An Open-Label, Multicenter, Single-arm Study to Evaluate the Immunogenicity of VARIVAX™ in Healthy Russian Individuals 12 Months of Age and Older
Phase: PHASE3
Conditions: Varicella
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
An Open-Label, Multicenter, Single-arm Study to Evaluate 
the Immunogenicity of VARIVAX™ in Healthy Russian 
Individuals 12 Months of Age and Older
18 April 2019
NCT03843632

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Title Page
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., NJ, U.S.A. 
(MSD).
Protocol Title: An Open-Label, Multicenter, Single-arm Study to Evaluate the 
Immunogenicity of VARIVAX™ in Healthy Russian Individuals 12 Months of Age and 
Older
Protocol Number: 058-05
Compound Number: V210
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
0375
EudraCT
Not Applicable
Approval Date: 18 April 2019
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
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.
Typed Name:
Title:
Date
 
 
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Table of Contents
DOCUMENT HISTORY ......................................................................................................10
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................12
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................22
1.3
Schedule of Activities (SoA)................................................................................23
1.3.1
Schedule of Activities (SoA) for Adults 18-75 Years (Stage 1) and 
Adolescents 13-17 Years (Stage 2)..............................................................23
1.3.2
Schedule of Activities (SoA) for Children 12 Months to 12 Years of 
Age...............................................................................................................27
2
INTRODUCTION..........................................................................................................29
2.1
Study Rationale....................................................................................................29
2.2
Background ..........................................................................................................29
2.2.1
VARIVAX™and Varicella Disease ...........................................................30
2.2.2
Preclinical and Clinical Studies ...................................................................31
2.2.3
Ongoing Clinical Studies.............................................................................31
2.2.4
Information on Other Study-related Therapy ..............................................31
2.3
Benefit/Risk Assessment......................................................................................31
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................35
4.2.1
Rationale for Endpoints ...............................................................................35
4.2.1.1
Immunogenicity Endpoints................................................................35
4.2.1.2
Safety Endpoints................................................................................35
4.2.1.3
Future Biomedical Research..............................................................36
4.3
Justification for Dose...........................................................................................36
4.4
Beginning and End of Study Definition .............................................................36
4.4.1
Clinical Criteria for Early Study Termination .............................................37
5
STUDY POPULATION ................................................................................................37
5.1
Inclusion Criteria.................................................................................................37
5.2
Exclusion Criteria................................................................................................38
5.3
Lifestyle Considerations......................................................................................40
5.3.1
Vaccine Virus Transmission........................................................................40
5.4
Screen Failures.....................................................................................................40
5.5
Participant Replacement Strategy......................................................................40
 
 
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STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................41
6.2
Preparation/Handling/Storage/Accountability .................................................43
6.2.1
Dose Preparation..........................................................................................43
6.2.2
Handling, Storage, and Accountability........................................................43
6.2.3
Replacement Vials .......................................................................................44
6.3
Measures to Minimize Bias: Randomization and Blinding..............................44
6.3.1
Intervention Assignment..............................................................................44
6.3.2
Stratification.................................................................................................44
6.3.3
Blinding........................................................................................................44
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................45
6.5.1
Rescue Medications and Supportive Care ...................................................46
6.6
Dose Modification (Escalation/Titration/Other)...............................................46
6.7
Intervention After the End of the Study............................................................46
6.8
Clinical Supplies Disclosure................................................................................46
6.9
Standard Policies..................................................................................................46
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................47
7.1
Discontinuation of Study Intervention...............................................................47
7.2
Participant Withdrawal From the Study...........................................................47
7.3
Lost to Follow-up .................................................................................................48
8
STUDY ASSESSMENTS AND PROCEDURES........................................................48
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent/Assent.............................................................................50
8.1.1.1
General Informed Consent/Assent.....................................................50
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................51
8.1.2
Inclusion/Exclusion Criteria ........................................................................51
8.1.3
Participant Identification Card.....................................................................51
8.1.4
Medical History ...........................................................................................51
8.1.5
Prior and Concomitant Medications Review...............................................52
8.1.5.1
Prior Medications...............................................................................52
8.1.5.2
Concomitant Medications..................................................................52
8.1.6
Assignment of Screening Number...............................................................52
8.1.7
Assignment of Treatment/Randomization Number.....................................52
8.1.8
Study Intervention Administration ..............................................................52
8.1.8.1
Timing of Dose Administration.........................................................53
 
 
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8.1.9
Discontinuation and Withdrawal .................................................................54
8.1.9.1
Withdrawal From Future Biomedical Research ................................54
8.1.10
Participant Blinding/Unblinding..................................................................54
8.1.11
Calibration of Equipment.............................................................................54
8.2
Immunogenicity Assessments .............................................................................54
8.2.1
Immunogenicity (VZV) Antibody Sample..................................................55
8.2.2
Detection of IgG Antibody to VZV (gpELISA)..........................................55
8.3
Safety Assessments...............................................................................................56
8.3.1
Safety Assessments and Use of the VRC ....................................................56
8.3.2
Clinical Safety Laboratory Assessments .....................................................57
8.3.2.1
Serum or Urine Pregnancy Test.........................................................58
8.3.2.2
Laboratory Measurements – CBC, Chemistry and Urinalysis...........58
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................59
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................59
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......62
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...62
8.4.4
Regulatory Reporting Requirements for SAE .............................................62
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................62
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................63
8.4.7
Events of Clinical Interest (ECIs) ................................................................63
8.5
Definition and Treatment of Overdose ..............................................................63
8.6
Pharmacokinetics.................................................................................................64
8.7
Pharmacodynamics..............................................................................................64
8.8
Future Biomedical Research...............................................................................64
8.9
Planned Genetic Analysis Sample Collection....................................................64
8.10
Biomarkers ...........................................................................................................64
8.11
Health Economics Medical Resource Utilization and Health Economics.......65
8.12
Visit Requirements...............................................................................................65
8.12.1
Screening......................................................................................................65
8.12.2
Treatment Period/Vaccination Visit ............................................................65
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........65
8.12.4
Poststudy......................................................................................................65
9
STATISTICAL ANALYSIS PLAN .............................................................................65
9.1
Statistical Analysis Plan Summary.....................................................................66
There are no planned interim analyses for this study. ...........................................66
 
 
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No multiplicity adjustment is required for this study ............................................66
9.2
Responsibility for Analyses/In-house Blinding .................................................67
9.3
Hypotheses/Estimation ........................................................................................67
9.4
Analysis Endpoints...............................................................................................67
9.4.1
Immunogenicity Endpoints..........................................................................67
9.4.2
Safety Endpoints..........................................................................................68
9.5
Analysis Populations............................................................................................68
9.5.1
Immunogenicity Analysis Populations ........................................................68
9.5.2
Safety Analysis Population..........................................................................70
9.6
Statistical Methods...............................................................................................70
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................70
9.6.2
Statistical Methods for Safety Analyses ......................................................72
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................73
9.7
Interim Analyses ..................................................................................................73
9.8
Multiplicity ...........................................................................................................73
9.9
Sample Size and Power Calculations .................................................................74
9.9.1
Sample Size and Power for  Immunogenicity Analyses..............................74
9.9.2
Sample Size and Power for Safety Analyses ...............................................75
9.10
Subgroup Analyses...............................................................................................76
9.11
Compliance (Medication Adherence).................................................................76
9.12
Extent of Exposure...............................................................................................76
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................77
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........77
10.1.1
Code of Conduct for Clinical Trials.............................................................77
10.1.2
Financial Disclosure.....................................................................................79
10.1.3
Data Protection.............................................................................................79
10.1.3.1
Confidentiality of Data ......................................................................80
10.1.3.2
Confidentiality of Participant Records...............................................80
10.1.3.3
Confidentiality of IRB/IEC Information............................................80
10.1.4
Publication Policy........................................................................................80
10.1.5
Compliance with Study Registration and Results Posting Requirements ...81
10.1.6
Compliance with Law, Audit, and Debarment ............................................81
10.1.7
Data Quality Assurance ...............................................................................82
10.1.8
Source Documents .......................................................................................82
10.1.9
Study and Site Closure.................................................................................83
10.2
Appendix 2: Clinical Laboratory Tests..............................................................84
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................85
10.3.1
Definition of AE ..........................................................................................85
10.3.2
Definition of SAE ........................................................................................86
10.3.3
Additional Events Reported.........................................................................88
10.3.4
Recording AE and SAE ...............................................................................88
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................91
10.3.6
Assessment of Injection-Site Complaints or Reactions...............................92
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................99
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................100
10.5.1
Definitions..................................................................................................100
10.5.2
Contraception Requirements......................................................................101
10.5.3
Pregnancy Testing......................................................................................102
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................103
10.6.1
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff............................................................................108
10.7
Appendix 7: Country-specific Requirements..................................................119
10.8
Appendix 8: Abbreviations ...............................................................................120
11
REFERENCES.............................................................................................................122
 
 
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LIST OF TABLES
Table 1
Study Design for Adults and Adolescents/Children......................................34
Table 2
Study Interventions........................................................................................42
Table 3
Approximate Blood Drawn/Collected by Study Visit and by 
Sample Type – Participants 7 Years of Age and Older .................................49
Table 4
Approximate Blood Drawn/Collected by Study Visit and by 
Sample Type – Participants 12 Months to 6 Years of Age............................50
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.....................................................................61
Table 6
Primary Analysis Strategy for Immunogenicity Variables............................72
Table 7
Response Rates and Associated 95% CI Based on Different 
Sample Sizes of Per-Protocol Population ......................................................74
Table 8
Expected Precision of GMTs under Different Sample Sizes of Per-
Protocol Population........................................................................................75
Table 9
Estimate of Incidence of Vaccine-Related Serious Adverse Events 
and Upper Bound of 95% Confidence Interval Based on 
Hypothetical Number of Participants with Vaccine-Related Serious 
Adverse Events ..............................................................................................76
Table 10
Protocol-required Safety Laboratory Assessments........................................84
 
 
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LIST OF FIGURES
Figure 1
V210-058 Study Design.................................................................................22
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
V210-058-00
30-AUG-2012
Base protocol
V210-058-01
06-DEC-2012
The pregnancy/contraceptive follow-up 
period text was changed to be consistent 
with the Investigator Brochure and the 
Product Label.
V210-058-02
18-APR-2013
The study design was updated to include 
the enrollment targets by age groups and 
specified the primary immunogenicity and 
safety endpoints of the study.
Laboratory tests were added for 
participants 7 years of age and older.
 
 
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Document
Date of Issue
Overall Rationale
V210-058-03
Approved by the Document Review 
Committee on 20-APR-2015; however, the 
clinical study was put on hold before study 
start, by the Sponsor.
Approved by Document Review Committee 
2 on 07-JUN-2018, by the Late Stage 
Development Review Committee on 02-
JUL-2018, and by the Protocol Review 
Committee on 17-JUL-2018.
Resubmitted to the Russian Ministry of 
Health on 03-OCT-2018.
The title of the study was edited to remove 
“safety” and “tolerability”, in order to align 
with the study’s primary focus of 
immunogenicity, and secondary objective 
related to safety and tolerability.
The study design was revised to include an 
adult cohort with a target enrollment of 
50 participants. This cohort is referred to as 
Stage 1. Stage 2 would then enroll children 
and adolescents and follow sequentially 
after Stage 1. Additionally, the ages of 
children and adolescent participants in 
Stage 2 of the study were specified. 
V210-058-04
18-DEC-2018
Added an exclusion criterion to exclude 
participants who have (or their parents 
have) a documented human 
immunodeficiency virus (HIV) infection, 
untreated syphilis infection or viral 
hepatitis infection (Hepatitis B or C).
V210-058-05
18-APR-2019
The protocol content was formatted to 
align with the current version of the 
Common Protocol Template (CPT).
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
The primary reason for Protocol Amendment 5 was to align it with the current version of the Common Protocol Template (CPT).
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Various sections
Protocol content formatted to align with 
current version of the Common Protocol
Template. Sections have been reorganized
and new content has been added to 
Sections 10.2 and 10.8.
Authoring template updated to align with 
the new version (V4.0) of the Common 
Protocol Template.
1.2 Schema
Revised study diagram to present the 
study design by stage.
To separate Stage 1 participants (adults) 
from Stage 2 participants (adolescents and 
children).
 
 
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA)
Created separate SoAs for 
adolescents/adults and children.
To more clearly reflect the different 
assessments performed in 
adolescents/adults vs. children.
Added indication for temperature 
assessment prior to each vaccination.
To provide specificity for temperature 
measurement pre-vaccination.
Added review of prior/concomitant 
medications and non-study vaccination to 
final study visit. 
To correct an inadvertent omission.
Removed the collection of blood for 
complete blood count (CBC), chemistry, 
and the urinalysis sample at Visit 1 for 
participants <7 years of age.
To correct an inadvertent/incorrect entry. 
The CBC, chemistry and, urinalysis tests 
are only performed for participants 7 years 
of age and older.
2.2 Background
Updated number participants exposed 
during clinical studies with VARIVAX™.
To reflect clinical study data accrued since 
the last amendment.
2.2 Background and 2.3 Benefit/Risk 
Assessment
Updated number of VARIVAX™ doses 
distributed worldwide.
To update the number of VARIVAX™
doses distributed worldwide as of 
16-MAR-2018.
4.1 Overall Design and 5 Study Population
Clarified enrollment eligibility of 
participants with a negative clinical 
history for varicella and/or herpes zoster.
To accurately reflect enrollment by clinical 
history, rather than laboratory history 
(serological status).
 
