, will be
enrolled regardless of whether they are receiving chemotherapy. (Note: In India only, 
patients 50 to 65 years of age who have HM, not in remission, will be enrolled 
regardless of whether they are receiving chemotherapy.) 
Approximately 5264 patients (~2632 in the vaccine group; ~2632 in the placebo group), 
18 years of age or older will be randomized to receive either V212 or placebo given as a 
4-dose regimen administered ~30 days apart. (Note: In India only, enrollment is 
restricted to patients 18 to 65 years of age.) Randomization will be stratified by 
baseline medical condition with approximately 2696 patients with STM (receiving 
chemotherapy) and 2568 patients with HM enrolled into the study.  Patients with HM 
will be further stratified into one of two strata, low immunocompromise (IC) or moderate 
to high IC, based on the patient's HM diagnosis and/or chemotherapeutic regimen (see 
Appendix 6.1).  The planned randomization schedule by vaccination group is shown in 
Section 2.4.2.  Enrollment for this study is expected to be completed in approximately 36 
months.

Product:  V212
Page 26
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
This is an event-driven study based upon the occurrence of confirmed HZ cases. The 
combined dropout rates and the combined HZ event rates will be monitored on an 
ongoing basis using the blinded database. Patients will remain in the study from the time 
of enrollment until accrual of the targeted number (~90) of confirmed HZ cases in the 
STM population.
The planned study duration stated in this protocol is estimated based upon assumptions 
related to enrollment rate and follow-up time and HZ incidence in these populations.  If 
these assumptions are met, the study will continue for approximately 5 years in order to 
accrue approximately 90 confirmed HZ cases.  However, it should be noted that:

Study duration may be less than or more than 5 years, depending upon the time it 
takes to accrue the necessary number of confirmed cases.

The HZ event rates will be monitored on an ongoing basis using the blinded 
database. If the observed HZ case accrual rate indicates that more than 5 years of 
patient follow-up will be necessary to accrue the targeted number of confirmed 
cases, then the SPONSOR will declare the trial infeasible and terminate the study 
after approximately 5 years of patient follow-up have occurred, from the date the 
first patient is enrolled.
This study will use an adaptive design based on pre-specified vaccine efficacy criteria, 
using an independent, external DMC. There will be one interim analysis and one final 
efficacy analysis. The interim analysis will consist of a futility analysis for each 
individual subgroup (HM and STM). 
The  interim (futility) analysis was conducted when at least 50% of the total number of 
required confirmed HZ cases had accrued in each patient population, HM and STM. The 
interim analysis was conducted on 29-Oct-2014 for both populations. Results of the 
analysis were reviewed by the DMC, who made recommendations to the Steering 
Committee (SC) to end the study in the HM population and continue the STM arm only.
Patients will be monitored for HZ for the entire duration of the study. To that end, 
patients will be educated on the signs and symptoms of HZ and instructed to call the 
study site immediately if such symptoms develop, to arrange an evaluation by a 
medically qualified investigator (medically qualified is defined as physician, or in 
accordance with local regulations, a nurse practitioner or physician assistant).  In 
addition, monthly efficacy contact by telephone, via the internet, or during a follow-up 
visit will be required for each patient until study completion, to determine if unreported 
HZ symptoms occurred.

Product:  V212
Page 27
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
It is important to note that HZ presentation in immunocompromised patients may be 
atypical, for instance with cases of rash over several dermatomes. Also, occurrence of 
severe complications is not uncommon. Finally, visceral involvement is possible and HZ
can occur without a rash.  In such cases, detection of VZV in diagnostic specimens from 
blood, cerebrospinal fluid (CSF), lung, liver or other organ may be a key element of the 
diagnosis of HZ. More information about identification of suspected HZ cases can be 
found in Section 3.2.17.2.
The follow-up of patients with suspected HZ (outlined in the flowchart in Section 1.8) 
will include the following steps:

Initial evaluation by a medically qualified investigator – All patients with 
suspected HZ will be assessed by a medically qualified investigator as soon as 
possible after HZ symptom onset. During this first evaluation, samples for VZV 
PCR testing will be collected from skin lesions in patients with a HZ or HZ-like 
rash. In addition, blood samples for VZV PCR testing will be collected from all 
patients.

Continued monitoring by a medically qualified investigator until no new lesions 
or symptoms of HZ appear – Patients will be subsequently assessed every 3-5 
days by a medically qualified investigator until no new lesions appear and no new 
acute HZ symptoms appear.  Subjects with a rash should be assessed for rash 
evolution and the signs and symptoms of the development of HZ-associated 
complications, and any relevant laboratory findings should be reported. For 
subjects without a rash, clinical findings and any relevant laboratory and 
radiologic results should be reported. Severity of HZ-related pain, the 
development of HZ-associated complications, interference with activities of daily 
living, functional health status, quality of life, HZ-related healthcare utilization 
and effect on work/productivity will be assessed through the use of interview 
questionnaires administered by site personnel.
Monthly follow-up assessment over a 6-month period – Patients will also undergo serial 
(monthly) assessments over the 6 months following the initial report of suspected-HZ to 
capture the progression and resolution of disease characteristics such as severity of HZ-
related pain, the development of HZ-associated complications, interference with activities 
of daily living, functional health status, quality of life, HZ-related healthcare utilization 
and effect on work/productivity.  These assessments will be conducted through the use of 
interview questionnaires administered by site personnel (WPQ, HCU), or completed by 
the patient (ZBPI, European Quality of Life [EurQoL/EQ5D]) as indicated.  Patients with 
a suspected case of HZ who have pain persisting longer than 6 months should continue in 
HZ follow-up until the pain resolves or the study ends.
The summary of clinical findings, including any results of non-study laboratory and 
radiologic assessments conducted locally to support the HZ diagnosis, and results from 
the blood VZV PCR testing will be provided to the Clinical Adjudication Committee 
(CAC).

Product:  V212
Page 28
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Another important goal of the study is to evaluate the safety and tolerability of V212 in 
the HM and STM patient populations. Adverse experiences will be collected from Visit 1 
through Visit 5 using a Vaccination Report card (VRC). All subjects will receive a VRC 
at each vaccination visit (Visits 1 through 4). The VRC will be used to collect safety 
information between each vaccination period (minimum 20 days postvaccination dose 1 
through 3, through 28 days postvaccination dose 4).  The VRC will be returned by the 
patient and reviewed by study site personnel at the next scheduled study visit.
Serious adverse experiences (SAE) will be collected, regardless of causality, for the 
entire duration of the study. Patients will be instructed to call the study site immediately, 
at any time during the study, if they develop an adverse experience that meets SAE 
criteria. In addition patients undergo periodic safety follow-up to assess whether they 
developed a clinical adverse experience that met SAE criteria since their last contact with 
site personnel. As indicated in the Study Flow Chart (Section 1.7), such safety follow-ups 
will occur at each scheduled study visit (Visit 1 through 5) and, after Visit 5, by 
telephone Periodic Safety Contact (approximately every 3 months, beginning 3 months 
following Visit 5, and continuing every 3 months for the duration of the study).
A pregnancy test will be performed on all female patients of childbearing potential at 
Visits 1, 2, 3, and 4 prior to vaccine administration. Any female patient with a positive 
pregnancy test at Visit 1 will not be vaccinated and will not be allowed to participate in 
the study. Female patients with a positive pregnancy test after Visit 1 will not receive 
additional doses of V212 or placebo, but will remain in the study to be followed for 
safety, efficacy and immunogenicity.
To ensure that no alarming, unusual, or unexpected safety problems are occurring with 
the vaccine in the HM or STM populations, safety will be monitored during the study by 
the same independent, external DMC that will monitor the interim futility and efficacy 
analyses. The DMC will periodically evaluate interim safety and efficacy data and will 
provide periodic recommendations to the SC, to continue, modify, or stop the clinical 
trial.  See section 3.2.21 for more details about the DMC and SC.
Overall, the study may be ended in the following situations:
1) When the required number of confirmed HZ cases has accrued; or
2) If the decision is made to end the study early following a recommendation made 
by the DMC based on safety concerns; or 
3) If the observed HZ case accrual rate indicates that more than 5 years of patient 
follow-up will be necessary to accrue the targeted number of confirmed cases, 
then the SPONSOR will declare the trail infeasible and terminate the study after 
approximately 5 years of patient follow-up have occurred, from the date the first 
patient is enrolled

Product:  V212
Page 29
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
In any of these situations, the study will begin to enter the close-out phase, and no 
additional suspected cases of HZ will be accrued beyond the date for initiation of close-
out procedures, as provided in the Close-Out Standard Operating Procedures (SOP) and 
patients already entered into the suspected HZ-follow-up will complete their 6-month 
assessment periods.  All patients will be contacted to complete the study close-out 
questionnaire.
Details of the close-out procedures will be provided in the Close-Out 
SOP. In the event the study ends sooner than 1 year after the last vaccine dose is 
administered, the study will continue to follow all patients for safety and efficacy until all 
patients have completed 1 year of follow-up.
The clinical, statistical and data management study personnel at the SPONSOR who are 
involved with study conduct will remain blinded to subject vaccination group allocations 
until the required number of cases of the primary efficacy endpoint have been observed, 
study close-out procedures have been completed, data discrepancies have been addressed, 
and the database is unblinded for the primary efficacy analysis.
2.4.2
Vaccination Plan
Approximately 5264 patients (~2632 vaccine recipients; ~2632 placebo recipients), 18 
years of age or older will be randomized 1:1 to receive either V212 or placebo given as a 
4-dose regimen approximately 30 days apart. (Note: In India only, enrollment is 
restricted to patients 18 to 65 years of age.) Each dose of V212 or placebo will be 
administered as a 0.5-mL subcutaneous injection preferably in the deltoid region of the 
arm, alternating arms for each V212 or placebo dose, if possible.  Placebo will be the 
vaccine stabilizer for V212 with no virus antigen.
Randomization will be stratified by disease type (i.e., HM or STM) with approximately 
2696 patients with STM (receiving chemotherapy) and approximately 2568 patients with 
HM enrolled into the study.  Patients with HM will be further stratified into one of two 
strata, low IC or moderate to high IC (see Appendix 6.1).  Randomization and 
stratification will be based upon a randomization schedule generated by the SPONSOR.  
The planned randomization schedule by vaccination group is shown in Table 2-1.
Table 2-1
Randomization Schedule
Vaccination Group
Stratification
STM
HM ‡
Total
V212
1348
1284
2632
Placebo
1348
1284
2632
Total
2696
2568
5264
‡ HM population will be further stratified into one of two strata, low IC or moderate to high IC which is 
expected to be in 1:3 ratio approximately.

Product:  V212
Page 30
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
An Interactive Voice Response System (IVRS) will be used to register patient visits upon 
randomization and at subsequent visits.  The IVRS will be used to allocate patients to 
vaccination group assignments during randomization according to a central 
randomization schedule generated by the SPONSOR.  For all sites, all vaccine doses will 
be shipped through the IVRS.
2.5
LIST OF EFFICACY/IMMUNOGENICITY MEASUREMENTS
2.5.1
HZ Case Determination
The primary clinical efficacy endpoint will be the incidence of HZ. Clinical criteria for 
suspected HZ cases are the development of a papular or vesicular rash with a dermatomal 
or generalized distribution, or in the absence of a rash, clinical suspicion of VZV 
infection with or without the detection of VZV in diagnostic specimens from blood, CSF, 
lung, liver, or other organ. In immunocompromised patients, the rash of HZ may be 
atypical, for example involving more than one dermatome, or it may not be present. 
Patients who develop suspected HZ will enter 6 months of HZ follow-up.
All suspected cases of HZ will go through case adjudication in a blinded fashion by the 
CAC. The CAC will determine if a suspected case is a confirmed case of HZ, in their 
clinical opinion, and if a confirmed case make the final determination of the confirmed 
HZ complication(s) present. HZ case determination will be based primarily upon the 
results of the skin lesion PCR assay, if applicable. For those cases that do not include a 
skin lesion PCR assay or if the skin PCR assay is inadequate, case confirmation will be 
based on the result of adjudication of the clinical case description by the CAC, conducted 
according to the CAC SOP.
The algorithm used for determination of HZ cases is shown in Figure 2-1.  PCR assays 
for the detection of VZV DNA will be conducted as described in Section 3.3. The 
summary of clinical findings, laboratory and radiologic results, and results from the blood 
VZV PCR will be provided to the CAC.

Product:  V212
Page 31
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Figure 2-1
HZ Case Determination

Product:  V212
Page 32
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
2.5.2
Secondary Efficacy Measurements
Three secondary efficacy endpoints are defined for this protocol which will be evaluated 
in the STM population only and in the HM population on an exploratory basis. The first 
is to assess the incidence of moderate to severe HZ-associated pain [defined as 2 or more 
occurrences of a score 3 or greater (0-to-10 scale) in response to the prompt to rate "your 
pain at its worst in the last 24 hours" on the ZBPI, at any time from HZ onset through the 
end of the 6 month HZ-follow-up period. The second is a composite efficacy endpoint of 
the incidence of HZ complications, defined as the occurrence of any of the following 
during the study: hospitalization or prolongation of hospitalization due to HZ, 
disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, 
ophthalmic HZ, neurological impairment due to HZ, or administration of intravenous 
acyclovir therapy for treatment of HZ. The third endpoint is the incidence of PHN 
[defined as a worst pain score (in the last 24 hours) of 3 or greater (0-to-10 scale) in 
response to the prompt to rate "your pain at its worst in the last 24 hours" on the ZBPI, 
that persists or appears greater than or equal to 90 days after the onset of the HZ rash].
The CAC will determine whether HZ complications have occurred based on the clinical 
findings, laboratory and radiologic results from subjects with suspected HZ cases, as well 
as results from the blood VZV PCR testing.
2.5.3
Immunogenicity Measurements
The study will provide an exploratory immunogenicity assessment of V212, as shown in 
Table 2-2. The goal is to assess the immunogenicity of the vaccine and to attempt to 
demonstrate correlation of immune responses to the vaccine with clinical efficacy. Serum 
VZV antibody levels will be measured by gpELISA in patients in the STM study group.  
Serum samples will be collected on Day 1/Visit 1 (prior to Dose 1) and Visit 5 (~28 days 
Postdose 4) based on the original enrollment plan (~2696 patients).  
A subset of the study population will be enrolled in an ELISPOT substudy to measure T 
cell response by IFN-ELISPOT.  Peripheral blood mononuclear cells (PBMC) will be 
collected from those enrolled in the ELISPOT substudy (n ~ 1000), on Day 1/Visit 1 
(prior to Dose 1) and Visit 5 (~28 days Postdose 4).  Participation in the ELISPOT 
substudy will be limited to select sites based upon accessibility to PBMC processing 
laboratories.  At these sites, the first 500 patients enrolled in the STM group and the first 
500 enrolled in the HM group will be enrolled in the ELISPOT substudy.
Patients enrolled in the ELISPOT substudy will have a separate allocation schedule to 
assure a well-balanced randomization ratio.  All investigative sites participating in the 
ELISPOT substudy will enroll each consented patient into the ELISPOT substudy until 
the target enrollment of 1000 patients has been met.

Product:  V212
Page 33
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 2-2
Exploratory Immunogenicity Assessment of V212
Assay
Goal
Population
gpELISA
Assess T cell-dependent 
antibody response

STM = ~2696 patients

HM = none
IFN-γ ELISPOT
Assess T cell response

STM = ~500 patients*

HM = ~500 patients*
* Limited to select sites with adequate laboratory processing capabilities
2.6
LIST OF SAFETY MEASUREMENTS
The safety evaluation will focus on the clinical safety and tolerability profile following 
all 4 vaccine doses. In addition, SAE will be collected for the entire duration of the study 
regardless of causality.
All subjects will receive a VRC at each vaccination visit (Visits 1 through 4). On the 
VRC, patients will be asked to record daily oral temperature measurement, local and 
systemic adverse experiences, as well as concomitant medications, and non-study 
vaccinations.  In addition, patients will be actively prompted to record on the VRC, 
injection-site adverse experiences for 5 days following each vaccination dose, exposure 
to varicella or HZ, and development of varicella/varicella-like or HZ/HZ-like rash.  
Patients will receive a new VRC for each dose of vaccine/placebo.  The VRC will be
used by the patients to collect safety information between each vaccination period 
(minimum 20 days postvaccination dose 1 through 3, through 28 days postvaccination 
dose 4).  The VRC will be reviewed by study site personnel at the end of the minimum 
20-day follow-up period following each V212 or placebo dose.
SAE will be collected as follows. Patients will be instructed to call the site immediately, 
at any time during the study, if they experience a clinical adverse experience that results 
in a hospitalization, prolongs a hospitalization, is a cancer or an overdose, or is another 
severe, unexpected, life-threatening event that could potentially be considered serious 
(see section 3.4.6 for a complete definition of a SAE).  An SAE that is a worsening of a 
pre-existing condition should also be reported.  Patients will also be asked, either at a 
scheduled study visit (Visit 1 through 5) or, after Visit 5, by telephone Periodic Safety
Contact (approximately every 3 months, starting approximately 3 months following Visit 
5), whether they developed a clinical adverse experience that met SAE criteria since the 
last contact with site personnel.  Using a pre-specified script (developed by the 
SPONSOR) that enables the collection of relevant information related to an SAE, site 
personnel will query the patient and record the patient's responses to facilitate reporting 
of the event.

Product:  V212
Page 34
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
As described in Section 3.4.1.3, toxicity grading will be applied for all serious and non-
SAEs in this study based on a toxicity grading scale. This is in addition to the grading of 
adverse experiences by maximum intensity described in Table 3-1.
Pregnancy information will be collected as described in Section 3.4.4.
2.7
STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the statistical analysis plan are summarized below; the comprehensive 
plan is provided in Section 3.5 of protocol details.
2.7.1
Efficacy
The primary efficacy endpoint is the incidence of HZ in the vaccine and placebo groups
in the STM population, defined as the number of HZ cases per 1000 person-years of 
follow-up from study enrollment to the end of study.  Vaccine efficacy for HZ (VEHZ) is 
defined as the relative reduction of the hazard rate of HZ in the V212 group compared 
with that in the placebo group.  The primary statistical hypothesis for the primary 
efficacy is H0: VEHZ 25% versus H1: VEHZ > 25%.  
Appropriate multiplicity adjustment will be made for the planned interim analyses.  The 
primary analysis will be based on a modified intent-to-treat (MITT) population, defined 
as all randomized patients who received at least one dose of the vaccination.  The 
hypothesis test and corresponding CI will be based on a Cox proportional hazards 
regression model stratified by age (< 50 years of age versus ≥50 years of age).
Three secondary efficacy endpoints are defined for STM population.  The three 
secondary efficacy endpoints are defined as follows: (1) incidence of moderate to severe 
HZ-associated pain (defined as 2 or more occurrences of a score of 3 or greater (0-to-10 
scale) in response to the prompt to rate "your pain at its worst in the last 24 hours" on the 
ZBPI), at any time from HZ onset through the end of the 6 month HZ-follow-up period.  
(2) composite efficacy endpoint of the incidence of HZ complications during the study, 
defined as the occurrence of any of the following during the study: hospitalization or 
prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ 
rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, 
or administration of intravenous acyclovir therapy for treatment of HZ.  (3) the incidence 
of PHN (defined as a worst pain score [in the last 24 hours] of 3 or greater [0-to-10 scale] 
in response to the prompt to rate "your pain at its worst in the last 24 hours" on the ZBPI 
that persists or appears greater than or equal to 90 days after the onset of the HZ rash). A 
Cox proportional hazards regression model will be fitted for each of these three 
secondary endpoints stratified by age (< 50 years of age versus ≥50 years of age).

Product:  V212
Page 35
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Additional supportive and exploratory efficacy analyses including safety and tolerability 
assessment and the impact of V212 on the development of HZ in the HM population, and  
the vaccine efficacy durability, other HZ-associated complications, the severity and 
duration of HZ-related pain and the interference on activities of daily living (ADL tool), 
Quality of Life (EuroQoL/EQ5D tool) and healthcare utilization (HCU tool) will also be 
provided for the HM and STM populations separately.
2.7.2
Immunogenicity
All immunogenicity analyses in this study are exploratory.  All patients in the STM study 
group will have serum samples collected at Day 1/Visit 1 and at Visit 5 (~28 days 
postvaccination dose 4) to assess a T-cell dependent antibody response by gpELISA.  In 
addition, a subset of study patients (n ~ 1000) in both the STM and HM populations will 
participate in the ELISPOT substudy and undergo testing for VZV T-cell responses by 
IFN-ELISPOT assay.  The geometric mean titer (GMT) or geometric mean count 
(GMC) and geometric mean fold rises (GMFR) for both the gpELISA and ELISPOT will 
be provided by vaccination group at scheduled time points (see Section 1.7) for the HM 
and STM populations separately.  A longitudinal regression model will be used to 
estimate the fold difference at these time points between the vaccination groups, while 
adjusting for the prevaccination titers (see Section 3.5.5.2) for the HM and STM 
populations separately.  Other exploratory analyses will also be performed to determine 
whether these VZV-specific immune responses are associated with protection against HZ 
using Cox proportional hazards models in the combined STM and HM populations.
2.7.3
Safety
Patients will be followed for safety for the duration of the study.  In the event study close-
out begins prior to all patients on study completing the required 1 year of follow-up from 
the time of the last vaccination dose, the study will continue to allow all patients to 
complete the required 1 year of follow-up.  Safety and tolerability of V212 will be 
assessed by evaluation of all relevant safety parameters for the HM and STM populations 
separately.  The primary safety endpoint of the study will be based on the incidence of 
SAE observed during the period up to 28 days Postdose 4 in each vaccination group for 
the STM population.  Two-sided 95% CI on the proportion of any vaccine-related SAE 
will be provided for each vaccination group based on the exact binomial distribution [19].  
The risk difference on SAE between the two groups and the corresponding two-sided 
95% CI on the risk difference will also be provided using the stratified asymptotic 
methods proposed by Miettinen and Nurminen [20].

Product:  V212
Page 36
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Other key safety evaluations will include summaries of the proportions of patients 
reporting the following adverse experiences: 1) systemic adverse experiences prompted 
for on the VRC, including varicella-like rash and HZ-like rash, occurring from Day 1 to 
Day 28 after any study vaccination, 2) injection-site complaints prompted for on the 
VRC, such as redness, swelling, and pain/tenderness/soreness occurring Day 1 through 
Day 5 after any vaccination, 3) elevated temperature (≥100.4°F [≥38.0ºC] oral or oral 
equivalent), from Day 1 to Day 28 after any study vaccination.  The risk differences 
between the two vaccination groups, corresponding two-sided 95% CI on the risk 
difference, and the p-value for the test of significant risk difference will be provided 
using an asymptotic method for differences of 2 independent binomial proportions 
adjusting for stratification factors.
The rate of SAEs, vaccine-related SAEs and death that occur throughout the entire study 
follow-up period will also be summarized per 1000 person-years of follow-up by 
vaccination group.  Additional safety summaries including SAEs, vaccine-related SAEs 
and death will be provided in each vaccination group for the HM and STM populations 
separately.
2.7.4
Power and Sample Size
This is an event-driven study.  With a 1:1 randomization ratio between the vaccine and 
placebo groups and a total of 90 HZ cases in the STM population with 2696 patients, the 
study will have an overall power of ~84.2% to detect 65% VEHZ at the overall two-sided 
0.025 significance level, based on the success criterion of the lower bound 97.5% CI for 
VEHZ being greater than 25%.
To accrue ~90 confirmed HZ cases in the STM population during the time period from 
enrollment through approximately the end of maximum 5 years postvaccination, 
enrollment of approximately 2696 patients (1348 receiving vaccine and 1348 receiving 
placebo) will be required, assuming 1) 30% total lost-to-follow-up, 2) an HZ rate of 17 
per 1000 in the placebo group for STM, 3) VEHZ=65% for STM, and 4) 36 months of 
study enrollment. The sample size calculation follows the methods described in Lachin 
[21].
The dropout rates and the combined HZ event rates will be monitored on an ongoing 
basis using the blinded database.  If ongoing blinded pooled event rate monitoring 
indicates that there may be fewer than 90 confirmed cases of HZ accrued for the STM 
population, then the follow-up time may be extended.  More specifically, if the observed 
HZ case accrual rate indicates that more than 5 years of patient follow-up will be 
necessary to accrue the targeted number of confirmed cases, then the SPONSOR will
consider it beyond the adjustment cap and terminate the study after 5 years of patient 
follow-up have occurred.

