A Phase 3, Multicenter, Randomized, Double-blind, Active-Comparator-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Healthy Japanese Infants
Phase: PHASE3
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04384107  
Document Date: 
07-Aug-2020
A Phase 3, Multicenter, Randomized, Double-blind, 
Active-Comparator-controlled Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of V114 in Healthy Japanese 
Infants

PRODUCT: V114  
1
PROTOCOL/AMENDMENT NO.: 033-01 
V114-033-01 FINAL PROTOCOL
07-AUG-2020
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: A Phase 3, Multicenter, Randomized, Double-blind, Active-Comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in 
Healthy Japanese Infants
Protocol Number: 033-01
Compound Number: V114
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
EudraCT
Not Applicable
2019-003644-68
Approval Date: 07 August 2020
 
 
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PRODUCT: V114  
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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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PRODUCT: V114  
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PROTOCOL/AMENDMENT NO.: 033-01 
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07-AUG-2020
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
07-AUG-2020
Amendment to change to the primary objectives for the evaluation of this study
Original Protocol
09-MAR-2020
Not applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
The purpose for this amendment is to change the objectives to more closely align with World Health Organization [World Health 
Organization 2013] guidelines for the assessment of immune responses to PCVs.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Section 3 Hypotheses, Objectives, 
and Endpoints 

Changed hypothesis 2 (H2) to evaluate 
non-inferiority of V114 to 
Prevenar 13™ for the 2 unique V114 
serotypes instead of an evaluation of 
superiority.

Changed the evaluation of anti-PnPs 
serotype-specific IgG Geometric Mean 
Concentrations (GMCs) for the 13 
shared serotypes compared with 
Prevenar 13™to the primary objective, 
and added hypothesis 3 (H3).
Revisions were made to more closely align 
with World Health Organization guidelines for 
the assessment of immune responses to PCVs.
Section 4.2.1.1 Immunogenicity
Endpoints
Changed the percentage of participants for 
whom OPA responses at 30 days PD3 and 
30 days PD4 will be evaluated.
Larger numbers of participants contributing to 
the OPA analysis will enable better precision in 
the evaluation of functional antibody responses.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
Section 9.1 Statistical Analysis 
Plan Summary
Section 9.3 Hypotheses/Estimation
Section 9.4.1 Immunogenicity 
Endpoints
Section 9.6.1 Statistical Methods 
for Immunogenicity Analyses
Section 9.8 Multiplicity
Section 9.9.1 Sample Size and 
Power for Immunogenicity 
Analyses
Updated these sections to align with changes 
to hypothesis 2 (H2) and addition of 
hypothesis 3 (H3)
Revisions were made to incorporate changes to 
the statistical analyses for the evaluation of the 
IgG response rates for the 2 unique V114 
serotypes and the IgG GMCs for the 13 shared 
serotypes, compared with Prevenar 13™.
Section 9.10 Subgroup Analyses
Added the analysis of IgG GMCs at 30 days 
PD3.
Revisions were made to incorporate changes to 
the subgroup analyses.
Throughout
Editorial revisions
Minor editorial changes to the text.
 
 
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PRODUCT: V114  
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................22
2.2.1
V114 and Pneumococcal Disease................................................................22
2.2.2
Preclinical and Clinical Studies ...................................................................23
2.2.3
Information on Other Study-related Therapy ..............................................23
2.3
Benefit/Risk Assessment......................................................................................24
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................24
4
STUDY DESIGN............................................................................................................27
4.1
Overall Design......................................................................................................27
4.2
Scientific Rationale for Study Design.................................................................28
4.2.1
Rationale for Endpoints ...............................................................................28
4.2.1.1
Immunogenicity Endpoints................................................................28
4.2.1.2
Safety Endpoints................................................................................29
4.2.1.3
Future Biomedical Research..............................................................29
4.2.2
Rationale for the Use of Comparator...........................................................30
4.3
Justification for Dose...........................................................................................30
4.4
Beginning and End of Study Definition .............................................................30
4.4.1
Clinical Criteria for Early Study Termination .............................................30
5
STUDY POPULATION ................................................................................................30
5.1
Inclusion Criteria.................................................................................................31
5.2
Exclusion Criteria................................................................................................31
5.3
Lifestyle Considerations......................................................................................33
5.4
Screen Failures.....................................................................................................33
5.5
Participant Replacement Strategy......................................................................33
6
STUDY INTERVENTION............................................................................................33
6.1
Study Intervention(s) Administered...................................................................33
6.1.1
Medical Devices...........................................................................................35
6.2
Preparation/Handling/Storage/Accountability .................................................35
 
 
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6.2.1
Dose Preparation..........................................................................................35
6.2.2
Handling, Storage, and Accountability........................................................35
6.3
Measures to Minimize Bias: Randomization and Blinding..............................36
6.3.1
Intervention Assignment..............................................................................36
6.3.2
Stratification.................................................................................................36
6.3.3
Blinding........................................................................................................36
6.4
Study Intervention Compliance..........................................................................37
6.5
Concomitant Therapy..........................................................................................37
6.5.1
Rescue Medications and Supportive Care ...................................................38
6.6
Dose Modification (Escalation/Titration/Other)...............................................38
6.7
Intervention After the End of the Study............................................................38
6.8
Clinical Supplies Disclosure................................................................................38
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................38
7.1
Discontinuation of Study Intervention...............................................................38
7.2
Participant Withdrawal From the Study...........................................................39
7.3
Lost to Follow-up .................................................................................................40
8
STUDY ASSESSMENTS AND PROCEDURES........................................................40
8.1
Administrative and General Procedures ...........................................................41
8.1.1
Informed Consent.........................................................................................41
8.1.1.1
General Informed Consent.................................................................41
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................42
8.1.2
Inclusion/Exclusion Criteria ........................................................................42
8.1.3
Participant Identification Card.....................................................................42
8.1.4
Medical History ...........................................................................................42
8.1.5
Prior and Concomitant Medications Review...............................................43
8.1.5.1
Prior Medications...............................................................................43
8.1.5.2
Concomitant Medications..................................................................43
8.1.6
Assignment of Screening Number...............................................................43
8.1.7
Assignment of Treatment/Randomization Number.....................................43
8.1.8
Study Intervention Administration ..............................................................44
8.1.8.1
Timing of Dose Administration.........................................................45
8.1.9
Vaccination Report Card..............................................................................45
8.1.10
Discontinuation and Withdrawal .................................................................45
8.1.10.1
Withdrawal From Future Biomedical Research ................................45
8.1.11
Participant Blinding/Unblinding..................................................................46
8.1.12
Calibration of Equipment.............................................................................46
 