 
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Section # and Name
Description of Change 
Brief Rationale 
4.1 Overall Design
Added mention of baseline blood sample 
collection for the evaluation of 
varicella-zoster virus (VZV) antibody 
responses prior to vaccination.
For clarity and to align with the Schedule 
of Activities (SoA).
5.1 Inclusion Criteria (Inclusion Criterion 
1)
Replaced “Be 12 months of age or older.” 
with “Be 12 months to 75 years of age 
(inclusive), at the time of signing the 
informed consent/assent form.”
For consistency with other sections of the 
protocol, which specify upper age limit 
eligible for enrollment at 75 years of age.
5.2 Exclusion Criteria 
Revised exclusion criterion 6: to also 
exclude study participants who live with a 
person who has any congenital or 
acquired immune deficiency, neoplastic 
disease, or depressed immunity.
To address potential risk of vaccine-type 
viral transmission to at-risk immediate 
contacts. 
8.4.7 Events of Clinical Interest (ECIs) and 
8.5 Definition and Treatment of Overdose
Revised the reporting timeframe for ECIs 
to the Sponsor from “within 24 hours” to 
“within 5 calendar days”.
To align with Patient Data Acquisition and 
Management - Next Generation 
requirements.
9.10 Subgroup Analyses
Added subgroup analyses for Stage 2 
portion of the study.
To include analysis by age and dosing 
schedule for Stage 2 participants.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
Various sections
Minor editorial and document formatting 
revisions.
To improve the clarity of the document.
Global terminology changes (eg, 
“subjects” to “participants”, “trial” to 
“study”, “violation” to “deviation”, 
“adverse experience” to “adverse event”, 
“parent/adoptive parent” to “participant’s 
legally acceptable representative”, 
“worksheets” to “case report 
forms/worksheets”).
Terminology changed in accordance with 
current Common Protocol Template.
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label, Multicenter, Single-arm Study to Evaluate the 
Immunogenicity of VARIVAX™ in Healthy Russian Individuals 12 Months of Age and 
Older
Short Title: Evaluation of the Immunogenicity of VARIVAX™in Healthy Russian 
Individuals
Acronym: V210-058
Hypotheses, Objectives, and Endpoints:
The following objectives and endpoints will be evaluated in Russian individuals 12 months 
to 75 years of age with a negative clinical history of varicella and/or herpes zoster. No formal 
hypotheses will be tested in the study.
 
 
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Primary Objectives
Primary Endpoints
Objective: To describe the immunogenicity 
of VARIVAX™ after:
- Two doses of VARIVAX™, given 6 weeks 
apart, in adults 18 to 75 years of age (Stage 
1).
- Two doses of VARIVAX™, given 6 weeks 
apart, in adolescents 13 to 17 years of age 
(Stage 2).
- One dose of VARIVAX™ in children 
12 months to 12 years of age (Stage 2).
Participants who are seronegative at baseline 
(baseline VZV antibody titer 
<1.25 gpELISA units/mL):
- Antibody response rate (percentage of 
participants with VZV antibody titer 
≥5 gpELISA units/mL at 6 weeks 
postvaccination for children and at 6 weeks 
postdose 2 for adolescents/adults).
- Geometric mean titers (GMTs) of VZV 
antibody as measured by gpELISA at 
6 weeks postvaccination for children and at 6 
weeks postdose 2 for adolescents/adults.
- VZV seroconversion rate (percentage of 
participants with VZV antibody titer 
≥1.25 gpELISA units/mL at 6 weeks 
postvaccination for children and at 6 weeks 
postdose 2 for adolescents/adults).
Participants who are seropositive at baseline 
(baseline VZV antibody titer ≥1.25 gpELISA 
units/mL):
- GMTs at Day 1 and 6 weeks 
postvaccination for children and at Day 1 and 
6 weeks postdose 2 for adolescents/adults.
- Geometric mean fold rise (GMFR) from 
Day 1 to 6 weeks postvaccination for 
children and from Day 1 to 6 weeks postdose 
2 for adolescents/adults.
- Percentage of participants with ≥4-fold rise 
in antibody titer from Day 1 to 6 weeks 
postvaccination for children and from Day 1 
to 6 weeks postdose 2 for adolescents/adults.
 
 
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Secondary Objectives
Secondary Endpoints
Objective: To summarize the safety and 
tolerability of VARIVAX™.
Following each vaccination with 
VARIVAX™:
- Solicited injection-site reactions (redness, 
swelling, and pain/tenderness) of any 
intensity or size from Day 1 through Day 5 
postvaccination. 
- Unsolicited injection-site adverse events 
from Day 1 through Day 42 postvaccination.
- Maximum reported temperature ≥39.0°C 
oral equivalent from Day 1 through Day 28 
postvaccination.
- Varicella-, and herpes zoster-like rashes 
occurring from Day 1 through Day 42 
postvaccination.
- Systemic adverse events from Day 1 
through Day 42 postvaccination. 
- Serious adverse events from Day 1 through 
Day 42 postvaccination.
Vaccine-related serious adverse events and 
death from Day 1 through the end of the 
study period (42 days following the last 
vaccination) for each participant.
A summary of blood and urine tests 
performed 3 days following each vaccination 
for participants 7 years of age and older.
 
 
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Active immunization for the prevention of varicella in
individuals 12 months of age and older
Population
Healthy individuals age 12 months to 75 years of age
Study Type
Interventional
Intervention Model
Single Arm
This is a multi-site study.
Type of Control
No control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 24 months from the time the first participant 
signs the informed consent/assent until the last participant’s 
last study-related telephone call or visit.
Number of Participants:
Approximately 150 participants will be allocated as described in Section 4.1.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Vaccination 
Regimen
Use
Stage 1: Adults 
(18 to 75 years 
of age)
VARIVAX™
Refer to 
product 
labeling
2 doses 
SC
2 doses given 
6 weeks apart 
(Day 1 and Day 
43 [+14])
Experimental
Stage 2: 
Adolescents 
(13 to 17 years 
of age)
VARIVAX™
Refer to 
product 
labeling
2 doses 
SC
2 doses given
6 weeks apart 
(Day 1 and Day 
43 [+14])
Experimental
Stage 2: 
Children (7 to 
12 years of 
age)
VARIVAX™
Refer to 
product 
labeling
Single dose 
SC
1 dose given on 
Day 1
Experimental
Stage 2: 
Children 
(12 months to 
6 years of age)
VARIVAX™
Refer to 
product 
labeling
Single dose 
SC
1 dose given on 
Day 1
Experimental
Abbreviations: Admin. = administration; SC = subcutaneous
Total 
Number
4 intervention groups: Stage 1 (adults 18 to 75 years), Stage 2 (adolescents 
13 to 17 years), Stage 2 (children 7 to 12 years), and Stage 2 (children 
12 months to 6 years)
Duration of 
Participation
Each participant who is 13 to 75 years of age (inclusive) will participate in 
the study for approximately 4 months, from the time the informed 
consent/assent form is signed through the final contact.
Each participant who is 12 months to 12 years of age (inclusive) will 
participate in the study for approximately 2 months, from the time the 
informed consent/assent form is signed through the final contact.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The study design is depicted in Figure 1.
*Visits 2 and 3 for children 12 months to 6 years of age occur at the same time as Visits 3 and 4, respectively, for participants 7 years of age and older.
Figure 1
V210-058 Study Design
 
 
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities (SoA) for Adults 18-75 Years (Stage 1) and Adolescents 13-17 Years (Stage 2)
Visit Number
1
2
3
4
5
6
7
Notes
Dose 1
Postdose 1
Dose 2
Postdose 2
Scheduled Day:
Day 1
Day 3 PD 1
Day 7 PD 1
Day 43 PD 1
Day 46 PD 1
Day 3 PD 2
Day 50 PD 1
Day 7 PD 2
Day 86 PD 1
Day 43 PD 2
Visit Window:
n/a
(+2 days)
(-2 days)
(+14 days)
(+2 days)
(-2 days)
(+14 days)
Administrative and General Procedures
Informed Consent
X
Consent must be 
obtained before 
any study 
procedures.
Informed Consent for FBR
X
Must be obtained 
before the 
collection of 
buccal swab 
DNA samples.
Assignment of Screening 
Number
X
Inclusion/Exclusion Criteria
X
Participant Identification 
Card
X
Temperature Assessment
X
X
Should be
performed
prevaccination.
Medical History 
X
Prior/Concomitant 
Medication and Non-Study 
Vaccination Review
X
X
X
Assignment of Treatment 
Number
X
 
 
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Visit Number
1
2
3
4
5
6
7
Notes
Dose 1
Postdose 1
Dose 2
Postdose 2
Scheduled Day:
Day 1
Day 3 PD 1
Day 7 PD 1
Day 43 PD 1
Day 46 PD 1
Day 3 PD 2
Day 50 PD 1
Day 7 PD 2
Day 86 PD 1
Day 43 PD 2
Visit Window:
n/a
(+2 days)
(-2 days)
(+14 days)
(+2 days)
(-2 days)
(+14 days)
VARIVAX™ 
Administration 
X
X
Review all 
eligibility 
criteria prior to 
vaccination.
Distribute Vaccination 
Report Card (VRC)
X
X
Use ruler and 
thermometer 
provided.
Educate Participants on the 
Definition and Reporting of 
SAEs
X
Immunogenicity Procedures
Blood Sample for 
Immunogenicity Testing
X
X
Blood samples 
must be 
collected 
before 
vaccination. 
Safety Procedures
Pregnancy Test (WOCBP 
only)
X
X
Performed by 
site/local 
laboratory.
Must have 
negative results 
prior to 
vaccination.
Blood for CBC and 
Chemistry
X
X
X
Visits 2 and 3 
may be 
combined.
Visits 5 and 6 
may be 
combined.
 
 
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Visit Number
1
2
3
4
5
6
7
Notes
Dose 1
Postdose 1
Dose 2
Postdose 2
Scheduled Day:
Day 1
Day 3 PD 1
Day 7 PD 1
Day 43 PD 1
Day 46 PD 1
Day 3 PD 2
Day 50 PD 1
Day 7 PD 2
Day 86 PD 1
Day 43 PD 2
Visit Window:
n/a
(+2 days)
(-2 days)
(+14 days)
(+2 days)
(-2 days)
(+14 days)
Urinalysis Sample
X
X
X
Visits 2 and 3 
may be 
combined.
Visits 5 and 6 
may be 
combined.
30-Minute Postvaccination 
Observation Period
X
X
Review VRC 
X
X
X
X
Includes 
varicella- and 
herpes-like 
rashes 
reporting. 
Refer to 
Section 8.3.1.
Review AEs and SAEs
X
X
X
X
 
 
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Visit Number
1
2
3
4
5
6
7
Notes
Dose 1
Postdose 1
Dose 2
Postdose 2
Scheduled Day:
Day 1
Day 3 PD 1
Day 7 PD 1
Day 43 PD 1
Day 46 PD 1
Day 3 PD 2
Day 50 PD 1
Day 7 PD 2
Day 86 PD 1
Day 43 PD 2
Visit Window:
n/a
(+2 days)
(-2 days)
(+14 days)
(+2 days)
(-2 days)
(+14 days)
Future Biomedical Research
Buccal Swab Samples for 
FBR
X
Should be 
collected prior 
to vaccination, 
on Day 1, from
enrolled 
participants 
who provide 
FBR consent 
only, or at a 
later date as 
soon as the 
informed 
consent is 
obtained.
AE = adverse event; CBC = complete blood count; DNA = deoxyribonucleic acid; FBR = future biomedical research; PD = postdose; SAE = serious adverse 
event; VRC = Vaccination Report Card; WOCBP = women of childbearing potential
 
 
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1.3.2
Schedule of Activities (SoA) for Children 12 Months to 12 Years of Age
Visit Number
1
2
3
4
Notes
Vaccination
Postvaccination
Scheduled Day and Window:
Day 1
Day 3
(+2 days)
Day 7
(-2 days)
Day 43 
(+14 days)
Administrative and General Procedures
Informed Consent
X
Consent must be 
obtained before any 
study procedures. 
Informed Consent for FBR
X
Must be obtained before 
the collection of buccal 
swab DNA samples.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Temperature Assessment
X
Should be performed 
prevaccination
Medical History
X
Prior/Concomitant Medication Review
X
X
Assignment of Treatment Number
X
VARIVAX™ Administration 
X
Review all eligibility 
criteria prior to 
vaccination.
Distribute Vaccination Report Card 
(VRC)
X
Use ruler and 
thermometer provided.
Educate Participants on the Definition 
and Reporting of SAEs
X
Immunogenicity Procedures
Blood Sample for Immunogenicity 
Testing
X
X
Blood samples must be 
collected before 
vaccination.
 