Product:  V212
Page 37
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
A subset of patients will participate in the ELISPOT substudy. Power and sample size of 
the ELISPOT substudy is discussed in Section 3.5.7.3.
2.7.5
Interim Analysis
The first interim analysis for futility was conducted on 29-Oct-2014.  Text describing the 
analysis strategy can be found in Appendix 6.3.

Product:  V212
Page 38
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3. PROTOCOL DETAILS
3.1
RATIONALE
3.1.1
General Background
HZ, commonly known as shingles or zoster, is a manifestation of the reactivation of 
VZV, which as a primary infection, produces chickenpox (varicella).  Following initial 
infection, the virus remains latent in the dorsal root or cranial sensory ganglia, until it 
reactivates, producing HZ.  HZ is usually characterized by a unilateral, painful, vesicular 
cutaneous eruption with a dermatomal distribution.  MRL developed ZOSTAVAX™ for 
the prevention of HZ and its complications, especially HZ-related pain and PHN, in 
immunocompetent older adults.
Immunocompromised patients have a higher incidence of HZ, compared to the general 
population, and are at increased risk for developing severe and life-threatening 
complications as well as severely disabling PHN [2-12].  In the immunocompromised 
population, the clinical presentation of HZ may be atypical and nonspecific, and include 
signs and symptoms such as fever, abdominal pain, altered mental status and respiratory 
symptoms in the presence or absence of a cutaneous eruption.  The incidence of HZ in 
such patients, including recipients of HCT and solid organ transplants, patients infected 
with HIV, patients on immunosuppressive therapies, and patients with autoimmune 
diseases such as systemic lupus erythematosus (SLE) ranges from 12 to over 50 cases per 
1000 person-years, compared with an incidence of 7 to 11 per 1000 person-years in 
immunocompetent community-dwelling older adults [22-32].
Current treatment for HZ in immunocompromised hosts may include intravenous 
administration of acyclovir due to the high risk of severe morbidity and mortality 
associated with HZ in these patients.  Antiviral therapy is most effective when given very 
early during the course of the disease.
The live, attenuated Oka/Merck varicella vaccine (VARIVAX™) has been studied in 
immunocompromised hosts in a variety of settings.  Due to the documented risk of severe 
VZV-like rash and an increased rate of vaccine-related SAEs, reported in acute 
lymphoblastic leukemia (ALL) children who received VARIVAX™, which may result 
from replication of the vaccine virus strain in this setting, all of the live attenuated 
Oka/Merck VZV vaccines (VARIVAX™, ZOSTAVAX™
and ProQuad™) are 
contraindicated in patients with compromised immune systems [33].
The development of a suitable vaccine for the prevention and amelioration of HZ and 
HZ-related complications in immunocompromised persons would therefore address a 
significant unmet medical need in particularly vulnerable populations. Inactivation of the 
live attenuated Oka/Merck VZV vaccine by treatment with gamma-irradiation limits the 
quantity of live virus to a minimal level, while preserving the quantity of vaccine viral 
antigen, and therefore could be the basis for the development of a suitable vaccine. 

Product:  V212
Page 39
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.1.1.1
Epidemiology of HZ in Patients with HM
In patients with HM, the incidence of HZ is significantly higher than that seen in the 
general population of the same age and that of immunocompetent older adults, and varies 
by the degree of immunosuppression caused by the underlying cancer diagnosis and 
treatments [22-30]. 
The incidence of HZ in Hodgkin's disease patients receiving 
chemotherapy was estimated to range from 50 to 70 per 1000 person-years within 3 years 
of follow-up [22-26].  For Non-Hodgkin lymphoma, HZ incidence was estimated to 
range from 25 to 50 per 1000 person-years over an average follow-up of 2 to 3 years [22, 
24, 27, 28].  In patients with multiple myeloma, HZ incidence was estimated to range 
from 40 to 60 per 1000 person-years after 2 to 3 years of follow-up.  The risk of HZ in 
multiple myeloma patients has been shown to significantly increase after treatment with 
bortezomib compared to no treatment or to high-dose dexamethasone [29, 30].
In a recent Merck-sponsored observational cohort study conducted at KPNC, a US 
managed care organization, in cancer patients with STM or HM diagnosed between 2001 
and 2005, among ~2700 HM patients, the estimated incidence of HZ was 31 per 1000 
person-years [13].  In this population, both the underlying cancer diagnosis and the 
treatment regimen resulted in immunosuppression.  In this study, a consensus algorithm 
developed for database studies by immunology and infectious disease experts was used to 
classify the level of immunocompromise (IC) of patients into none/low, medium, or high.  
IC classification, updated on a monthly basis throughout the study period for each 
patient, was based on (1) the type of chemotherapy agents and/or corticosteroids used, (2) 
time since last chemotherapy/corticosteroid treatment, and (3) specific type of HM [31].  
Corticosteroid therapy was classified into levels of IC based on dose and duration of 
treatment.  Among HM patients, the incidences of HZ were 13, 25, and 48 per 1000 
person-years in the low, moderate, and high IC groups respectively.  The incidence of HZ 
was higher for patients who were receiving chemotherapy or corticosteroids during the 
study period (47 per 1000 person-years) than those who were not (17 per 1000 person-
years).  The incidences of HZ among patients with multiple myeloma, Hodgkin's 
lymphoma, non-Hodgkin lymphoma, and myeloid leukemia were 56, 51, 25, and 23 per 
1000 person-years respectively.  HZ can also be a significant source of morbidity in HM 
patients.  The proportion of HZ cases complicated by PHN and disseminated zoster was 
estimated to range from ~5% to 33% and 5% to 19%, respectively [22-24, 28-29, 32-33].  
In the KPNC study, among 140 incident HZ cases in the HM patients, approximately one 
in three patients (33.6%) developed at least one complication. PHN (zoster-associated 
pain persisting or appearing at or beyond 90 days post-HZ onset) occurred in 5.7% HZ 
cases.  The proportion of cases with multiple dermatome involvement, skin-related, eye-
related, or neurological complications was 7.9%, 19.3%, 3.6%, and 2.9% respectively.

Product:  V212
Page 40
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.1.1.2
Epidemiology of HZ in Patients with STM
Published data of HZ in the STM patient population are much more limited than for other 
IC populations.  HZ incidence in this population was reported to range from 12 to 15 per 
1000 person-years [33-39].  Aggressive and prolonged chemotherapy was widely 
identified as the primary factor for VZV reactivation [33-39].  In the KPNC study, the 
incidence of HZ among ~12,000 STM patients diagnosed during the study time period 
was 12 per 1000 person-years [13].  The incidence was 19, 20, and 10 per 1000 person-
years in the high, moderate, and low IC groups respectively.  The incidence of HZ among 
patients with breast, prostate, lung and bronchus, colon and melanoma cancer was 15, 10, 
21, 8, and 9 per 1000 person-years respectively.  When compared with the general 
population, adjusting for age and gender, STM patients in general had ~2-fold increased 
risk of the general population while patients currently on chemotherapy or corticosteroid 
therapy had ~3 fold increased risk.  Complications of HZ can be a significant burden to 
the STM patient.  The proportion of HZ cases with PHN was estimated to be as 
frequently as 8% to 42% [13, 35, 36].  Among the HZ cases in STM patients in the 
KPNC study, it was shown that ~23% had at least one complication (PHN or any non-
pain related complications) [13].  PHN (defined as zoster-associated pain persisting or 
appearing at or beyond 90 days post-HZ onset) occurred in 8.6% of the patients.  
Multiple dermatome involvement, skin-related, eye related, and neurological 
complications occurred in 8.5%, 7.7%, 3.2%, and 0.4% of HZ cases respectively.
3.1.2
Rationale for This Study
The epidemiology study conducted by KPNC recently characterized the epidemiology of 
HZ and its complications in the STM and HM populations.  Results of that study confirm 
that the level of immunocompromise (IC) plays a significant role in the development of 
HZ and associated complications.  Compared to individuals of similar age and sex in the 
general population, rates of HZ were approximately 5-fold higher in individuals with HM 
and ~2-fold higher in individuals with STM (~3 fold higher in individuals with STM on 
chemotherapy or corticosteroid therapy).  Among those patients with HM and STM, rates 
of HZ were higher in individuals with higher levels of IC, than those with low IC levels.  
The availability of a vaccine to prevent HZ and associated complications in these patient 
populations represents a significant medical need, as the live attenuated vaccine is 
contraindicated in immunocompromised individuals.
POC for a VZV vaccine inactivated by heat-treatment for use in HCT recipients was 
demonstrated in two clinical trials conducted by Arvin, et al. [14, 15].  These trials 
utilized inactivated Oka/Merck varicella vaccine supplied by Merck & Co., Inc.  One of 
the studies demonstrated reduced morbidity following a 3-dose vaccine regimen, and the 
other a decreased incidence of disease due to VZV reactivation following a 4-dose 
vaccine regimen [14, 15].  The results of these two studies demonstrated that inactivated 
VZV vaccine given to recipients of HCT had significant impact on the development of 
HZ.  Protection appeared to correlate with the reconstitution of T cell immunity against 
VZV.  A 4-dose regimen, with doses given 30 days prior to HCT and 30, 60, and 90 days 
post-HCT, resulted in a significant reduction in the risk of HZ [15].

Product:  V212
Page 41
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
The Phase I clinical study of inactivated VZV vaccine, Protocol 002, was conducted by 
the SPONSOR.  Protocol 002 was a randomized, double-blind, multicenter study to 
evaluate the safety and immunogenicity of VZV vaccine inactivated by heat-treatment in 
4 distinct immunocompromised populations: recipients of HCT (allogeneic and 
autologous), patients infected with HIV with CD4 counts <200/mm3, patients with HM 
and patients with STM receiving chemotherapy.  The study enrolled 341 adults (50 
autologous HCT, 51 allogeneic HCT, 80 HIV-infected, 81 HM, and 79 STM), 18 years of 
age or older, who were randomized to receive either a 4-dose regimen of V212 
inactivated by heat-treatment or placebo.  Of the 81 patients with HM, 62 were 
vaccinated with inactivated VZV vaccine and 19 were vaccinated with placebo; whereas 
among the 79 patients with STM, 59 received inactivated VZV vaccine and 20 received 
placebo.  The objective of the study was to provide assess the immunogenicity and safety 
of the inactivated VZV vaccine in a broad group of immunocompromised patients. No 
safety signals were identified in any of the immunocompromised populations studied. 
The study demonstrated promising immunogenicity results in the autologous-HCT, STM 
and HM populations, however less robust responses were seen in the HIV population 
with low CD4 counts, and responses were poor among those in the allogeneic-HCT study 
population.
The inactivated VZV vaccine was found to be generally safe and well-tolerated in the 
POC and Phase I studies, and no differences in the safety profile were observed following 
1, 2, 3, or 4 doses of inactivated VZV vaccine in the POC or Phase I studies. The 
frequencies of injection site adverse experiences, systemic adverse experiences, and 
SAEs were not higher following subsequent doses for any patient population assessed in 
Protocol 002.
Overall, the results of the Phase I clinical study, Protocol 002, indicated that the 
inactivated VZV vaccine is immunogenic and has a favorable safety profile when 
administered as a 4-dose regimen to adults with HM or STM receiving chemotherapy, 
which provided a rationale for further development of the inactivated VZV vaccine in the 
HM and STM populations.
Of important note, formal dose ranging studies are not feasible in HM and STM patients 
because studies to formally compare the efficacy of different dose regimens would be 
extremely large and not feasible to conduct in a timely manner.  Therefore, this Phase III 
study has been designed based on the results of the POC and Phase I studies summarized 
above.

Product:  V212
Page 42
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
V212-011 is an adaptively designed study which included a planned interim analysis for 
futility when 50% of the targeted cases of HZ had accrued in each population.  The 
interim analysis was conducted on 29-Oct-2014 for both populations.  At this time, clear 
evidence of futility was demonstrated in the HM arm and on 04-Nov-2014, enrollment 
and vaccination were stopped in this population.  On 19-Nov-2014 close-out procedures 
were initiated in the HM population.  As per the protocol in the event that one population 
is futile, the other population may continue and contribute to the final analysis.  As a 
result, the use of V212 in patients with STM will be the targeted indication supported by 
this study, and the objectives have been modified accordingly (Section 2.1).  However, 
additional subjects will not be enrolled in the STM population, and the current sample 
size will support the final analysis.  Thus, the originally planned second interim analysis 
for futility and efficacy has been canceled because of the risk of a false negative result 
due to the small number of cases.  Furthermore, a final case count of 90 (reduced from
the original planned 210) will be targeted in the STM population; this will provide 
adequate power for the primary endpoint without the need for enrollment of additional 
subjects.
3.1.2.1
Rationale for Choice of Vaccine Inactivation Method
Inactivation of the VZV vaccine via the heat-treatment targets a reduction of VZV 
infectious particles to <10 PFU per dose.  POC studies of this vaccine in HCT/Bone 
Marrow Transplant (BMT) recipients demonstrated that this level of residual infectivity 
content is not required for vaccine efficacy.  Inactivation by gamma irradiation further 
reduces VZV infectious particle content to <0.1 PFU per dose, while preserving antigen 
level.  In Protocol 004, the Phase I study that assessed the safety and immunogenicity of 
vaccine inactivated by gamma irradiation in healthy 50- to 59-year-old adults, 
immunogenicity was not affected when the vaccine was inactivated by gamma irradiation 
doses up to 25 kGy. Therefore, the VZV vaccine to be used for this study and future 
studies of V212 will be inactivated by gamma irradiation.

Product:  V212
Page 43
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.1.2.2
Rationale for Dose Regimen
This protocol will assess the safety and efficacy of a 4-dose vaccine regimen in patients 
with STM and HM.  Formal dose ranging studies are not feasible in these patient 
populations because of the large numbers of subjects that would be required to 
demonstrate statistical differences in immunogenicity or clinical efficacy across study 
groups receiving different numbers of vaccine doses. Therefore, the decision to assess a 
4-dose vaccine regimen in patients with HM, and STM is based upon the considerations 
presented below.
POC and Phase I Study Results in Autologous HCT Patients
1. The POC studies conducted in patients undergoing HCT evaluated a single-dose 
post-transplant, a 3-dose regimen post-transplant, as well as a 4-dose regimen, 
which added a pre-transplant dose [14, 15].  No efficacy was observed in patients 
who received the single-dose regimen given 30 days post-transplant.  The regimen 
of 3 doses given 30, 60 and 90 days post-transplant resulted in significant 
decreases in HZ severity but did not impact HZ incidence [14].  The 4-dose 
regimen with doses given 30 days prior to transplant and 30, 60 and 90 days post-
transplant resulted in a significant reduction in the risk of HZ [15]. 
Phase I Study Results in HM and STM Patients
2. In the Phase I study, Protocol 002, 3 doses of vaccine induced a robust immune 
response in patients receiving chemotherapy for STM. A small increment in 
response was shown postdose 4 as indicated measured by IFN-γ ELISPOT or 
gpELISA [16], which suggests additional benefit of further immunization. A 
similar kinetics of T cell response was noted in the HM population, even though 
the overall magnitude of the response was lower in that population. There is a 
possibility that the increase in immune response following the fourth vaccine dose 
could confer a true advantage in efficacy (as it does in auto-HCT patients) or 
duration or protection in STM and HM patients. However, a direct demonstration 
would require clinical efficacy studies that assess different dose regimens, as was 
done for the auto-HCT group to establish POC.  Such studies are not feasible for 
the HM and STM populations because of the very large number of patients that 
would be required.
3. In the Phase I study, Protocol 002, the postdose 4 responses measured by IFN-γ
ELISPOT GMC were generally of comparable magnitude in the auto-HCT and 
STM groups.  At postdose 3, responses were higher in the STM group than in the 
autologous HCT group.  However, the postdose 3 response for STM patients was 
not as high as the postdose 4 response for auto-HCT patients. These findings raise 
the possibility that, as was demonstrated in the POC studies for autologous HCT, 
3 doses of vaccine may not provide sufficient protection in STM patients.

Product:  V212
Page 44
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
4. The IFN-γ ELISPOT GMC observed postdose 3 and postdose 4 for the HM group 
was substantial since the fold rise in GMC was comparable to that seen for older 
subjects in the ZOSTAVAX™ pivotal study. However, it was lower than for 
either the autologous HCT or STM groups. Therefore, a 3-dose regimen may not 
provide sufficient protection in HM patients, and a 4-dose regimen may be an 
appropriate choice in HM patients to further enhance immune responses and 
establish protective immunity. 
Additional Comments
5. An additional consideration is that HM and STM patients undergoing 
chemotherapy may present varying levels of immunosuppression over time 
throughout the vaccination period. Thus, if a dose of vaccine is administered at a 
time of high immunocompromise, this could potentially result in suboptimal 
responses. Administering multiple doses may help establish more robust and 
consistent overall immune responses across these populations of patients and 
result in improved vaccine efficacy.
6. It is not known why a 3-dose regimen of inactivated VZV vaccine does not reduce 
HZ incidence in auto-HCT patients, while a 4-dose regimen does. This dramatic 
difference in efficacy between the 2 dose regimens is not reflected in 
immunogenicity measurements: in the Phase I study, Protocol 002, 3 doses of 
vaccine induced a robust IFN-γ ELISPOT response in auto-HCT patients while 
the increase in response postdose 4 was proportionally less. It is possible that the 
fourth dose of vaccine primarily enhances aspects of the immune response that are 
critical for efficacy but not captured by the IFN-γ ELISPOT assay. One may 
speculate that a fourth dose may help with avidity maturation of the T cell 
response, a relevant consideration since T cell avidity is a major determinant of 
antiviral immunity. Preliminary animal data support the concept that more 
immunizations are required for robust avidity maturation than for T cell 
expansion [40]. Obviously, a formal demonstration in human patients would be 
too resource intensive to be feasible.
7. Collectively, the above considerations support the use of a 4-dose regimen of the 
inactivated VZV vaccine in this Phase III efficacy study in the HM and STM 
populations. Of note, a 4-dose regimen of V212 will also be used in a concurrent 
Phase III efficacy study in auto-HCT patients.

Product:  V212
Page 45
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.1.2.3
Rationale for Selection of Efficacy Endpoint Measures
This study will use HZ case definitions that are consistent across both the 
ZOSTAVAX™ and V212 programs.  In addition, HZ-associated pain and PHN will be 
assessed using a validated instrument and procedures common to both programs.  
Patients with suspected HZ will be evaluated for 6 months to obtain information on the 
duration and severity of HZ-related pain, the development of HZ complications, and the 
development of PHN.  Pain severity will be measured using the ZBPI, a modified version 
of the Brief Pain Inventory (BPI) developed by Cleeland et al., to evaluate cancer pain 
[41].  The ZBPI is specifically designed to measure HZ-related pain and its impact on 
daily living.  The validity and reliability of the ZBPI pain items have been established for 
HZ through a prospective validation study conducted in 121 patients with HZ [42].
Data for exploratory endpoints, including interference of HZ on ADL, HZ-related HCU, 
and HZ-related WPQ will be collected, using qualified or validated tools, in order to 
assess the frequency and magnitude of these HZ outcomes and provide additional 
confirmation that the vaccine has clinically meaningful impact on HZ disease [41, 42].
3.1.2.4
Rationale for the Immunogenicity Endpoint Measures
An exploratory objective of the study will be to evaluate the immunogenicity of the 
vaccine in patients with HM and STM.  Two candidate immunologic markers of efficacy 
will be assessed.  T-cell-dependent antibody response measured by gpELISA will be 
assessed only in the STM study group. T-cell response directly measured by VZV IFN-γ 
ELISPOT will be assessed in a subset of the study population including both the STM 
and HM study groups.
The gpELISA has been validated and is the primary assay used by the central laboratory
for detection of VZV antibodies before and after vaccination with a VZV-containing 
vaccine.  The T-cell dependent antibody response measured by gpELISA was 
demonstrated to correlate with vaccine efficacy against HZ in two independent large 
efficacy trials of immunocompetent older adults [43, 44].  The VZV IFN-γ ELISPOT 
assay has been validated and is used to detect IFN-γ-secreting VZV-specific cells from 
PBMC before and after vaccination with VZV-containing vaccine(s), thus providing a 
direct assessment of cell-mediated immunity. Data from ZOSTAVAX™pivotal efficacy 
study show that in immunocompetent subjects, immune responses to the vaccine 
measured by gpELISA and by VZV IFN-γ ELISPOT both correlated with efficacy of the 
live attenuated zoster vaccine [43].

Product:  V212
Page 46
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
To assess the gpELISA and IFN-γ ELISPOT results as potential correlates of V212 
efficacy in patients with HM and/or STM, serum samples will be collected from all STM 
patients in the main portion of the study at Day 1/Visit 1 and at Visit 5 and tested via 
gpELISA.  Antibody measurements via gpELISA will not be conducted in patients with 
HM because the nature of the disease and treatments (e.g., blood products) can bias the 
results of an antibody assay.  A subset (n=1000) of the study population (the first 500 
patients with STM and the first 500 patients with HM at participating sites) will 
participate in a substudy whereby whole blood samples will be collected and tested using 
the VZV  IFN-γ ELISPOT at Day 1/Visit 1 and at Visit 5.
Endpoints for gpELISA include GMT and GMFR from Day 1, and endpoints for IFN-γ 
ELISPOT include GMC and GMFR. For both assays, the exploratory objective endpoint 
is the GMFR, since patients are not seronegative at baseline.  Also, data from the 
ZOSTAVAX™program suggest that baseline values influence postvaccination values.
3.2
STUDY PROCEDURES
Refer to the study flow chart (Section 1.7) for a concise view and timing of the study 
procedures.
3.2.1
Visit Windows
Each dose of V212 or placebo should be administered every ~30 days.  There is a 
minimum of 20 days of postvaccination follow-up required prior to the subsequent dose 
of vaccine.  The allowable window between each vaccine dose is 20 to 40 days.  The 
minimum follow-up period postvaccination dose 4 is 28 days; the maximum allowable 
window at Visit 5 is 60 days postvaccination dose 4.  Deviations from the permitted visit 
windows (i.e., the patient meets deferment criteria or the patient is not able to complete 
the visit as scheduled per protocol because of medical or logistical reasons) require 
consultation between the investigator and the SPONSOR and written documentation of 
the collaborative decision on patient management.  All study procedures should be 
performed at the vaccination visits.
3.2.2
Informed Consent
Study personnel must obtain written informed consent from each patient prior to 
performing any study procedures (e.g., collection of blood sample, vaccination, or rash 
lesion sample)  Consent must be documented by obtaining the dated signatures of both 
the patient and the person conducting the consent discussion, on the consent form.  A 
copy of the signed and dated consent form will be given to the patient for his/her records.
Should a patient sign a consent form but not enroll in the study on that same day (i.e. no 
study procedures are performed) that signed consent form would be valid for up to 14 
days.  If the patient returns after more than 14 days have elapsed, consent procedures 
must begin again and a new written consent must be obtained.

Product:  V212
Page 47
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.3
Assignment of Baseline Number
Baseline numbers will be automatically generated by the SPONSOR via an electronic 
data management system.  Each patient will be assigned a unique baseline number 
immediately after the informed consent is signed.  The baseline number identifies the 
patient for all study-related procedures that occur prior to receiving an allocation number.  
Baseline numbers are a combination of the site number and the patient number and are 
assigned sequentially from the lowest number to the highest number at each site.  
Baseline numbers should never be skipped and may not be reassigned for any reason.  A 
single study patient cannot be assigned more than 1 baseline number.
3.2.4
Non-Randomized Patients
If a patient has signed a consent form, but the patient is not randomized, the patient's 
basic demographic information and the reason(s) for exclusion from the study must be 
reported.  The baseline number previously assigned to the patient should be used to 
uniquely identify this nonrandomized patient.  For detailed information on entering data 
into the data collection system for these patients, consult the electronic data capture 
(EDC) data entry guidelines provided by the SPONSOR.
3.2.5
Study Participation Patient Identification Card
All subjects/patients will be given a card, at the time of screening, identifying them as 
participants in a research study.  The card will contain contact information (including 
direct telephone numbers) to be utilized in the event of an emergency.
3.2.6
Physical Examination
A physical examination, including weight, will be performed at Day 1 by a physician, 
nurse practitioner, or physician's assistant (in accordance with local law) and will include 
a general review and evaluation of body systems to determine whether the patient meets 
enrollment criteria for this study.  Physical examination details will be documented in the 
patient's chart.
3.2.7
Medical History/Conditions
The patient’s medical conditions during the 5 years prior to enrollment should be 
reported, capturing any chronic or serious conditions. In addition, the primary cancer 
diagnosis, type of malignancy, grade, and stage or classification of disease should also be 
collected and entered into the database.