 
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8.2
Immunogenicity Assessments .............................................................................47
8.2.1
Pneumococcal Electrochemiluminescence ..................................................47
8.2.2
Multiplex Opsonophagocytic Assay............................................................48
8.3
Safety Assessments...............................................................................................48
8.3.1
Physical Examinations.................................................................................48
8.3.2
Body Temperature Measurements ...............................................................48
8.3.3
Safety Assessment and Use of the VRC......................................................49
8.3.4
Clinical Safety Laboratory Assessments .....................................................49
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................49
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................50
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......51
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...51
8.4.4
Regulatory Reporting Requirements for SAE .............................................52
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................52
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................52
8.4.7
Events of Clinical Interest............................................................................52
8.4.8
Combination Products – Medical Device Incident ......................................52
8.5
Treatment of Overdose........................................................................................53
8.6
Pharmacokinetics.................................................................................................53
8.7
Pharmacodynamics..............................................................................................53
8.8
Biomarkers ...........................................................................................................53
8.8.1
Planned Genetic Analysis Sample Collection..............................................53
8.9
Future Biomedical Research Sample Collection...............................................53
8.10
Medical Resource Utilization and Health Economics.......................................53
8.11
Visit Requirements...............................................................................................54
8.11.1
Screening......................................................................................................54
8.11.2
Treatment Period/Vaccination Visit ............................................................54
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........54
9
STATISTICAL ANALYSIS PLAN .............................................................................54
9.1
Statistical Analysis Plan Summary.....................................................................55
9.2
Responsibility for Analyses/In-house Blinding .................................................56
9.3
Hypotheses/Estimation ........................................................................................56
9.4
Analysis Endpoints...............................................................................................57
9.4.1
Immunogenicity Endpoints..........................................................................57
9.4.2
Safety Endpoints..........................................................................................58
 
 
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PRODUCT: V114  
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9.5
Analysis Populations............................................................................................58
9.5.1
Immunogenicity Analysis Population..........................................................58
9.5.2
Safety Analysis Population..........................................................................59
9.6
Statistical Methods...............................................................................................60
9.6.1
Statistical Methods for Immunogenicity Analyses......................................60
9.6.2
Statistical Methods for Safety Analyses ......................................................61
9.6.3
Summary of Baseline Characteristics ..........................................................64
9.7
Interim Analyses ..................................................................................................64
9.8
Multiplicity ...........................................................................................................64
9.9
Sample Size and Power Calculations .................................................................64
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................64
9.9.2
Sample Size and Power for Safety Analyses ...............................................65
9.10
Subgroup Analyses...............................................................................................66
9.11
Compliance (Medication Adherence).................................................................66
9.12
Extent of Exposure...............................................................................................66
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................67
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........67
10.1.1
Code of Conduct for Clinical Trials.............................................................67
10.1.2
Financial Disclosure.....................................................................................69
10.1.3
Data Protection.............................................................................................69
10.1.3.1
Confidentiality of Data ......................................................................70
10.1.3.2
Confidentiality of Participant Records...............................................70
10.1.3.3
Confidentiality of IRB/IEC Information............................................70
10.1.4
Publication Policy........................................................................................70
10.1.5
Compliance with Study Registration and Results Posting Requirements ...71
10.1.6
Compliance with Law, Audit, and Debarment ............................................71
10.1.7
Data Quality Assurance ...............................................................................72
10.1.8
Source Documents .......................................................................................73
10.1.9
Study and Site Closure.................................................................................73
10.2
Appendix 2: Clinical Laboratory Tests..............................................................74
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................75
10.3.1
Definition of AE ..........................................................................................75
10.3.2
Definition of SAE ........................................................................................76
10.3.3
Additional Events Reported.........................................................................77
10.3.4
Recording AE and SAE ...............................................................................77
 
 
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PRODUCT: V114  
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................81
10.4
Appendix 4: Combination Products: Medical Device Incident: 
Definitions, Recording and Follow-up ...............................................................82
10.4.1
Definition of Medical Device Incident ........................................................82
10.4.2
Recording, Assessment and Follow-up of Medical Device Incident 
Recording.....................................................................................................82
10.5
Appendix 5: Contraceptive Guidance................................................................84
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................85
10.7
Appendix 7: Country-specific Requirements....................................................90
10.8
Appendix 8: Abbreviations .................................................................................91
11
REFERENCES...............................................................................................................92
 
 
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PRODUCT: V114  
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................34
Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................51
Table 3
Analysis Strategy for Key Immunogenicity Variables....................................61
Table 4
Analysis Strategy for Safety Parameters..........................................................63
Table 5
Assumptions of the True Response Rates at 30 Days PD3 .............................65
Table 6
Differences in Incidence of Adverse Events Between the 2 Vaccination 
Groups That Can be Detected With an ~80% Probability (Assuming 2-
sided 5% Alpha Level With 330 Participants in Each Group) ........................66
 
 
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PRODUCT: V114  
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LIST OF FIGURES
Figure 1
V114-033 Study Design.............................................................................18
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active-Comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in 
Healthy Japanese Infants
Short Title: A Phase 3 study of V114 in healthy Japanese infants
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives and endpoints will be evaluated in healthy Japanese infants enrolled 
at 2 to 6 months of age (from 2 months to 1 day prior to 7 months of age [inclusive]) 
administered V114 or Prevenar 13™.
Objectives
Endpoints
Primary
•
Objective 1: To evaluate the safety and
tolerability of V114 with respect to the 
proportion of participants with adverse
events (AEs).
Following any vaccination with V114:
•
Solicited injection-site AEs from Day
1 (the day of vaccination is considered 
Day 1) through Day 14 
postvaccination
•
Solicited systemic AEs from Day 1
through Day 14 postvaccination
•
Vaccine-related serious adverse events
(SAEs) through completion of study
participation
•
Objective 2: To compare the anti-
pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G
(IgG) response rates (proportion of
participants meeting serotype-specific IgG 
threshold value of ≥0.35 μg/mL) at 30 
days following Dose 3 for participants
administered V114 versus participants 
administered Prevenar 13™.
•
Anti-PnPs serotype-specific IgG
responses for the 15 serotypes
contained in V114 at 30 days Postdose
3 (PD3)
 