 
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Visit Number
1
2
3
4
Notes
Vaccination
Postvaccination
Scheduled Day and Window:
Day 1
Day 3
(+2 days)
Day 7
(-2 days)
Day 43 
(+14 days)
Administrative and General Procedures
Safety Procedures
Blood for CBC and Chemistry
X
X
Participants 7 years of 
age and older ONLY. 
Visits 2 and 3 may be 
combined.
Urinalysis Sample
X
X
Participants 7 years of 
age and older ONLY.
Visits 2 and 3 may be
combined.
Postvaccination Observation Period
X
Observe children 
<3 years of age for at 
least 60 minutes; 
children ≥3 years of age 
for at least 30 minutes.
Review VRC 
X
X
Includes varicella- and 
herpes-like rashes 
reporting. Refer to 
Section 8.3.1
Review AEs and SAEs
X
X
Future Biomedical Research
Buccal Swab Samples for FBR Research
X
Should be collected prior 
to vaccination, on Day 1, 
from enrolled
participants who provide 
FBR consent only, or at 
a later date as soon as the 
informed consent is 
obtained.
AE = adverse event; CBC = complete blood count; DNA = deoxyribonucleic acid; FBR = future biomedical research; SAE = serious adverse event; VRC = 
Vaccination Report Card.
 
 
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2
INTRODUCTION
VARIVAX™is a live-attenuated vaccine indicated for the prevention of varicella in 
individuals 12 months of age and older.
2.1
Study Rationale
VARIVAX™ is not currently licensed in Russia. This is an open-label, multicenter, single-
arm bridging study to evaluate the immunogenicity of VARIVAX™in healthy Russian 
individuals. The study will enroll eligible individuals, 12 months through 75 years of age, 
which represents the age range for which a license is sought.
2.2
Background
The long-standing VARIVAX™ clinical development program has demonstrated 
VARIVAX™to be highly immunogenic in healthy children, adolescents, and adults within 
6 weeks after the recommended number of injections (1 injection for healthy children and 
2 injections 4 to 8 weeks apart for healthy adolescents and adults). An optional 2-dose 
regimen of VARIVAX™in children 12 months to 12 years of age induces higher 
varicella-zoster virus (VZV) antibody responses postvaccination compared with a 1-dose 
regimen, as measured by the percentage of participants with VZV antibody titers ≥5 
glycoprotein antigen-based enzyme-linked immunosorbent assay (gpELISA) units/mL and
geometric mean titers (GMTs). A second dose of VARIVAX™induces a strong VZV 
antibody response, whether given 3 months or 3 to 6 years after the first dose. VZV 
antibodies persist in a very high proportion of healthy children, adults, and adolescents for at 
least 10 years after vaccination with the recommended number of injections (1 or 2 injections 
for healthy children and 2 injections 4 to 8 weeks apart for healthy adolescents and adults).
Long-term follow-up of vaccinees for up to 15 years has shown that low varicella 
breakthrough rates are maintained, suggesting that the protection afforded by the vaccine is 
durable [Ray, P., et al 2010][Saddier, P., et al 2009]. Epidemiologic studies in the US and 
other countries, conducted since VARIVAX™ licensure, have shown that varicella incidence 
rates are declining in children and adolescents regardless of vaccination status and that 
herpes zoster rates are no higher in vaccinated children compared with children with previous 
wild-type infection.
More than 49 studies have been conducted with VARIVAX™. In these clinical studies, 
VARIVAX™ has been administered to 28,772 participants, including 11,648 healthy 
children and 3257 healthy adolescents and adults who received only VARIVAX™ and 
13,867 children who received VARIVAX™ concomitantly with other pediatric vaccines. 
VARIVAX™ was generally well tolerated. In a double-blind placebo-controlled study 
among 956 healthy children and adolescents, 914 of whom were serologically confirmed to 
be susceptible to varicella, the only adverse reactions that occurred at a significantly greater 
rate in vaccine recipients than in placebo recipients were pain and redness at the injection site 
and varicella-like rash. 
 
 
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The safety results from the Phase 1 to 3 clinical studies are supported by the results of a large 
postmarketing study, which did not identify any significant vaccine-related adverse events 
(AEs) in more than 89,000 vaccinees, and by extensive postmarketing safety surveillance, 
which has not identified new safety signals, with approximately 226 million doses of 
VARIVAX™ distributed as of 16-MAR-2018. To date, VARIVAX™ has been licensed in 
over 60 countries, including countries in Europe and Asia. There is no evidence suggesting 
the response profile to VARIVAX™ differs across nationalities or ethnic groups.
In summary, vaccination with VARIVAX™has been demonstrated to be highly efficacious 
against varicella infection, highly immunogenic, and generally well tolerated. The
postmarketing safety profile continues to support the positive benefit/risk ratio of the 
vaccine.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on VARIVAX™.
2.2.1
VARIVAX™and Varicella Disease
Varicella is a generalized illness with an incubation period of about 12 to 16 days, is highly 
contagious, and is characterized by a generalized, papulovesicular rash which typically 
resolves in 5 to 6 days. The most common complications of varicella include secondary 
bacterial infection, encephalitis, Reye syndrome, pneumonia, and death. Less common 
complications include nephritis, arthritis, orchitis, uveitis, thrombocytopenia, and purpura 
fulminans. Although immunity following varicella infection is generally long-lasting, the 
virus may persist in latent form in the peripheral nerve tissue (ganglia). Herpes zoster (or 
shingles) may develop as a result of the reactivation of latent VZV.
Before the introduction of a varicella vaccine (VARIVAX™), an estimated 4 million cases of 
varicella occurred annually in the United States (US) [Wharton, M. 1996], resulting in
10,000 yearly hospitalizations and over 100 deaths [Galil, K., et al 2002][Meyer, P. A., et al 
2000]. VARIVAX™ was licensed in 1995 on the basis of studies that demonstrated single-
dose efficacy of 70% to 95% against clinical disease and 95% against severe disease over
a 7- to 10-year follow-up period [Kuter, B. J., et al 1991]. Following licensure, vaccine
coverage has increased to an estimated 90% of the pediatric population in the US [Guris, 
D., et al 2008][Luman, Elizabeth T., et al 2006], reducing varicella incidence by up to 91%
[Guris, D., et al 2008], and varicella-related hospitalizations by 75% to 88% [Zhou, 
Fangjun, et al 2005][Centers for Disease Control and Prevention, et al 2007]. During the
first 12 years following licensure of VARIVAX™in the US, the incidence of varicella-
related mortality was reduced by 88%, including a 97% reduction in individuals under
20 years of age and a 96% reduction in individuals under 50 years of age [Marin, M., et al 
2011]. Recent epidemiologic studies have demonstrated VARIVAX™affords long-term 
protection over 15 years against varicella, and also imparts herd immunity to unvaccinated 
individuals in settings where vaccine adoption is widespread [Post-Licensure Studies to 
Evaluate the... 2010].
 
 
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2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on preclinical and clinical studies conducted with 
VARIVAX™.
2.2.3
Ongoing Clinical Studies
Refer to the IB for information on ongoing studies with VARIVAX™.
2.2.4
Information on Other Study-related Therapy
Refer to the IB for VARIVAX™.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
In the VARIVAX™clinical development program, a single dose of VARIVAX™has been 
shown to be highly efficacious in the prevention of varicella in children 12 years of age by 
multiple, complementary methods, including a placebo-controlled study, evaluation of the 
varicella attack rate following household exposure, and long-term follow-up of vaccinated 
cohorts in comparison to historical controls. Postvaccination breakthrough cases of varicella 
were significantly milder than wild-type disease. Studies with 2 doses of VARIVAX™
demonstrated a significant increase in vaccine efficacy as compared with a 1-dose regimen, 
regardless of whether the 2 doses were administered 3 months or 3 to 6 years apart. Although 
it is more difficult to estimate vaccine efficacy in adolescents/adults, administration of 
2 doses of VARIVAX™4 to 8 weeks apart is associated with very low rates of 
postvaccination breakthrough disease and protection against household exposure to varicella. 
The data from the clinical development program are supported by postmarketing studies of 
vaccine effectiveness.
With approximately 226 million marketed doses of VARIVAX™distributed worldwide 
from market introduction to 16-MAR-2018, the postmarketing safety profile continues to 
support the positive benefit/risk ratio of the vaccine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The following objectives and endpoints will be evaluated in Russian individuals 12 months 
to 75 years of age with a negative clinical history of varicella and/or herpes zoster. No formal 
hypotheses will be tested in the study.
 
 
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Objectives
Endpoints
Primary
Objective: To describe the 
immunogenicity of VARIVAX™
after:
•
Two doses of VARIVAX™,
given 6 weeks apart, in
adults 18 to 75 years of age 
(Stage 1).
•
Two doses of VARIVAX™,
given 6 weeks apart, in
adolescents 13 to 17 years
of age (Stage 2).
•
One dose of VARIVAX™
in children 12 months to 12
years of age (Stage 2).
Participants who are seronegative at baseline (baseline 
VZV antibody titer <1.25 gpELISA units/mL):
•
Antibody response rate (percentage of participants
with VZV antibody titer ≥5 gpELISA units/mL at 
6 weeks postvaccination for children and at
6 weeks postdose 2 for adolescents/adults).
•
Geometric mean titers (GMTs) of VZV antibody 
as measured by gpELISA at 6 weeks 
postvaccination for children and at 6 weeks 
postdose 2 for adolescents/adults.
•
VZV seroconversion rate (percentage of
participants with VZV antibody titer
≥1.25 gpELISA units/mL at 6 weeks 
postvaccination for children and at 6 weeks 
postdose 2 for adolescents/adults).
Participants who are seropositive at baseline (baseline
VZV antibody titer ≥1.25 gpELISA units/mL):
•
GMTs at Day 1 and 6 weeks postvaccination for 
children and at Day 1 and 6 weeks postdose 2 for 
adolescents/adults.
•
Geometric mean fold rise (GMFR) from Day 1 to
6 weeks postvaccination for children and from 
Day 1 to 6 weeks postdose 2 for
adolescents/adults.
•
Percentage of participants with ≥4-fold rise in
antibody titer from Day 1 to 6 weeks 
postvaccination for children and from Day 1 to
6 weeks postdose 2 for adolescents/adults.
 
 
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Secondary
Objective: To summarize the safety 
and tolerability of VARIVAX™.
Following each vaccination with VARIVAX™:
•
Solicited injection-site reactions (redness, 
swelling, and pain/tenderness) of any intensity or
size from Day 1 through Day 5 postvaccination.
•
Unsolicited injection-site adverse events from 
Day 1 through Day 42 postvaccination.
•
Maximum reported temperature ≥39.0°C oral 
equivalent from Day 1 through Day 28
postvaccination.
•
Varicella-, and herpes zoster-like rashes occurring 
from Day 1 through Day 42 postvaccination.
•
Systemic adverse events from Day 1 through
Day 42 postvaccination.
•
Serious adverse events from Day 1 through Day 42
postvaccination.
Vaccine-related serious adverse events and death from
Day 1 through the end of the study period (42 days 
following the last vaccination) for each participant.
A summary of blood and urine tests performed 3 days
following each vaccination for participants 7 years of 
age and older.
4
STUDY DESIGN
4.1
Overall Design
This is an open-label, multicenter, single-arm bridging study to evaluate the immunogenicity 
of VARIVAX™ in healthy Russian individuals. This study will be conducted as a staged
approach as outlined in Table 1, with approximately 150 participants. Participants 12 months 
of age to 75 years of age (inclusive) with a negative clinical history of varicella (ie, history of 
a generalized, pruritic, papulovesicular rash, often associated with fever) and/or herpes zoster
(painful, dermatomal, papulovesicular rash), are eligible for enrollment in the study.
 