Product:  V212
Page 48
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.8
History of Varicella-Zoster Virus Infection
To be enrolled in the study, patients must have a prior history of varicella, antibodies to 
VZV (documented prior to receipt of blood products), or residence in a country with 
endemic VZV infection.  A validated list of countries where VZV is considered endemic 
does not exist.  Operationally, VZV is assumed to be endemic in countries where 
chickenpox is a typical childhood disease.  Patients who reside in regions that have 
implemented universal varicella vaccination programs will be considered to have resided 
in endemic regions if they attended school in an endemic region where varicella 
vaccination had not yet been widely implemented. In areas of the world where it is 
uncertain if VZV is endemic, study sites are encouraged to perform VZV antibody testing 
(local laboratory) of potential study participants prior to administration of blood products 
consistent with standard medical practice.  VZV seronegative patients should not be 
enrolled.
3.2.9
Concomitant Medication(s)/Treatment(s)
Specific prohibited medications/treatments in this study include the following:

Live virus vaccines at any time beginning 4 weeks prior to dose 1 through 28 
days postvaccination dose 4;

Any varicella or non-study zoster vaccine for the duration of the study; 

Inactivated vaccines beginning 7 days prior to through 7 days following any 
dose of vaccine or placebo.
o
Thus, inactivated influenza vaccines should not be administered in the 
time period beginning 7 days prior to through 7 days following any dose 
of study vaccine or placebo. It is understood that this study will be 
conducted over multiple influenza seasons. The allowed window for 
administration of inactivated vaccines should be sufficient to allow for 
administration of inactivated influenza vaccines. Of important note, Live 
influenza vaccine is prohibited at any time beginning 4 weeks prior to 
dose 1 through 28 days postvaccination dose 4.

Receipt of any long term antiviral prophylaxis (duration greater than 4 weeks) 
with activity against HSV, VZV, or CMV.
All medications, including standard antiviral therapy and pain medications administered 
for HZ treatment of a HZ case will be permitted as clinically indicated.  Other 
prescription or over-the-counter medications that may be required for pre-existing or 
concurrent conditions may be used during the study.  Chemotherapeutic regimens and/or 
radiotherapy may be used throughout the study.

Product:  V212
Page 49
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
It is imperative that all medications administered to the patient 90 days prior to 
enrollment and any new medications or procedures (e.g. radiation therapy, blood 
transfusions, chemotherapy, etc.) starting/occurring through 28 days Postvaccination 4 be 
recorded.
Medications administered for the treatment of HZ and/or HZ symptom relief, and those 
medications administered within 14 days of an SAE, and as treatment for an SAE, will be 
collected for the duration of the study.
3.2.10 Contraception
Women who are not of reproductive potential are not required to use contraceptive 
methods in this study.  A female patient who is not of reproductive potential is defined 
as: one who has either (1) reached natural menopause (defined as 6 months of 
spontaneous amenorrhea with serum follicle stimulating hormone [FSH] levels in the 
postmenopausal range as determined by a laboratory, or 12 months of spontaneous 
amenorrhea), (2) post-surgical bilateral oophorectomy and/or hysterectomy, or (3) 
bilateral tubal ligation.  Note that the definition surrounding the term "natural 
menopause" as it relates to 6 or 12 months of amenorrhea is specific to women who are 
of the expected age of natural menopause and does not pertain to conditions occurring in 
younger women.  Younger women who experience spontaneous amenorrhea are 
considered to be of childbearing potential.
Women of reproductive potential may be enrolled into the study.  However, female 
patients must agree to remain abstinent or use (or have their partner use) adequate 
contraception during the time period starting 2 weeks prior to enrollment through 6 
months from the last vaccination dose.  Acceptable methods of birth control include use 
of hormonal contraceptives, intrauterine device (IUD), diaphragm combined with 
spermicidal agent, contraceptive sponge, bilateral tubal ligation, condoms combined with 
spermicidal agent, or abstinence.  Simultaneous use of two reliable forms of 
contraception is recommended.  Females of reproductive potential must have been 
consistently using these barriers for at least 2 weeks prior to screening to be eligible for 
randomization.
If there is any question that a patient will not be reliable in the use of the appropriate 
contraceptive methods, the patient should not be enrolled into the study.  Patients must be 
completely informed of the unknown risk of the vaccine during pregnancy and agree not 
to become pregnant during the time they enter the study through 6 months from the last 
vaccination dose.

Product:  V212
Page 50
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.11 Pregnancy Testing
A serum or urine pregnancy test (sensitive to 25IU β-hCG) will be performed at the 
investigative site prior to each vaccination for all female patients of childbearing 
potential.  Pregnancy test results must be available before vaccination.  Any patient with 
a positive pregnancy test must not be vaccinated.  Any patient found to be pregnant at the 
Day 1 visit will not be randomized and will not participate in the study.  If pregnancy 
develops after Visit 1 but before completion of the vaccination regimen, the patient will 
not receive subsequent vaccine doses but should remain in the study for safety, efficacy 
and immunogenicity follow-up. The physician will maintain regular contact with the 
subject for the purpose of pregnancy assessment (term, miscarriage, abortion, etc.).  All 
pregnancies should be reported to one of the study personnel listed on the SPONSOR 
Contact Information page (located in the Administrative Binder) as soon as the situation 
becomes known.
NOTE: If required by an institution's IRB/ERC, more frequent pregnancy testing may be 
performed in accordance with local regulations.
3.2.12 Stratification/Randomization/Allocation
Randomization will be stratified by patient population (STM or HM) with approximately 
2696 patients with STM and 2568 patients with HM enrolled into the study.  Patients 
with HM will be further stratified into one of two strata (low IC; moderate to high IC), 
based on the patient's specific HM diagnosis (underlying cancer diagnosis) and/or 
chemotherapeutic regimen (see Appendix 6.1). The planned randomization schedule by 
vaccination group is shown in Section 2.4.2.
An IVRS will be used to register patient visits at the time of randomization and at 
subsequent visits.  The IVRS will be used to allocate the patient to the vaccination group 
assignment and to assign either V212 or placebo to the patient during randomization, 
according to a centralized randomization schedule generated by the SPONSOR.  Study 
site personnel accessing the IVRS will be assigned an individual unique personal 
identification number (PIN).  Site personnel must use only their specific assigned PIN to 
access the IVRS and must not share their assigned PIN with anyone.
A separate allocation schedule will be used to allocate those patients participating in the 
ELISPOT substudy to assure a well-balanced randomization ratio. All investigative sites 
participating in the immunogenicity substudy will enroll each consented substudy patient 
until the target enrollment of 1000 patients has been met.

Product:  V212
Page 51
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
At Visit 1, after the patient has signed the consent form, the medical history has been 
collected, all inclusion/exclusion criteria are met, a negative serum or urine pregnancy 
test (sensitive to 25IU β-hCG) has been obtained, and the prevaccination blood sample 
has been collected (if applicable), site personnel will access the IVRS using their PIN  
The IVRS will assign an allocation number to the patient, followed by the assignment of 
unique component identification number (CID) corresponding to the vial of 
vaccine/placebo and diluent the patient should receive at that visit.  The CID on the 
vaccine/placebo vial and the CID on the diluent vial will be unique.  The IVRS will 
automatically assign the appropriate clinical material based on the patient's treatment 
allocation.
At subsequent vaccination visits (Visits 2, 3, and 4), study personnel will access the 
IVRS using their PIN and the IVRS will assign a unique CID number corresponding to 
the vial of V212 or placebo and diluent the patient should receive at that visit.  The CID 
on the V212 or placebo vial and the CID on the diluent vial will be unique from each 
other as well as previous CID assignments.
The patient's allocation number will remain the number that was assigned to the patient at 
Visit 1 and will never change.
At the conclusion of each transaction, the IVRS confirms the transaction audibly and 
provides a detailed confirmation sheet via FAX to the investigator site.  This 
documentation must be retained in the patient’s file.
A single patient/subject cannot be assigned more than 1 allocation number.
3.2.13 Blood Collection for Immunoassays
Blood will be collected at Visit 1/Day 1 and at Visit 5 (~28 days Postdose 4) in a subset 
of patients. This study procedure is described in Section 3.3.  Blood collection at Day 1 
must take place prior to administration of Dose 1 of V212 or placebo.
3.2.14 Vaccination
Approximately 5264 patients (~2632 vaccine recipients; ~2632 placebo recipients), 18 
years of age or older (Note: In India only, enrollment is restricted to patients 18 to 65 
years of age.) will be randomized 1:1 to receive either V212 or placebo given as a 4-dose 
regimen approximately 30 days apart.  Placebo will be the vaccine stabilizer for the V212 
with no virus antigen.

Product:  V212
Page 52
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.14.1 Dosage and Administration
This is a 4-dose vaccination study.  On the day of enrollment, patients will be randomized 
to the vaccine or placebo group.  Each dose of study vaccine or placebo will be 
administered as a 0.5-mL (do not administer all of the contents from the vial)
subcutaneous injection preferably in the deltoid region of the arm, alternating arms for 
each vaccination dose if possible.  Each dose should be administered approximately 30 
days apart.  The minimum window between 2 vaccine doses should be 20 days.  All 
vaccinations should be appropriately recorded in the study data collection system.
3.2.14.2 General Precautions for Administration
Adequate treatment provisions, including epinephrine, should be available for immediate 
use, should an anaphylactic or anaphylactoid reaction occur.
A separate, sterile syringe and needle or sterile disposable unit should be used for each 
injection for each patient, to prevent transmission of infectious agents from person to 
person.  Needles should not be recapped and safe disposal procedures for sharps should 
be followed.
Before subcutaneous injection, the skin over the site to be injected should be cleansed 
with a suitable antiseptic.  After insertion of the needle into the skin, aspirate to ensure 
the needle has not entered a blood vessel.  Should this occur, remove the needle/syringe 
and discard the needle/syringe and study vaccine or placebo according to local 
regulations regarding medical/biohazardous waste and note on the Vaccine 
Accountability Form in the Administrative Binder.  Call the IVRS for a replacement vial 
of study material.
3.2.14.3 Preparation of the Vaccine
Use only the diluent that is provided by the SPONSOR to reconstitute the vaccine.  The 
diluent is sterile distilled water and contains no preservatives or other substances that 
might adversely affect the vaccine.  To reconstitute the vaccine, first withdraw the entire 
contents of the diluent vial into a syringe.  Inject all of the diluent in the syringe into the 
vial of lyophilized vaccine (approximately 0.7 mL) and gently agitate to mix thoroughly.  
Withdraw and administer 0.5-mL of the reconstituted vaccine.
Do not freeze reconstituted vaccine.
CAUTION:  A sterile syringe free of preservatives, antiseptics, and detergents should be 
used for each injection and/or reconstitution of the vaccine because these substances may 
adversely affect the vaccine.  A 5/8-inch (16-mm), 25-gauge needle is recommended for 
subcutaneous administration of the vaccine/placebo to an average adult.

Product:  V212
Page 53
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.14.4 Administration of the Study Vaccine
The study vaccine or placebo should be administered via subcutaneous injection 
preferably in the upper, outer aspect of the arm (deltoid region), alternating arms for each 
vaccination dose, if possible.
Details of all vaccinations, including the time the vaccine vial is removed from the 
refrigerator, administered, site of injection, route of administration, and dose volume 
should be recorded at the site.  Study vaccine or placebo should be administered as soon 
as possible after reconstitution.  If the study vaccine or placebo is not administered within 
30 minutes after reconstitution, it should be discarded according to applicable local 
regulations for medical/biohazardous waste, noted on the vaccine accountability log in 
the Administrative Binder, and a replacement vial should be obtained.  All unused, non-
reconstituted study vaccine and diluent should be returned to the SPONSOR upon 
completion of the study.
3.2.14.5 Replacement Vials
Additional supplies of V212 or placebo will be packaged to account for any unplanned 
losses.  Replacement vials are to be used if an error is made in reconstituting V212 or 
placebo, if V212 or placebo is not administered within 30 minutes after reconstitution or 
if a vial of vaccine is accidentally destroyed or improperly handled.  Replacement vials 
for Doses 1 through 4 will be made through IVRS.  Refer to the IVRS instruction 
materials supplied to the study sites.
3.2.15 Clinical follow-up for safety
Please refer to Section 3.4 for safety follow-up information, including VRC data 
collection and information on adverse event reporting.
3.2.16 Exposure Survey
At Visits 2, 3, 4, and 5, patients will be questioned regarding their exposure to varicella 
and/or HZ since their last visit.  Study personnel will obtain information detailing the 
patient’s exposure to varicella and/or HZ since vaccination.  Exposure is defined as 
contact with an individual from 5 days prior to the onset of a chickenpox rash, or from 
the day of onset of an HZ rash, until crusting of lesions.

Product:  V212
Page 54
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.17 Follow-up of Suspected HZ Cases
3.2.17.1 Definition of a Suspected Case of HZ
Criteria for a suspected HZ case are the development of a papular or vesicular rash with a 
dermatomal or generalized distribution, or in the absence of a rash, clinical suspicion of 
VZV infection with or without the detection of VZV in diagnostic specimens from blood, 
CSF, lung, liver or other organ.  In immunocompromised patients, HZ rashes may be 
atypical, for example involving more than one dermatome, or rash may not be present.
3.2.17.2 Identification of Suspected HZ Cases
Patients will be monitored through the entire study period for clinical signs and 
symptoms of HZ.  Prior to vaccination, study personnel will instruct all patients on the 
signs and symptoms of HZ.
Typically, acute HZ may include numbness, burning or tingling sensation, and pain at or 
beneath the skin; maculo-papular lesions along one or more dermatomes which progress 
to vesicles, followed by crusted lesions.  Immunocompromised individuals, however, are 
at increased risk for developing severe and life-threatening complications as well as 
severely disabling PHN. For instance, HZ rash may involve 3 or more dermatomes, 
possibly resulting from hematogenous spread.  Also, clinical presentation of HZ may be 
atypical and non-specific, and include signs and symptoms such as fever, abdominal pain, 
altered mental status, and respiratory symptoms with or without a rash. Possible serious 
complications of HZ in immunocompromised individuals include neurological (PHN, 
cranial neuritis, motor neuropathy, transverse myelitis), ophthalmic (keratitis, iritis, 
retinitis, visual impairment), and cutaneous (scarring, disfigurement, bacterial 
superinfection) morbidities. Visceral involvement can also occur which can lead to death 
due to meningoencephalitis, hepatitis or pneumonitis [45].
Patients will be monitored through the entire study period for clinical signs and 
symptoms of HZ.  Prior to vaccination, all patients will be instructed by study personnel 
regarding the signs and symptoms of HZ.  Patients will be asked to notify study personnel 
if they experience a rash or other symptoms suggestive of HZ at any time during the 
study.
All VRCs should be reviewed through 28 days post-dose 4 to identify any 
varicella/varicella-like or HZ/HZ-like rashes that were not previously examined by study 
personnel. The patient should be questioned for information on these rashes and the 
information should be recorded on the appropriate forms.
Monthly contact by telephone, via the internet, or during a follow-up visit will be 
required for each patient to ascertain complete reporting of suspected HZ. 

Product:  V212
Page 55
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.17.3 Suspected HZ Case Follow-Up (Cases With HZ and HZ-like Rash)
All patients who experience rash or other symptoms that could be due to a suspected case 
of HZ should be seen by a medically qualified investigator, (defined as a physician, or in 
accordance with local regulations, a nurse practitioner or physician assistant) as soon as 
possible, preferably within 24 to 72 hours of rash onset.  The medically qualified 
investigator's description and assessment of the rash, associated complications and 
complaints, and the patient’s history of exposure to varicella and/or HZ should be 
recorded on the appropriate eCRFs.  In addition, the patient should have a skin lesion 
swab and blood sample collected for VZV identification by PCR at the initial rash visit.  
The patient should be evaluated by a medically qualified investigator every 3-5 days until 
no new skin lesions appear.  If the rash is a suspected case of HZ, the patient should 
undergo all procedures and follow-up visits required for suspected HZ cases.
All patients with suspected cases of HZ will be entered into a 6-month suspected HZ case 
follow-up.  Deviations from the 6-month suspected HZ case follow-up period due to 
medical or logistical reasons require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision.  If a patient has 
multiple suspected cases of HZ, each case must go through the 6-month follow-up 
procedures.  If a patient with a suspected case of HZ has pain persisting longer than 6 
months, he/she should continue in HZ follow-up until the pain resolves or the study ends.
Initial Evaluation of a Suspected Case of HZ With HZ or HZ-like Rash
At the initial evaluation of a suspected case of HZ with HZ or HZ-like rash, the following 
procedure should be followed:
a) Perform a full physical examination and report relevant clinical findings.  These 
findings include the dermatome(s) involved, morphologic characteristics of the rash, 
(including number and type of lesions and extent of rash), and any signs of HZ-
associated complications such as disseminated HZ, secondary infections, and 
hospitalizations and/or mortality related to HZ.  At the time of the initial rash 
assessment, varicella or HZ exposure history should also be obtained.  Collect and 
record all medications administered for HZ treatment or HZ symptom relief.
b) If rash is present, perform rash assessment to monitor for rash evolution
c) If skin lesions are present, collect 2 swabs from the skin lesions to send for analysis 
by PCR as described below.  PCR testing is required to confirm the presence of the 
virus in the lesion as well as to differentiate vaccine-strain from wild-type VZV.
NOTE:  If both vesicles and pustules are present, vesicles are the preferred source for 
specimens.  Follow the procedures on lesion sample collection/storage and shipping 
provided in the Laboratory/Procedures or Administrative Binder.

Product:  V212
Page 56
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
1) Obtaining the lesion specimen
For vesicular (clear fluid-filled or blister-like) or pustular lesions:  Using the 
scalpel blade, unroof one or more vesicular lesions.  Swab and vigorously rub the 
base of the lesion, absorbing any lesion fluid onto the swab.  If lesions are 
ulcerative, swab and vigorously rub the ulcer base to obtain cellular material.  
Ensure there is plenty of cellular material and vesicle fluid on/in the swab.  
Remember to use 1 swab per skin lesion.
NOTE:  If both vesicles and pustules are present, vesicles are the preferred source 
for specimens.
When only macular (i.e. red, flat) and/or papular (raised bump) lesions are 
present:  Use the sterile scalpel blade to unroof one or more lesions. Swab and rub 
the lesion vigorously enough to ensure that epithelial tissue is obtained.  It is more 
difficult to obtain adequate skin cells from a maculopapular lesion; therefore, this 
procedure should only be used when there are no vesicular or pustular lesions 
present.
Scabs or crusted lesions:  Using the scalpel, gently lift the scab from the lesion to 
obtain a piece of the scab and place the scab in the sterile tube. This procedure 
should only be used when there are no vesicular or pustular lesions present.
NOTE:  If the patient develops a suspicious rash after the first evaluation for a 
suspected case of HZ, the skin lesion specimens should be obtained when the rash 
is first observed.
2) Confirm that the swab contains adequate lesion fluid/cellular material for testing.
3) Break off the handle and place the swab in a sterile tube, making sure to securely 
tighten the screw-top tube.  Using the label provided by the SPONSOR, with a 
fine-point permanent marker include the following information:
Allocation number, baseline number, date, type of specimen (skin lesion) and site 
(left arm, etc.).
4) Repeat steps #1 through #3 for a second skin lesion.
5) Place each labeled, screw-top tube into a centrifuge tube.  Samples can be stored 
at –15°C or lower pending shipment.  
NOTE:  Lesion samples and cold packs should be stored in separate freezers.  Skin 
lesion specimens cannot be stored in a freezer containing a VZV vaccine.
d) Collect blood sample for VZV detection by PCR.

Product:  V212
Page 57
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
e) Pain and interference with ADLs will be assessed by completion of the ZBPI by the 
patient.
f)
HZ-related non-protocol healthcare utilization will be assessed by a study personnel 
conducted interview with the patient using the HCU questionnaire.
g) Work and productivity loss will be assessed by a study personnel conducted interview 
with the patient using the WPQ form.
h) Functional health status and QoL will be assessed by completion of the EuroQoL 
questionnaire by the patient.
Visits During Rash Progression
a) Perform a full physical exam every 3-5 days until no new skin lesions appear.  
Clinical findings as well as relevant laboratory results must be reported.  These 
findings will include descriptions of the evaluation of dermatomal involvement, and 
the morphologic characteristics of the rash, including new vesicle formation, number 
of lesions, and the extent of rash, and any HZ-associated complications.  Record all 
medications administered for HZ treatment or HZ symptom relief.
b) Repeat steps e through h as above.
Visits Following Cessation of New Lesion Formation
a) Conduct monthly evaluations for 6 months from HZ rash onset.  Assessments may be 
obtained by telephone or at a study visit.  All information should be reported.
b) Repeat steps e through h as above. 

Product:  V212
Page 58
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.17.4 Suspected HZ Case Follow-Up (Cases Without HZ/HZ-like Rash)
In immunocompromised patients, the clinical presentation of HZ may not include a rash.  
In the absence of a rash, suspected cases of HZ will be identified based upon clinical 
suspicion of VZV infection with or without the detection of VZV in diagnostic specimens 
from blood, CSF, lung, liver or other organ.  Patients will be asked to notify study 
personnel if they experience other acute symptoms which may be suspicious for HZ, at 
any time during the study.  All patients with suspected acute HZ symptom(s) should be 
seen by a medically qualified investigator (defined as a physician, or in accordance with 
local regulations, a nurse practitioner or physician assistant) as soon as possible, 
preferably within 24 to 72 hours of onset of symptom(s). The medically qualified 
investigator’s description and assessment of the symptoms, associated complications and 
complaints, and the patient’s history of exposure to varicella and/or HZ should be 
recorded on the appropriate eCRFs.  In addition, the patient should have a blood sample 
collected for VZV identification by PCR at the initial HZ case evaluation visit.  The 
patient should be evaluated by a medically qualified investigator every 3-5 days until no 
new acute HZ symptoms appear.  If a HZ case is suspected, the patients should undergo 
all procedures and follow-up visits required for suspected HZ cases.
All patients with suspected cases of HZ will be entered into a 6-month suspected HZ case 
follow-up.  Deviations from the 6-month suspected HZ case follow-up period due to 
medical or logistical reasons require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision.  If a patient has 
multiple suspected cases of HZ, each case must go through the 6-month follow-up 
procedures.  If a patient with a suspected case of HZ has pain persisting longer than 6 
months, he/she should continue in HZ follow-up until the pain resolves or the study ends.
Initial Evaluation of a Suspected Case of HZ Without HZ and HZ-like Rash
At the initial evaluation of a suspected case of HZ without HZ or HZ-like rash, the 
following procedure should be followed: 
a) Perform a full physical examination and report relevant clinical findings.  These 
findings include any signs of HZ and HZ-associated complications such as 
disseminated HZ, visceral or CNS involvement, secondary infections, and 
hospitalizations and/or mortality related to HZ.  At the time of the initial assessment, 
varicella or HZ exposure history should also be obtained.  Collect and record all 
medications administered for HZ treatment or HZ symptom relief.
b) Verify that a rash is not present. If rash is present, refer to Section 3.2.17.3.
c) Collect blood sample for VZV detection by PCR.
d) Pain and interference with ADLs will be assessed by completion of the ZBPI by the 
patient.

Product:  V212
Page 59
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
e) HZ-related non-protocol healthcare utilization will be assessed by a study personnel 
conducted interview with the patient using the HCU questionnaire.
f)
Work and productivity loss will be assessed by a study personnel conducted interview 
with the patient using the WPQ form.
g) Functional health status and QoL will be assessed by completion of the EuroQoL 
questionnaire by the patient.
Visits During Acute Phase Progression
a) Perform a full physical exam every 3-5 days until no new acute HZ symptoms appear.  
Clinical findings as well as all relevant radiologic and laboratory results must be 
reported to allow proper adjudication of the case.  Local laboratory results of 
specimens obtained because of clinical need, in the context of standard clinical care 
may be included in the adjudication package.  Record all medications administered 
for HZ treatment or HZ symptom relief.
b) Repeat steps d through g as above.
Follow-up Visits
a) Conduct monthly evaluations for 6 months from HZ rash onset.  Assessments may be 
obtained by telephone or at a study visit.  All information should be reported.
b) Repeat steps d through g as above. 
3.2.17.5 Treatment of HZ in Study Patients
Patients who develop suspected HZ should be promptly treated with appropriate antiviral 
therapy, as well as pain medication and other supportive therapy, as clinically indicated 
according to the judgment of the treating clinician, guidelines established by the 
participating institution, and consistent with usual clinical practice.  Therapy for HZ, and 
any HZ- associated pain, or other complications will not be provided as part of the 
protocol study medications.  Any medications administered to the patient should be 
reported on the appropriate eCRF.