 
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Objectives
Endpoints
Hypothesis (H1): V114 is non-inferior to
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based 
on response rates at 30 days following 
Dose 3.
(The statistical criterion for non-
inferiority requires the lower bound of the 
2-sided 95% CI for the difference in the 
response rates [V114 minus Prevenar
13™] to be greater than -0.1).
Hypothesis (H2): V114 is non-inferior to
Prevenar 13™ for the 2 serotypes unique
to V114 based on the response rate of the 
2 unique V114 serotypes compared with 
the lowest response rate of any of the 
shared serotypes in Prevenar 13™at 30
days following Dose 3.
(The statistical criterion for non-
inferiority requires the lower bound of the 
2-sided 95% CI for the difference in the 
response rates [V114 minus Prevenar
13™] to be greater than -0.1).
•
Objective 3: To compare anti-PnPs 
serotype-specific IgG Geometric Mean 
Concentrations (GMCs) for the 13 shared 
serotypes between V114 and Prevenar
13™ at 30 days following Dose 3 for 
participants administered V114 versus 
participants administered Prevenar 13™.
•
Hypothesis (H3): V114 is non-inferior to 
Prevenar 13™for the 13 shared serotypes 
between V114 and Prevenar 13™based 
on anti-PnPs serotype-specific IgG GMCs 
at 30 days following Dose 3.
(The statistical criterion for non-
inferiority requires the lower bound of 
two-sided 95% CI for anti-PnPs serotype-
specific IgG GMC ratios (V114/Prevenar
13™) to be greater than 0.5.)
•
Anti-PnPs serotype-specific IgG 
responses for the 13 shared serotypes
between V114 and Prevenar 13™at 
30 days PD3
 
 
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Objectives
Endpoints
Secondary
•
Objective 1: To compare anti-PnPs 
serotype-specific IgG Geometric Mean 
Concentrations (GMCs) for the 2 unique 
V114 serotypes at 30 days following Dose 
3 for participants administered V114 
versus participants administered Prevenar 
13™.
•
Anti-PnPs serotype-specific IgG 
responses for the 2 unique V114 
serotypes at 30 days PD3
•
Objective 2: To compare the anti-PnPs 
serotype-specific IgG response rates 
(proportion of participants meeting 
serotype-specific IgG threshold value of 
≥0.35 μg/mL) at 30 days following Dose 4
for participants administered V114 versus 
participants administered Prevenar 13™.
•
Anti-PnPs serotype-specific IgG
responses for the 15 serotypes
contained in V114 at 30 days Postdose 
4 (PD4)
•
Objective 3: To compare anti-PnPs
serotype-specific IgG GMCs at 30 days 
following Dose 4 for participants 
administered V114 versus participants 
administered Prevenar 13™.
•
Anti-PnPs serotype-specific IgG
responses for the 15 serotypes
contained in V114 at 30 days PD4
•
Objective 4: To evaluate the anti-PnPs 
serotype-specific opsonophagocytic 
activity (OPA) response rates and 
Geometric Mean Titers (GMTs) at 30 
days following Dose 3 by each 
vaccination group.
•
Anti-PnPs serotype-specific OPA
responses for the 15 serotypes
contained in V114 at 30 days PD3
•
Objective 5 (OPA Subset): To evaluate
the anti-PnPs serotype-specific OPA
response rates and GMTs at 30 days 
following Dose 4 by each vaccination 
group.
•
Anti-PnPs serotype-specific OPA
responses for the 15 serotypes
contained in V114 at 30 days PD4
 
 
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Healthy Japanese infants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control without placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Care Provider
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 23 months from the time that written 
informed consent is provided for the first participant until 
the last participant’s last study-related telephone call or 
visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result 
or at the time of final contact with the last participant, 
whichever comes last.
Number of Participants:
Approximately 660 participants will be randomized with approximately 330 in each 
intervention group. 
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name Vaccine
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Vaccination 
Regimen
Use
V114
V114
Refer to IB
4 doses
SC
Single dose at 
Visits 1, 2, 3, 
and 5
Experimental
Prevenar 13™Prevenar
13™
Refer to 
product 
labeling
4 doses
SC
Single dose at 
Visits 1, 2, 3, 
and 5 
Experimental
Admin.: Administration, IB: Investigator’s Brochure, SC: Subcutaneous
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 7 to 14 
months from the time the participant’s legally acceptable representative
signs the Informed Consent Form (ICF) through the final contact. 
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.
Figure 1
V114-033 Study Design
 
 
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1.3
Schedule of Activities
Study Period
Screening／Intervention
Notes
Visit Number:
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
See Section 8.1.10 for details on 
discontinuation.
Scheduled Time:
Age: 2-6 months
(Dose 1)
~1 month 
after Dose 1
(Dose 2)
~1 month 
after Dose 2
(Dose 3)
~1 month
after Dose 3
Age: 12 to 15 
months
(Dose 4)
~1 month 
after Dose 4
Months of age is calculated according to the 
participant’s birth date.
Visit Window:
2 months of age 
to
1 day prior to
7 months of age
28 to 56 days
after Dose 1
28 to 56 days
after Dose 2
28 to 42 days
after Dose 3
12 months of age 
to
1 day prior to 
16 months of age
28 to 42 days
after Dose 4
Visit 2 (Dose 2) and Visit 3 (Dose 3) could 
be later than the upper limit of visit window 
but Visit 3 (Dose 3) must be before 12 
months of age and at least 60 days interval 
is needed between Visit 3 (Dose 3) and Visit 
5 (Dose 4).
Administrative and General Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study 
procedures.
Informed Consent for 
Future Biomedical 
Research (FBR)
X
Participation in FBR is optional and consent 
must be obtained before collection of buccal 
swab DNA samples.
Assignment of 
Screening Number
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Review of prior medications/vaccinations, a 
complete physical examination, and 
temperature measurement are required at 
Visit 1 to determine eligibility.
Medical History
X
Post-Randomization Procedures
Assignment of 
Randomization 
Number
X
Prior/Concomitant 
Medication and Non-
Study Vaccination 
Review
X
X
X
X
X
X
 