 
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Note: The Stage 1 portion of the study will be conducted and completed first. The Stage 2 
portion of the study will commence once an acceptable document for the Stage 1 portion of 
the study, such as a Clinical Study Report (CSR), has been submitted to the Russian Ministry 
of Health.
Enrollment will end when the minimum enrollment is attained for each age group as 
indicated in Table 1. For Stage 2, a minimum of 30 participants will be enrolled per age 
group, for a total of 100 participants overall. 
Table 1
Study Design for Adults and Adolescents/Children  
Intervention
Groups
Target
(Approximate) 
Enrollment (n)
VARIVAX™
Vaccination(s)
Duration
(from first visit 
to last contact)
Stage 1 (n=50)
Adults 18 to 75 years of age
50
2 doses given 
~6 weeks apart
4 months
Stage 2 (n=100)
Adolescents 13 to 17 years of age
Minimum 30
2 doses given 
~6 weeks apart
4 months
Children 7 to 12 years of age
Minimum 30
1 dose
2 months
Children 12 months to 6 years of age
Minimum 30
1 dose
2 months
Serum samples will be obtained for evaluation of VZV antibody responses by gpELISA at 
baseline (Visit 1, prevaccination) and at 6 weeks following the last study vaccination
(postvaccination for children 12 months to 12 years of age, and postdose 2 for 
adolescents/adults 13 to 75 years of age).
All participants will be followed for safety for 6 weeks (42 days) following each vaccination.
For participants 7 years of age and older, blood samples for complete blood count (CBC) and
blood chemistry and a urine sample for urinalysis will be collected prior to vaccination 
(Visit 1) and 3 days after each vaccination.
In addition, injection-site reactions and general AEs will be evaluated for all participants by
an investigator or qualified designee 7 days (-2 days) after each vaccination.
A participant is considered to have completed the study when (1) has received the scheduled 
number of study vaccinations (1 dose for children or 2 doses for adolescents/adults), (2) all 
blood samples for the immunogenicity assessment have been collected, and (3) the 42-day
safety data post each vaccination have been collected.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
 
 
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4.2
Scientific Rationale for Study Design
VARIVAX™ is not currently licensed in Russia. This study will describe the safety, 
tolerability and immunogenicity of VARIVAX™in healthy Russian individuals, 12 months 
through 75 years of age, which represents the age range for which a license is sought. The 
purpose of this study is to generate sufficient clinical data for VARIVAX™ in the Russian 
population in order to demonstrate generalizability of the large amount of existing 
VARIVAX™ clinical data to the Russian population.
The study will be conducted as a staged approach study (2 stages): 
Stage 1 participants are adults (n=50) with the age range of 18 years to 75 years (inclusive).
To ensure the age of the participants is well distributed across all age groups, the target 
enrollment of Stage 2 participants (n=100 total) will be as follows:

Adolescent 13 to 17 years of age (minimum 30)

Children 7 to 12 years of age (minimum 30)

Children 12 months to 6 years of age (minimum 30)
As described below, the dose regimen, immunogenicity endpoints, and safety endpoints 
utilized in this study are consistent with those of past VARIVAX™ clinical studies. This will 
allow comparisons to existing global data, in order to bridge the safety, tolerability and 
immunogenicity of VARIVAX™ observed in global clinical studies to the Russian 
population.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
VZV seroconversion rates (measured by gpELISA), antibody response rates, and GMTs will 
be the primary endpoints of this study. These immunogenicity endpoints are consistent with 
those used in previous clinical studies of VARIVAX™. The primary time points for the 
immunogenicity analyses are 6 weeks postvaccination for children and 6 weeks postdose 2 
for adolescents and adults, following completion of the indicated vaccination regimen for 
each age group.
4.2.1.2
Safety Endpoints
Clinical AEs defined in Section 3.0, which include solicited injection-site reactions, 
unsolicited injection-site AEs, serious adverse events (SAEs), and vaccine-related SAEs, will 
be the safety endpoints of this study. These safety endpoints are consistent with the labeled 
safety profile of VARIVAX™ in the US and European Union (EU), and with the safety 
endpoints used in previous clinical studies of VARIVAX™.
 
 
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4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on buccal swab deoxyribonucleic acid 
(DNA) specimens and serum specimens collected during the study. This research may 
include genetic analyses (DNA), gene expression profiling (ribonucleic acid [RNA]), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic (PGt) studies may be performed if significant 
pharmacokinetic/pharmacodynamic relationships are observed or AEs are identified. 
Genomic markers of disease may also be investigated. Such retrospective pharmacogenetic 
studies will be conducted with appropriate biostatistical design and analysis and compared to 
pharmacokinetic/pharmacodynamic results or clinical outcomes. Any significant PGt 
relationships to outcome would require validation in future clinical studies. The overarching 
goal is to use such information to develop safer, more effective drugs/vaccines, and/or to
ensure that participants receive the correct dose of the correct drug/vaccine at the correct 
time. The details of this future biomedical research substudy are presented in Appendix 6.
Additional informational material for Institutional Review Boards/Independent Ethics 
Committees (IRBs/IECs) and investigational site staff is provided in Section 10.6.1.
4.3
Justification for Dose
In the US and EU, VARIVAX™ is indicated for active immunization for the prevention of 
varicella in individuals 12 months of age and older. VARIVAX™ is administered as a 
0.5-mL subcutaneous dose, which is comprised of a minimum 1350 Plaque Forming Units 
(PFU).
In this study, 1 dose of VARIVAX™ will be administered to children 12 months to 12 years 
of age. Two doses of VARIVAX™ will be administered 6 weeks apart to adolescents and 
adults (13 to 75 years of age), as VARIVAX™ is less immunogenic in these age groups 
[Kuter, Barbara J., et al 1995].
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form. 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).
 
 
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the benefit/risk ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at particular study
sites may be stopped due to insufficient compliance with the protocol, Good Clinical Practice 
(GCP) and/or other applicable regulatory requirements, procedure-related problems or the 
number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Healthy male and female participants with a negative clinical history of varicella and/or 
herpes zoster who are 12 months to 75 years of age (inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
In order to be eligible for the study, the participant must:
1. Be 12 months to 75 years of age (inclusive), at the time of signing the informed 
consent/assent form.
2. Be in good health based on medical history (physical examination is not required).
3. Have a negative clinical history for varicella and herpes zoster.
Female participants of reproductive potential must:
4. Have a negative serum pregnancy test or urine pregnancy test (sensitive to 25 mIU/mL 
beta human chorionic gonadotropin [β-hCG]) prior to each study vaccination (on the day 
the participant is vaccinated and before vaccine is administered).
5. Agree to remain abstinent, or use (or have their partner use) 2 acceptable methods of birth 
control. Abstinence or 2 acceptable methods of birth control must be practiced or used 
from the day of enrollment, throughout the duration of the study, and continued until 3 
months following the last study vaccination. In areas where abstinence is not a locally 
acceptable method of contraception, 2 acceptable methods of birth control must be used 
through 3 months following the last study vaccination. An acceptable method of birth 
control is defined as: intrauterine device (IUD), oral contraception, diaphragm with 
spermicide, contraceptive sponge, condom, vasectomy.
Note: Female participants who are not of reproductive potential are eligible for the study 
without the use of contraceptives or pregnancy test. Female participants who are not of 
reproductive potential are defined as those who either (1) have not reached menarche; (2) 
have undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; or (3) 
 
 
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have reached menopause. Menopausal is defined as 1) no menses for >1 year but <3 
years and confirmed by follicle stimulating hormone (FSH) levels elevated into the 
postmenopausal range, or 2) no menses for at least 3 years.
The participant OR the participant’s legally acceptable representative must:
6. Understand the study procedures, alternative treatments available, and risks involved with 
the study, and voluntarily agrees to participate by giving written informed consent. 
7. Provide consent for future biomedical research. However, enrollees may participate in the 
main study without participating in future biomedical research.
8. Be able to read, understand, and complete study questionnaires (eg, Vaccination Report 
Card [VRC]).
9. Be able to complete all scheduled visits and comply with the study procedures.
5.2
Exclusion Criteria
The participant must be excluded from the study if he/she:
1.
Has a history of allergy or anaphylactic reaction to neomycin, gelatin, or any 
component of VARIVAX™ as listed in the IB.
2.
Has received vaccination with any varicella or herpes zoster vaccine in either 
monovalent or combination form at any time prior to the study or is anticipated to 
receive one of these vaccines during the study.
3.
Has received immune globulin, a blood transfusion or blood-derived products (does not 
include autologous blood/blood products) within 5 months prior to vaccination or plans 
to receive while enrolled in this study.
4.
*Has received salicylates (eg, aspirin or any aspirin-containing products) within 
14 days prior to vaccination.
5.
*Has had an exposure to varicella or herpes zoster in the last 4 weeks prior to the study 
vaccination involving:
1) Continuous household contact, or
2) Playmate contact, (generally >1 hour of play indoors) or
3) Hospital contact (in the same 2- to 4-bed room or in adjacent beds in a large ward or 
prolonged face-to-face contact with an infectious staff member or patient), or
4) Contact with a newborn whose mother had onset of chickenpox 5 days or less 
before delivery or within 48 hours after delivery.
 
 
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6.
Has, or lives with a person who has, any congenital or acquired immune deficiency, 
neoplastic disease, or depressed immunity, including those resulting from corticosteroid 
use (see Exclusion Criterion #8 and Section 6.5 Concomitant Therapy) or other 
immunosuppressive therapy.
7.
Has, or his/her mother or father has, a documented human immunodeficiency virus 
(HIV) infection, untreated syphilis infection, or viral hepatitis infection (Hepatitis B or
Hepatitis C).
8.
Has received 1) corticosteroids (systemic immunomodulatory steroids) (greater than the 
equivalent of 2 mg/kg total daily dose of prednisone [children] or greater than the 
equivalent of 20 mg total daily dose of prednisone [adolescents/adults]) for more than 5 
consecutive days within 3 months prior to entering study, or 2) any dose of 
corticosteroids within 7 days prior to entering study, or 3) is expected to require 
corticosteroids (greater than 2 mg/kg total daily dose of prednisone [children] or greater 
than the equivalent of 20 mg total daily dose of prednisone [adolescents/adults] through 
the course of the study. 
Exception:  Participants using non-systemic corticosteroids (eg, topical, ophthalmic, 
and inhaled) will be eligible for vaccination.
9.
*Was vaccinated with a licensed, non-live vaccine (eg, Inactivated Poliovirus [IPV], 
Diphtheria, Tetanus, and Acellular Pertussis [DTaP], Haemophilus influenzae type b 
[Hib]) 30 days or less prior to vaccination or expected during the 42-day safety follow-
up period postvaccination.
10.
*Was vaccinated with any licensed live vaccine 30 days or less prior to any dose of the 
study vaccines or expected within the 42-day safety follow-up period postvaccination.
11.
*Has a recent (<72 hours) febrile illness 38.9C oral equivalent) prior to the study 
vaccination. Temperature may be converted to oral equivalent by adding 0.6C to 
axillary temperatures and subtracting 0.6C from rectal temperatures.
12.
Is currently participating in (30 days or less prior to enrollment) or scheduled to 
participate in any other clinical study other than a surveillance study during the planned 
study period for this study.
13.
Has any other underlying medical condition that, in the opinion of the investigator, may 
interfere with the evaluation of study objectives.
14.
Is pregnant or nursing. 
15.
Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this study.
(If a participant meets any of the exclusion criteria marked with an asterisk (*), the Day 1 
visit may be rescheduled for a time when these criteria are no longer met.)
 
 
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5.3
Lifestyle Considerations
No special restrictions on diet or activity apply.
5.3.1
Vaccine Virus Transmission
Postmarketing experience with VARIVAX™ suggests that the varicella vaccine virus may 
rarely be transferred between healthy people who were vaccinated and developed a 
chickenpox-like rash, and healthy people who are not immune to chickenpox (those who 
have not had chickenpox, or the vaccine for chickenpox). Transfer of vaccine virus from 
people who were vaccinated and did not have a chickenpox-like rash has been reported. 
Therefore, vaccine recipients should attempt to avoid close contact with high-risk individuals 
who are not immune to chickenpox for up to 42 days after vaccination with VARIVAX™. In 
circumstances where contact with high-risk individuals cannot be avoided, the potential risk 
of transfer of vaccine virus should be weighed against the risk of getting and spreading 
natural chickenpox virus. Individuals with high-risk include:
1. Individuals with poor immune systems (such as individuals with leukemia, lymphoma, or 
HIV);
2. Pregnant women without documented history of chickenpox or laboratory evidence of 
prior infection;
3. Newborn infants of mothers without a documented history of chickenpox or laboratory 
evidence of prior infection and all newborn infants born at <28 weeks gestation 
regardless of maternal varicella immunity.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from vaccination OR withdraws from the study will not be 
replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
 
 
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Clinical supplies provided by the Sponsor will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
Open-label, single-dose vials of VARIVAX™ and Sterile Diluent for reconstitution will be 
supplied to the clinical sites. No participant-specific kitting is required.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
 
 
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Table 2
Study Interventions
Arm
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength
Dosage 
Level(s)
Route of 
Administration
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
1
Experimental
Varicella Virus 
Vaccine Live
Biological
/Vaccine
Sterile 
Suspension
after 
reconstitution
Refer to 
product 
labeling
0.5 mL
Subcutaneous
Adults 18-75 
years of age and 
adolescents 13-17 
years of age:
2 doses ~6 weeks 
apart
---------------------
Children 12 
months to 12 
years of age: 
1 dose 
Experimental
IMP
Provided 
centrally by 
the Sponsor
1
Experimental
Sterile Diluent 
for 
Reconstitution 
of Merck Live 
Virus Vaccines 
(Sterile Water)
Biological
/Vaccine
Sterile Solution 
for 
Reconstitution
N/A
0.7 mL
Subcutaneous
N/A
Experimental
IMP
Provided 
centrally by 
the Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional and/or 
Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Varicella Virus Vaccine Live = VARIVAX™
 