Product:  V212
Page 60
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.18 Blinding/Unblinding
This is a double-blind (operating under in-house blinding procedures) study in which the 
patients enrolled, the investigator(s), and the SPONSOR clinical and laboratory personnel 
who are directly involved with this study will be blinded to the vaccination group 
assignment.  Additionally, members of the CAC are also blinded to the vaccination group 
assignment.  An unblinded statistician will provide summary data to the DMC, who will 
be unblinded to vaccination group assignment.  The SPONSOR personnel will remain 
blinded until all patients have completed the study follow-up period, the data have been 
screened for completeness and accuracy, and any protocol violators have been identified.  
In addition, all contract laboratory personnel will be blinded to the vaccination group 
assignment.  In order to maintain blinding at the site, the contents of each vial of V212 or 
placebo, as well as the vial labels, will look identical except for vial specific identifying 
information (e.g. CID number).
Study personnel should use the IVRS to unblind a patient and to unmask vial identity 
(vaccine/placebo), if necessary.  The SPONSOR will not provide disclosure envelopes 
with the clinical supplies.  Vaccine identification information is to be unmasked ONLY if 
necessary for the welfare of the patient.  Every effort should be made to avoid unblinding 
the patient unless necessary.  Prior to unblinding, every effort should be made to contact 
one of the study personnel listed on the SPONSOR Contact Information page in the 
Administrative Binder.  If unblinding should occur for any reason (either accidental 
unblinding or emergency unblinding for a SAE), the investigator must promptly 
document the circumstances on the unblinding log and immediately notify the Merck 
Clinical Monitor listed on the SPONSOR Contact Information page in the Administrative 
Binder.
3.2.19 Study Completion Procedures
When the required number of confirmed cases of HZ have accrued, or if the decision is 
made to terminate the study early following a recommendation made by the DMC based 
on safety concerns, futile efficacy results from the interim futility analyses, or successful 
efficacy results from the interim efficacy analysis (see Section 3.5.8.1), the study will 
begin to enter the close-out phase.  If this occurs, the study will continue to allow all 
patients to complete a minimum of 1 year post-vaccination follow-up for safety and 
efficacy (including new cases of HZ in these patients).
At that time, no additional 
suspected HZ cases will be accrued, and any patient currently entered into suspected HZ 
follow-up will complete their 6-month assessment period.  All patients must complete at 
least 1 year of follow-up following the last vaccination prior to completing the study.  At 
the end of the safety follow-up period, all patients will be contacted by telephone to 
complete the study close-out questionnaire.  Data generated from these questions will 
include any previously unreported symptoms of suspected HZ and SAEs, as well as the 
patient's final study disposition (e.g., completed, lost to follow-up, death).

Product:  V212
Page 61
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.2.20 Discontinuation/Withdrawal from Study
Subjects/patients may withdraw at any time or be dropped from the study at the discretion 
of the investigator should any untoward effects occur. In addition, a subject/patient may 
be withdrawn by the investigator or the SPONSOR if he/she violates the study plan or for 
administrative and/or other safety reasons. The investigator or study coordinator must 
notify 
the 
SPONSOR 
immediately 
when 
a 
subject/patient 
has 
been 
discontinued/withdrawn due to an adverse experience (telephone or FAX). When a 
subject/ patient discontinues/withdraws prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. 
Any adverse experiences which are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in section 
3.4 SAFETY MEASUREMENTS - DETAILS.
3.2.20.1 Discontinuation/Withdrawal Criteria
As indicated in Section 2.3.2, a patient who discontinues from the study due to pregnancy 
or allergic reaction to a component of the vaccine, or who unexpectedly undergoes HCT
should not receive subsequent vaccinations but should remain in the study for safety, 
efficacy and immunogenicity follow-up.
3.2.21 Committees 
3.2.21.1 Clinical Adjudication Committee
The CAC is composed of clinical evaluators who are experts in the fields of infectious
diseases and oncology, who will adjudicate all suspected cases of HZ as well as any HZ-
related complications.  Members are external to the SPONSOR, and may include 
principal or secondary investigators of this study or other V212 studies.  No SPONSOR 
employees are members of the CAC.  CAC members are blinded to the study vaccination 
group assignment.  Guidelines that detail the CAC process are described in separate 
documentation.
3.2.21.2 Scientific Advisory Committee
The Scientific Advisory Committee (SAC), composed of a Merck Clinical Monitor, 
Merck statistician, Merck Communications Department (MCD) representative and 
external scientific leaders in the therapeutic area/disease area, convenes to provide advice 
on the protocol design and statistical analysis plan and to interpret and publish the study 
results of the clinical trial.  The SAC is an advisory collaborative group.
3.2.21.3 Data Monitoring Committee
An independent DMC will be established for continuous safety oversight during the study 
and to review data at each of the planned interim analyses.  To fulfill its responsibilities, 
the DMC will review safety, tolerability, efficacy and demographic data according to 
vaccination group assignments periodically during the course of the study (prior to end-
of-study unblinding).

Product:  V212
Page 62
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
The DMC will consist of individuals with pertinent expertise in the field.  An unblinded 
SPONSOR statistician will perform analyses of the unblinded data to be provided to the 
DMC, but will not be a voting member of the committee.  The DMC guidelines and 
details related to the unblinded statistical analysis of the data will be described in separate 
documentation.
The board will be responsible for periodically reviewing the available safety data to 
identify any critical safety issues in adverse experiences or other safety measures in order 
to make periodic recommendations to the SPONSOR, including recommending whether 
to terminate the study based on safety concerns. Interim efficacy analyses (details in 
Section 3.5.8) will also be provided to the DMC for review and recommendations 
regarding terminating the study early for futility or early success.
The DMC Chairman will be responsible for reporting post-meeting recommendations to a 
Steering Committee (SC) comprised of Merck Senior Management members who will 
hold the authority to discontinue the study in the event of overwhelmingly favorable or 
unfavorable efficacy results or safety concerns.
3.2.21.4 Steering Committee
The Steering Committee (SC), composed of members of Merck Senior Management, will 
provide the overall scientific direction for the program and will receive and be 
responsible for deciding upon any recommendations made by the DMC to stop the study 
early.
3.3
EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC. 
MEASUREMENTS
3.3.1
HZ Case Determination
3.3.1.1
Clinical Adjudication
All suspected cases of HZ will go through case adjudication by the CAC in a blinded 
fashion.  The CAC is a committee of adjudicators with expertise in the diagnosis and 
management of HZ as well as the medical aspects of clinical trials.  The CAC will 
determine if a suspected case is a confirmed case of HZ, in their clinical opinion, and if it 
is determined that this is a confirmed case; the CAC will make the final determination of 
the confirmed HZ complication(s) present.  Upon case confirmation by the CAC, 
members will adjudicate the case relative to the composite HZ complication endpoint.  
For each case of suspected HZ, the study site must obtain all necessary information 
required for suspected cases of HZ (see Sections 2.5 and 3.2.17).  Adjudication packages 
(AP) consisting of all documents related to the suspected case of HZ will be assembled 
and distributed to the CAC members for review.  Specific details regarding AP contents, 
endpoint definitions, and adjudication procedures will be found in the V212 HZ Case 
Adjudication Committee SOP.

Product:  V212
Page 63
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.3.1.2
Final Case Determination
A final confirmed case of HZ is defined primarily on the PCR detection of VZV DNA in 
a skin lesion specimen.  If the skin lesion PCR result is reported as VZV positive, HZ is 
confirmed.  If the skin lesion PCR result is VZV negative, HZ is ruled out.  If the skin 
lesion PCR sample is missing or the result is reported as inadequate, or if the clinical 
presentation of HZ did not include a rash, the final determination as to whether the 
suspected HZ case is confirmed is based upon the final CAC adjudication decision in 
accordance with the CAC SOP.
3.3.2
PCR Assay for Lesion Samples
Lesion samples should be obtained from all patients presenting with a rash associated 
with varicella or HZ or varicella-like/HZ-like rash at the first evaluation for suspected 
HZ.  If both vesicles and pustules are present, vesicles are the preferred source for 
specimens.  Samples should be collected using the kit supplied by the SPONSOR, and 
stored immediately at –20ºC until shipment.  Detailed procedures on lesion sample 
collection/storage and shipping are provided in the Laboratory Manual. 
The purpose of the VZV PCR assay is to detect VZV and herpes simplex virus (HSV) 
deoxyribonucleic acid (DNA) in specimens obtained from subjects suspected of having 
varicella or HZ.  This is the primary assay used by the central laboratory.  The assay is a 
real-time PCR assay that uses virus-specific primers and probes to detect and 
discriminate among wild-type/Oka-parent VZV (VZV-WT/VZV-P), Oka-type attenuated 
VZV (VZV-O), and HSV DNA (HSV types 1 and 2). Virus-specific amplification is 
multiplexed with β-globin-specific primers and VIC-labeled fluorescent probe to 
demonstrate the presence of amplifiable host cell DNA in the clinical specimen [46].
The PCR assay is based on TaqMan® sequence detection chemistry utilizing an 
oligonucleotide probe that is labeled at the 5’ end with a fluorescent reporter dye and at 
the 3’ end with a fluorescent quencher dye.  This probe sequence lies between 2 
amplification primer sequences on the target DNA. When the probe is intact, the 
proximity of the quencher dye greatly reduces the fluorescence emitted by the reporter 
dye.  If the target sequence is present in the PCR reaction, then the probe anneals between 
the primer sites and is hydrolyzed by the 5’ nuclease activity of TAQ DNA polymerase 
as this primer is extended.  The hydrolysis of the probe separates the reporter dye from 
the quencher dye, thus increasing the reporter dye signal.  As TAQ extends the primer, 
the probe is removed from the target strand so that the overall PCR process is not 
inhibited.  With each PCR cycle, additional reporter dye molecules are cleaved from their 
respective probes, resulting in an increase in fluorescence intensity.  Each reporter signal 
is normalized to an internal passive reference dye to adjust for fluorescence fluctuations 
and baseline corrected.  After analysis of the raw fluorescent data by the instrument 
software, a fixed threshold value of 0.05 is assigned and a threshold cycle (Ct) is 
determined, which represents the PCR cycle at which reporter fluorescence increased 
above a baseline signal.  The threshold cycle is inversely proportional to the starting 
concentration of DNA. Results for the assay are reported as the virus type for which the 
sample is positive:  VZVWT, VZV-O, HSV or Negative.

Product:  V212
Page 64
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.3.3
PCR Assay for Whole Blood Samples
All patients presenting with varicella/varicella-like or an HZ/HZ-like rash or acute HZ 
symptom(s) will have two 10 mL whole blood samples collected in plastic Vacutainer 
tubes containing EDTA at the first evaluation for suspected HZ. The blood samples 
should be stored frozen at -20ºC until they are shipped to the central laboratory. The 
DNA isolated from the blood sample will be analyzed by VZV PCR analysis as described 
in Section 3.3.2.  Further details on collection, handling, storage and shipment will be 
provided in the Administrative or Laboratory Binder.
3.3.4
VZV Antibody gpELISA
Serum samples will be obtained from all patients in the STM study group Day 1 (prior to 
Dose 1) and at Visit 5 (~28 days Postdose 4) to measure VZV antibody concentrations by 
gpELISA.  Five (5) mL of blood will be collected into a serum separator VACUTAINER 
tube WITHOUT GEL SEPARATOR.  The blood should be allowed to clot in the 
collection tube for 30 to 60 minutes.  Once clotted, the collection tube should not be 
allowed to sit at room temperature or refrigerated for more than 2 hours prior to 
centrifugation and separation of the serum from the clot.  Do not refrigerate newly 
collected blood specimens; this will cause hemolysis.  Serum should be frozen 
immediately into approximately 2 to 3 (2-mL) Starstedt tubes, using a sterile pipette, and 
stored at -20°C until shipment to the central laboratory. The freezer used to store the 
specimens must be a non-frost-free freezer. 
The purpose of the gpELISA is to detect IgG antibody to VZV before and after 
vaccination with VZV-containing vaccine(s).  This is the primary assay used to evaluate 
the serological response to the vaccine(s).  This method detects antibodies to VZV 
glycoproteins (gp), which are purified by lectin affinity chromatography from MRC-5 
cells infected with the KMcC strain of VZV.  The reactivity of the sera to the gp antigens 
from uninfected MRC-5 cells (denoted as Tissue Culture Control [TCC] wells]) is 
subtracted from the reactivity of the sera to the purified gp antigens.  The assay and the 
purification of the VZV gp from VZV-infected cells are described [47-49].  Serum 
sample gpELISA titers correlate with neutralizing antibody titers [50].
For the gpELISA, VZV gp or TCC antigen is adsorbed to polystyrene microtiter wells 
and used as the solid phase antigen.  Experimental, control, and standard curve sera are 
incubated in these wells (2 wells for each antigen).  For each serum sample, a delta 
optical density (DOD) is calculated as the difference between the average optical density 
(OD) of the 2 VZV antigen wells and the average OD of the 2 TCC wells.  Quantitation 
is obtained by comparison of sample DOD with a standard curve.  Results for the assay 
are reported as concentration of antibody in gpELISA units/mL.

Product:  V212
Page 65
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.3.5
VZV IFN-γ ELISPOT
Approximately 1000 patients from select study sites will be enrolled in the ELISPOT 
substudy and will have blood samples collected for exploratory purposes to assess for 
lymphocyte stimulation response to VZV antigen as measured by VZV-specific IFN-γ 
ELISPOT.  The blood samples will be collected for IFN-γ ELISPOT on Day 1 (prior to 
Dose 1) and at Visit 5 (~28 days Postdose 4).  The first 500 patients with STM and the 
first 500 patients with HM at participating sites will be enrolled into the study.  
Approximately 60-mL of blood will be collected into tubes containing EDTA or sodium 
heparin for isolation of PBMCs.  Blood samples will be sent to a laboratory qualified in 
the Merck PBMC procedure for isolation and freezing of PBMCs.  The isolated PBMCs 
will be tested by VZV-specific IFN-γ ELISPOT assay at a central laboratory.
The purpose of the VZV ELISPOT assay is to detect interferon gamma (IFN-γ) secreting 
VZV-specific cells from PBMCs before and after vaccination with VZV-containing 
vaccine(s).  This assay is performed by IBT Laboratories to evaluate the cellular immune 
response to the vaccine(s).  Results for the assay are expressed as the frequency of spot 
forming cells (SFCs) per million PBMCs.
The IFN-γ ELISPOT assay utilizes 2 high-affinity IFN-γ specific monoclonal antibodies 
that are directed against different epitopes on the IFN-γ molecule.  In the VZV-specific 
IFN-γ ELISPOT assay, 5 x 105 PBMCs are stimulated by VZV antigen in wells of cell 
culture plates that have been precoated with one mouse monoclonal antibody to human 
IFN-γ.  IFN-γ released by the VZV-specific T-cells then binds to the first antibody 
present in close proximity to the cells that produced it.  After ~18 hours in culture, the 
cells are washed away, and a biotinylated form of the second antibody to IFN-γ is added 
to the wells of the plate and incubated overnight at 4ºC.  The plates are washed and then 
alkaline phosphatase-streptavidin is added to each well of the plate.  After 2 hours of 
incubation at room temperature, the plates are washed again and a chromogenic substrate 
(NBT/BCIP) is added to react with the alkaline phosphatase.  As a result, dark blue spots 
develop against the white background of the plates.  The IFN-γ produced by each cell 
results in the formation of a spot on the culture plate and the number of spots 
approximates the number of cells that produced IFN-γ in response to VZV antigen.  The 
frequency of SFCs is usually expressed per million input PBMCs.  This reflects the T-cell 
precursor frequency specific to VZV circulating in the blood at a defined time point.  The 
source of antigen used to stimulate VZV-specific responses is a UV-inactivated virus 
stock of the Oka/Merck vaccine strain that was produced in MRC-5 cells.  A similar 
preparation from uninfected MRC-5 cells is used as the negative control.
Patients in the ELISPOT substudy will have a separate allocation schedule to assure a 
well-balanced randomization ratio.

Product:  V212
Page 66
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.4
SAFETY MEASUREMENTS
3.4.1
Clinical Measurements for Safety/Vaccination Report Card
3.4.1.1
Safety Follow-up During the Vaccination Period
Each patient will receive a VRC at Visits 1, 2, 3, and 4. On the VRC, patients will be 
asked to record daily oral temperature measurements on the VRC. Patients should take 
oral temperature measurements using only the SPONSOR provided standard oral 
thermometer. Temperature measurements via the otic or axillary methods are not 
permitted. Patients will also be asked to record on the VRC all adverse experiences 
during the primary safety follow-up period (postvaccination dose 1 through 28 days 
postvaccination dose 4), including injection-site adverse experiences and systemic 
adverse experiences occurring from Day 1 through 28 days postvaccination dose 4. 
Patients will be asked to record on the VRC any rash at the injection site, as well as any 
varicella/varicella-like or HZ/HZ-like rashes postvaccination Day 1 through 28 days 
postvaccination dose 4. Any vaccines other than study vaccines and any medications that 
are administered during that period should also be documented on the VRC.
The patient will be asked to bring the VRC to the study site at the next scheduled visit. 
Study personnel will review the VRC for completeness, accuracy, and clarity at each 
scheduled visit from Visit 2 through Visit 5.  All comments are to be reviewed by study 
personnel and discussed with the patient for clarification, as necessary.  Any information 
gained during VRC review with the patient should be clearly documented, initialed, and 
dated at the bottom of the VRC.  The VRC is considered a source document and no 
original information recorded by the patient should be crossed out or altered in any 
manner by study personnel.
All VRC information will be recorded in the Electronic Data Capture (EDC) system. The 
physician investigator/sub-investigator will determine causality of systemic and injection 
site adverse experiences recorded on the VRC using the reporting guidelines given in the 
protocol (Table 3-1) and will classify each event as a SAE (SAE) or nonserious adverse 
experience (NSAE). If an oral temperature measurement indicates a fever (defined in this 
study as an oral temperature of ≥100.4°F or ≥38.0ºC), the adverse experience must be 
reported as such in the database. However, if the fever is a symptom of another reported 
adverse experience, a separate AE report of fever is not necessary. Refer to the eCRF 
entry guidelines for details related to AE reporting.

Product:  V212
Page 67
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.4.1.2
Post-Vaccination Safety Follow-up
After the end of the vaccination period (i.e., 28 days postvaccination dose 4), patients will 
continue to be followed for SAE, regardless of causality, through the end of the study 
(see Section 3.4.6.1 for additional information on SAEs).  Patients will be educated on 
the criteria for SAE and instructed to call the site immediately if a SAE occurs. In 
addition, every 3 months (+/- 1 month) beginning 3 months following Visit 5 through the 
duration of the study, patients will be contacted by study staff either at a scheduled study 
visit or by telephone, using a pre-specified script, to determine if the patient had a 
previously unreported clinical adverse experience that met SAE criteria and collect 
relevant information on SAEs. SAE will be collected as described in Section 3.4.5.1.
In the event the study is terminated sooner than 1 year after the last vaccine dose is 
administered in this study, the study will continue to allow all patients to complete at 
least a 1 year post-vaccination safety and efficacy follow-up (including new cases of HZ 
in these patients).
3.4.1.3
Adverse Experience Toxicity Grading
A vaccine specific toxicity grading scale (Grades 1 through 4) will be applied to all 
serious and non-serious adverse experiences in this study.  During the primary safety 
follow-up period (through ~28 days postvaccination dose 4), clinical adverse experiences 
will be recorded on the VRC by the patient at the time of occurrence.  The investigator 
will use the information provided by the patient both on the VRC, and verbally at the 
time of VRC review, to apply the appropriate toxicity grade (1 through 4).  Serious 
adverse experiences occurring beyond ~28 days postvaccination dose 4 are not reported
on the VRC. For these events, the investigator will assign the toxicity grade based upon 
information received at the initial report (and/or subsequent follow-up) of the event.  The 
grade assigned by the investigator will be recorded in the electronic database on the 
corresponding eCRF.  Refer to Appendix 6.2 for Toxicity Grading Tables for injection-
site and systemic AEs, respectively.
This adverse experience toxicity grading is in addition to the grading of adverse 
experiences by maximum intensity (mild, moderate, severe) described in Table 3-1.

Product:  V212
Page 68
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.4.1.4
PCR testing for Miscellaneous Samples in Patients with Serious Adverse 
Experiences
SAEs suspicious for a VZV infection following the administration of V212 may be 
associated with the presence of wild-type VZV or with the presence of the Oka vaccine 
strain. These SAEs may include but are not limited to: pneumonia, pneumonitis, 
meningitis, 
cerebritis 
(encephalitis), 
cerebellitis 
(cerebellar 
ataxia), 
cerebral 
vasculopathy, myocarditis, pericarditis, and ocular syndromes (such as retinitis, retinal 
necrosis and uveitis).  At times, it may be important for epidemiological and/or safety 
purposes to identify the presence of either the circulating wild-type VZV or the Oka 
vaccine strain of VZV. This identification cannot be made definitively on the basis of 
clinical presentation or serologic tests. A PCR test has been developed to help distinguish 
between wild-type and Oka vaccine strain VZV (including differentiation between Oka 
vaccine strain and wild-type Japanese/Oka strain). This test can be done on live or dead 
viral specimens. The PCR testing is performed by an independent, academic laboratory at 
Columbia University, New York, NY.
If a patient develops an SAE suspicious for a VZV infection following the administration 
of V212, any specimen (e.g., fluid or tissue) that remains following the completion of 
routine diagnostic testing may be sent to Columbia University College of Physicians and 
Surgeons, Division of Pediatric Infectious Disease laboratory for VZV PCR testing.  This 
testing is optional for the patient.  Written informed consent for PCR testing of these 
specimens must be obtained.  Information regarding the collection, labeling, and shipping 
of these specimens is provided in the Administrative Binder.
3.4.2
Recording Adverse Experiences
An adverse experience is defined as any unfavorable and unintended change in the 
structure, function, or chemistry of the body temporally associated with the use of the 
SPONSOR’s product, whether or not considered related to the use of the product. Any 
worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of 
a preexisting condition which is temporally associated with the use of the SPONSOR’s 
product, is also an adverse experience.
Changes resulting from normal growth and development which do not vary significantly 
in frequency or severity from expected levels are not to be considered adverse 
experiences. Examples of this may include, but are not limited to, teething, typical crying 
in infants and children, and onset of menses or menopause occurring at a physiologically 
appropriate time.
All adverse experiences will be collected from the time the consent form is signed 
through 28 days following the last vaccine dose (i.e., Dose 4), and such events will be 
recorded 
at 
each 
examination 
on 
the 
Adverse 
Experience 
Case 
Report 
Forms/Worksheets.

Product:  V212
Page 69
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.4.3
Definition of an Overdose for This Protocol
Administration of more than one dose of V212 in any 24-hour period, regardless of 
whether it results in an adverse experience, is considered an overdose for this protocol 
and must be reported to SPONSOR within 24 hours.
3.4.3.1
Reporting of Overdose to SPONSOR
If an adverse experience(s) is associated with (“results from”) the overdose of test drug or 
vaccine, the adverse experience(s) is reported as a serious adverse experience, even if no 
other criteria for serious are met.
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse experience must be reported within 
24 hours to one of the individuals listed on the sponsor contact information page found in 
the Administrative Binder. 
3.4.4
Reporting of Pregnancy to SPONSOR
Although not considered an adverse experience, it is the responsibility of investigators or 
their designees to report any pregnancy in a subject/patient (spontaneously reported to 
them) which occurs during the study or within 14 days of completing the study. All 
subjects/patients who become pregnant must be followed to the completion/termination 
of the pregnancy. If the pregnancy continues to term, the outcome (health of infant) must 
also be reported to one of the individuals listed on the SPONSOR Contact Information 
page found in the Administrative Binder.
3.4.5
Immediate Reporting of Adverse Experiences to the SPONSOR
3.4.5.1
Serious Adverse Experiences
Any serious adverse experience, including death due to any cause, which occurs to any 
subject from the time the consent is signed through the duration of the study, whether or 
not related to the investigational product, must be reported within 24 hours to the 
SPONSOR by the electronic data capture system or by paper as outlined in the 
Administrative Binder.