 
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Study Period
Screening／Intervention
Notes
Visit Number:
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
See Section 8.1.10 for details on 
discontinuation.
Scheduled Time:
Age: 2-6 months
(Dose 1)
~1 month 
after Dose 1
(Dose 2)
~1 month 
after Dose 2
(Dose 3)
~1 month
after Dose 3
Age: 12 to 15 
months
(Dose 4)
~1 month 
after Dose 4
Months of age is calculated according to the 
participant’s birth date.
Visit Window:
2 months of age 
to
1 day prior to
7 months of age
28 to 56 days
after Dose 1
28 to 56 days
after Dose 2
28 to 42 days
after Dose 3
12 months of age 
to
1 day prior to 
16 months of age
28 to 42 days
after Dose 4
Visit 2 (Dose 2) and Visit 3 (Dose 3) could 
be later than the upper limit of visit window 
but Visit 3 (Dose 3) must be before 12 
months of age and at least 60 days interval 
is needed between Visit 3 (Dose 3) and Visit 
5 (Dose 4).
V114 or 
Prevenar 13™ 
Administration 
(Blinded)
X
X
X
X
Before each vaccine administration, the 
investigator must review medical history to 
ensure the participant has no new 
contraindication to the vaccine(s) scheduled 
to be given (Section 8.1.8).
Non-study Pediatric 
Vaccines
(X)
(X)
(X)
(X)
(X)
(X)
Non-study pediatric vaccines are permitted. 
If given at the same time, oral vaccines are 
recommended to be given prior to the study 
vaccine and other injectable vaccines. Other
injectable vaccines are administered after
the study vaccine and in a separate limb.
See Section 6.5 for details on concomitant 
vaccines.
Provide VRC
X
X
X
X
Review VRC data
X
X
X
X
See Section 8.1.9 for details.
Collect VRC
X
X
X
X
Safety Procedures
Complete Physical 
Examination
X
To be performed by the investigator before 
vaccine is administered (see Section 8.3.1).
Targeted Physical 
Examination
X
X
X
To be performed by the investigator before 
vaccine is administered (see Section 8.3.1).
Body Temperature 
Measurement
X
X
X
X
Each participant’s body temperature must 
be taken before vaccination (see 
Section 8.3.2 for method). Participants who 
have febrile illness at or within 72 hours of 
vaccination must be rescheduled. 
 
 
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Study Period
Screening／Intervention
Notes
Visit Number:
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
See Section 8.1.10 for details on 
discontinuation.
Scheduled Time:
Age: 2-6 months
(Dose 1)
~1 month 
after Dose 1
(Dose 2)
~1 month 
after Dose 2
(Dose 3)
~1 month
after Dose 3
Age: 12 to 15 
months
(Dose 4)
~1 month 
after Dose 4
Months of age is calculated according to the 
participant’s birth date.
Visit Window:
2 months of age 
to
1 day prior to
7 months of age
28 to 56 days
after Dose 1
28 to 56 days
after Dose 2
28 to 42 days
after Dose 3
12 months of age 
to
1 day prior to 
16 months of age
28 to 42 days
after Dose 4
Visit 2 (Dose 2) and Visit 3 (Dose 3) could 
be later than the upper limit of visit window 
but Visit 3 (Dose 3) must be before 12 
months of age and at least 60 days interval 
is needed between Visit 3 (Dose 3) and Visit 
5 (Dose 4).
30-Minute 
Postvaccination 
Observation Period
X
X
X
X
To be performed by blinded study site 
personnel only.
AE Monitoring
X
X
X
X
X
X
Nonserious AEs are to be reported from 
Days 1 through 14 following each 
vaccination. SAEs, deaths and medical 
device incidents are to be reported 
throughout the duration of an individual’s 
study participation.
See Section 8.4, 10.3 and 10.4 for details. 
Immunogenicity Procedures
Collect Blood 
(Serum) for 
Immunogenicity 
Assays
X
X
X
Blood samples must be collected before 
vaccination where applicable. 
Future Biomedical Research
Collect Buccal Swabs
for FBR
X
Buccal swab DNA samples for analysis 
should be obtained prior to vaccination at 
Visit 1, on randomized and FBR consented 
participants only.
AE = adverse event; DNA = deoxyribonucleic acid; VRC = Vaccination Report Card; FBR = Future Biomedical Research; SAE = serious adverse event
 
 
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2
INTRODUCTION
Merck Sharp & Dohme Corp. (MSD) is developing an investigational 15-valent
pneumococcal conjugate vaccine (PCV) (referred to as V114) for the prevention of
pneumococcal disease caused by the serotypes in the vaccine. V114 contains the 13 serotypes
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) present in the licensed vaccine 
Prevenar 13™ (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein], 
Wyeth Pharmaceuticals, a subsidiary of Pfizer, Inc., Philadelphia, PA), plus 2 additional 
serotypes (22F and 33F).
2.1
Study Rationale
Routine PCV immunization of children is effective in preventing vaccine serotype-specific 
pneumococcal disease. Despite the availability of PCVs, pneumococcal disease remains a 
concern as non-vaccine serotypes have gradually emerged in increasing frequency in 
invasive pneumococcal disease (IPD) isolates. Given the high morbidity and mortality of IPD 
worldwide, the evolving serotype distribution, and the value of multiple suppliers to 
strengthen global supply, there is a continued need to develop new PCVs with comparable 
immunogenicity to licensed PCVs for shared serotypes and expanded serotype coverage. 
V114 includes an additional 2 key serotypes compared with Prevenar 13™ and will address 
an unmet medical and public health need for a PCV with expanded coverage.
The purpose of this clinical study is to evaluate the safety and immunogenicity of a 4-dose
schedule (3-dose primary series followed by a toddler dose) of V114 compared with
Prevenar 13™. Country-specific routine immunization regimens vary by schedule and
number of doses. In Japan, a 4-dose schedule, consisting of a 3-dose primary series at 
approximately 2, 3 and 4 months of age followed by a toddler dose at 12 to 15 months of age,
is currently recommended by Japan Pediatric Society. In this study, the first dose is given at 2 
to 6 months of age and 2nd and 3rd dose is given with an interval of ≥27 days from the prior 
doses.  
It is generally recommended that Prevenar 13™ is to be given at the same time as other
National Immunization Program (NIP) pediatric vaccines. The concomitant administration of 
V114 with most NIP pediatric vaccines will be allowed in this Phase 3 clinical study at the 
discretion of investigators.
2.2
Background
2.2.1
V114 and Pneumococcal Disease
Refer to the Investigator’s Brochure (IB) for V114 for detailed background, including 
information on pneumococcal disease burden.
Streptococcus pneumoniae remains a significant cause of disease worldwide, with clinical
manifestations include both invasive infections (meningitis, bacteremic pneumonia, and 
bacteremia), and noninvasive infections (acute otitis media, non-bacteremic pneumonia, and 
sinusitis). 
 