 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
The designated study site personnel will reconstitute the study vaccine using only the diluent 
provided by the Sponsor. The diluent for the vaccine is sterile distilled water and contains no 
preservatives or other substances that might inactivate 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 and gently swirl to mix thoroughly. 
Withdraw the entire contents into the syringe and inject the total volume (approximately
0.5 mL) of reconstituted vaccine subcutaneously (refer to Section 8.1.8 - Study Intervention 
Administration). Reconstituted vaccine should be administered within 30 minutes of removal 
from refrigerator.
Do not freeze reconstituted vaccine.
CAUTION: Sterile syringe should be free of preservatives, antiseptics, and detergents as 
these substances may inactivate the vaccine virus.
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
 
 
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For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.2.3
Replacement Vials
A replacement vial of vaccine will be needed if an error is made in reconstituting the vaccine, 
if the reconstituted vaccine is not administered within 30 minutes of removal from the 
refrigerator, or if a vial of vaccine is accidentally destroyed or improperly handled. In this
event, a small quantity of additional vials will also be available as replacement supplies. 
Complete and accurate information about these events must be reported and documented on 
the vaccine accountability log. The original treatment/randomization number assigned to the 
participant will not be changed. The original vial designated for use must be explained on the 
Clinical Supplies Return Form in the Administrative Binder.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
Minimum target enrollment by age group is presented in Table 1.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the vaccine administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
 
 
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6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (see Section 5.2 for details). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
All medications administered from 14 days prior to study vaccination until 42 days following 
each study vaccination should be recorded on the appropriate case report form(s) (CRFs) or 
worksheet(s). Participants should not have received any previous varicella vaccine, either 
alone or in combination, or receive any such vaccines outside of study protocol for the 
duration of the study. 
Other vaccines that are routinely administered should be given outside of the study period, at 
time points appropriate to those vaccines so as not to confound the results from this study. 
These vaccines will not be provided by the Sponsor or Sponsor designee. Enrollment in the 
study should be delayed if a medically important product needs to be administered. A full 
30 days must elapse between the receipt of inactivated non-study (eg, pneumococcal 
conjugate, influenza, Hib) vaccines and enrollment into the study. A full 30 days must elapse 
between the receipt of live non-study vaccines (eg, measles, yellow fever) and enrollment 
into the study. Both inactivated and live non-study vaccines may be administered following 
the successful conclusion of study procedures (ie, completed safety follow-up period, and 
blood sample if indicated) at Visit 4 postvaccination [children] and Visit 7 postdose 2 
[adolescents/adults].
Participants should not receive salicylates (eg, aspirin or any aspirin-containing products) 
from 14 days prior to vaccination until 42 days following the last study vaccination, because 
the use of salicylates in children and young adults with wild-type (natural) varicella infection 
has been associated with Reye syndrome.
Participants should not have received any immune globulin for at least 5 months (150 days) 
before receipt of study vaccine or be scheduled to receive these products within 12 weeks of 
enrollment unless there is a medical necessity warranting their use.
Use of immunosuppressive therapies is a reason for exclusion, with the following exceptions:
•
Use of topical, ophthalmic, and inhaled steroids is permitted.
•
Use of systemic corticosteroids must meet the following criteria:
 
 
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-
Participants should not have received systemic corticosteroids (greater than the 
equivalent of 2 mg/kg total daily dose of prednisone [children] or greater than the 
equivalent of 20 mg total daily dose of prednisone [adolescents/adults]) for more than 
5 consecutive days within 3 months prior to entering the study; 
-
Participants should not receive any dose of systemic corticosteroids within 7 days 
prior to or following each vaccination;
-
Participants should not receive systemic corticosteroids (greater than the equivalent of 
2 mg/kg total daily dose of prednisone [children] or greater than the equivalent of 
20 mg total daily dose of prednisone [adolescents/adults]) for more than 
5 consecutive days from the time of study start through the end of the safety 
follow-up period.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
See Section 8.1.8 regarding administration of epinephrine in the event of an anaphylactic 
reaction.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is specified to be used in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Vaccine (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Study site personnel will have access to a central electronic treatment 
allocation/randomization system (interactive voice response system [IVRS]/interactive web 
response system [IWRS]) to allocate participants, to assign vaccine to participants 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 their assigned PIN with anyone.
 
 
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period/vaccination regimen will still continue to participate in the study as specified in the 
SoA and Section 8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and 
Section 8.12.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum or urine pregnancy test.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
 
 
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to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
Participants may withdraw from the study at any time for any reason. If a participant 
withdraws from the study, they will no longer receive study intervention or be followed at 
scheduled protocol visits.
A participant must be withdrawn from the study if:
1. The participant or participant’s legally acceptable representative withdraws consent 
from the study.
2. The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, places the participant at unnecessary risk 
through continued participation in the study or does not allow the participant to 
adhere to the requirements of the protocol.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
 
 
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•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent, and assent if applicable, be obtained from 
the participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
The maximum amount of blood collected from each participant 7 years of age and older over 
the duration of the study will not exceed 33 mL (Table 3). The maximum amount of blood 
collected from each participant 12 months to 6 years of age during the duration of the study 
will not exceed 10 mL (Table 4).
Table 3
Approximate Blood Drawn/Collected by Study Visit and by Sample Type –
Participants 7 Years of Age and Older
Study Visit/Cycle/etc.
Visit 1
Baseline
Pre-
vaccination 1
Visit 2
Post-
vaccination 1 
Visit 4
Post-
vaccination 1  
(children 
12 months to 
12 years)
Visit 5
Post-
vaccination 2
(adolescents/
adults)
Visit 7
Post -
vaccination 2
(adolescents/
adults)
Blood Parameter
Volume 
(approximate)
Volume 
(approximate)
Volume 
(approximate)
Volume 
(approximate)
Volume
(approximate)
Immunogenicity 
(VZV Antibody) Sample
3.0 to 5.0 mL
3.0 to 5.0 mL
3.0 to 5.0 mL
Safety (CBC and Blood 
Chemistry) Sample
6.0 mL
6.0 mL
6.0 mL
Expected Total (mL)
9.0 to 11.0 mL
6.0 mL
3.0 to 5.0 mL
6.0 mL
3.0 to 5.0 mL
CBC = complete blood count; VZV = varicella-zoster virus
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples.
 
 
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Table 4
Approximate Blood Drawn/Collected by Study Visit and by Sample Type –
Participants 12 Months to 6 Years of Age
Study Visit/Cycle/etc.
Visit 1 Baseline
Prevaccination
Visit 4
Postvaccination
Blood Parameter
Volume (approximate)
Volume (approximate)
Immunogenicity (VZV Antibody) Sample
3.0 to 5.0 mL
3.0 to 5.0 mL
Expected Total (mL)
3.0 to 5.0 mL
3.0 to 5.0 mL
VZV = varicella-zoster virus
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples
Note: Safety laboratory samples are not applicable for participants 12 months to 6 years of age.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical study or 
future biomedical research.If there are changes to the participant’s status during the study 
(eg, health or age of majority requirements), the investigator or medically qualified designee 
must ensure the appropriate consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form, and any written information provided to the participant must receive the 
Institutional Review Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable 
opinion in advance of use. The participant or his/her legally acceptable representative should 
be informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent/assent form or 
addendum to the original consent/assent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level.
 
 
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant or the participant’s legally acceptable representative, answer 
all of his/her questions, and obtain written informed consent/assent before performing any 
procedure related to the future biomedical research substudy. A copy of the informed 
consent/assent will be given to the participant or the participant’s legally acceptable 
representative.
Informed consent/assent for future biomedical research samples must be obtained before the 
collection of the buccal swab DNA samples.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent/assent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The eligibility of 
a participant will be assessed, and a medical history obtained to ensure that he/she satisfies 
the inclusion and exclusion criteria of the study. No physical exam is required for entry into 
the study.
 
 
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 14 days before the first vaccination. A full 30 days 
must elapse between the receipt of inactivated non-study (eg, pneumococcal conjugate, 
influenza, Hib) vaccines and enrollment into the study. A full 30 days must elapse between 
the receipt of live non-study vaccines (eg, measles, yellow fever) and enrollment into the 
study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. All medications administered from 14 days prior to study vaccination until 
42 days following each study vaccination should be recorded on the appropriate
CRF(s)/worksheet(s). 
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.12.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment number. The treatment number identifies the participant for all procedures 
occurring after treatment allocation. Once a treatment number is assigned to a participant, it 
can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 treatment number.
8.1.8
Study Intervention Administration
All participants who are 12 months of age to 12 years of age will receive 1 dose of
VARIVAX™. Participants who are 13 years of age and older will receive 2 doses of
VARIVAX™ administered approximately 6 weeks apart (see Section 1.3 – Schedule of 
Activities). Vials of vaccine will be labeled with treatment numbers and/or component 
identification numbers (CID) specific to each individual participant. Care should be taken to 
ensure that each participant receives the appropriate clinical materials labeled with their 
specific CID. This study will be conducted as a staged approach study. Administration of 
 
 
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study vaccine for Stage 2 participants (children/adolescents) will commence upon completion 
of Stage 1 (adults) portion of the study.
Study vaccines should be prepared and administered by appropriately qualified members of 
the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacist 
or medical assistant) as allowed by local, state, country and institutional guidance.
A separate, sterile syringe and needle or sterile disposable unit should be used for the
administration of vaccine to each participant to prevent transmission of infectious agents 
from one person to another. Needles should not be recapped. Safe disposal procedures should 
be followed.
VARIVAX™ should be administered subcutaneously in the outer aspect of the upper arm
(deltoid) or anterolateral thigh for children; in the outer aspect of the upper arm (deltoid) for
adolescents/adults. All vaccinations and location of injection should be recorded on the
appropriate CRF(s)/worksheet(s). Participants should be observed for anaphylaxis or other 
reactions for at least 30 minutes following vaccination (at least 60 minutes for children 
3 years of age or younger).
Adequate treatment provision, including epinephrine and equipment for maintaining an 
airway should be available for immediate use should an anaphylactic or anaphylactoid 
reaction occur [Centers for Disease Control and Prevention 2015].
Protect the vaccine from light at all times since such exposure may inactivate the vaccine
virus. It is recommended that the vaccine be administered immediately after reconstitution to
minimize loss of potency.
Details of the vaccination, including the time the vaccine vial is removed from the
refrigerator, the time of reconstitution, the time of administration of the vaccine, the site and
route of administration, and the dose volume administered should be documented. If the
reconstituted vaccine is not used within 30 minutes of removal from the refrigerator, a new
vial will need to be reconstituted. Do not freeze reconstituted vaccine. Vials that are
reconstituted and not used should be disposed of as biohazardous waste and noted on the
Clinical Supplies Return Form located in the Administrative Binder.
8.1.8.1
Timing of Dose Administration
VARIVAX™ will be administered as indicated in the SoA (Section 1.3).
Participants who are 12 months of age to 12 years of age will receive one 0.5-mL 
subcutaneous dose of VARIVAX™ in the upper deltoid region of the arm or anterolateral 
thigh at Visit 1 on Day 1 of the study. 
Participants who are 13 years to 75 years of age will receive a 0.5-mL subcutaneous dose 
VARIVAX™in the upper deltoid region of the arm at 2 separate time points: Visit 1 and 
Visit 4.
 