Product:  V212
Page 70
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Additionally, any serious adverse experience brought to the attention of an investigator 
who is a qualified physician at any time outside of the time period specified in the 
previous paragraph also must be reported immediately to one of the individuals listed on 
the sponsor contact information page (found in the administrative binder) if the event is 
either:
1. A death which resulted in the subject/patient discontinuing the study
or
2. A serious adverse experience that is considered by an investigator who is a 
qualified physician to be possibly, probably, or definitely vaccine related.
All subjects/patients with serious adverse experiences must be followed up for outcome.
3.4.6
Evaluating Adverse Experiences
Refer to Table 3-1 for instructions in evaluating adverse experiences.

Product:  V212
Page 71
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 3-1
An investigator who is a qualified physician, will evaluate all adverse experiences as to:
Maximum
Mild
awareness of sign or symptom, but easily tolerated (for pediatric studies, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric studies, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric studies, extremely distressed or unable to do usual activities) Injection site redness 
or swelling from the day of vaccination through Day 5 post-vacc will be evaluated by maximum size.
Seriousness
A serious adverse experience is any adverse experience occurring at any dose that:
†Results in death; or
†Is life threatening; or places the subject/patient, in the view of the investigator, at immediate risk of death from the experience as it occurred [Note: This does not include an 
adverse experience that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a 
precautionary measure for continued observation.   (Note:  Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not 
worsened does not constitute a serious adverse experience.); or
†Is a congenital anomaly/birth defect  (in offspring of subject/patient taking the product regardless of time to diagnosis); or
Is a cancer; or
Is an overdose (Whether accidental or intentional.  Any overdose whether or not associated with an adverse experience must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the subject/patient and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse experience.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse experience cause the test vaccine to be discontinued?
Relationship to 
test vaccine 
Did the test vaccine cause the adverse experience?   The determination of the likelihood that the test vaccine caused the adverse experience will be provided by an investigator 
who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet, that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The criteria below are intended as 
reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test vaccine and the adverse experience based upon the available 
information.  
The following components are to be used to assess the relationship between the test vaccine and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the test vaccine caused the adverse experience (AE):
Exposure
Is there evidence that the subject/patient was actually exposed to the test vaccine such as:  reliable history, acceptable compliance assessment (e.g. diary), 
seroconversion or identification of vaccine virus in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the test vaccine? 
Is the time of onset of the AE compatible with a vaccine-induced effect?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
Relationship
The following components are to be used to assess the relationship between the test vaccine and the AE:  (continued)
to test vaccine 
Dechallenge
(not applicable for vaccines)
(continued) 
Rechallenge
Was the subject/patient reexposed to the test vaccine in this study?
      If yes, did the AE recur or worsen?

Product:  V212
Page 72
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the study is a single-dose vaccine study.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED 
BY THE TEST VACCINE, OR IF REEXPOSURE TO THE TEST VACCINE POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT/PATIENT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AND THE 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency with 
Study Vaccine 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test vaccine or vaccine class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.  
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a vaccine relationship).
Yes, there is a reasonable possibility 
of vaccine relationship.
There is evidence of exposure to the test vaccine.  The temporal sequence of the AE onset relative to the administration of the test vaccine is reasonable.  
The AE is more likely explained by the test vaccine than by another cause.
Depending on data collection method employed, vaccine relationship may be further graded as follows:
Definitely related 
There is evidence of exposure to the test vaccine.  The temporal sequence of the AE onset relative to administration of the test vaccine is reasonable.   The 
AE is more likely explained by the test vaccine than by another cause.  Dechallenge is positive.  Rechallenge (if feasible) is positive.  The AE shows a 
pattern consistent with previous knowledge of the test vaccine or test vaccine class.
Probably related 
There is evidence of exposure to the test vaccine.  The temporal sequence of the AE onset relative to administration of the test vaccine is reasonable.  The 
AE is more likely explained by the test vaccine than by another cause.  Dechallenge (if performed) is positive.
Possibly related 
There is evidence of exposure to the test vaccine.  The temporal sequence of the AE onset relative to administration of the test vaccine is reasonable.  The 
AE could have been due to another equally likely cause.  Dechallenge (if performed) is positive.
No, there is not a reasonable 
possibility of vaccine relationship
Subject did not receive the test vaccine OR temporal sequence of the AE onset relative to administration of the test vaccine is not reasonable OR there is 
another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
Depending on data collection method employed, vaccine relationship may be further graded as follows:
Probably not 
related 
There is evidence of exposure to the test vaccine.  There is another more likely cause of the AE.  Dechallenge (if performed) is negative or ambiguous.  
Rechallenge (if performed) is negative or ambiguous.
Definitely not 
related 
The subject/patient did not receive the test vaccine.   OR    Temporal sequence of the AE onset relative to administration of the test vaccine is 
not reasonable.   OR   There is another obvious cause of the AE.

Product:  V212
Page 73
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.4.7
SPONSOR Responsibility for Reporting Adverse Experiences
All adverse experiences will be reported to regulatory agencies, IRB/IECs, and 
investigators in accordance with all applicable global laws and regulations.
3.5
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, 
after the study has begun, but prior to any unblinding, changes are made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, 
then the protocol will be amended (consistent with ICH Guideline E-9).  Changes to 
exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, along with an explanation as to when and why they occurred, will be listed in 
the Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be 
clearly identified in the CSR.  No separate Statistical Analysis Plan (SAP) will be issued 
for this study.
3.5.1
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of 
the designee/Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
This study is event-driven, with one interim futility analysis and one final efficacy 
analysis. The interim analysis included futility analyses for individual subgroups (HM 
and STM).  The interim futility analysis was done when at least 50% of the total number 
of required evaluable HZ cases in each patient population, HM and STM, had accrued. 
More specifically, the  futility analysis was conducted on the HM population when at 
least 68 cases had accrued in the HM subgroup and the  futility analysis was conducted 
on the STM population when at least 48 cases had accrued in the STM subgroup.
The DMC will monitor safety periodically and will be responsible for reviewing the 
results of the planned formal interim analyses.  The DMC may recommend stopping the 
study early based on safety concerns or futile efficacy results from the interim futility 
analysis (see Section 3.5.8.1 and DMC guidelines).
An unblinded SPONSOR statistician who is otherwise unrelated to this protocol will 
serve as a non-voting member of DMC and will be responsible for performing these 
preliminary/interim analyses for DMC.  Detailed implementation of the interim analysis 
is described in the DMC charters (separate documentation).

Product:  V212
Page 74
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
All the interim analysis data will remain blinded to SPONSOR study personnel, the study 
investigator, the laboratory staff, the CAC members, and the patients throughout the 
study, until the final database unblinding when all required evaluable HZ cases are 
accrued.
3.5.2
Hypotheses
Objectives and hypotheses of the study are stated in Section 2.1.
3.5.3
Analysis Endpoints
3.5.3.1
Efficacy
The primary efficacy endpoint is the incidence of confirmed HZ postvaccination in the 
vaccine and placebo groups in the STM population, defined as the number of HZ cases 
per 1000 person-years of follow-up (from study enrollment to the end of study).  A 
supportive analysis will consider cases following 4 doses of vaccination based on the 
time period from the date of Dose 4 to the end of study.  Final HZ case determination will 
be based primarily on the results of the skin lesion PCR.  If the skin lesion PCR result is 
inadequate or missing, or if HZ presentation did not include a rash, case confirmation will 
be based on the results of case adjudication by the CAC.
Three secondary endpoints are defined for the STM population and in the HM population 
on an exploratory basis. The three secondary endpoints are defined as follows:
(1) Each suspected case of HZ will undergo 6 months of follow-up for HZ-associated 
pain and HZ-associated complications.  Moderate to severe HZ-associated pain 
[defined as 2 or more occurrences of scores 3 or greater (on a 0-to-10 scale)] will be 
assessed by the ZBPI questionnaire at any time from HZ onset through the end of the 
6 month HZ-follow-up period).  The response to the question, “Rate your worst pain 
in the last 24 hours on a 0-to-10 scale” from the ZBPI will be used for the 
aforementioned HZ pain analyses.
(2) The HZ-associated complications endpoint is a composite endpoint that is defined as 
the proportion of patients experiencing at least one of the following HZ 
complications:

Hospitalization or prolongation of hospitalization due to HZ 

Disseminated HZ (including disseminated HZ rash or VZV viremia)

Visceral HZ 

Ophthalmic HZ 

Neurologic impairment due to HZ 

Intravenous acyclovir therapy for HZ 

Product:  V212
Page 75
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
(3) The incidence of PHN in randomized patients is another secondary endpoint. PHN is 
defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” 
score of 3 or greater (on a 0 to 10 scale) on the ZBPI that persists or appears greater 
than or equal to 90 days after HZ rash onset.  Sensitivity analyses on the comparison 
of the incidence of PHN persisting or appearing more than 30, 60, 120 and 182 days 
after HZ rash onset between the vaccination groups will also be performed.
Exploratory efficacy endpoints include:

The severity-by-duration of HZ pain (defined as the average area under the “worst 
pain in the last 24 hours” versus time curve) from the first day of HZ onset 
through 6 months after HZ onset.

The duration of pain (defined as number of days from rash onset to the first visit 
when pain score on the ZBPI became persistently < 3).

The numbers of lesions, number of dermatomes and extent of rash (defined as the 
maximum area of the HZ rash at each HZ follow-up visit).

The impact of HZ on ADL, as measured by the score-by-duration of activity-of-
daily-interference (ADLI) (defined as the average area under ADLI versus time 
curve) from the first day of HZ onset through 6 months after HZ onset.  ADLI is a 
single combined score calculated by averaging 7 separate items (regarding general 
activity, mood, walking ability, normal work, relations with others, sleep, and 
enjoyment of life) collected in the ZBPI at each HZ follow-up visit.

The impact of HZ on general health status, as measured by the score-by-duration 
in the EuroQoL from the first day of HZ onset through 6 months after HZ.

HZ-related non-protocol-mandated HCU and work and productivity loss.  The 
analyses will be covered in a separate internal SAP, prepared by the Health 
Economist of the study.
Of note, the exploratory efficacy analyses will be evaluated for the HM and STM 
populations separately. 

Product:  V212
Page 76
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.3.2
Immunogenicity
The key immunogenicity endpoints include the GMT and the GMFR from Day 1 (prior to 
Dose 1), to Visit 5 (28 to 60 days Postdose 4) for the VZV antibody titers as measured by 
gpELISA in all subjects from STM group.  In addition, other endpoints include the 
percent of patients with 2-fold, 3-fold and 4-fold rises at each time point 
postvaccination.  The same endpoints as for VZV antibody titers measured by gpELISA 
will be used for GMC as measured by VZV IFN-γELISPOT.  Using the natural log scale 
of GMC, the analyses will be performed similarly as for gpELISA to summarize the VZV 
IFN-γ ELISPOT results collected in the participants in the ELISPOT substudy (n ~ 1000) 
at Day 1 [prior to Dose 1], and Visit 5 [28 to 60 days Postdose 4] for the comparison of 
GMC between 2 vaccination groups. The exploratory immunogenicity analyses will be 
evaluated for the HM and STM populations separately.
3.5.3.3
Safety
The minimum safety follow-up period is at least 1 year following the last study 
vaccination.
The primary safety endpoint of the study will be based on the incidence of SAEs 
observed during the period up to 28 days Postdose 4 in each vaccination group.  Key 
safety measures for an overall assessment include proportions of patients with (1) any 
adverse experience, (2) any injection-site adverse experience, (3) any systemic adverse 
experience, (4) any SAE, (5) any vaccine-related SAE, and (6) any discontinuation due to 
an adverse experience.  Other key safety parameters include proportions of patients 
reporting the following adverse experiences:
1. SAEs observed Vaccination Day 1 through 28 days Postdose 4.
2. VRC-prompted systemic adverse experiences (including non-injection site varicella-
like rash or HZ-like rash) following any vaccination of V212 or placebo through 28 
days Postdose 4.
3. VRC-prompted injection site adverse experiences (such as redness, swelling, and 
pain/tenderness/soreness) Day 1 to Day 5 following any vaccination of V212 or 
placebo.
4. Elevated temperature (≥100.4°F [≥38.0ºC] oral or oral equivalent) following any 
vaccination of V212 or placebo through 28 days Postdose 4.
5. Any other systemic and injection-site adverse experiences not prompted for on the 
VRC following any vaccination with V212 or placebo through 28 days Postdose 4.
6. SAEs observed at any time for the duration of the study.

Product:  V212
Page 77
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
For other adverse experiences not prompted for on VRC, the safety parameters include
the incidences of injection-site adverse experiences or systemic adverse experiences after 
any study vaccination through 28 days Postdose 4 occurring in at least 1% of the patients 
in either vaccination group.
Incidence of varicella/varicella-like or an HZ/HZ-like rash occurring during the period up 
to 28 days Postdose 4 will be summarized by skin lesion type (wild type versus vaccine 
strain) determined by PCR.  The rate of SAEs, vaccine-related SAEs and death during the 
whole period of the study will be summarized per 1000 person-years of follow-up.
The safety analyses will be evaluated for the HM and STM populations separately
3.5.4
Analysis Populations
3.5.4.1
Efficacy Analysis Populations
Modified Intent-To-Treat (MITT) Population
The key summaries and analyses for the primary, secondary and exploratory efficacy 
endpoints will be based on the MITT population (see Table 3-2). This population will 
include all randomized patients who received at least one dose of the vaccination.  Those 
randomized patients who are excluded from the MITT population will be listed.  The 
efficacy analyses will be performed based on the treatment group to which those subjects 
are randomized.
Per Protocol Efficacy (PPE) Population
Supportive analyses for the primary and key secondary endpoints will be conducted in 
the PPE population (see Table 3-2). This population will include those patients who 
received all 4 vaccination doses and did not present a case of HZ from Day 1 through 28 
days post-dose 4.
To evaluate the risk of PHN or other complications, additional exploratory analyses will 
also be based on a subset of PPE population that developed HZ. 

Product:  V212
Page 78
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.4.2
Immunogenicity Analysis Populations
Per Protocol Immunogenicity (PPI) Populations
The immunogenicity summaries and analyses will be provided for the PPI population.  
To be included in this population, patients must:
(1) Have received all 4 vaccination doses 
(2) Have not reported any exposure to varicella/HZ within 4 weeks prior to blood draw
(3) Have not develop any suspected varicella/HZ before the relevant blood sampling 
(4) Have not received medical treatments (such as blood products, immunoglobulin 
therapy) that may interfere with one or both of the proposed immunogenicity 
measurements. 
Based on criterion (4), some patients may be excluded from only one of the 2 
immunogenicity analysis (gpELISA, ELISPOT). The final determination of patients 
excluded from one or both immunogenicity analyses, and thereby the composition of the 
Per Protocol immunogenicity analysis populations, will be made prior to the final 
unblinding of the database and will be documented in a separate memo.
3.5.4.3
Safety Analysis Populations
All patients who receive at least 1 dose of vaccine/placebo and have follow-up data will 
be included in the safety and tolerability summaries and analyses. The safety analyses 
will be based on the All Subjects as Treated (ASaT) approach.
3.5.5
Statistical Methods
3.5.5.1
Analysis of Vaccine Efficacy
Table 3-2 summarizes the key efficacy analyses to be performed.  The details are given in 
the following subsections.

Product:  V212
Page 79
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 3-2
Summary of Key Efficacy Analyses Performed
Analysis
Method
Patient population
Primary
HZ incidence - VEHZ
Cox proportional hazards regression 
model with Efron's method of tie 
handling
MITT 
Secondary
(1)Incidence of moderate to severe HZ-
associated pain
(2)A composite efficacy endpoint of the 
incidence of HZ complications during 
the study
(3)Incidence of PHN
Cox proportional hazards regression 
model with Efron's method of tie 
handling
Same as above
Same as above
MITT
MITT
MITT
Supportive
HZ incidence -
       Vaccine efficacy
     
     Durability of efficacy
      
     
Cox proportional hazards regression 
model with Efron's method of tie 
handling
Kaplan-Meier method 
Piecewise exponential  
model
PP
MITT
MITT
Exploratory endpoints -
     Severity-by-duration of  
      HZ pain 
   Duration of pain 
   Score-by-duration of  
      ADLI 
   Score-by-duration of  
      general health 
      status score (EuroQoL)
   Impact of HCU and Work  
      and Productivity Loss
HZ incidence
ANCOVA 
Summaries
ANCOVA
ANCOVA
Poisson regression with generalized
estimating equations
Summaries by age categories and HM 
population
MITT
It should be noted that if a given patient develops two or more episodes of confirmed HZ, 
only the first episode will be used in the vaccine efficacy analyses.  The patients with 
multiple episodes of HZ will be listed.  Exploratory analysis of multiple episodes of HZ 
(such as the Wei, Lin and Weissfeld method [51]) may also be performed if a sizable 
proportion (e.g., >10%) of HZ patients develop multiple episodes.

Product:  V212
Page 80
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.5.1.1
Analysis of Vaccine Efficacy on Incidence of HZ Cases
The primary efficacy endpoint is the incidence of HZ in the vaccine and placebo groups
in the STM population, defined as the number of HZ cases per 1000 person-years of 
follow-up from study enrollment to the end of study.  Vaccine efficacy for HZ (VEHZ) is 
defined as the relative reduction of the hazard rate of HZ in the V212 group compared 
with that in the placebo group in STM population.  The primary statistical hypothesis for 
the primary efficacy is H0: VEHZ 25% versus H1: VEHZ > 25%.  
To address the primary hypothesis, a Cox proportional hazards regression model in VZV 
vaccine and placebo recipients stratified by age (< 50 years of age versus ≥50 years of 
age based on a MITT population as described in section 3.5.4.1) will be used as the 
primary analysis to compare the incidence of HZ between the vaccine and placebo 
groups. The study time period in the primary analysis will be from the enrollment to the 
stop date of HZ surveillance.  Patients who do not develop HZ will be censored at the 
stop date of HZ surveillance. The follow-up time for patients who develop HZ will be 
from the enrollment to their HZ onset date.  For the interim analysis, this stop date will be 
the corresponding database cutoff date for the analysis.  Efron’s method will be used to 
handle ties in event times.
A key supportive analysis will include calculation of VEHZ using a PP population as 
described in section 3.5.4.1 based on Cox proportional hazards regression model. The 
study time period in the primary analysis will be from the date of Dose 4 to the stop date 
of HZ surveillance. The model and covariate adjustment will be similar to that noted in 
the MITT approach. In addition, incidence of HZ and VEHZ will also be summarized by 
age group (50 to 59, 60 to 69, and 70+) as exploratory analyses.
The results of HZ case determination (PCR versus case adjudication by the CAC) will be 
summarized by vaccination group.  The probability of developing HZ will be estimated 
and displayed by the Kaplan-Meier method.  The incidence rates of HZ post 
randomization (enrollment) in each group will be compared by the nonparametric log-
rank statistic without covariate adjustment.  Also, the incidence of HZ will be 
summarized by vaccination group in terms of number of cases per 1000 person-years in 
those patients who only received a total of 1 dose, 2 doses, and 3 doses of 
vaccine/placebo using the MITT population if a sizable proportion (>10%) is observed in 
each category (1 dose, 2 doses, and 3 doses).
3.5.5.1.2
Analysis of Vaccine Efficacy on Secondary Efficacy Endpoints 
Three secondary efficacy endpoints are defined for the STM population and in the HM 
population on an exploratory basis.

Product:  V212
Page 81
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Since the incidences of moderate to severe HZ-associated pain, HZ-complications as 
defined by the composite endpoint, and PHN are unknown in this population, formal 
hypothesis testing for these secondary endpoints will not be performed.  The incidence of 
the secondary efficacy endpoints of moderate to severe HZ-associated pain, composite 
complication endpoint, and the incidence of PHN, defined as pain in the area of the HZ 
rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0 to 10 scale) on 
the ZBPI that persists or appears greater than or equal to 90 days after HZ onset, (point 
estimate and 95% CI) will be compared between vaccine and placebo groups using Cox 
proportional hazards regression stratified by age (< 50 years of age versus ≥50 years of 
age) based on the MITT population. For patients who develop PHN, the PHN event 
onset will be the date of HZ rash onset.  Patients who do not develop PHN will be 
considered as censored at the stop date of their HZ surveillance.  Furthermore, the count 
and proportion of each component of the secondary efficacy composite endpoint among 
all randomized patients in the vaccine and placebo groups will be summarized.
Sensitivity analyses for vaccine efficacy on PHN based on alternative definitions [pain in 
the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 
0 to 10 scale) on the ZBPI that persists or appears more than 30, 60 120, and 180 days 
after HZ rash onset] will be compared between the vaccine and placebo groups in the 
MITT population.
To evaluate the vaccine effect on PHN above and beyond that on HZ incidence, the 
proportions of patients who develop PHN among HZ cases will be provided by 
vaccination group. A generalized linear regression model with log-link will be used to 
estimate the relative risk reduction of PHN among HZ cases in vaccine recipients 
compared with placebo recipients. This model will include incidence of PHN as a binary 
response variable, and include vaccination group, and age as covariates. An exploratory 
analysis will be performed using the similar model, with the use of antiviral drug initiated 
within 72 hours of HZ rash onset (Yes versus No) added as an additional covariate. Note 
that these analyses are not protected by randomization, and with the post-randomization 
variable, antiviral use in the model, the results might be subject to potential bias.

Product:  V212
Page 82
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.5.1.3
Analysis of Vaccine Efficacy on Exploratory Endpoints
The following exploratory efficacy analyses will be conducted for the STM and HM 
populations separately.
To evaluate the vaccine effect on the severity of HZ pain among HZ cases, the severity-
by-duration of HZ pain (calculated as the area under the “worst pain in the last 24 hours” 
versus time curve) will be summarized by vaccination group on a MITT population.  To 
compare the mean severity-by-duration measure of HZ pain among patients who develop 
HZ between the two vaccination groups, an analysis of covariance (ANCOVA) model 
adjusting for similar covariates as for the primary efficacy analysis will be used to get the 
point estimate and a bootstrap method will be used to obtain 95% CI of HZ severity-by-
duration scores difference between the vaccination groups. Additional exploratory 
analysis may include the use of antiviral drug initiated within 72 hours of HZ rash onset 
(Yes versus No) as an additional covariate.
In addition, the mean and median duration of HZ pain (time from rash onset to the first 
visit when pain score became persistently < 3) will be provided by vaccination group. 
The mean HZ pain score, the numbers of lesions, dermatomes and extent of rash (defined 
as the maximum area of the HZ rash at each HZ follow-up visit), the mean ADLI score 
and the mean EuroQoL score will be summarized by vaccination group.  ANCOVA 
models will also be used to compare these mean scores between the two vaccination 
groups at each HZ follow-up visit.  In addition, the score-by-duration of ADLI and score-
by-duration of general health status score in EuroQoL over 6 months post-HZ onset 
(calculated by area under the ADLI curve and general health status score curve, 
respectively) will be summarized by vaccination group and compared by ANCOVA 
model.
Poisson regression with generalized estimating equations will be used to evaluate the 
effect of the vaccine on the rates of non-protocol mandated health care utilization and 
work loss.  If the counts of health care contacts in each treatment group are less than 10, 
then an exact binomial method will be used to calculate the CIs rather than generalized 
estimating equations.
3.5.5.1.4
Analysis on the Durability of Vaccine Efficacy
To evaluate the durability of vaccine efficacy, the incidence of HZ will be summarized 
by vaccination group and by every 6 months of follow-up post vaccination.  A piecewise 
exponential model will also be carried out to estimate the vaccine efficacy and the 
corresponding 95% CI by follow-up interval post vaccination.  Note that the estimate 
may be less precise than the overall estimate, due to smaller numbers of events and 
follow up in time interval. The durability assessment will be conducted for the HM and 
STM populations separately.

Product:  V212
Page 83
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.5.1.5
Additional Evaluation of Vaccine Efficacy
To further evaluate the vaccine efficacy for HZ, summaries for the incidence of HZ, 
secondary composite endpoint and PHN in each vaccination group will also be provided 
by the following subgroups:

Disease type and HM immunocompromise category (STM, HM low IC or HM 
moderate to high IC).