 
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Infection surveillance in Japan (2017) indicates that the total number of reports of IPD was 
3,139, and prevalence was 9.37 per 100,000 population for children <5 years of age and 5.34 
per 100,000 population for adults 65 years of age and older.
Currently, many countries worldwide have incorporated licensed PCVs (eg, Prevenar 13™) 
into their infant immunization programs. In Japan emergency promotion fund project with 
Prevenar™was initiated in November 2010 and introduced into pediatric NIP in April 2013.
Prevenar™was then replaced by Prevenar 13™in November 2013. Since PCVs have been
introduced into the NIP, the overall burden of IPD in children caused by vaccine serotypes 
has decreased by 97% in 2017. On the other hand, the proportion of IPD in children caused 
by serotypes not included in Prevenar 13™is increasing.
The investigational Merck Sharp & Dohme Corp. (MSD), PCV, V114 is a 15-valent vaccine, 
containing pneumococcal polysaccharide conjugates of the 13 serotypes in Prevenar 13™(1, 
3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) plus 2 additional serotypes (22F and 
33F).
In Japan, the rate of serotypes 22F and 33F isolates from children <15 years with IPD in 
2014 were 11.1% and 0.8% [Nakano S., et al 2016]. Both 22F and 33F have been associated
with serious clinical outcomes, including IPD, as demonstrated by their high degree of 
invasiveness compared with other serotypes not currently covered by licensed PCVs. 
Furthermore, serotypes 22F and 33F have shown relative resistance to certain antibiotics 
used in the treatment of community acquired pneumonia [Golden AR., et al 2016]. Thus, it is 
anticipated that vaccination with V114 will contribute further to prevention of disease in both 
children and adults due to clinically important strains of S. pneumoniae compared to 
Prevenar 13™.
2.2.2
Preclinical and Clinical Studies
A Phase 1 study evaluating the safety and immunogenicity of V114 administered 
subcutaneously or intramuscularly to healthy Japanese infants (V114-028) is still ongoing.
A Phase 1 study has demonstrated the safety and immunogenicity of V114 administered 
intramuscularly to healthy Japanese adults 50 years of age and older (V114-015) has
completed. A Phase 3 study involving healthy Japanese adults 65 years of age and older
(V114-019) is still ongoing.
Refer to the IB for detailed information on completed preclinical and clinical studies 
conducted with V114.
2.2.3
Information on Other Study-related Therapy
Prevenar 13™contains the 7 pneumococcal serotypes included in Prevenar™(4, 6B, 9V, 14,
18C, 19F and 23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A).
Prevenar 13™ will be EU commercial product in this study. Refer to approved labeling for 
detailed background information on Prevenar 13™.
 
 
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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.
Approximately 50% of participants will be assigned to Prevenar 13™ and receive 4 doses of 
Prevenar 13™, the standard of care, as the active comparator in this study. V114 is expected 
to provide comparable immune responses and a comparable safety profile to Prevenar 13™
for the shared pneumococcal serotypes while providing additional coverage for the 2 
serotypes (22F and 33F) unique to V114. It is unknown if the investigational V114 will have 
the same benefit/risk profile as Prevenar 13™. V114 has the potential to prevent IPD caused 
by serotype 22F and 33F.
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
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives and endpoints will be evaluated in healthy Japanese infants enrolled 
at 2 to 6 months of age (from 2 months to 1 day prior to 7 months of age [inclusive])
administered V114 or Prevenar 13™. 
 
 
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Objectives
Endpoints
Primary
•
Objective 1: To evaluate the safety and
tolerability of V114 with respect to the 
proportion of participants with adverse events 
(AEs).
Following any vaccination with V114:
•
Solicited injection-site AEs from 
Day 1 (the day of vaccination is 
considered Day 1) through Day 14 
postvaccination
•
Solicited systemic AEs from Day 1
through Day 14 postvaccination
•
Vaccine-related serious adverse 
events (SAEs) through completion 
of study participation
•
Objective 2: To compare the anti-
pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
response rates (proportion of participants 
meeting serotype-specific IgG threshold value 
of ≥0.35 μg/mL) at 30 days following Dose 3 
for participants administered V114 versus 
participants administered Prevenar 13™.
Hypothesis (H1): V114 is non-inferior to
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based on 
response rates at 30 days following Dose 3.
(The statistical criterion for non-inferiority 
requires the lower bound of the 2-sided 95% 
CI for the difference in the response rates 
[V114 minus Prevenar 13™] to be greater 
than -0.1).
Hypothesis (H2): V114 is non-inferior to
Prevenar 13™ for the 2 serotypes unique to 
V114 based on the response rate of the 2 
unique V114 serotypes compared with the 
lowest response rate of any of the shared 
serotypes in Prevenar 13™ at 30 days 
following Dose 3.
(The statistical criterion for non-inferiority
requires the lower bound of the 2-sided 95% 
CI for the difference in the response rates 
[V114 minus Prevenar 13™] to be greater 
than -0.1).
•
Anti-PnPs serotype-specific IgG
responses for the 15 serotypes
contained in V114 at 30 days 
Postdose 3 (PD3)
 
 
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Objectives
Endpoints
•
Objective 3: To compare anti-PnPs serotype-
specific IgG Geometric Mean Concentrations 
(GMCs) for the 13 shared serotypes between 
V114 and Prevenar 13™ at 30 days following 
Dose 3 for participants administered V114 
versus participants administered Prevenar
13™.
•
Hypothesis (H3): V114 is non-inferior to 
Prevenar 13™for the 13 shared serotypes 
between V114 and Prevenar 13™based on 
anti-PnPs serotype-specific IgG GMCs at 30 
days following Dose 3.
(The statistical criterion for non-inferiority 
requires the lower bound of two-sided 95% CI 
for anti-PnPs serotype-specific IgG GMC 
ratios (V114/Prevenar 13™) to be greater 
than 0.5.)
•
Anti-PnPs serotype-specific IgG 
responses for the 13 shared 
serotypes between V114 and 
Prevenar 13™at 30 days PD3
Secondary
•
Objective 1: To compare anti-PnPs serotype-
specific IgG Geometric Mean Concentrations 
(GMCs) for the 2 unique V114 serotypes at 
30 days following Dose 3 for participants 
administered V114 versus participants 
administered Prevenar 13™.
•
Anti-PnPs serotype-specific IgG 
responses for the 2 unique V114 
serotypes at 30 days PD3
•
Objective 2: To compare the anti-PnPs 
serotype-specific IgG response rates 
(proportion of participants meeting serotype-
specific IgG threshold value of ≥0.35 μg/mL) 
at 30 days following Dose 4 for participants
administered V114 versus participants 
administered Prevenar 13™.
•
Anti-PnPs serotype-specific IgG
responses for the 15 serotypes
contained in V114 at 30 days 
Postdose 4 (PD4)
•
Objective 3: To compare anti-PnPs serotype-
specific IgG GMCs at 30 days following Dose 
4 for participants administered V114 versus 
participants administered Prevenar 13™.
•
Anti-PnPs serotype-specific IgG
responses for the 15 serotypes
contained in V114 at 30 days PD4
•
Objective 4: To evaluate the anti-PnPs 
serotype-specific opsonophagocytic activity 
(OPA) response rates and Geometric Mean 
Titers (GMTs) at 30 days following Dose 3 
by each vaccination group.
•
Anti-PnPs serotype-specific OPA
responses for the 15 serotypes
contained in V114 at 30 days PD3
 