 
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8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the vaccination
regimen should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.3 and Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Serum samples will be tested for antibody to VZV using the gpELISA assay as described in 
Section 8.2.2. VZV seroconversion rates, antibody response rates, and GMTs will be used as 
 
 
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the primary immunogenicity endpoints in this study. The seroconversion rate for VZV is 
defined as the percentage of participants with VZV antibody titer ≥1.25 gpELISA units/mL 
in participants with a baseline VZV antibody titer <1.25 gpELISA units/mL. The antibody 
response rate for VZV is defined as the percentage of participants with a postvaccination 
VZV antibody titer ≥5 gpELISA units/mL for participants whose baseline VZV antibody titer 
was <1.25 gpELISA units/mL. Antibody titers ≥5 gpELISA units/mL have been shown to be 
highly correlated with long-term protection [Kuter, B., et al 2004].
8.2.1
Immunogenicity (VZV) Antibody Sample
For children, approximately 3.0- to 5.0-mL of blood will be collected prior to vaccination at 
Visit 1 (Day 1) and at Visit 4 (Day 43 [+14 days] postvaccination). For adolescents/adults, 
approximately 3.0- to 5.0-mL of blood will be collected prior to vaccination at Visit 1 
(Day 1) and at Visit 7 (Day 43 [+14 days] postdose 2). The total amount of blood to be 
drawn/collected over the course of the study, including approximate blood volumes 
drawn/collected by visit and by sample type per participant, can be found in Table 3 and 
Table 4. For all participants, the immunogenicity blood sample at Visit 1 (Day 1) is 
mandatory for enrollment. Any leftover serum will be stored for future biomedical research if 
the participant signs the future biomedical research consent. Instructions regarding the 
labeling, storage, and shipment of serum samples for laboratory measurements will be 
provided separately by the Sponsor or Sponsor designee in the laboratory manual. All serum 
specimens will be sent to the designated testing laboratory. 
Levels of VZV antibodies will be measured at each of these time points for the entire study 
population. Serologic testing will be performed at the designated laboratory. 
8.2.2
Detection of IgG Antibody to VZV (gpELISA)
The purpose of the gpELISA is to detect immunoglobulin G (IgG) antibody to VZV before 
and after vaccination with VZV-containing vaccine(s). This is the primary assay used by the 
Vaccines and Biologics Laboratory of PPD to evaluate the serological response to the 
vaccine(s). This method detects antibodies to VZV glycoprotein (gp), which has been 
purified from Medical Research Council cell strain 5 (MRC-5) cells infected with the KMcC 
strain of VZV by lectin affinity chromatography. 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 gp antigens purified from VZV-infected MRC-5 cells. 
The assay and the purification of the VZV gp from VZV-infected cells are described [Keller, 
P. M., et al 1986][Wasmuth, E. H. and Miller, W. J. 1990][Provost, P. J., et al 1991]. Serum 
sample titers as determined by gpELISA are shown to correlate with neutralizing antibody 
titers [Krah, D. L., et al 1997].
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 VZV gp-coated and TCC-coated 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 optical density (OD) of the 2 TCC 
 
 
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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.
The negative control used for this assay is an individual human serum at a dilution of 1:50, 
found to be negative for anti-VZV. The high-positive control is a VZV antibody-positive 
serum, diluted 1:500, which gives a response in the assay at the upper end of the standard 
curve. The low-positive control is a VZV antibody-positive serum diluted 1:50, which gives 
a response in the assay at the lower end of the standard curve. A VZV antibody-positive 
individual human serum will be used to generate a standard curve.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study, 
including approximate blood volumes drawn/collected by visit and by sample type per 
participant, can be found in Table 3 and Table 4.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Safety Assessments and Use of the VRC
Unless otherwise stated, all AEs will be collected for 42 days following each vaccination 
with VARIVAX™ using a VRC as detailed in Section 8.4.
Each participant or participant’s legally acceptable representative will be given a VRC 
following vaccination and will be instructed to record the safety data on the VRC. The VRC 
is required to be completed for a full 42 days following each vaccination. The participant or 
the participant’s legally acceptable representative will return the completed VRC to the site 
at the visit on Day 43 (+14 days) following each vaccination.
On Days 7 and 43 following each vaccination study personnel will review the information 
with the participant or the participant’s legally acceptable representative for completeness, 
accuracy, and clarity. All information will be accurately recorded on the appropriate 
CRFs/worksheets.
The following AEs will be recorded on the VRC and reported for all participants:

Solicited local (injection-site) AEs for Days 1 to 5 following vaccination. Solicited 
local (injection-site) AEs include redness, swelling, and pain/tenderness. The 
maximum intensity (mild, moderate, or severe) for pain/tenderness and the maximum 
size (using a scale provided on the VRC) for redness and swelling will be recorded on 
the VRC (refer to Section 10.3.6).

Unsolicited injection-site AEs regardless of severity or causality through Day 42 
following vaccination.
 
 
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
The participant's temperature, including the route used to measure the temperature 
(oral, axillary or rectal [according to the local standard of care for temperature
measurement]), 4 to 6 hours postvaccination and then daily, preferably at the same
time each day, through Day 28 following vaccination.
o
For participants <3 years of age, it is recommended that the temperature be
measured by the axillary method. The temperature reading including the route
used to measure the temperature, must be recorded in the VRC. Study
personnel should advise the participant’s legally acceptable representative on 
the proper manner in which to measure axillary temperatures to ensure that 
accurate measurements are obtained.
o
For participants ≥3 years of age it is recommended that the temperature be
measured using the oral method; however, the local standard of care method 
of temperature measurement may be used as an alternative method.

The development of varicella-like and herpes zoster-like rashes through 42 days
following vaccination. The participant or the patient’s legally acceptable 
representative will be instructed to contact study personnel immediately if the 
participant develops a varicella- or herpes zoster-like rash during the 42-day safety 
follow-up periods. Participants should be seen at the clinic within 72 hours of the rash 
presentation. Study personnel will review the completed VRC to identify any 
unreported occurrences of these vaccine virus-specific conditions.

The occurrence of all systemic AEs regardless of severity or causality through Day 42 
following vaccination.

SAEs occurring at any time from study enrollment through study completion. These 
events should be reported immediately to study personnel regardless of causality. 
Study personnel should report any SAE within 24 hours to one of the individuals 
listed on the sponsor contact information page in the Administrative Binder.

Vaccine-related SAEs and death from study start through the end of the study for 
each participant (Day 42 following the last vaccination).
8.3.2
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
 
 
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•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 42 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.2.1
Serum or Urine Pregnancy Test
Female participants of reproductive potential (See Inclusion Criterion #4) will have a serum 
pregnancy test or urine pregnancy test sensitive to 25 mIU/mL β-hCG administered on the 
day of the first vaccination. For female participants of reproductive potential, another serum 
pregnancy test or urine β-hCG pregnancy test will also be performed on the day of the second 
vaccination. Pregnancy test results must be obtained before study vaccine is administered. 
All materials used for serum and urine pregnancy testing will be provided by the study sites. 
The serum pregnancy test or the urine pregnancy test will be performed according to the 
manufacturer’s instructions. Any participant with a positive pregnancy test result at Day 1 
(Visit 1) will not participate in the study. Any participant with a positive pregnancy test at or 
prior to Visit 4 will not receive the second study vaccination.
8.3.2.2
Laboratory Measurements – CBC, Chemistry and Urinalysis
Participants 7 years of age and older will have approximately 2.0 mL of whole blood drawn 
for CBC, approximately 4.0 mL of whole blood drawn for blood chemistry, and urine 
collected for urinalysis including macroscopic plus microscopic evaluation (see Appendix 2).
For participants 7 to 12 years of age, blood (approximately 6 mL) and urine will be collected 
at 2 time points: prior to vaccination (Visit 1), and 3 days postvaccination. For adolescents 
and adults 13 to 75 years of age, blood (approximately 6 mL) and urine will be collected at 
3 time points: prior to vaccination (Visit 1), and 3 days after each of the 2 vaccinations.
 
 
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The total amount of blood/tissue to be drawn/collected for safety laboratory assessments over
the course of the study, including approximate blood/tissue volumes drawn/collected by visit 
and by sample type per participant can be found in Table 3.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3. Note: 
Rechallenge is not applicable for this study.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.
From the time of allocation/randomization through 42 days following the first vaccination(s) 
and from the time of any subsequent vaccination(s) through 42 days thereafter, all AEs, 
SAEs, and other reportable safety events must be reported by the investigator. Pregnancy 
exposure and infant exposure during lactation must be reported to the sponsor through 
3 months post each vaccination.
 
 
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Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
A death that occurs prior to the participant completing the study, but outside the time 
period specified in the previous paragraph.
OR
An SAE that is considered by an investigator who is a qualified physician to be vaccine 
related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
 
 
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion of 
study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- ECIs and those 
not requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study (within 3 months following 
vaccination) are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest (ECIs)
Selected non-serious and SAEs are also known as events of clinical interest (ECI) and must 
be reported to the Sponsor.
For the time period beginning when the consent/assent form is signed until treatment
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant
must be reported within 5 calendar days to the Sponsor if it causes the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through 42 days
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to
the Sponsor’s product, must be reported within 5 calendar days to the Sponsor, either by 
electronic media or paper. Electronic reporting procedures can be found in the electronic data 
collection (EDC) data entry guidelines. Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5 - Definition and Treatment 
of Overdose, that is not associated with clinical symptoms or abnormal laboratory results.
8.5
Definition and Treatment of Overdose
In this study, an overdose is any dose greater than one dose of study vaccine within 24 hours.
If an AE is associated with (“results from”) the overdose of Sponsor's product or vaccine, the 
AE is reported as an SAE, even if no other seriousness criteria are met.
If a dose of Sponsor's product 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 ECI, using the terminology “accidental or intentional overdose 
without adverse effect.”
 
 
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All reports of overdose with and without an AE must be reported by the investigator within 
5 calendar days to the Sponsor either by electronic media or paper. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Buccal swabs for genomics use. Buccal swab DNA samples for analysis should be 
obtained prior to vaccination, on Day 1, or at a later date as soon as the informed 
consent/assent is obtained.

Leftover serum immunogenicity samples collected in the main study.
8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.10
Biomarkers
Biomarkers will not be evaluated in this study.
 
 
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8.11
Health Economics Medical Resource Utilization and Health Economics
Health Economics OR Medical Resource Utilization and Health Economics are not evaluated 
in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Prior to intervention allocation, potential participants will be evaluated to determine that they 
fulfill the entry requirements as set forth in Section 5. Screening procedures may be repeated 
after consultation with the Sponsor.
8.12.2
Treatment Period/Vaccination Visit
Specific procedures to be performed during the treatment period, as well as their prescribed 
times and associated visit windows, are outlined in the SoA in Section 1.3
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period/vaccination regimen will still continue to participate in the study.
8.12.4
Poststudy
Participants will be required to return to clinic approximately 42 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 42 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
42 days (+14 days) post the last dose of study intervention to determine if any AEs have 
occurred since the poststudy clinic visit.
9
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 database lock, changes are made to primary and/or key 
secondary analyses, or the statistical methods related to those analyses, then the protocol will 
be amended (consistent with International Council for Harmonisation [ICH] Guideline E-9). 
Changes to exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, but prior to final database lock, will be documented in a supplemental statistical 
analysis plan and referenced in the CSR for the study. Post hoc exploratory analyses will be 
clearly identified in the CSR. The Stage 1 portion of the study will be conducted and 
 
 
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completed first. The Stage 2 portion of the study will commence once the CSR for Stage 1 
has been submitted to the Russian Ministry of Health. A separate CSR for the Stage 2 portion 
of the study will be submitted to the Russian Ministry of Health when Stage 2 is completed. 
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
An open-label, multicenter, single-arm study to evaluate the 
immunogenicity of VARIVAX™in healthy Russian individuals 
12 months of age to 75 years of age
Treatment Assignment
All participants will receive VARIVAX™
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All-Participants-as-Treated (APaT)
Primary Endpoint(s)

For participants who are seronegative at baseline, VZV antibody 
response rate, seroconversion rate, and GMTs will be summarized 
at 6 weeks following vaccination for children, and at 6 weeks 
postdose 2 for adolescents/adults.

For participants who are seropositive at baseline, following 
endpoints will be summarized at Day 1 and 6 weeks 
postvaccination for children and at Day 1 and 6 weeks postdose 2 
for adolescents/adults: GMTs, GMFR from Day 1 to 6 weeks
postvaccination, and the percentage of participants with ≥4-fold rise 
in antibody titer from Day 1 to 6 weeks postvaccination.
Key Secondary Endpoints

Solicited injection-site reactions (redness, swelling, and 
pain/tenderness) of any intensity or size from Day 1 through 5 
postvaccination for children and from Day 1 through 5 postdose 1 and 
2 for adolescents/adults.

Maximum reported temperature ≥39.0°C oral equivalent from Day 1 
through Day 28 postvaccination for children and from Day 1 through 
Day 28 postdose 1 and 2 for adolescents/adults.

Systemic AEs from Day 1 through Day 42 postvaccination for 
children and from Day 1 through Day 42 postdose 1 and 2 for 
adolescents/adults.

Vaccine-related SAEs and death from Day 1 through the end of the 
study period (42 days following the last vaccination) for each 
participant.
Statistical Methods for Key 
Immunogenicity Analyses
No formal hypothesis will be tested. VZV immunogenicity will be 
summarized separately for adults, adolescents, and children. Exact one-
sample binomial distribution will be used to estimate the response rate, 
seroconversion rate, and the associated 95% confidence intervals (CIs). 
The estimation of GMTs and the computation of corresponding 95% CIs 
will be calculated using t-distribution for one-sample mean based on 
log-transformed titers.
Statistical Methods for Key 
Safety Analyses
No formal hypothesis will be tested. Summary statistics for safety 
endpoints listed in Section 3 will be provided.
Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
No multiplicity adjustment is required for this study
 
 
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Sample Size and Power 
Immunogenicity:
No formal power calculation for immunogenicity was performed to 
determine the current sample size. Section 9.9.1 provides information 
about the expected precision of estimation for response rates and 
GMTs under different sample size.
Safety:
Section 9.9.2 provides information about the ability of this study to 
estimate the incidence of vaccine-related SAEs within the vaccination 
group based on hypothetical number of participants.
9.2
Responsibility for Analyses/In-house Blinding
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 (through completion of the 42 days of each postvaccination safety follow-up 
period) will be conducted as an open-label, single-arm study, ie, participants, investigators, 
and Sponsor personnel will be aware of vaccination assignments after each participant is 
enrolled and the vaccination is assigned.
The allocation schedule will be generated by an external vendor.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3. No formal hypotheses will be 
tested in this study.
9.4
Analysis Endpoints
9.4.1
Immunogenicity Endpoints
The immunogenicity endpoints for VZV are:

The response rates (defined as the percentage of participants with VZV antibody titer 
≥5 gpELISA units/mL) 6 weeks postvaccination [for children] or 6 weeks postdose 2 
[for adolescents/adults] among participants who are seronegative to VZV at baseline 
(titer <1.25 gpELISA units/mL).