Gender (male versus female)

Number of vaccine doses received

Age categories (< 50 years, 50 to 69, and 70+)
3.5.5.2
Analysis of Vaccine Immunogenicity
All immunogenicity analyses are exploratory in this study.  The key immunogenicity 
endpoints include the GMT and the GMFR from prevaccination (Visit 1) at (Day 1 [prior 
to Dose 1], to Visit 5 [28 to 60 days Postdose 4]) for the VZV antibody titers as measured 
by gpELISA in all subjects in STM group.  A linear mixed longitudinal model will be 
used on the natural log transformed antibody titers, for the comparison of GMT between 
2 vaccination groups across the time points after vaccination. The longitudinal regression 
analysis model developed by Liang and Zeger [52] will include prevaccination antibody 
titers and postvaccination antibody titers as response variables.  The covariates in the 
analysis model will include vaccination group, continuous age, visit (indicator for 
baseline or postvaccination) and vaccination group-by-visit interaction. The antibody 
titers will be natural-log-transformed in the analyses.  The fold-difference between the 
vaccine and placebo groups and the corresponding 95% CI at the respective visit will be 
obtained from this model.  This analysis will be based on the per-protocol approach.  For 
patients who receive treatments that may interfere with the measurements of VZV-
specific antibody response (including those receiving immunoglobulin therapy) or who 
report an exposure to varicella/HZ within 4 weeks prior to blood draw, or who develop 
suspected varicella/HZ before the relevant blood sampling, the measurements at 
corresponding time points and thereafter will be excluded from the gpELISA analysis.  
The summaries of VZV antibody titers at each time point will also be carried out by 
vaccine lot at each time point.  Patients who receive immunoglobulin therapies will be 
included in VZV IFN-γ ELISPOT analysis as described below.
To evaluate the association between the immune responses and the risk of HZ, a Cox 
regression model will be used, which will use the immune responses measured by 
gpELISA at baseline and at 28 days postvaccination dose 4 as covariates.  The GMT and 
GMFR will also be summarized at these time points by vaccination group and HZ 
outcome (patients who developed confirmed HZ during the study versus those who did 
not).

Product:  V212
Page 84
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
In addition, Cox proportional hazards model will be used to estimate the relation between 
the occurrence of HZ and the gpELISA titers.  The gpELISA titers will be used as the 
covariate to obtain a risk ratio for HZ per unit increase in the titer.
The percent of patients with 2-fold, 3-fold and 4-fold rises in gpELISA at Visit 5 
[28 to 60 days Postdose 4] by vaccination group will also be provided.
The proportion of patients achieving seroresponse 400 gpELISA units/mL at Visit 5 
[28 to 60 days Postdose 4] will be summarized by vaccination group and by HZ status. A 
supportive analysis may be provided, including all valid immunogenicity results, 
regardless of protocol deviations. Patients who reported an exposure to varicella/HZ (if 
any) will be listed and the corresponding count and proportion will be summarized by 
vaccination group in the tables regarding the exclusion of patients from the per protocol 
immunogenicity analyses and a brief description of these patients will be provided in the 
clinical summary section of the Clinical Study Report.
In addition, direct T cell response to VZV antigen as measured by VZV IFN-γ ELISPOT 
in the ELISPOT substudy participants will be performed at each time point (Day 1 [prior 
to Dose 1], and Visit 5 [28 to 60 days Postdose 4]).  The blood samples will be collected 
on a subset of ~1000 patients.  Similar to gpELISA, VZV IFN-γ ELISPOT related 
summaries and analyses will be considered as exploratory in this study.  The same 
endpoints as for VZV antibody titers measured by gpELISA will be used for GMC as 
measured by VZV IFN-γ ELISPOT.  Using the natural log scale of GMC, the analyses 
will be performed similarly as for gpELISA for the comparison of GMC between 2 
vaccination groups and for the evaluation of the association between the GMC and the 
risk of HZ.
The key immunogenicity measurements will be summarized at each time point (Day 1 
[prior to Dose 1], and Visit 5 [28 to 60 days Postdose 4]) by HZ outcome (patients who 
developed subsequent confirmed HZ during the study versus those who did not) at each 
time point. It should be noted that VZV IFN-γ ELISPOT will be performed in a subset of 
the study population. 
3.5.5.3
Analysis of Vaccine Safety
The safety follow-up period will occur for at least 1 year following the last VZV 
vaccination. Safety and tolerability of V212 will be assessed by evaluation of all relevant 
safety parameters, focusing on the 28-day follow-up period after any vaccination. The 
following safety analyses will be evaluated for the HM and STM populations separately.

Product:  V212
Page 85
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
The primary safety endpoint of the study will be based on the incidence of SAEs 
observed during the period up to 28 days Postdose 4 in each vaccination group.  Two-
sided 95% CI on the proportion of any SAE will be provided for each vaccination group 
based on the exact binomial distribution [19].  To provide an overall assessment, safety 
measures such as the proportion of patients with (1) any adverse experience, (2) any 
injection-site adverse experience, (3) any systemic adverse experience, (4) any SAE, (5) 
any vaccine-related SAE, and (6) any discontinuation due to an adverse experience will 
be summarized for both vaccination groups (across any vaccination dosing period and by 
each vaccination dosing period). The risk differences on these overall safety parameters 
between the two groups and the corresponding two-sided 95% CI on the risk difference 
will be provided using the stratified asymptotic methods proposed by Miettinen and 
Nurminen [20].
To assess the risks of the adverse experiences temporally associated with vaccination, a 
multi-tiered approach will be used for the analysis of specific safety parameters.
For Tier-1 adverse experiences, risk differences between the two groups, corresponding 
two-sided 95% CI on the risk difference, and the p-value for the test of significant risk 
difference will be provided.  The corresponding p-value will be based on the normal 
approximation for testing two independent binomial proportions at the two-sided 0.05 
level adjusting for stratification factors.  The risk difference and 95% CI will be 
calculated using the methods proposed by Miettinen and Nurminen [20].  Tier 1 adverse 
experiences include (1) systemic adverse experiences prompted for on the VRC, 
including varicella/varicella-like or an HZ/HZ-like rash occurring after any study 
vaccination through 28 days Postdose 4, (2) injection-site complaints prompted for on the 
VRC, such as redness, swelling, and pain/tenderness/soreness occurring Day 1 through 
Day 5 after any vaccination, and (3) elevated temperature (≥100.4°F [≥38.0ºC]), after any 
study vaccination through 28 days Postdose 4.
Additional summaries on Tier-1 safety parameters will also be provided by the dosing 
period..
For Tier-2 adverse experiences, risk differences between the two groups and the 
corresponding two-sided 95% CI on the risk difference will be provided using the 
methods proposed by Miettinen and Nurminen.  This Tier-2 approach will be applied to 
the proportions of any other injection-site adverse experiences or systemic adverse 
experiences after any study vaccination through 28 days Postdose 4 that are not prompted 
for on the VRC but occurred in at least 1% of the patients in either treatment group.
Additional summaries on Tier-2 safety parameters will also be provided by the dosing 
period,  and gender in each vaccination group.
Tier 3 adverse experiences will include summaries for any other adverse experiences 
after any study vaccination through 28 days Postdose 4.

Product:  V212
Page 86
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
The rate of SAEs, vaccine-related SAEs and death that occur throughout the entire study 
follow-up period will also be summarized per 1000 person-years of follow-up by 
vaccination group, to account for potential differential follow-up time by vaccination 
group.  The probability of mortality will also be estimated and displayed by the Kaplan-
Meier curve for each vaccination group.  Risk difference and the corresponding 95% CI 
of these long-term safety parameters between the vaccine group and placebo group will 
be provided using an asymptotic method for differences of 2 independent Poisson rates. 
Mortality and SAEs, including vaccine-related SAEs will also be listed by patient with 
more detailed information.
SAEs and Tier-1 adverse experiences during the primary safety follow-up period will be 
summarized by body system.
Summaries of varicella/varicella-like or an HZ/HZ-like rash occurring during the primary 
safety period, through 28 days postvaccination 4, will be provided by vaccination group 
and by lesion type (wild type versus vaccine strain) determined by PCR. Occurrence of 
opportunistic infections during the primary safety period (from Day 1 to Day 28 Postdose 
4) will also be summarized as adverse experiences. Occurrence of opportunistic 
infections and recurrence of disease that are SAEs at any time during the study will also 
be summarized.
3.5.6
Multiplicity
With the decision made from the first interim futility analysis (provided in Sections 1.3 
and 1.4), there is only one efficacy analysis performed for the primary efficacy
hypothesis in the STM population.  As no population enrichment is planned, no 
multiplicity adjustment will be made for primary efficacy analysis in the STM population 
and the primary efficacy hypothesis will be tested at one sided α=0.0125. 
No multiplicity adjustment will be made for the analyses related to the secondary 
objective and exploratory objectives, including any analyses related to immunogenicity, 
due to their exploratory nature.
For comparisons of adverse experiences between the vaccine and placebo groups, the 
goal is to investigate if there exists an overall trend of risk difference between the 2 
groups. It is recognized that there exists a multiplicity issue for conducting multiple 
comparisons on these items, with each comparison being performed at the two-sided 0.05 
level (corresponding to the 95% CI). Since the overall significance level for these 
comparisons will be much >0.05, caution should be exercised when interpreting the 
results.

Product:  V212
Page 87
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.7
Sample Size and Power
3.5.7.1
Efficacy Analysis
This is an event-driven study.  With a 1:1 randomization ratio between the vaccine and 
placebo groups and a total of 90 HZ cases in the STM population with 2696 patients, the 
study will have an overall power of ~84.2% to detect 65% VEHZ at the overall two-sided 
0.025 significance level, based on the success criterion of the lower bound 97.5% CI for 
VEHZ being greater than 25%. Table 3-3 also provides power for a variety of assumed 
vaccine efficacy.
Table 3- 3 Power for Primary Efficacy in the STM Population with 90 Cases
Cases
Power at assumed vaccine efficacy (VE)
VE=80
VE=75
VE=70
VE=65
VE=60
VE=55
90
99.9%
99.2%
95.0%
84.2%
66.6%
46.7%
To accrue ~90 confirmed HZ cases in the STM population during the time period from 
enrollment through approximately the end of maximum 5 years postvaccination, 
enrollment of approximately 2696 patients (1348 receiving vaccine and 1348 receiving 
placebo) will be required, assuming 1) 30% total lost-to-follow-up, 2) an HZ rate of 17 
per 1000 in the placebo group, 3) VEHZ=65%, and 4) 36 months of study enrollment. The 
sample size calculation follows the methods described in Lachin [21].
The dropout rates and the HZ event rates will be monitored on an ongoing basis using the 
blinded database. If the observed HZ case accrual rate indicates that more than 5 years of 
patient follow-up will be necessary to accrue the targeted number of confirmed cases, 
then the SPONSOR will consider it beyond the adjustment cap and terminate the study
without extended follow-up time and increasing enrollment. Because of the event driven 
design, no additional interim analysis is expected to be performed when follow-up time is 
extended or when enrollment is increased.  Should enrollment increase, patients enrolled 
under this scenario will also be followed for safety and efficacy for at least 1 year 
following receipt of their last dose of V212 or placebo.

Product:  V212
Page 88
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Since the incidence of clinically significant pain, complications as defined by the 
composite secondary endpoint and PHN are unknown in this population, formal 
hypothesis testing for these secondary endpoints will not be performed, but rather the 
analysis will focus on the estimation of the vaccine efficacy on these endpoints. To 
quantify the precision of the analysis, as an example, if the underlying true vaccine 
efficacy for any one of these secondary endpoints is 52%, and 10% of HZ cases 
developed a secondary endpoint for vaccine and placebo group, then at interim and final 
analysis where the HZ case split between vaccine and placebo has met the statistical 
success criterion for the primary hypothesis, the point estimates and CIs (adjusting for 
multiplicity) on the secondary endpoints efficacy are roughly 50% (- 80%, 88%) and 40% 
(-50%, 77%), respectively. If 20% of HZ cases developed a secondary endpoint, then the 
above point estimates and CIs are 48% (-24%, 80%) and 44% (-1%, 71%), respectively.  
If 40% of HZ cases developed a secondary endpoint, then the above point estimates and 
CIs are 48% (5%, 72%) and 43% (11%, 64%), respectively.
3.5.7.2
Safety Analysis
If no SAEs are observed in 1348 STM patients who received V212, this study provides 
97.5% confidence that the true SAE rate is <0.28% (1 out of every 362 patients).
The probability of observing at least one SAE in this study depends on the number of 
patients enrolled and the incidence rate of SAEs in the general population.  If the 
incidence rate of a SAE is 1 of every 838 recipients of the vaccine (0.12%), then there is 
an 80% chance of observing at least one such SAE among 1348 patients in the vaccine 
group.  If the incidence rate is 1 of every 1943 recipients (0.05%), there is a 50% chance 
of observing at least one SAE.
For safety comparisons, risk differences between the 2 vaccination groups that could be 
detected with a 80% probability are summarized in Table 3-4 for a variety of hypothetical 
true incidence rates.  These calculations assume there are 1348 and 1348 STM patients 
for safety in the vaccine and placebo groups and are based on a 2-sided significance level 
of α = 0.05.  No multiplicity adjustments were made in these calculations.
Table 3-4
Differences in Incidence of Adverse Experience Rates Between the Two 
Vaccination Groups That Can Be Detected With an ~80% Probability and a Two-Sided
Significance Level of 0.05, With Total 2696 STM Patients
True Incidence Rate of Adverse 
Experience in Vaccine Group (%)
True Incidence Rate of Adverse 
Experience in Placebo Group (%)
Detectable Percentage Points 
Difference in Incidence Rates of 
Adverse Experiences
0.5
1.59
1.09
1
2.39
1.39
3
5.12
2.12
5
7.61
2.61
8
11.16
3.16
10
13.45
3.45
20
24.46
4.46
30
35.03
5.03
Note: These incidence rates are hypothetical and do not represent actual incidence rates of specific adverse experiences in either 
group.

Product:  V212
Page 89
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.7.3
Immunogenicity Analysis
All immunogenicity analyses in this study are exploratory.  A subset of patients (n ~ 
1000) will participate in the ELISPOT substudy and undergo testing for direct VZV T-
cell responses by IFN-ELISPOT assay. This substudy size is required to adequately 
power (≈70%) the study to detect correlation with efficacy for combined STM and HM 
population when assuming the true correlation is one unit increase of log scaled post dose 
4 ELISPOT GMC will reduce the HZ risk by 18% and standard deviation of log scaled 
post dose 4 ELISPOT GMC is 2.2 for HM and 1.6 for STM. This substudy size also 
provides sufficient power (>88%) for each subgroup population for testing fold 
difference at lower bound of 1.0 when the true fold difference between two groups is 2.0.
In addition, T-cell responses will be indirectly measured using an antibody measure, 
gpELISA in all patients from STM subgroup. The GMT or GMC and GMFR for 
gpELISA and ELISPOT will be provided by vaccination group at scheduled time points 
(see Section 1.7).  A longitudinal regression model will be used to estimate the fold 
difference at these time points between the vaccination groups, while adjusting for the 
prevaccination titers.  Other exploratory analyses will also be performed to determine 
whether these VZV-specific immune responses are associated with protection against HZ 
using Cox proportional hazards models.
3.5.8
Interim Analysis
There was one interim futility analysis for individual subgroups (HM and STM). The 
purpose of the interim futility analysis was to terminate the study if vaccine efficacy was 
lower than expected in either population or to terminate the combined study if vaccine 
efficacy was lower than expected in both populations. See Appendix 6.3 for a summary 
of the interim analysis strategy.
3.5.8.1
Interim Analyses of Futility/ Efficacy for Potential Early Study 
Termination
The first interim analysis for futility was conducted on 29-Oct-2014.  Text describing the 
analysis strategy can be found in Appendix 6.3.
3.5.8.2
Interim Monitoring of Safety by Data Monitoring Committee
The DMC will monitor safety closely during the study enrollment period in order to 
ensure the safety of the participants.  In the event that SAEs, vaccine related death, or 
incidence of HZ are noted to be excessive in the vaccine group relative to the placebo 
group, the DMC may consider stopping recruitment into the study.  In the planned formal 
interim  analyses, the SAEs, Tier-1 and Tier-2 vaccine safety parameters will be 
summarized and analyzed according to the plan specified in Section 3.5.5.3.
An unblinded SPONSOR statistician who is otherwise unrelated to this protocol will 
serve as a non-voting member of DMC and will be responsible for performing the interim 
analyses for DMC. Detailed implementation of the interim analyses is described in the 
DMC guidelines (separate documentation).

Product:  V212
Page 90
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.8.3
Interim Monitoring Guidelines for the Data Monitoring Committee
Interim Monitoring Guidelines for the DMC have been developed to describe in detail the 
membership, organization, functions and responsibilities of the DMC. These guidelines 
also include the detailed implementation plan of the interim monitoring of efficacy and 
safety as described in the previous subsections. The DMC guidelines will be described in 
a separate document.
3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES
3.6.1
Product Description
Investigational materials will be provided by the SPONSOR as summarized in 
Table 3-5.
Table 3-5
Product Descriptions
Product Name & Target 
Potency
Dosage Form
Comments
Single 0.5mL Dose 
Lyophilized Powder for 
Subcutaneous Injection
Store refrigerated at 2°C to 8°C 
or colder. Protect from light.
Placebo
Single 0.5mL Dose 
Lyophilized Powder for 
Subcutaneous Injection
Store refrigerated at 2°C to 8°C 
or colder. Protect from light.
Sterile Diluent for 
reconstitution of vaccines 
(sterile water)
0.7mL (fill volume) Sterile 
solution for reconstitution
Store at room temperature 20°-
25°C or refrigerated at 2°C to 
8°C.
V212† = Inactivated Varicella Zoster Virus Vaccine
3.6.2
Packaging Information
Blinded, single-dose vials will be supplied to the clinical sites. Supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
3.6.3
Clinical Supplies Disclosure
The IVRS should be used in order to unblind patients and to unmask drug identity. The 
SPONSOR will not provide disclosure envelopes with the clinical supplies. Drug 
identification information is to be unmasked ONLY if necessary for the welfare of the 
patient. Every effort should be made not to unblind the patient unless necessary. Prior to 
unblinding, the investigator will attempt to contact the Clinical Monitor or Clinical 
Research Associate. Any unblinding that occurs at the site must be documented.
CCI

Product:  V212
Page 91
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
If unblinding should occur for any reason (either accidental unblinding or emergency 
unblinding for a SAE), the investigator must promptly document the circumstance on the 
unblinding log and immediately notify the Merck Clinical Monitor listed on the 
SPONSOR Contact Information page in the Administrative binder.
3.6.4
Storage and Handling Requirements
Please see Product Description Table (Table 3-5).
Store V212/placebo, and sterile diluent according to their respective product labels.
V212/placebo and sterile diluent supplies will be shipped to the sites at room temperature 
or refrigerated, and will contain a temperature monitoring device. Upon receipt at the 
investigational site, supplies should be removed from the outer secondary shipping box.
V212/placebo must be placed immediately into the refrigerator. The temperature 
monitoring device must be de-activated upon receipt of the shipment. Directions for de-
activation are specified in the Temp Tale Form (Instructions to Site), which are enclosed 
with each shipment. The temperature monitoring device will indicate whether the 
shipment has remained within the specified temperature range during transit. If a 
temperature excursion is indicated, immediately store the product according to the labeled storage 
conditions (until instructed otherwise), confirm the shipment in the IVRS, and immediately notify 
the SPONSOR (Clinical Research Associate [CRA]).  Return the temperature monitoring 
device according to instructions accompanying the shipment.
Sterile diluent for reconstitution of vaccines may be stored at room temperature 20 to 
25°C (68 to 77°) or at 2°C to 8°C (35.6°F to 46.4°F).
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in this 
protocol or in the product label attached to the protocol.  Documentation of temperature 
monitoring should be maintained. Supplies should be stored in the original nested box 
with the lid closed to minimize exposure to light.
For V212/placebo, if the refrigerator rises above 8°C, study vaccinations should be 
suspended, the excursion must be registered in the IVRS and the SPONSOR (CRA) 
should be contacted immediately.
For sterile diluent (if storing refrigerated), if the refrigerator deviates from the 2°C to 8°C 
(35.6°F to 46.4°F) range, study vaccinations should be suspended, the excursion must be 
immediately registered in the IVRS and the SPONSOR (CRA) should be contacted 
immediately.
Vaccine and sterile diluent must NOT be frozen.

Product:  V212
Page 92
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
It is strongly recommended that a non-frost free laboratory grade refrigerator is used to 
store the study vaccine. This type of refrigerator is less likely to have wide temperature 
fluctuations, so it will be more likely to stay within the 2°C to 8°C (35.6°F to 46.4°F) 
temperature range. A daily refrigerator temperature log must be maintained at the site. 
The refrigerator must be equipped with an appropriately calibrated min/max thermometer 
and/or circular chart temperature recorder. The temperature log will be reviewed by the 
CRA throughout the study. An appropriate back up system (i.e. alarm, generator) and 
study site personnel telephone numbers should be in place in the event of a refrigerator 
failure.
3.6.5
Standard Policies / Return of Clinical Supplies 
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designated assistants have access. Clinical supplies are to be dispensed 
only in accordance with the protocol. The investigator is responsible for keeping accurate 
records of the clinical supplies received from the SPONSOR, the amount dispensed to 
and returned by the patients, and the amount remaining at the conclusion of the study. 
The CRA should be contacted with any questions concerning investigational products 
where special or protective handling is indicated. At the end of the study, all unused 
clinical supplies must be returned as indicated in the Sponsor Contact Information.  
Partial or empty vaccine vials should be properly discarded as biohazardous waste. U.S. 
sites should follow instructions for the Clinical Supplies Return Form and contact your 
SPONSOR representative for review of shipment and form before shipping. Sites outside 
of the United States should check with local country Merck personnel for appropriate 
documentation that needs to be completed for vaccine accountability.
3.6.6
Distributing to Sites and Dispensing to Patients 
Study personnel will have access to an IVRS to allocate patients, to assign vaccine to 
patients and to manage the distribution of clinical supplies. Each person accessing the 
IVRS system must be assigned an individual unique PIN. They must use only their 
assigned PIN to access the system and they must not share 
3.7
DATA MANAGEMENT
Information regarding Data Management procedures for this protocol will be provided by 
the SPONSOR.

Product:  V212
Page 93
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.8
BIOLOGICAL SPECIMENS
Information regarding biological specimens (VZV Identification) for this protocol will be 
provided by the SPONSOR as follows:

Lesion specimens and whole blood specimens for varicella zoster virus (VZV) 
identification by polymerase chain reaction (PCR) assay which are required to 
be collected as per protocol (Sections 3.3.2 & 3.3.3).  Procedures for the 
collection, storage and shipping of these samples are available in the 
Laboratory Binder provided by the Central Laboratory.

If a patient develops an SAE suspicious for a varicella zoster infection 
following the administration of V212, optional testing of any specimen (e.g., 
fluid or tissue) that remains following the completion of routine diagnostic 
testing may be sent (with the permission of the patient) to Columbia 
University College of Physicians and Surgeons, Division of Pediatric 
Infectious Disease laboratory for PCR testing to determine if VZV is present, 
and if so, which strain (Oka or wild-type, including differentiation between 
Oka vaccine strain and wild-type Japanese/Oka strain) is present (Section 
3.4.1.4).  Information regarding the collection, labeling and shipping of these 
specimens is provided in the Administrative Binder, provided by the 
SPONSOR.  A separate informed consent, provided by the SPONSOR must 
be obtained for these specimens.

Product:  V212
Page 94
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
4. ADMINISTRATIVE AND REGULATORY DETAILS
4.1
CONFIDENTIALITY
4.1.1
Confidentiality of Data
For Studies Conducted Under the U.S. IND
Particular attention is drawn to the regulations promulgated by the Food and Drug 
Administration under the Freedom of Information Act providing, in part, that information 
furnished to clinical investigators and Institutional Review Boards will be kept 
confidential by the Food and Drug Administration only if maintained in confidence by 
the clinical investigator and Institutional Review Board.
For All Studies
By signing this protocol, the investigator affirms to the SPONSOR that information 
furnished to the investigator by the SPONSOR will be maintained in confidence and such 
information will be divulged to the Institutional Review Board, Ethics Review 
Committee, or similar or expert committee; affiliated institution; and employees only 
under an appropriate understanding of confidentiality with such board or committee, 
affiliated institution and employees. Data generated by this study will be considered 
confidential by the investigator, except to the extent that it is included in a publication as 
provided in the Publications section of this protocol.
4.1.2
Confidentiality of Subject/Patient Records
For All Studies
By signing this protocol, the investigator agrees that the SPONSOR (or SPONSOR 
representative), Institutional Review Board/Independent Ethics Committee (IRB/IEC), or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/case report form data. By signing the consent form, the subject/patient 
agrees to this process. If study documents will be photocopied during the process of 
verifying worksheet/case report form information, the subject/patient will be identified by 
unique code only; full names/initials will be masked prior to transmission to the 
SPONSOR.
For Studies Conducted Under the U.S. IND
By signing this protocol, the investigator agrees to treat all patient data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, 
rules and regulations, including all applicable provisions of the Health Insurance 
Portability and Accountability Act and its implementing regulations, as amended from 
time to time. (“HIPAA”).