 
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Objectives
Endpoints
•
Objective 5 (OPA Subset): To evaluate the 
anti-PnPs serotype-specific OPA response 
rates and GMTs at 30 days following Dose 4 
by each vaccination group.
•
Anti-PnPs serotype-specific OPA
responses for the 15 serotypes
contained in V114 at 30 days PD4
Exploratory
•
Objective 1: To evaluate anti-PnPs serotype-
specific IgG response rates and GMCs
immediately prior to Dose 4 by each 
vaccination group.
•
Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes
contained in V114 immediately 
prior to Dose 4 (Predose 4)
•
Objective 2 (OPA Subset): To evaluate the 
anti-PnPs serotype-specific OPA response 
rates and GMTs immediately prior to Dose 4
by each vaccination group.
•
Anti-PnPs serotype-specific OPA
responses for the 15 serotypes
contained in V114 Predose 4
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active comparator-controlled, parallel-group, multi-site, double-blind, 
study of V114 in healthy Japanese infants enrolled at 2 to 6 months of age. Approximately 
660 infants will be randomly assigned, in 1:1 ratio with stratification into 3 categories by age 
category (2 months,3 months and 4 to 6 months of age), to receive either V114 (330 
participants) or Prevenar 13™(330 participants).
A 0.5 mL subcutaneous dose of V114 or Prevenar 13™will be administered (blinded) to 
healthy Japanese infants with the 1st dose given at 2 to 6 months of age and 2nd and 3rd dose is 
given at an interval of ≥27 days from the prior dose. Then, the 4th dose at 12 to 15 months of 
age is administered. 
Participants will be followed for injection-site and systemic AEs through Day 14 following 
each vaccination with V114 or Prevenar 13™. Information for SAEs and deaths, regardless 
of whether the events are considered vaccine-related by the investigator, will be collected 
from the time consent is signed through completion of participation in the study. 
Blood samples for immunogenicity assays will be collected at 3 timepoints: (1) 30 days after 
the completion of the 3-dose primary series (PD3), (2) immediately before receipt of Dose 4 
(Predose 4), and (3) 30 days after Dose 4 (PD4).
After completion of immunogenicity testing to evaluate the study objectives and hypotheses, 
serum samples will be stored to conduct any additional study-related testing as required by 
regulatory agencies or the Sponsor. For randomized study participants who provided consent 
for Future Biomedical Research, leftover sera from the study may be used for other purposes 
 
 
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such as the development and/or validation of pneumococcal assays after completion of all 
study-related immunogenicity testing.
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.
4.2
Scientific Rationale for Study Design
This is a Phase 3 study to assess the safety, tolerability, and immunogenicity of V114 in
healthy Japanese infants. Prevenar 13™is indicated for healthy infants from 2 months to 5 
years of age in Japan with official funding (NIP) since 2013. In Japan, the first dose of 
Prevenar 13™should be given by 6 months of age.
The safety and immunogenicity in subcutaneous administration of V114 will be assessed in 
this study because subcutaneous administration is typically selected for most pediatric 
vaccines in Japan.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Sera from participants will be used to measure vaccine-induced, serotype-specific immune
responses for all 15 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 
33F) included in V114 using the pneumococcal electrochemiluminescence (PnECL) assay 
and the Multiplexed Opsonophagocytic Assay (MOPA). PnECL assay measures serotype-
specific IgG response rates and IgG GMC. MOPA measures serotype-specific OPA response 
rates and GMTs. OPA GMTs represent functional antibodies capable of inhibiting growth of 
S. pneumoniae in culture. Additional information on the immunogenicity assays can be found 
in Section 8.2.
The PnECL will be used to test the primary immunogenicity hypotheses in this study. The 
PnECL assay requires less serum, and several studies have shown a positive correlation 
between serotype-specific IgG antibody concentrations and OPA titers in children and adults 
[Centers for Disease Control and Prevention 2010] [Anttila, M., et al 1999] [Romero-Steiner, 
S., et al 1997].
The use of the serotype-specific IgG antibody level of ≥0.35 μg/mL has been recommended
by a World Health Organization (WHO) expert panel as an acceptable threshold value for
evaluating the clinical performance of PCVs following a routine childhood vaccination
regimen [World Health Organization 2013] [World Health Organization 2008]. The response
rate (ie, the proportion of participants meeting the serotype-specific IgG threshold value of
≥0.35 μg/mL) is one of primary endpoints in this study.
 
 
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Anti-PnPs serotype-specific IgG and OPA responses will be measured at 3 time points:

Approximately 30 days following Dose 3 to evaluate the immune response to the 
primary vaccination series (IgG response rates, IgG GMCs, OPA response rates and 
OPA GMTs)

Immediately prior to Dose 4 to evaluate the persistence of protective immunity (IgG 
response rates, IgG GMCs, OPA response rates and OPA GMTs)

Approximately 30 days following Dose 4 to evaluate anamnestic antibody responses 
(IgG response rates, IgG GMCs, OPA response rates and OPA GMTs)
Functional antibody activity (as measured by OPA GMTs) will be assessed in all participants 
with sufficient serum volume at PD3 to evaluate OPA responses. Additionally, evaluation of
OPA responses will be conducted at Predose 4 for the first 25% of the participants who had
OPA performed at PD3, for whom there is sufficient volume, and at PD4 for the first 50% of 
the participants who had OPA performed at PD3, for whom there is sufficient volume.
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in previous studies, published data from marketed PCVs. The paper
Vaccination Report Card (VRC) used to record AEs during the postvaccination periods, as 
defined in Section 8.1.9.
Details on the safety endpoints evaluated in this study can be found in Section 8.3.3 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in Appendix 
3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this 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. 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 future biomedical research are presented in Appendix 6.
 