GMTs of VZV antibody as measured by gpELISA.

The seroconversion rates (defined as the percentage of participants with VZV
antibody titer ≥1.25 gpELISA units/mL) 6 weeks postvaccination [for children] or 
6 weeks postdose 2 [for adolescents/adults] among participants who are seronegative
to VZV at baseline (titer <1.25 gpELISA units/mL).
 
 
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
For participants who are seropositive at baseline (baseline VZV antibody titer ≥1.25 
gpELISA units/mL), the GMFR from Day 1 and the percentage of participants with 
≥4-fold rise in antibody titer from Day 1 will be summarized at Day 1 and 6 weeks 
postvaccination for children and 6 weeks postdose 2 for adolescents/adults. 
Immunogenicity summaries will be provided at Day 1 for all participants, at 6 weeks
following vaccination for children, and at 6 weeks postdose 2 for adolescents and adults 
separately.
9.4.2
Safety Endpoints
The safety endpoints are:

Solicited injection-site reactions (redness, swelling, pain/tenderness) of any intensity 
or size from Days 1 through 5 following each vaccination.

Unsolicited injection-site AEs, regardless of severity or causality, from Day 1 through
Day 42 of each postvaccination.

Maximum reported temperature ≥39.0°C oral equivalent from Day 1 through Day 28 
following each vaccination. Recorded temperatures will be converted to oral 
equivalents by adding 0.6°C to axillary temperatures and subtracting 0.6°C from 
rectal temperatures.

Varicella-, and herpes zoster-like rashes occurring from Day 1 through Day 42 
following each vaccination.

Systemic AEs from Day 1 through Day 42 following each vaccination.

SAEs from Day 1 through Day 42 following each vaccination.

Vaccine-related SAEs and death from Day 1 through the end of the study for each 
participant (Day 42 following the last vaccination).

A summary of blood and urine tests performed 3 days following each vaccination for 
participants 7 years of age and older
Unless otherwise stated, all AEs will be collected for 42 days postvaccination after each dose 
of VARIVAX™.
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The Per-Protocol (PP) population will serve as the primary population for the analysis of 
immunogenicity data in this study. The PP population consists of all allocated participants 
without deviations from the protocol that may substantially affect the results of the 
 
 
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immunogenicity endpoint(s). Potential deviations that may result in the exclusion of a 
participant from the PP population for all immunogenicity analyses include:

Missing either a baseline or postvaccination blood sample.

Deviations from of inclusion/exclusion criteria, including:
o
Recent exposure (<4 weeks) to varicella or herpes zoster prior to vaccination
(duration of exposure as defined in Section 5.2) or prior to the completion of
clinical and serological follow-up in this study (exclusion from the PP 
population would only affect data collected subsequent to the deviation).
o
History of varicella or herpes zoster prior to study entry, or development of 
varicella prior to the completion of clinical and serological follow-up in this 
study (exclusion from the PP population would only affect data collected 
subsequent to the deviation).
o
Receipt of varicella or herpes zoster vaccine either alone or in combination at 
any time prior to the study or during the study.
o
Receipt of immune globulin, a blood transfusion, or blood-derived products 
(does not include autologous blood/blood products) within 5 months 
(150 days) prior to receipt of a study vaccine, or receipt of these products 
prior to completion of clinical and serological follow-up in this study 
(exclusion from the PP population would only affect data collected subsequent 
to the deviation).
o
Age of participant at study entry is <12 months. (Deviations of the lower age 
limit will result in exclusion from the PP population due to the potential 
presence of maternal antibody, which might interfere with the evaluation of 
the vaccine response).
o
Any congenital or acquired immune deficiency, neoplastic disease, or 
depressed immunity, including those resulting from steroid use or other 
immunosuppressive therapy (see Section 8.1.5.2 for definition of steroid use 
warranting exclusion).

Postvaccination blood sample is outside the allowable day range, which is 27 to 
84 days after the associated dose of vaccine was administered for 6-week serology
samples. This window for inclusion of samples in the statistical analysis is wider than 
the window provided earlier in this protocol (+14 days for the 6-week serology
testing); however, it is being used to be consistent with other studies evaluating VZV
containing vaccines.

Participant is participating in another clinical study (other than a surveillance study).
 
 
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
In addition, the primary analysis requires specific baseline criteria be met for VZV: 
antibody titer (<1.25 gpELISA units/mL).
The final determination on major protocol deviations, and thereby the composition of the PP 
population, will be made prior to the finalization of the database and will be documented in a 
separate memo.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed 
for the immunogenicity endpoints. The FAS population consists of all allocated participants 
who received all study vaccinations required at the time point for the analysis and have 
serology result. 
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the All-Participants-as-Treated (APaT) population, 
which consists of all allocated participants who received at least one dose of study vaccine 
and who have some safety follow-up data after respective vaccination. 
For participants 7 years of age or older, at least one laboratory measurement obtained 
subsequent to at least one dose of study vaccination is required for inclusion in the analysis 
of the respective safety parameter. For all participants, at least one temperature measurement 
obtained subsequent to at least one dose of study vaccination is required for inclusion in the 
analysis of the maximum temperature. To assess change from baseline, a baseline 
measurement is also required.
9.6
Statistical Methods
Statistical methods for immunogenicity and safety analyses are described in Section 9.6.1 
and Section 9.6.2, respectively. No formal hypothesis will be tested in this study.
Section 9.6.3 describes how demographic and baseline characteristics will be summarized.
9.6.1
Statistical Methods for Immunogenicity Analyses
Immunogenicity summaries will be provided at baseline (prevaccination) for all participants,
and at 6 weeks postvaccination for children, at 6 weeks postdose 2 for adolescents, and at
6 weeks postdose 2 for adults. The primary time points for immunogenicity summaries will
be 6 weeks postvaccination for children and 6 weeks postdose 2 for adolescents/adults. For 
each interval, immunogenicity will be evaluated by determining baseline and postvaccination 
serum concentrations of VZV antibody measured by gpELISA.
The first endpoint that will be used to evaluate the immunogenicity of VARIVAX™is 
response rate, which is defined as the percentage of participants with VZV-specific antibody
titer ≥5 gpELISA units/mL 6 weeks postvaccination for children and 6 weeks postdose 2 for 
adolescents/adults, in participants who have a VZV–specific antibody titer of
<1.25 gpELISA units/mL at baseline. A 95% CI for this endpoint will be calculated using the
exact CI method for a single binomial proportion given in Collett [Collett, D. 1999].
 
 
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The second endpoint that will be used to evaluate the immunogenicity of VARIVAX™is the 
GMT. The GMT will be calculated at each time point by taking the log of the titers, 
averaging over all participants values, and then back-transforming to the original scale. A
95% CI for the GMTs will be calculated based on the t-distribution.
The third endpoint that will be used to evaluate the immunogenicity of VARIVAX™is the 
seroconversion rate. The observed VZV seroconversion rate (the percentage of participants
with VZV titer ≥1.25 gpELISA units/mL 6 weeks postvaccination for children and 6 weeks 
postdose 2 for adults, in participants who have a VZV–specific antibody titer of
<1.25 gpELISA units/mL at baseline) will be summarized along with two-sided 95% CIs. 
The CIs will be computed using the exact method for a single binomial proportion given in
Collett [Collett, D. 1999]. This will be computed on the PP population of participants
(restricted to those with baseline titer <1.25 gpELISA units/mL) and on the FAS population 
(regardless of baseline status).
For participants in the PP population only, graphical displays of the reverse cumulative 
distribution function of antibody titers will be illustrated at 6 weeks postvaccination for 
children and 6 weeks postdose 2 for adolescents/adults.
Table 6 summarizes the key immunogenicity analyses. For participants who are seropositive 
at baseline (baseline VZV antibody titer ≥1.25 gpELISA units/mL), the following parameters 
and 95% CIs will be summarized at Day 1 and 6 weeks postvaccination for children and 
6 weeks postdose 2 for adolescents/adults: the GMTs, the GMFR from Day 1, and the 
percentage of participants with ≥4-fold rise in antibody titer from Day 1. CIs will only be 
calculated if there are at least 5 participants who are seropositive at baseline in a given age 
stratum.
 
 
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Table 6
Primary Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical 
Method
Analysis 
Population
Missing 
Data 
Approach
Summaries of response rates 
at 6 weeks postvaccination 
for children and at 6 weeks 
postdose 2 for adolescents 
and adults, separately
P 
Exact One-
Sample Binomial;
corresponding 
95% CIs
PP
Observed 
data only
S
FAS
Summaries of GMTs at 
6 weeks postvaccination for 
children and at 6 weeks 
postdose 2 for adolescents 
and adults, separately
P
One-sample mean 
and 95% CI based 
on log-
transformed titers 
and t-distribution
PP
Observed 
data only
S
FAS
Summaries of 
seroconversion rates at 
6 weeks postvaccination for 
children and at 6 weeks 
postdose 2 for adolescents 
and adults, separately
P
Exact One-
Sample Binomial:
methodology, 
95% CIs
PP
Observed 
data only
S
FAS
CI = confidence interval; GMT = geometric mean titer; FAS = Full Analysis Set; P=Primary approach; PP = 
Per Protocol; S=Secondary approach.
9.6.2
Statistical Methods for Safety Analyses
The APaT population will be employed for safety analyses. Safety analyses will be presented 
by Stage, and within Stage, Postdose 1, Postdose 2, and Postdose 1 or 2. All participants 
vaccinated and who have safety follow-up data will be included in the analysis of safety. 
Clinical AEs for 42 days following each of the study vaccination and the number and
proportion of participants with the following clinical AEs will be tabulated as follows:

Solicited injection-site reactions (redness, swelling, and pain/tenderness) of any 
intensity or size from Days 1 through 5 postvaccination for children and from Days 1 
through 5 postdose 1 and 2 for adolescents/adults.

Unsolicited injection-site AEs, regardless of severity or causality, from Day 1 through
Day 42 postvaccination for children and from Days 1 through 42 postdose 1 and 2 for 
adolescents/adults.

Maximum reported temperature ≥39.0°C oral equivalent from Day 1 through Day 28 
postvaccination for children and from Days 1 through 28 postdose 1 and 2 for 
adolescents/adults.
 
 
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
Varicella- and herpes zoster-like rashes occurring from Day 1 through Day 42 
postvaccination for children and from Days 1 through 42 postdose 1 and 2 for 
adolescents/adults.

Systemic AEs from Day 1 through Day 42 postvaccination for children and from
Days 1 through 42 postdose 1 and 2 for adolescents/adults.

SAEs from Day 1 through Day 42 postvaccination for children and from Days 1 
through 42 postdose 1 and 2 for adolescents/adults.

Vaccine-related SAEs and death from Day 1 through the end of the study (Day 42 
following the last vaccination).
Unless otherwise stated, all AEs will be collected for 42 days postvaccination after each dose 
of VARIVAX™.
In addition, all CBC, blood chemistry and urinalysis data collected at Visit 1 and 3 days 
postvaccination for participants 7 years of age and older, will be summarized at all time
points that these laboratory data are collected. However, no formal statistical testing will be 
conducted.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Participant characteristics of age, gender, and race/ethnicity will be summarized for all
participants who enter the study. In addition, baseline serostatus for VZV will be presented.
The number (%) of participants with specific prior medications (incidence rate >0%) within
14 days prior to the vaccination will be summarized.
The number (%) of participants with specific concomitant medications (incidence rate >0%) 
within 42 days following each vaccination will be summarized.
A detailed participant accounting will be provided. This accounting will describe the number
of participants allocated at study start, the number vaccinated at the vaccination visit, and the 
number of discontinuations and withdrawals during the safety follow-up period. This
participant accounting will also indicate the number of participants who completed the study.
No other analyses are planned for this study.
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
No multiplicity adjustment is required for this study.
 