Product:  V212
Page 95
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
4.1.3
Confidentiality of Investigator Information
For All Studies
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and study site 
personnel, may be used and disclosed for study management purposes, as part of a 
regulatory submissions, and as required by law. This information may include:

name, address, telephone number, and email address;

hospital or clinic address and telephone number;

curriculum vitae or other summary of qualifications and credentials; and

other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
SPONSOR, and subsidiaries, affiliates and agents of the SPONSOR, in your country and 
other countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory agencies or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses 
and disclosures.
For Multicenter Studies
In order to facilitate contact between investigators, the SPONSOR may share an 
investigator’s name and contact information with other participating investigators upon 
request.
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of 
Good Clinical Practice; and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is attached. 
The investigator also agrees to allow monitoring, audits, Institutional Review 
Board/Independent Ethics Committee review, and regulatory agency inspection of trial-
related documents and procedures and provide for direct access to all study-related source 
data and documents.
The investigator agrees not to seek reimbursement from subjects/patients, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the SPONSOR.

Product:  V212
Page 96
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
The Investigator shall prepare and maintain complete and accurate study documentation 
in compliance with Good Clinical Practice standards and applicable federal, state, and 
local laws, rules and regulations; and, for each subject/patient participating in the study, 
provide all data, and upon completion or termination of the clinical study submit any 
other reports to the SPONSOR as required by this protocol or as otherwise required 
pursuant to any agreement with the SPONSOR.
Study documentation will be promptly and fully disclosed to the SPONSOR by the 
investigator upon request and also shall be made available at the investigator’s site upon 
request for inspection, copying, review, and audit at reasonable times by representatives 
of the SPONSOR or any regulatory agencies. The investigator agrees to promptly take
any reasonable steps that are requested by the SPONSOR as a result of an audit to cure 
deficiencies in the study documentation and worksheets/case report forms. 
International Conference of Harmonization Good Clinical Practice guidelines (Section 
4.3.3) recommend that the investigator inform the subject’s primary physician about the 
subject’s participation in the trial if the subject has a primary physician and if the subject 
agrees to the primary physician being informed.
According to European legislation, a SPONSOR must designate a principal or 
coordinating investigator (CI) to review the report (summarizing the study results) and 
confirm that to the best of his/her knowledge the report accurately describes conduct and 
results of the study. The SPONSOR may consider one or more factors in the selection of 
the individual to serve as the CI (e.g., thorough understanding of clinical trial methods, 
appropriate enrollment of subject/patient cohort, timely achievement of study milestones, 
availability of the CI during the anticipated review process). 
The investigator will promptly inform the SPONSOR of any regulatory agency 
inspection conducted for this study.
Persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on this SPONSOR’s studies. 
The investigator will immediately disclose in writing to the SPONSOR if any person who 
is involved in conducting the study is debarred, or if any proceeding for debarment is 
pending or, to the best of the investigator’s knowledge, threatened.
In the event the SPONSOR prematurely terminates a particular trial site, the SPONSOR 
will promptly notify that site’s IRB/IEC.

Product:  V212
Page 97
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS
By signing this protocol, the investigator agrees to provide to the SPONSOR accurate 
financial information to allow the SPONSOR to submit complete and accurate 
certification and disclosure statements as required by U.S. Food and Drug Administration 
regulations (21 CFR Part 54). The investigator further agrees to provide this information 
on a Financial Disclosure/Certification Form that is provided by Merck Sharp & Dohme 
Corp., a subsidiary of Merck & Co., Inc. This requirement also extends to 
subinvestigators. The investigator also consents to the transmission of this information to 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. in the United States for 
these purposes. This may involve the transmission of information to countries that do not 
have laws protecting personal data.
4.4
QUALITY CONTROL AND QUALITY ASSURANCE
By signing this protocol, the SPONSOR agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written SOPs to ensure 
that trials are conducted and data are generated, documented, and reported in compliance 
with the protocol, accepted standards of Good Clinical Practice, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical 
study.
4.5
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL 
TRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS
Under the terms of The Food and Drug Administration Modernization Act (FDAMA), 
the SPONSOR of the study is solely responsible for determining whether the study is 
subject to the requirements for submission to the Clinical Trials Data Bank, 
http://clinicaltrials.gov/.  Merck, as SPONSOR of this study, will review this protocol and 
submit the information necessary to fulfill this requirement.  Merck entries are not limited 
to FDAMA mandated trials.  Merck’s voluntary listings, beyond those mandated by 
FDAMA, will be in the same format as for treatments for serious or life-threatening 
illnesses.  Information posted will allow patients to identify potentially appropriate trials 
for their disease conditions and pursue participation by calling a central contact number 
for further information on appropriate study locations and site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligation 
under FDAMA is that of the SPONSOR and agrees not to submit any information about 
this study to the Clinical Trials Data Bank.

Product:  V212
Page 98
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
4.6
PUBLICATIONS
This study is intended for publication, even if terminated prematurely. Publication may 
include any or all of the following: posting of a synopsis online, abstract and/or 
presentation at a scientific conference, or publication of a full manuscript.  The 
SPONSOR will work with the authors to submit a manuscript describing study results 
within 12 months after the last data become available, which may take up to several 
months after the last patient visit in some cases such as vaccine trials.  However, 
manuscript submission timelines may be extended on OTC studies.   For studies intended 
for pediatric-related regulatory filings, the investigator agrees to delay publication of the 
study results until the SPONSOR notifies the investigator that all relevant regulatory 
requirements on the study drug have been  fulfilled with regard to pediatric-related 
regulatory filings.   Merck will post a synopsis of study results for approved products on 
www.clinicalstudyresults.org and www.clinicaltrials.gov by 12 months after the last 
patient's last visit or within 7 days of product approval in any major markets (United 
States, Europe or Japan), whichever is later.  These timelines may be extended for 
products that are not yet marketed, if additional time is needed for analysis, to protect 
intellectual property, or to comply with confidentiality agreements with other parties.  
Authors of the primary results manuscript will be provided the complete results from the 
Clinical Study Report, subject to the confidentiality agreement. 
For multicenter studies, subsequent to the multicenter publication (or after public 
disclosure of the results online at www.clinicalstudyresults.org if a multicenter 
manuscript is not planned), an investigator and his/her colleagues may publish their data 
independently.  In most cases, publication of individual site data does not add value to 
complete multicenter results, due to statistical concerns.  In rare cases, publication of 
single site data prior to the main paper may be of value.  Limitations of single site 
observations in a multicenter trial should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and 
design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article 
or revising it critically for important intellectual content; and 3) final approval of the 
version to be published. Authors should meet conditions 1, 2, and 3.  Significant 
contributions to study execution may also be taken into account to determine authorship, 
provided that contributions have also been made to all three of the preceding authorship 
criteria. Although publication planning may begin before conducting the study, final 
decisions on authorship and the order of authors’ names will be made based on 
participation and actual contributions to the study and writing, as discussed above. The 
first author is responsible to defend the integrity of the data, method(s) of data analysis, 
and the scientific content of the manuscript.  
The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, 
or 
presentations 
regarding 
this 
study 
60 
days 
prior 
to 
submission 
for 
publication/presentation. Any information identified by the SPONSOR as confidential 
must be deleted prior to submission. SPONSOR review can be expedited to meet 
publication timelines.

Product:  V212
Page 99
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
5. LIST OF REFERENCES
1.
Schmader K. (2007) Herpes zoster and postherpetic neuralgia in older adults. Clin 
Geriatr Med 23, 615-632.
2.
Gebo KA, Kalyani R, Moore RD, Polydefkis MJ.  The incidence of, risk factors for, 
and sequelae of herpes zoster among HIV patients in the highly active antiretroviral 
therapy era.  Acquir Immune Defic Syndr. 2005; 40(2): 169-174.
3.
Mattiuzzi GN, Cortes MT, Reuben J, Rios MB, Shan J, et al. Development of
varicella-zoster infection in patients with chronic myelogenous leukemia treated 
with imatinib mesylate.  Clin Cancer Res. 2003; 9:976-80.
4.
Wung PK, Holbrook JT, Hoffman GS, Tibbs AK, Specks U, Min Y, et al.  Herpes 
zoster in immunocompromised patients: incidence, timing, and risk factors.  Am J 
Med. 2005;118 (12):1416e9-1416e18.
5.
Gourishankar S., McDermid J.C., Jhangri G.S., & Preiksaitis J.K. (2004) Herpes 
zoster infection following solid organ transplantation: Incidence, risk factors and 
outcomes in the current immunosuppressive era. Am J Transplant 4, 108-115.
6.
Dworkin RH, Schmader KE. Treatment and prevention of postherpetic neuralgia.  
Clin Infect Dis. 2003; 36: 877-82.
7.
Ragozzino M.W., Melton L.J., III, Kurland L.T., Chu C.P., & Perry H.O. (1982) 
Population-based study of herpes zoster and its sequelae. Medicine (Baltimore) 61, 
310-316.
8.
Hope-Simpson RE.  The nature of herpes zoster: a long-term study and a new 
hypothesis. Proc Royal Soc Med. 1965; 58: 9-20.
9.
Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster.  Arch 
Intern Med. 1995; 155: 1605-9.
10.
Dworkin R.H., Corbin A.E., Young J.P., Jr., Sharma U., LaMoreaux L., Bockbrader 
H., Garofalo E.A., & Poole R.M. (2003) Pregabalin for the treatment of postherpetic 
neuralgia.  A randomized, placebo-controlled trial. Neurology 60, 1274-1283.
11.
Tauro S., Toh V., Osman H., & Mahendra P. (2000) Varicella zoster 
meningoencephalitis following treatment for dermatomal zoster in an alloBMT 
patient. Bone Marrow Transplant 26, 795-796.
12.
Walton R.C. & Reed K.L. (1999) Herpes zoster ophthalmicus following bone 
marrow transplantation in children. Bone Marrow Transplant 23, 1317-1320.

Product:  V212
Page 100
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
13.
Habel L.A., Ray G.T., Horberg M., Yawn,B.,Li Y. et al. Herpes zoster in solid 
tumor and hematologic malignancy patients - A cohort study in a managed care 
organization [poster]. Presented at the 34th Annual Meeting of the European Society 
of Medical Oncology;2009 Sep 20-24; Berlin, Germany; ESMO;2009. Poster.
14.
Redman R.L., Nader S., Zerboni L., Liu C., Wong R.M., Brown B.W., & Arvin 
A.M. (1997) Early reconstitution of immunity and decreased severity of herpes 
zoster in bone marrow transplant recipients immunized with inactivated varicella 
vaccine. Journal of Infectious Diseases 176, 578-585.
15.
Hata A., Asanuma H., Rinki M., Sharp M., Wong R.M., Blume K., & Arvin A.M. 
(2002) Use of an inactivated varicella vaccine in recipients of hematopoietic-cell 
transplants. New England Journal of Medicine 347, 26-34.
16.
MRL Data on File, Multicenter study trial of safety and immunogenicity of 
inactivated varicella zoster vaccine in immunocompromised patients (Protocol 002).
17.
MRL Data on File, Multicenter study trial of safety and immunogenicity of 
inactivated varicella zoster vaccine in healthy adults (Protocol 004)
18.
StatXact 7 PROCs for SAS Users Manual 2005; 241-254.
19.
Clopper CJ and Pearson ES. The use of confidence or fiducial limits illustrated in 
the case of binomial. Biometrika 1934; 26:404-13.
20.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
21.
Lachin JM. Biostatistical methods: the assessment of relative risks. 2000; 409-412.
22.
Goffinet D.R., Glatstein E., & Kaplan H.S. (1973) Herpes zoster infections in 
lymphoma patients. Natl Cancer Inst Monogr 36, 464.
23.
Guinee V.F., Guido J.J., Pfalzgraf K.A., Giacco G.G., Lagarde C., Durand M., Van 
Der Velden J.W., Löwenberg B., Jereb B., Bretsky S., Meilof J., Hamersma E.A.M., 
Dische S., & Anderson P. (1985) The incidence of herpes zoster in patients with 
Hodgkin's disease. Cancer 56, 642-648.
24.
Gopal R., Advani S.H., Dinshaw K.T., Nair C.N., & Desai P.B. (1980) Herpes-
zoster in malignancy. J Assoc Physicians India 28, 125-132.
25.
Pahuja R., Parikh P.M., Charak B.S., Rawat R.S., Gopal R., Saikia T.K., & Advani 
S.H. (1988) Zoster-varicella infection in Hodgkin's disease. J Assoc Physicians 
India 36, 321-322.

Product:  V212
Page 101
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
26.
Rusthoven J.J., Ahlgren P., Elhakim T., Pinfold P., Reid J., Stewart L., & Feld R. 
(1988) Varicella-zoster infection in adult cancer patients. A population study. 
Archives of Internal Medicine 148, 1561-1566.
27.
Morison W.L. (1974) Herpes simplex and herpes zoster in neoplasia [letter]. Lancet
1, 1293.
28.
Maung Z.T., Taylor P.R.A., Robinson P., Moore J., Lucraft H.H., Evans R.G.B., & 
Proctor S.J. (1993) Patient education for self-referral and on-demand treatment for 
herpes zoster in lymphoma patients. Leuk Lymphoma 11, 447-452.
29.
Kim S.J., Kim K., Kim B.S., Lee H.-J., Kim H., Lee N.-R., Nam S.-H., Kwon J.H., 
Kim H.J., Sohn S.K., Won J.-H., Lee J.H., Suh C., Yoon S.-S., Kim H.J., Kim I., 
Do Y.-R., Lee W.-S., Joo Y.-D., Shin H.J., & Korean Multiple Myeloma Working 
Party (2008) Bortezomib and the increased incidence of herpes zoster in patients 
with multiple myeloma. Clin Lymphoma Myeloma 8, 237-240.
30.
Chanan-Khan A., Sonneveld P., Schuster M.W., Stadtmauer E.A., Facon T., 
Harousseau J.-L., & Ben-Yehuda D. (2008) Analysis of Herpes Zoster Events 
Among Bortezomib-Treated Patients in the Phase III APEX Study. J Clin Oncol 26, 
4784-4790.
31.
Tran T.N., Ray G.T., Saddier, P, Trigg, M & Hayes, N. Immunocompromised status 
of patients with hematologic and solid tumor malignancies: construction of a 
practical algorithm[abstract]. In: Proceedings of the 51st Annual Meeting of the  
American Society of Hematology;2009 Dec 5-8; New Orleans, Louisiana (LA); 
ASH;2009. p 980. Abstract nr 2484.
32.
Hughes B.A., Kimmel D.W., & Aksamit A.J. (1993) Herpes zoster-associated 
meningoencephalitis in patients with systemic cancer. Mayo Clin Proc 68, 652-655.
33.
Feld R. & Bodey G.P. (1977) Infections in patients with malignant lymphoma 
treated with combination chemotherapy. Cancer 39, 1018-1025.
34.
Eilers Jr. R.E., Gandhi M., Patel J.D., Mulcahy M.F., Agulnik M., Hensing T., & 
Lacouture M.E. (2010) Dermatologic infections in cancer patients treated with 
epidermal growth factor receptor inhibitor therapy. JNCI Cancer Spectrum 102, 47-
53.
35.
Dunst J., Steil B., Furch S., Fach A., Bormann G., & Marsch W. (2000) Herpes 
zoster in breast cancer patients after radiotherapy. Strahlenther Onkol 176, 513-516.
36.
Huberman M., Fossieck B.E.J., Bunn P.A.J., Cohen M.H., Ihde D.C., & Minna J.D. 
(1980) Herpes zoster and small cell bronchogenic carcinoma. Am J Med 68, 214-
218.

Product:  V212
Page 102
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
37.
Feld R., Evans W.K., & DeBoer G. (1980) Herpes zoster in patients with small-cell 
carcinoma of the lung receiving combined modality treatment. Ann Intern Med 93, 
282-283.
38.
Masci G., Magagnoli M., Gullo G., Morenghi E., Garassino I., Simonelli M., & 
Santoro A. (2006) Herpes infections in breast cancer patients treated with adjuvant 
chemotherapy. Oncology 71, 164-167.
39.
Feld R., Evans W.K., & DeBoer G. (1982) Herpes zoster in patients with carcinoma 
of the lung. Am J Med 73, 795-801.
40.
Turner MJ et al. Avidity maturation of CD8+ memory T cells is limited by self-
antigen expression. J Exp Med 205(8) 1859-1868
41.
Cleeland CS. et al. Assessment of Pain in Cancer: Measurements Issues. Advances 
in Pain Research and Therapy 1990; 16: 47-55.
42.
Coplan PM. et al. Development of a Measure of the Burden of Pain Due to Herpes 
Zoster and Postherpetic Neuralgia for Prevention Trails: Adaptation of the Brief 
Pain Inventory. The Journal of Pain 2004; 5(6): 344-356.
43.
MRL Clinical Study Report, Multicenter Study: Trial of varicella-zoster vaccine for 
the prevention of herpes zoster and its complications (Protocol 004).
44.
Oxman MN. A Vaccine to Prevent Herpes Zoster and Postherpetic neuralgia in 
Older Adults. NEJM 2005: 22:2271-2284. 
45.
Dworkin RD et al. Recommendations for the management of herpes zoster. CID 
2007:44 (Suppl 1) SI-26
46.
Harbecke R, Oxman MN, Arnold BA, Ip C, Johnson GR, Levin MJ, et al. A Real-
Time PCR Assay to Identify and Discriminate Among Wild-Type and Vaccine 
Strains of Varicella-Zoster Virus and Herpes Simplex Virus in Clinical Specimens, 
and Comparison With the Clinical Diagnoses. J Med Virol 2009;81:1310-22.
47.
Keller PM, Lonergan K, Neff BJ, Morton DA, Ellis RW. Purification of individual 
varicella-zoster virus (VZV) glycoproteins gpI, gpII, and gpIII and their use in 
ELISA for detection of VZV glycoprotein-specific antibodies. J Virol Methods 
1986;14(2):177-88.
48.
Wasmuth EH, Miller WJ. Sensitive enzyme-linked immunosorbent assay for 
antibody to varicella-zoster virus using purified VZV glycoprotein antigen. J Med 
Virol 1990;32(3):189-93.
49.
Provost PJ, Krah DL, Kuter BJ, Morton DH, Schofield TJ, Wasmuth EH, et al. 
Antibody assays suitable for assessing immune responses to live varicella vaccine. 
Vaccine 1991;9(2):111-6.

Product:  V212
Page 103
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
50.
Krah DL, Cho I, Schofield T, Ellis RW. Comparison of gpELISA and neutralizing 
antibody responses to Oka/Merck live varicella vaccine (Varivax®) in children and 
adults. Vaccine 1997;15(1):61-4.
51.
Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete 
failure time data by modeling marginal distributions. J Am Stat Assoc 
1989;84(408):1065-73.
52.
Liang K. and Zeger S.  Longitudinal data analysis of continuous and discrete 
response for pre-post designs.  Sankhya 2000; 62:134-8.
53.
Hwang IK, Shih WJ and Decani JS. Group sequential designs using a family of type 
I error probability spending functions. Statistics in medicine 1990; 1439-1445. 
54.
East Version 4 User Manual 2005; 897-899.
55.
Jennison C and Turnball BW. Group Sequential Methods with Application to 
Clinical Trials. 2000; 171-181.

Product:  V212
Page 104
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
6. APPENDICES
6.1
IMMUNOSUPPRESSION CATEGORIES: HEMATOLOGIC 
MALIGNANCY
The 
following 
information 
provides 
guidance 
on 
the 
determination 
of 
Immunosuppression Category in individuals diagnosed with a hematologic malignancy.  
The list of treatment regimens is not intended to be an all-inclusive list as it is recognized 
that treatment regimens will change over the course of the study.  Among individuals 
diagnosed with hematologic malignancy, both the specific HM diagnosis and treatment 
regimen cause immunosuppression.  The impact of the disease and stage of the disease on 
immune status depends largely on the specific HM diagnosis, as does the treatment 
prescribed.  Table 6-1 presents the decision criteria for determination of the 
Immunocompromised Category used for stratification of study participants.
Table 6-1
Decision Criteria for Immunosuppression Category
The specific HM diagnosis and/or disease stage is classified as 
moderate or high for potential to cause immunosuppression (see 
Table 6-2)
OR
Treatment regimen includes agents listed in the moderate, 
high/very high class up to and including 6 months post-cessation of 
treatment (see Table 6-3 and Table 6-4) 
Moderate to High 
Immunosuppression
None of the above conditions have been met
Low 
Immunosuppression
The following information and accompanying tables provide support for decision making 
related to the determination of the Immunosuppression Category.  Table 6-2 provides a 
list of diagnoses within the HM group and the expected level of immunosuppression 
related to that disease entity.

Product:  V212
Page 105
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 6-2
Levels of Immunosuppression by HM and Stage
HM Diagnosis
Level of Immunosuppression
Acute leukemia and high grade lymphoma (i.e. Burkitt's 
lymphoma or T cell lymphoblastic lymphoma) 
High
All HM diagnoses not listed as high or low level of 
immunosuppression in this table
Moderate
Chronic myelogenous leukemia (CML), chronic 
myelomonocytic leukemia (CMML),  low grade 
lymphoma including small lymphocytic lymphoma (SLL)
Low stage CLL, follicular lymphoma (Stage 0 or 1), 
Hodgkin's disease (HD) (Stage 1), multiple myeloma, and 
MDS International Prognostic Scoring System 0-1 
(IPSS)*
Low
*For low stage CLL, follicular lymphoma, Hodgkin's disease and multiple myeloma, stage/grade of 
disease (if available) may be important in determining level of immunosuppression. For patients with 
MDS, an IPSS score of greater than 0-1 may indicate moderate or high level of immunosuppression 
depending upon degree of cytopenia, number of blasts present in bone marrow and genetic changes 
associated with the disease.  
The following information and accompanying tables provide support for decision making 
related 
to 
Immunosuppression 
Category. 
 
Chemotherapeutic 
and 
other 
immunosuppressive agents, as well as corticosteroids (based upon dose and duration) 
have been classified according to their potential effect on immune status.
Effect of Treatment on Immune Status
Chemotherapeutic and Other Immunosuppressive Agents (Not Corticosteroids)
The following tables list chemotherapeutic agents according to their propensity to cause 
immunosuppression.  In some cases, combining chemotherapeutic agents into a treatment 
regimen increases the risk/level of immunosuppression, therefore the decision on 
risk/level of immunosuppression for combined regimens should be determined on the 
basis of the drug with the highest propensity for immunosuppression.