 
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4.2.2
Rationale for the Use of Comparator
Placebo-controlled clinical studies for new PCVs are no longer acceptable given the proven 
clinical efficacy, public health impact, and widespread use of licensed PCVs worldwide. 
Prevenar 13™is currently the only recommended vaccine for the prevention of 
pneumococcal disease in Japanese infants and is also used in many other countries 
worldwide. It will be used as the active comparator in this study.
Refer to package insert for detailed background information on Prevenar 13™.
4.3
Justification for Dose
The dose and dosing schedule of V114 is similar to that used in previous pediatric V114 
clinical studies, which demonstrated safety and comparable immune responses to those of 
Prevenar 13™. Refer to V114 IB for details on dosing schedule. Subcutaneous route is 
typically selected for most pediatric vaccines in Japan and subcutaneous route is the same as 
Prevenar 13™.
4.4
Beginning and End of Study Definition
The overall study begins when written informed consent is provided for the first participant. 
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).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
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 risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) 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 Japanese male and female infants at 2 to 6 months 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.
 
 
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Is healthy (based on a review of medical history and physical examination) based on the 
clinical judgement of the investigator.
Demographics
2. Is Japanese male or female, 2 months of age to 6 months of age inclusive, at the time of 
randomization.
Informed Consent
3.
Has a legally acceptable representative who understands the study procedures, alternate 
treatments available, and risks involved with the study and voluntarily agrees to 
participate by giving written informed consent. The legally acceptable representative 
may also provide consent for future biomedical research. However, the participant may 
participate in the main study without participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or other 
sterile site) or known history of other culture positive pneumococcal disease.
2. Has a known hypersensitivity to any component of the PCV, or any diphtheria toxoid-
containing vaccine.
3. *Had a recent febrile illness (axillary temperature ≥37.5°C) occurring within 72 hours 
prior to receipt of study vaccine.
4. Has a known or suspected impairment of immunological function.
5. Has a history of congenital or acquired immunodeficiency.
6. Has or his/her mother has a documented human immunodeficiency virus (HIV) infection.
7. Has or his/her mother has a documented hepatitis B surface antigen – positive test.
8. Has known or history of functional or anatomic asplenia.
9. Has failure to thrive based on the clinical judgement of the investigator.
 
 
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10. Has a history of autoimmune disease (including but not limited to systemic lupus 
erythematosus, antiphospholipid syndrome, Behcet’s disease, autoimmune thyroid 
disease, polymyositis and dermatomyositis, scleroderma, type 1 diabetes mellitus, or 
other autoimmune disorders).
11. Has a known neurologic or cognitive behavioral disorder, including encephalitis/myelitis, 
acute disseminating encephalomyelitis, pervasive development disorder, and related 
disorders.
Prior/Concomitant Therapy
12. Has received a dose of any pneumococcal vaccine prior to study entry.
13. *Meets one or more of the following systemic corticosteroid exclusion criteria:
a.
Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/d for persons weighing >10 kg) for ≥14 consecutive days and 
has not completed this course of treatment at least 30 days prior to the first dose of 
study vaccine at randomization.
b. Has received or is expected to receive systemic corticosteroids within 14 days prior to
any dose of study vaccine.
c.
Is expected to require systemic corticosteroids within 30 days after each study 
vaccination.
Note: Topical, ophthalmic, and inhaled steroids are permitted.
14. *Has received other licensed non-live vaccines within 14 days before receipt of study 
vaccines or is scheduled to receive any licensed non-live vaccine within 14 days 
following receipt of study vaccines. Exception: Inactivated influenza vaccine may be 
administered but must be given at least 7 days before receipt of study vaccines or at least 
15 days after receipt of study vaccines.
15. *Has received a licensed live vaccine within 28 days before receipt of study vaccines or
is scheduled to receive any live vaccine within 14 days following receipt of study 
vaccines.
16. Has received a blood transfusion or blood products, including immunoglobulins.
Prior/Concurrent Clinical Study Experience
17. Has participated in another clinical study of an investigational product before the 
beginning or anytime during the duration of the current clinical study. Participants 
enrolled in observational studies may be included; these will be reviewed on a 
case-by-case basis for approval by the Sponsor.
 
 
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Other Exclusions
18. Has any other reason that, in the opinion of the investigator, may interfere with the 
evaluation required by the study. Reasons may include, but are not limited to, being 
unable to keep appointments or planning to relocate far away during the study.
19. 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.
For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants whose legally acceptable representative provides 
consent to participate in the clinical study, but are not subsequently randomized in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the 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 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.
Clinical supplies (V114 and Prevenar 13™) will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
 
 
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Table 1
Study Interventions
Arm Name
Arm Type
Inter-
vention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
V114
Experimental
V114
Biological/
Vaccine
Sterile 
Suspensi
on 
(Prefilled 
Syringe)
Refer to IB
0.5 mL
SC
Single dose 
at Visits 1, 2, 
3, and 5
Experi
mental
IMP
Central
Prevenar 
13™
Active
Comparator
Prevenar 
13™*
Biological/
Vaccine
Sterile 
Suspensi
on 
(Prefilled 
Syringe)
Refer to 
product 
labeling
0.5 mL
SC
Single dose 
at Visits 1, 2, 
3, and 5
Experi
mental
IMP
Central
Admin. = administration; IB = Investigator’s Brochure; SC = Subcutaneous; IMP = investigational medicinal product; NIMP = non-investigational medicinal 
product
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.
*: Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein), EU commercial product
 
 
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All supplies indicated in Table 1 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.
6.1.1
Medical Devices
Study vaccine will be provided as a single dose pre-filled syringe, which is defined as a 
combination product (syringe device and vaccine). A syringe device corresponds to a 
medical device.
Medical device incidents for a syringe device, including those resulting from malfunctions of 
a syringe, must be reported to the Sponsor in Japan. Refer to Section 8.4.8 and Appendix 4 
for details.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
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. Information on preparation and administration of 
study vaccines is provided in Section 6.3.3 and Section 8.1.8.
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).
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.
 