 
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9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
Since this is an estimation study, no formal power calculation for immunogenicity was 
performed to determine the current sample size. However, the expected precision of 
estimation is given below. For immunogenicity summaries, the response rates and the 
associated 95% CI under different sample sizes of the adult, adolescents and children PP 
populations are estimated and presented in Table 7. In addition, the expected precision of the 
GMTs under different sample sizes of the adult and adolescents and children PP populations 
is presented in Table 8.
Table 7
Response Rates and Associated 95% CI Based on Different Sample Sizes of Per-
Protocol Population
95% Confidence Interval
Population
Sample Size of 
Per-Protocol 
Population
Hypothetical 
Response 
Rate
Lower
Upper
Adult
40
0.80
0.64
0.91
0.85
0.70
0.94
0.90
0.76
0.97
45
0.80
0.65
0.90
0.84
0.71
0.94
0.91
0.79
0.98
Adolescent
25
0.80
0.59
0.93
0.84
0.64
0.95
0.92
0.74
0.99
30
0.80
0.61
0.92
0.83
0.65
0.94
0.90
0.73
0.98
Children
55
0.80
0.67
0.90
0.85
0.74
0.94
0.91
0.80
0.97
60
0.80
0.68
0.89
0.85
0.73
0.93
0.90
0.79
0.96
 
 
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Table 8
Expected Precision of GMTs under Different Sample Sizes of Per-Protocol
Population 
Population
Sample Size of 
Per-Protocol 
Population
95% Confidence Interval
Hypothetical 
GMT
Lower
Upper
Adult 
(Postdose 2)
40
80.0
58.1
110.1
100.0
72.6
137.7
120.0
87.2
165.2
45
80.0
59.2
108.0
100.0
74.0
135.0
120.0
88.9
162.1
Adolescent 
(Postdose 2)
25
80.0
52.9
120.9
100.0
66.2
151.1
120.0
79.4
181.3
30
80.0
55.1
116.2
100.0
68.8
145.3
120.0
82.6
174.3
Children
(Postvaccination)
55
10.0
7.6
13.1
12.0
9.2
15.7
14.0
10.7
18.3
60
10.0
7.7
12.9
12.0
9.3
15.5
14.0
10.8
18.1
Based on an assumed standard deviation of the 1.0 for the log antibody titers.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an SAE in the study 
population. In Stage 1, it is expected that approximately 50 participants will contribute to the
analysis of safety Postdose 1. In Stage 2, it is expected approximately 100 participants will 
contribute to the analysis of safety Postdose 1.
If no serious vaccine-related AEs are observed in this study in Stage 1 with 50 participants
evaluable for safety, there will be a 97.5% probability that the true incidence rate is no more
than 7.1%. If no serious vaccine-related AEs are observed in this study in Stage 2 with 100
children/adolescents in this study evaluable for safety, there will be a 97.5% probability that 
the true incidence rate is no more than 3.6%. The estimate of and the upper bound of the 95%
CI for the underlying percentage of participants with a serious vaccine- related AEs given
various hypothetical observed number of participants with a serious vaccine-related AEs
among approximately 50 adult and approximately 100 adolescents/children are provided in 
Table 9.
 
 
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Table 9
Estimate of Incidence of Vaccine-Related Serious Adverse Events and Upper 
Bound of 95% Confidence Interval Based on Hypothetical Number of Participants with 
Vaccine-Related Serious Adverse Events
Population
Sample 
Size
Hypothetical 
Number of 
Participants
With VR-SAE
Estimate 
of 
Incidence
Upper Bound 
of 95% 
Confidence 
Interval †
Adult
50
0
0.0%
7.1%
1
2.0%
10.7%
2
4.0%
13.7%
Adolescent/children
100
0
0.0%
3.6%
1
1.0%
5.4%
2
2.0%
7.0%
† Based on the two-tailed exact CI of a binomial proportion given in Collett [Collett, D. 
1999].
VR-SAE = vaccine-related serious adverse event
9.10
Subgroup Analyses
For participants enrolled in the Stage 2 portion of the study, a summary of immunogenicity 
and safety endpoints will be provided based on following variables:

Age: 12 months to 6 years, 7 to 12 years, and 13 to 17 years of age

Dosing schedule: 
o
participants receiving 1 dose of VARIVAX™(12 months to 12 years of age)
o
participants receiving 2 doses of VARIVAX™ (13 to 17 years of age)
9.11
Compliance (Medication Adherence)
The number and proportion of allocated participants receiving each vaccination will be 
summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of allocated 
participants administered VARIVAX™ at each scheduled vaccination.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
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 MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD 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
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
 
 
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
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 IRB, IEC, 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.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
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 GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); 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 MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority 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 
 
 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
 
 
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contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10 will be performed by the central laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 10
Protocol-required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
WBC count with differential 
Hemoglobin
Hematocrit
Platelet Count
Chemistry
Sodium 
Potassium
Chloride
CO2/Bicarbonate
Blood Urea Nitrogen
Creatinine
Glucose (nonfasting)
Routine Urinalysis

Macroscopic panel: Appearance, Bilirubin, Blood, Color, Glucose, 
Ketones, Leukocyte Esterase (LE), Nitrites, pH, Protein, Specific 
Gravity, Urobilinogen 

Microscopic panel (reflex test): Amorphous Crystals, Bacteria, 
Calcium Carbonate Crystals, Calcium Oxalate Crystals, Calcium 
Phosphate Crystals, Cysteine Crystals, Granular Casts, Hyaline 
Casts, RBC, RBC Casts, Renal Epithelial Cells, Squamous Epithelial 
Cells, Transitional Epithelial Cells, Uric Acid Crystals, WBC and 
WBC Casts 
Other Screening Tests
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test 
(as needed for WOCBP)
NOTES: All study-required laboratory assessments will be performed by a central laboratory, with 
the exception of the serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as 
needed for WOCBP).
RBC = red blood cells; WOCBP = woman/women of childbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
 
 
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•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
 
 
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c.
Requires inpatient hospitalization or prolongation of existing 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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
 
 
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10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
 
 
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•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
•
Injection site redness, swelling, or hard lump from the day of vaccination through 
Day 4 postvaccination will be evaluated by maximum size (Section 10.3.6).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or CRF/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 product and the AE based upon the available 
information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
 
 
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-
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.
-
Dechallenge: Not applicable for vaccines.
-
Rechallenge:  Was the participant re-exposed to the Sponsor’ s product in this study?
-
If yes, did the AE recur or worsen?
-
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 drug study; or (3) Sponsor’ s product(s) is/are used 
only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’ S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE  
IRB/IEC.
-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of the 
AE onset relative to the administration of the Sponsor’s product is reasonable. The 
AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the AE 
onset relative to administration of the Sponsor’s product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product. (Also entered 
for a participant with overdose without an associated AE.)
 
 
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•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
 
 
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•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
10.3.6
Assessment of Injection-Site Complaints or Reactions
The following instructions are excerpted from the Vaccination Report Cards (VRCs) and are 
included for reference only. Refer to the complete VRC provided when performing the actual 
measurements.
A. Adolescent/Adult Vaccination Report Card (Over 13 Years of Age)
Swelling and Redness
To Measure Swelling: Look at the injection site complaint and determine what area of the 
swollen region is the largest. Place the VRC-provided ruler on the edge of where the swollen 
area begins across to where it ends (measuring in whatever direction is the largest area). Use 
the VRC-provided ruler marks to determine which letter area (A through E→) the swelling 
falls into.
 
 
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To Measure Redness: Look at the injection site complaint and determine where the red area 
is the largest. Place the VRC-provided ruler on the edge of where the red area begins across 
to where it ends (measuring in whatever direction has the largest area). Use the VRC-
provided ruler marks to determine which letter are (A thru E→) the redness falls into.
Mark the boxes that best describe the size of the swelling and/or redness complaints;

None if there is no swelling or redness at the injection site

A if the greatest width is anywhere in the area marked A

B if the greatest width is anywhere in the area marked B

C if the greatest width is anywhere in the area marked C

D if the greatest width is anywhere in the area marked D

E or greater if the greatest width is anywhere in the area marked E→
 
 
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Pain or Tenderness or Other Reactions
Mark the box that best describes the severity of the complaint using the following definitions:

None is if you do not experience any pain or tenderness

Mild is awareness of symptom, but easily tolerated

Moderate is discomfort enough to cause interference with usual activities

Severe is inability to do work or usual activities
B. Pediatric Vaccination Report Card (3-13 Years of Age)
Swelling and Redness
Estimate the size of the reaction at its largest from edge to edge. Use the VRC-provided ruler 
marks along the bottom of the page
Mark the box that best describes the size of the reaction:

1 if the greatest width is anywhere in the area marked 1 (Example A)

2 if the greatest width is anywhere in the area marked 2

3 if the greatest width is anywhere in the area marked 3 (Example B)

Over 3 if the greatest width is in any area marked with a number over 3. Write in the 
number (Example C)

If the reaction is wider than the area marked 7, write in 8.
Pain or Tenderness or Other Reactions
Mark the box that best describes the severity of the reaction using the following definitions:

Mild is awareness of symptom, but easily tolerated

Moderate is definitely acting like something is wrong

Severe is extremely distressed or unable to do usually activities
 
 
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C. Pediatric Vaccination Report Card (Less than 3 Years of Age)
Swelling and Redness
Estimate the size of the reaction at its largest from edge to edge. Use the VRC-provided ruler 
marks along the bottom of the page
Mark the box that best describes the size of the reaction:

1 if the greatest width is anywhere in the area marked 1 (Example A)

2 if the greatest width is anywhere in the area marked 2

3 if the greatest width is anywhere in the area marked 3 (Example B)

Over 3 if the greatest width is in any area marked with a number over 3. Write in the 
number (Example C)

If the reaction is wider than the area marked 7, write in 8.
Pain or Tenderness or Other Reactions
Mark the box that best describes the severity of the reaction using the following definitions:

Mild is awareness of symptom, but easily tolerated

Moderate is definitely acting like something is wrong

Severe is extremely distressed or unable to do usually activities
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc,d
•
Intrauterine hormone-releasing system (IUS)c,e
•
IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
 
 
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Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double barrier 
methods)e
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those 
which inhibit ovulation.
d
IUS is a progestin releasing IUD.
e
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, 
but not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-
Male and female condom should not be used together (due to risk of failure with friction).
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be used 
in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations with 
the greatest need. All specimens will be used by the Sponsor or those working for or with the 
Sponsor.
 
 
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3. Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical study data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant 
characteristics like gender, age, medical history and intervention outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future biomedical 
research, the Sponsor has developed secure policies and procedures. All specimens will be 
single-coded per ICH E15 guidelines as described below.
 
 
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At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally identifying 
information embedded within it. The link (or key) between participant identifiers and this 
unique code will be held at the study site. No personal identifiers will appear on the specimen 
tube.
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific practices. 
Analyses utilizing the future biomedical research specimens may be performed by the 
Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the specific 
scope of analysis outlined in this substudy. Future biomedical research specimens remaining 
with the third party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw consent 
at any time by contacting the principal investigator for the main study. If medical records for 
the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study use 
only. If specimens were collected from study participants specifically for future biomedical 
research, these specimens will be removed from the biorepository and destroyed. 
Documentation will be sent to the investigator confirming withdrawal and/or destruction, if 
applicable. It is the responsibility of the investigator to inform the participant of completion 
of the withdrawal and/or destruction, if applicable. Any analyses in progress at the time of 
request for withdrawal/destruction or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being answered. 
In this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
 
 
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Specimens from the study site will be shipped to a central laboratory and then shipped to the 
Sponsor-designated biorepository. If a central laboratory is not utilized in a particular study, 
the study site will ship directly to the Sponsor-designated biorepository. The specimens will 
be stored under strict supervision in a limited access facility which operates to assure the 
integrity of the specimens. Specimens will be destroyed according to Sponsor policies and 
procedures and this destruction will be documented in the biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research personnel 
and/or collaborators. Database user authentication is highly secure, and is accomplished 
using network security policies and practices based on international standards to protect 
against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present results 
in national meetings, and make results accessible on a public website in order to rapidly 
report this information to doctors and participants. Participants will not be identified by name 
in any published reports about this study or in any other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor clinical 
studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
 
 
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10.6.1
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
APaT
All-Participants-as-Treated
b-hCG
beta human chorionic gonadotropin
CBC
complete blood count
CI
confidence interval
CID
Component identification numbers
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
clinical study report
CTFG
Clinical Trial Facilitation Group
DNA
deoxyribonucleic acid 
DOD
delta optical density
DTaP
Diphtheria, Tetanus and Acellular Pertussis
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
EU
European Union
FAS
Full Analysis Set
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GMFR
geometric mean fold rise
GMT
geometric mean titer
gp
glycoprotein
gpELISA
glycoprotein antigen-based enzyme-linked immunosorbent assay
Hib
Haemophilus influenzae type b
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IPV
inactivated poliovirus
IRB
Institutional Review Board 
IVRS
interactive voice response system
IWRS
interactive web response system
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MRC-5
Medical Research Council cell strain 5
MSD
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc.
OD
optical density
PD
postdose
PFU
plaque forming units
PGt
pharmacogenetic
PK
pharmacokinetic
 
 
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Abbreviation
Expanded Term
PP
Per-protocol
RNA
ribonucleic acid
SAE
serious adverse event 
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
TCC
tissue culture control
OD
optical density
US
United States 
VRC
Vaccination Report Card
VZV
varicella-zoster virus
WOCBP
woman/women of childbearing potential 
 
 
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PRODUCT: V210  
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11
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