Product:  V212
Page 106
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 6-3
Immunosuppressive Effect/Classification of Chemotherapeutic and Other Agents
Immunosuppressive Effect
None
Low
Moderate
High
Very High
Abarelix
Anastrozole
Bicalutamide
Dexrazoxane
Exemestane
Flutamide
Fulvestrant
Goserelin
GW572016 (lapatinib)
Letrozole
Leuprolide
Megestrol 
Nilutamide
Octreotide Acetate
Octreotide Pamoate
Oprelvekin
Testolactone
Toremifene
Tamoxifen
Triptorelin
Bevacizumab
Cetuximab
Erlotinib
Gefitinib
Hydroxyurea
Lenograstim
Megace
Methoxsalen
Mitotane
Panitumumab
Pegfilgrastim
Rhumab VEGF
Sargramostim (G-CSF)
Sorafenib (Bay 43-9006)
Sunitinib
TevaGrastim
Trastuzumab
Vorinostat
ZD1839
Abatacept
Adalimumab
Aldesleukin
Aminoglutethimide
Anakinra
Arsenic trioxide
Auranofin 
BCG live vaccine
Bexarotene
Bortezomib
Dasatinib
Eculizumab
Imatinib Mesylate
Interferon alfa-2A
Interferon alfa-2B
Interferon alfa-N3
Interferon beta-1A
Interferon beta-1B
Interferon gamma-1B
Lenalidomide
MAB-B43.13
Nilotinib
Peginterferon alfa-2A
Peginterferon alfa-2B
Penicillamine
Rituximab
Thalidomide
Tretinoin
Alimta
Altretamine
Asparaginase
Azacitidine
Bleomycin
Busulfan
Carboplatin
Carmustine
Chlorambucil
Chromic or Na P-32
Cisplatin
Cyclophosphamide
Cytarabine
Dacarbazine
Dactinomycin
Daunorubicin
Decitabine
Docetaxel
Doxorubicin
Epirubicin
Estramustine
Etoposide
Floxuridine
Fluorouracil
Gemcitabine
Hexamethylmelamine
Idarubicin
Ifosfamide/mesna
Irinotecan
Ixabepilone
Leflunomide
Lomustine
Mechlorethamine
Melphalan
Mercaptopurine
Methotrexate
Mitomycin
Mitoxantrone
Nelarabine
Nitrogen Mustard
Oxiplatin/Oxaliplatin
Paclitaxel
Pegaspargase
Pemetrexed disodium 
(Alimta)
Pipobroman
Procarbazine
Streptozocin
Temozolomide
Teniposide
Thioguanine
Thiotepa
TLK286
Topotecan
Trimetrexate
Vinblastine
Vincristine
Vinorelbine
Alemtuzumab
Antithymocyte 
Globulin
Azathioprine
Basiliximab
Capecitabine
Cladribine
Clofarabine
Cyclosporin
Daclizumab
Denileukin deftitox
Etanercept
Fludarabine
Gemtuzumab
Ibritumomab 
Tiuxetan
Infliximab
Muromonab-CD3
Mycophenolate 
mofetil
Pentostatin
Sirolimus
Tacrolimus
Temsirolimus
Tositumomab

Product:  V212
Page 107
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Systemic Corticosteroid Therapy
Table 6-4 provides a list of corticosteroids for systemic and accompanying dosage and 
duration of treatment related to level of immunosuppression.  Levels of 
immunosuppression are comparable to the levels listed in Table 6-3 and should be used to 
assist in the decision making relative to IC determination.
Table 6-4
Immunosuppressive Effect/Classification of Systemic Corticosteroids
Agent, Dose and Duration of Therapy
Cumulative dose
Level of 
Immunosuppression
Systemic Corticosteroids, for > 14 days
Prednisone or prednisolone >20mg/d
Hydrocortisone > 80 mg/day
Methylprednisolone > 16 mg/day
Dexamethasone > 3 mg/day (if Dexamethasone 
is given 10 mg once every 3 weeks for less than 
6 months, it is considered mild IC – see 
category 4 below)
≥700 mg regardless of duration 
of treatment 
Very high
Systemic Corticosteroids, > 14 days
Prednisone 7.5-20 mg/day
Prednisolone 7.5-20 mg/day
Hydrocortisone 30-80 mg/d
Methylprednisolone 6-16 mg/day
Dexamethasone 1.125-3 mg/day
70-280 mg for ≥2 weeks or
<700 mg regardless of duration 
of treatment
High
Systemic Corticosteroids, for < 14 days
Prednisone or prednisolone > 7.5 mg/day
Hydrocortisone > 30 mg/day
Methylprednisolone > 6 mg/day
Dexamethasone > 1.125 mg/day
<70mg for ≥2 weeks or 
70-280 mg for <2weeks
Moderate
Systemic Corticosteroids, regardless of 
duration:
Prednisone or prednisolone,  <  7.5 mg/day
Hydrocortisone,  < 30 mg/day
Methylprednisolone,  < 6 mg/day
Dexamethasone,  < 1.125 mg/day
Dexamethasone 10 mg once every 3 weeks
< 70 mg for less than 2 weeks
Mild

Product:  V212
Page 108
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
6.2
ADVERSE EXPERIENCE TOXICITY GRADING SCALE
A toxicity grading scale will be assigned to all clinical adverse experiences in this study.  
Table 6-5 and Table 6-6 outline the Toxicity Grading Scale for injection-site and 
systemic adverse experiences, respectively.
Table 6-5
Injection-Site AE Toxicity Grading Scale
Injection Site 
Reaction to Study 
Vaccine/Placebo*
Grade 1
Grade 2
Grade 3
Grade 4
Injection-site AEs occurring days 1 through 5 following receipt of study vaccine/placebo
Pain/Tenderness
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
Emergency room 
(ER) visit or 
hospitalization
Erythema/Redness
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or 
exfoliative 
dermatitis or results 
in ER visit or 
hospitalization
Induration/Swelling
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or ER visit 
or hospitalization
Other 
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Any injection-site reaction that begins  ≥ 6 days after receipt of study vaccine/placebo
Pain/tenderness
Erythema/Redness
Induration/Swelling
Other
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
*Based upon information provided by the patient on the Vaccine Report Card (VRC) and verbally during VRC 
review.  Erythema/Redness/Induration and Swelling are specific injection-site AEs with size designations of letters 
A through E→, based upon a graphic in the VRC. Size A is not assigned a toxicity grade; however, injection-site 
AEs that measure size A should be reported as adverse experiences.  If the subject has an ER visit or is hospitalized 
for any injection-site AE, that AE is to be assigned a toxicity grade of 4, regardless of the size measured.

Product:  V212
Page 109
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 6-6
Systemic AE Toxicity Grading Scale
Systemic Illness*
Grade 1
Grade 2
Grade 3
Grade 4
Illness or clinical 
adverse experience 
(as defined according 
to applicable 
regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
required medical 
intervention
Emergency room 
visit or 
hospitalization
*Based upon information provided by the patient on the VRC and verbally during VRC review during the primary 
safety follow-up period.
For SAEs reported beyond the primary safety follow-up period, grading will be based upon the initial report and/or 
follow-up of the event
Note: Events determined to be life-threatening or resulting in death are also assigned a Toxicity Grade = 4.

Product:  V212
Page 110
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
6.3
INTERIM ANALYSIS PLAN STRATEGY 
This section contains original text from V212-011-03 describing the plan for interim 
futility analyses (performed on 29-Oct-2014) and the interim efficacy analysis (which 
will not be conducted due to the futile outcome in the interim futility analysis in the HM 
arm and the risk of a false negative result due to the small number of cases in the STM 
arm).
2.4.1 Summary of Study Design (from V212-011-03)
The first interim (futility) analysis will be conducted when at least 50% of the total 
number of required confirmed HZ cases has accrued in each patient population, HM and 
STM. Depending on respective accrual rates of HZ cases in HM and STM patients, 
interim analysis may or may not be conducted at the same time for the 2 populations. 
Results of the analysis will be reviewed by the DMC, who will make recommendations to 
the Steering Committee (SC) to continue, modify, or end the study according to the 
following plan:

If vaccine efficacy meets expectation with both populations, the study will 
continue with both populations according to the initial plan.

If vaccine efficacy meets expectation with the HM population, but is lower than 
expected for the STM population,
o
The study will be considered to have failed with the STM arm; the 
study will enter close-out phase for the STM arm; no additional HZ 
case will be accrued for the STM arm; all STM patients will be 
contacted to complete the study close-out questions.
o
The study will continue with the HM arm only; the sample size will be 
increased for the HM population from 2568 to 6067 and the study will 
continue to accrue approximately 328 confirmed HZ cases.

If vaccine efficacy meets expectation with the STM population, but is lower than 
expected for the HM population:
o
The study will be considered to have failed with the HM arm; the 
study will enter close-out phase for the HM arm; no additional HZ 
case will be accrued for the HM arm; all HM patients will be contacted 
to complete the study close-out questionnaire.
o
The study will continue with the STM arm only; the sample size for 
the STM population will be increased from 2696 to 5836 and the study 
will continue to accrue approximately 210 confirmed HZ cases.

If vaccine efficacy is lower than expected in both populations, the study will be 
considered to have failed and will be terminated.

Product:  V212
Page 111
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
2.7.5 Interim Analysis (from V212-011-03)
There will be two interim analyses, and one final efficacy analysis.  The purpose of the 
futility analysis at the first interim is to terminate the whole study or either subgroup 
population if vaccine efficacy is lower than expected. The purpose of the second interim 
analysis is to terminate the study if vaccine efficacy is much lower or higher than 
expected.
Table 2-3 and Figure 2-2 summarize the interim analysis strategy. Details regarding the 
interim analysis plan are specified in Section 3.5.8.1.
Table 2-3
Summary of Interim Analysis Strategy
Interim 
Analysis 
Number
Key Endpoints 
for Interim 
Analysis
Anticipated Timing of Interim Analysis
Purpose of Interim 
Analysis
First 
incidence of 
HZ in the 
vaccine and 
placebo 
groups in HM 
and STM 
subgroup 
population 
individually
50% of the required confirmed cases of HZ in each 
individual population has accrued.
● at least 68 cases have accrued for HM subgroup
● at least 48 cases have accrued for STM subgroup
Of note, the futility analysis for HM and STM populations 
may not be conducted concurrently
Stop for futility
Potential to stop 
one arm and 
enrich the 
population in the 
remaining arm
Second
incidence of 
HZ in the 
vaccine and 
placebo group
75% of the total number of required confirmed cases of HZ
Total evaluable cases required at second interim:
If move forward with combined HM and STM
● at least 174 cases (with a minimum of 64 and 95 
confirmed HZ cases in the STM and HM populations, 
respectively) have accrued for combined population.
If move forward with STM subgroup population alone
● at least 158 cases have accrued for STM subgroup
If move forward with HM subgroup population alone
● at least 246 cases have accrued for HM subgroup
Of note: the second interim analysis will not be performed 
until the first interim analysis is completed on both 
populations.  The second interim analysis may not be 
performed if, based upon the enrollment rate and the time to
confirm the required number of HZ cases, either of the 
following scenarios occur: 1) timing of the first interim 
analyses in the individual subpopulations approximates the 
timing of accrual of the required 75% of the confirmed HZ 
cases that trigger the second interim analysis; 2) the study is 
nearing completion at the time the results of the second 
interim analysis would be available.  In either of these 
scenarios, the final analysis may be performed in lieu of the 
second interim analysis.
Stop for futility
Stop for efficacy 

Product:  V212
Page 112
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Figure 2-2
Interim Analysis Flow Chart

Product:  V212
Page 113
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
3.5.8.1 Interim Analyses of Futility/ Efficacy for Potential Early Study Termination 
(from V212-011-03)
The first interim (futility) analysis will be done on the HM and STM populations when at 
least 50% of the total number of required evaluable cases of HZ in each individual 
population has accrued.  More specifically, the first futility analysis will be done on the 
HM population and the STM population individually. When at least 68 cases have 
accrued in the HM population, the futility check on the HM population will be 
conducted; when at least 48 cases have accrued in the STM population, the futility check 
on the STM population will be conducted.  It should be noted that this first futility 
analysis for the HM and STM population might not occur concurrently as one subgroup 
might accrue HZ cases in the speed much slower than expected.
Table 3-4 and Table 3-5 illustrate the probabilities to observe a VE lower than futility 
cutoff.  The result indicated that given the true vaccine efficacy for HM and STM is as 
low as 25%, the probability to observe vaccine efficacy lower than 30% at first interim is 
about 0.560 and 0.620 for HM and STM respectively. The probability to terminate the 
whole study (both HM and STM) is ≈35% when the true vaccine efficacy for HM and 
STM is as low as 25%.
Table 3-4
Probabilities to Observe a VE Lower than Futility Cutoff 
50%  information fraction (68 HZ cases accrued for HM group)
If TRUE VE=
Probability(interim_VE≤0.3)
0.20
0.661
0.25
0.560
0.30
0.448
0.35
0.333
0.40
0.225
0.50
0.069
50%  information fraction (48 HZ cases accrued for STM group)
0.20
0.701
0.25
0.620
0.30
0.527
0.35
0.427
0.40
0.324
0.50
0.142
0.55
0.078

Product:  V212
Page 114
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 3-5
Probabilities the Trial will Stop Completely at First Interim Analysis
TRUE VE for STM
TRUE VE for HM
Prob(interim_VE≤0.3)
0.20
0.20
0.463
0.25
0.25
0.347
0.30
0.30
0.236
0.35
0.35
0.142
0.40
0.40
0.073
0.50
0.50
0.010
Table 3-6 illustrates the overall type I error rate and power comparison based on the 
futility boundary and timepoints proposed for the first futility analysis. The result 
indicated that given futility boundary for observed vaccine efficacy to be 30% and 30% 
for the STM and HM populations at 50% information fraction, the overall power would 
be around 90% and type one error is controlled under 0.025. It also provided sufficient 
power (≈0.70) when one of the subgroups has much lower VE than expected.
Table 3-6
Overall Type I Error Rate and Power Comparison by Futility Boundary and
Information Fraction for the First Futility Analysis
First futility analysis
Vaccine Efficacy assumed
VE_HM=25%
VE_STM=25%
(Type I error 
rate)
VE_HM=25%
VE_STM=55%
(Power)
VE_HM=50%
VE_STM=25%
(Power)
VE_HM=35%
VE_STM=55%
(Power)
VE_HM=50%
VE_STM=55%
(Power)
Futility 
boundary
Information 
fraction
Ob_HM 
>30%
Ob_STM>
30%
40% 
(N_HM=54, 
N_STM=39)
0.025
0.655
0.660
0.718
0.928
50% 
(N_HM=68, 
N_STM=48)
0.025
0.679
0.698
0.730
0.928
60% 
(N_HM=81, 
N_STM=58)
0.028
0.703
0.721
0.743
0.930

Product:  V212
Page 115
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
For the first futility analysis, a conditional power approach will be used. More 
specifically, when at least 50% of the total number of required evaluable cases of HZ 
have accrued and if the point estimates of vaccine efficacy is no more than 30% and 30% 
for the STM and HM populations, respectively, then the study may be stopped due to 
futility since the conditional power (probability of having a successful trial) at the end of 
study would be <1% based on the observed information.
If the HM portion of the study is terminated and the STM portion of the study continues 
based the first futility analysis, the enrollment for the STM portion of the study will be 
increased from to 2596 to 5836 to accrue 210 HZ cases.  If the STM portion of the study 
is terminated and the HM portion of the study continues based the first futility analysis,
the enrollment for HM study will be increased from 2568 to 6067 to accrue 328 HZ 
cases.  If the point estimate of the vaccine efficacy is no more than 30% in the HM 
interim futility analyses and the point estimate of the vaccine efficacy is no more than 
30% in the STM interim futility, then the whole study may be stopped, i.e. if the vaccine 
efficacy is lower than expected in both populations, the study will be stopped.
The second futility interim analysis will be done together with the formal interim efficacy 
analysis when at least 75% of the total number of required evaluable cases has accrued. 
Of note, the population for this second futility interim and formal interim efficacy 
analysis depends on the decision made at the first futility interim analysis. The second 
interim analyses will not be performed until the first interim analysis is completed on 
both populations.  The population for analysis can be (1) combined population (HM and 
STM) if both populations pass the futility check at interim; or (2) STM population alone 
if the HM portion of the study is terminated based on the futility interim analyses; or (3) 
HM population alone if the STM portion of the study is terminated based on the futility
interim analyses.  If  the combined HM and STM population moves forward, to ensure 
that there is sufficient information for each population for the secondary hypotheses in 
the event that the study stops early for overwhelming efficacy, a minimum of ~70% of 
the targeted number of HZ cases in each population is also required for the 2nd interim 
analysis. That is at least 174 cases in combined population (with a minimum of 64 and 95 
confirmed HZ cases in the STM and HM populations, respectively) is required for the 
second interim analysis. If the HM population only moves forward, at least 246 cases is 
required for second interim analysis. If  STM population only moves forward, at least 158 
cases is required for second interim analysis.
For the second futility analysis, a conditional power approach will be used similar to the 
first futility analysis. More specifically, when at least 75% of the total number of required
evaluable cases have accrued and if the point estimate of the vaccine efficacy is no more 
than 30%, then the study may be stopped due to futility since the conditional power 
(probability of having a successful trial) at the end of study would be <0.1% based on the 
observed information.

Product:  V212
Page 116
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
The purpose of the interim efficacy analysis is to terminate the study if overwhelming 
efficacy is shown. Both the results from the per-protocol population and the modified 
intent-to-treat population have to meet the early stopping criteria in order to end the study 
early.
To control the overall Type I error at two-sided 0.05 level for the combined study or on 
each individual subgroup population, Hwang, Shih and DeCani (gamma family) -
spending function [53] with the parameter γ = -3.5 will be used for the interim 
monitoring.  If
(1) the primary hypothesis is tested on HM and STM populations combined given the 
vaccine efficacy for both populations exceed the futility boundary at interim, the type 
I errors spent and the corresponding 2-sided symmetric boundaries computed for the 
2 looks are (0.02, 0.03) and (2.33, 2.02).  The corresponding 2-sided nominal 
significance levels are 0.02, 0.044, respectively.
(2) primary hypothesis is tested on a single subgroup population only given one subgroup 
fails at the futility check at interim, to control the overall Type I error at two-sided 
0.023 level for the individual population (HM subgroup or STM subgroup), then the 
type I errors spent and the corresponding 2-sided symmetric boundaries computed for 
the 2 looks are 0.009, 0.014 and 2.61, 2.33.  The corresponding 2-sided nominal 
significance levels are 0.009, and 0.020, respectively.
The lower bound of CIs for vaccine efficacy corresponding to these significance levels 
will be provided for study stopping criterion.
Of note, the 2nd interim analysis will not be performed until the 1st interim analysis is 
completed on both populations otherwise the decision on whether both populations 
should be moved forward could not have been made. To account for the potential change 
of information fraction, i.e. the second interim analysis might not occur at 75% 
information fraction, the test levels at the 2nd interim analysis and the final analysis will 
be adjusted.  This adjustment would be updated based on the real information fraction at 
the 2nd interim analysis using the alpha-spending function specified in the protocol so 
that the overall type I error rate of the study will be controlled as planned.
An unblinded SPONSOR statistician who is otherwise unrelated to this protocol will 
serve as a non-voting member of DMC and will be responsible for performing the 
required analyses. The DMC will monitor safety closely and will be responsible for 
reviewing the planned formal interim analyses results. The DMC may recommend 
stopping the study early based on successful interim efficacy analysis results or safety 
concerns.

Product:  V212
Page 117
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
At the interim efficacy look when at least 75% of the total expected events have accrued, 
the DMC will consider stopping the study early for efficacy if the lower bound of the 
specified CIs on VEHZ is > 25%; otherwise, the study will continue. If the study 
terminates early for the primary endpoint efficacy at the interim look, the adjusted point 
estimate, CI and p-value from the interim analysis for the vaccine efficacy for HZ (VEHZ) 
will be provided using stage-wise ordering [54, 55].
While the HZ cases will be monitored closely, at the time when the interim analysis 
actually occurs, the actual information might not be exactly the same as pre-specified as 
above. The corresponding type I error spent, 2-sided symmetric boundary and 2-sided 
nominal p-value to be used as the study stopping criteria at interim look will be updated 
with the actual information accordingly.
The power of the interim efficacy analysis depends upon the proportion of the required 
number of evaluable cases of HZ that is included in the analysis.  When at least 75% of 
the total number of required evaluable cases has accrued and satisfactory efficacy is 
shown, the study has adequate power to claim success. The power (probability of having 
a successful trial) would be >0.9 if the observed vaccine efficacy is 60% at interim 
efficacy analysis for combined (HM+STM) population given both subgroups pass the 
futility check at interim. The power would be >0.83 if the observed vaccine efficacy is 
60% at interim efficacy analysis for STM subgroup primary hypothesis is tested on HM 
subgroup population. The power would be >0.9 if the observed vaccine efficacy is 60% at 
interim efficacy analysis for HM subgroup given primary hypothesis is tested on HM 
subgroup population (Table 3-7).
Table 3-7
Power for Interim Efficacy Analysis at 75% Information Fraction
If primary hypothesis is tested on combined (HM+STM) population
Vaccine efficacy observed
VE=52%
VE=55%
VE=60%
Power
0.572
0.719
0.903
If primary hypothesis is tested on STM subgroup population
VE=55%
VE=60%
VE=65%
Power
0.603
0.828
0.956
If primary hypothesis is tested on HM subgroup population
VE=50%
VE=55%
VE=60%
Power
0.583
0.838
0.967
Table 3-8 lists the alpha spent, the critical value, and the nominal p-value for the analysis 
at the design stage. The values in this table will be updated based on the actual 
information from the data.

Product:  V212
Page 118
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Table 3-8
Critical Values and Other Related Parameters at the Interim Efficacy and Final Analyses
HM/STM combined study
Individual  population  HM/STM
if one subgroup population fails at 
interim
Alpha-spending 
Function
Hwang, Shih and DeCani
(gamma family) (γ = -3.5)
Hwang, Shih and DeCani
(gamma family) (γ = -3.5)
Time Point
1 (interim 
analysis)
2 (final 
analysis)
1 (interim analysis)
2 (final analysis)
Information 
Fraction (%)
75
100
75
100
Alpha Spent
0.02
0.03
0.009
0.014
Critical Value
2.33
2.02
2.61
2.33
2-sided Nominal p-
Value
0.02
0.044
0.0092
0.0196
Population 
Combined
STM
HM
STM
HM
Maximum numbers 
of cases allowed in 
the vaccine group
59
83
51
84
72
119
Minimum numbers 
of cases required in 
the placebo group
115
149
107
162
138
209
Estimated VEHZ
0.49
0.44
0.52
0.48
0.48
0.43
If the study terminates early for the primary endpoint efficacy at the interim look, the 
adjusted point estimate, CI and p-value from the interim analysis for VEHZ will be 
provided using stage-wise ordering [54, 55]. To evaluate the utility of the immune 
markers, the key immunogenicity endpoints will also be analyzed in the interim analysis 
according to the plan specified in Section 3.5.5.2. A CSR may be written and submitted 
to regulatory agencies based on the data available up to the time point of data frozen for 
the interim look. The decision to stop the study and end enrollment will be made by the 
Steering Committee, based on the recommendation of the DMC. 

Product:  V212
Page 119
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
In the event that the study terminates early at the interim analysis and the CSR is written 
for regulatory submission, for those patients that are still in their 1 year safety and 
efficacy follow-up or those HZ cases that are still in their 6-month follow-up at the time 
when the data was frozen for the interim analyses, the remaining endpoints will continue 
to be collected until the minimum 1 year postvaccination safety and efficacy follow-up is 
completed for all patients and all suspected HZ cases complete their 6-month follow-up. 
Data collected from the remaining study follow-up time and the corresponding analysis 
results will be provided in a supplemental summary document, as needed. Under this 
scenario, the SPONSOR personnel directly involved in the study, investigators, site 
personnel, clinical adjudicators, and patients will remain blinded until the end of the 
study (i.e., until final database lock), while a separate unblinded team of SPONSOR 
personnel not involved in the data review and data cleaning of the ongoing study will be 
responsible for authoring the CSR.

Product:  V212
Page 120
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
7. ATTACHMENTS
Merck Code of Conduct for Clinical Trials

Product:  V212
Page 121
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these 
trials in compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding 
concern in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with 
local and/or national regulations and in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of 
the party (parties) employed for their execution (e.g., contract research organizations, collaborative research 
efforts). This Code is not intended to apply to trials which are observational in nature, or which are retrospective. 
Further, this Code does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific 
purpose of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus 
source documentation according to standard operating procedures.  Per Merck policies and procedures, if 
fraud, misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When 
necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review committees 
notified and data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase 
or pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication 
of results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical 
issues of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able 
to defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 

Product:  V212
Page 122
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, 
except that changes required urgently to protect subject safety and well-being may be enacted in anticipation of 
IRB/ERC approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  
Potential subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.  Subjects are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed 
consent for participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their 
access to, or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to 
confidential medical records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized 
by an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives 
to enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may 
be made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or 
sponsoring institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC 
may wish to alter the wording of the disclosure statement to be consistent with financial practices at that 
institution.  As noted above, publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will 
be consistent with local guidelines and practices including, in the U.S., those established by the American 
Medical Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in 
signing the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."

Product:  V212
Page 123
Protocol/Amendment No.: 011-04
30-Jun-2015
Confidential
8. SIGNATURES
8.1
SPONSOR’S REPRESENTATIVE
TYPED NAME
SIGNATURE
DATE
8.2
INVESTIGATOR
I agree to conduct this clinical study in accordance with the design outlined in this 
protocol and to abide by all provisions of this protocol (including other manuals and 
documents referenced from this protocol); deviations from the protocol are acceptable 
only with a mutually agreed upon protocol amendment. I agree to conduct the study in 
accordance with generally accepted standards of Good Clinical Practice. I also agree to 
report all information or data in accordance with the protocol and, in particular, I agree to 
report any serious adverse experiences as defined in the SAFETY MEASUREMENTS 
section of this protocol. I also agree to handle all clinical supplies provided by the 
SPONSOR and collect and handle all clinical specimens in accordance with the protocol. 
I understand that information that identifies me will be used and disclosed as described in 
the protocol, and that such information may be transferred to countries that do not have 
laws protecting such information. Since the information in this protocol and the 
referenced Investigator’s brochure is confidential, I understand that its disclosure to any 
third parties, other than those involved in approval, supervision, or conduct of the study is 
prohibited. I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure, or access by third parties.
TYPED NAME
SIGNATURE
DATE