 
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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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to receive V114 or 
Prevenar 13™.
6.3.2
Stratification
Intervention randomization will be stratified according to the age category (2 months, 3 
months and 4 to 6 months of age).
Each age category is defined as follows:
・2 months of age category：2 months of age to 1 day prior to 3 months of age 
・3 months of age category：3 months of age to 1 day prior to 4 months of age
・4 to 6 months of age category：4 months of age to 1 day prior to 7 months of age
6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevenar 13™will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study site personnel. The 
participant, the participant’s parent/guardian, and the investigator who are involved in the 
clinical evaluation of the participants will remain blinded to the group assignments.
Because V114 and Prevenar 13™have a different appearance, a member of the study site 
staff will be unblinded for the purposes of receiving, maintaining, preparing, and 
administering these study vaccines. Procedures for handling, preparing, and administering 
the unblinded vaccines are in the Investigator Trial File Binder.
To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel and the participant’s parent/guardian will remain blinded such as not to be present 
in the same room or to be separated with a curtain when study vaccines are administered.
Contact between participants or the participant’s parent/guardian and unblinded study 
 
 
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personnel after vaccination administration is strictly prohibited. Blinded site personnel will 
be responsible for all safety and immunogenicity follow-up procedures after vaccine 
administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) directly involved with the conduct of this 
study will remain blinded to the participant-level intervention assignment until the end of the 
study.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified plan for V114 and Prevenar 13™vaccination as 
indicated in Section 1.3 require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for that medication or vaccination (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’s legally acceptable representative. 
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin,
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate electronic Case Report Form (eCRF). It is important to record the use of any 
analgesic or antipyretic medication that occurs on the day of vaccination on the VRC and 
appropriate eCRF.
During influenza season, it is anticipated that participants 6 months of age and older may be 
given inactivated influenza vaccine. Inactivated influenza vaccine should be administered 
either 7 days prior to or 15 days after the administration of V114 or Prevenar 13™. The 
influenza vaccine should not be administered at the same time as V114 or Prevenar 13™.
Other non-study pediatric vaccines (oral or injectable) including NIP vaccines can be 
administered on the same time as V114 or Prevenar 13™. Rotavirus vaccine administered 
orally is recommended to be given before V114 or Prevenar 13™ and other injectable 
concomitant vaccines. Other pediatric injectable vaccines are administered after V114 or 
 
 
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Prevenar 13™and in a separate limb. When the non-live or live vaccine is administered on a 
different day from V114 or Prevenar 13™, these vaccines can be administered from 15 days 
after V114 or Prevenar 13™. These vaccines should be recorded on the appropriate eCRF.
V114 or Prevenar 13™ are administered in either arm. To avoid any confounding results, 
non-study injectable vaccines should not be administered in the same limb as V114 or 
Prevenar 13™. Documentation of which limb was used for the administration of V114 or 
Prevenar 13™ must be recorded on the VRC and appropriate eCRF. 
No other investigational compound or device may be administered at any time during this 
study without prior approval by the Sponsor.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is allowed 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 blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity. The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.11). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
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.
 
 
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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 vaccination 
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.3.
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 8.1.10 and Section 
8.11.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant’s legally acceptable representative requests to discontinue study 
intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
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.
For participants who are discontinued from study intervention but continue to be monitored
in the study, see Section 1.3 and Section 8.11.3 for those procedures to be completed at each
specified visit.
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
A participant must be withdrawn from the study if the participant’s legally acceptable 
representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
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 8.1.10. The procedures to be performed should a participant repeatedly 
 
 
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fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
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’s legally acceptable representative and 
reschedule the missed visit. If the participant’s legally acceptable representative is 
contacted, the participant’s legally acceptable representative 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’s legally acceptable representative at each missed visit (eg, telephone calls 
and/or a certified letter to the legally acceptable representative 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 (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
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.
 
 
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•
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 be obtained from the participant’s legally 
acceptable representative. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
Approximately 5 mL of blood will be drawn at each of Visits 4, 5, and 6 for immunogenicity 
assays. The maximum amount of blood collected from each participant over the duration of 
the study will not exceed approximately 15 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from 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 is in place.
8.1.1.1
General Informed Consent
Consent must be documented on the consent form by the dated signature of the participant’s 
legally acceptable representative along with the dated signature of the person conducting the 
consent discussion.
A copy of the signed and dated consent form should be given to the participant’s legally 
acceptable representative before the individual’s participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant’s legally acceptable representative must receive the Institutional Review 
Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable opinion in advance 
of use. The participant’s legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the willingness for the 
participant to continue participation in the study. The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the dated signature of the participant’s legally acceptable representative.
 
 
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Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the future biomedical research consent to 
the participant’s legally acceptable representative, answer all of his/her questions, and obtain 
written informed consent before performing any procedure related to future biomedical 
research. A copy of the informed consent will be given to the participant’s legally acceptable 
representative.
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. The investigator should
consult with the Sponsor’s Clinical Director for any questions about participant eligibility.
If the participant meets any of the Exclusion Criteria with an asterisk (*), Visit 1 may be
rescheduled for a time when these criteria are not met.
8.1.3
Participant Identification Card
The legally acceptable representative for each participant will be given a Participant 
Identification Card identifying the individual as a participant in a research study. The card 
will contain study site contact information (including direct telephone numbers) to be utilized 
in the event of an emergency. The investigator or qualified designee will provide the legally 
acceptable representative for each participant with a Participant Identification Card 
immediately after written informed consent is provided. 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 before
vaccination at Visit 1. Birth weight and gestational age will be recorded on the appropriate 
eCRF.
 
 
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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 and record prior vaccinations from birth
and medications taken by the participant within 30 days before the first dose of study vaccine
at Visit 1. 
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record vaccination and medication, if any, taken 
by the participant during the study.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin,
blood, or blood products during a participant’s participation in this study, one of the
individuals listed on the Sponsor Contact Information page must be notified as soon as
possible. Any concurrent medication or medical treatment must be recorded on the
appropriate eCRF.
It is important to record any analgesic or antipyretic use that occurs on the day of vaccination
on the VRC and appropriate eCRF. Concomitant medications taken after Visit 1 and non-
study vaccines received since Visit 1 will be recorded with the VRC as specified in Section 
8.3.3.
Non-study pediatric vaccines administered during the study should be recorded on the
appropriate eCRF. Injectable vaccines should not be administered in the same limb as V114
or Prevenar 13™. Documentation of which limb was used for the administration of V114 or
Prevenar 13™must be recorded on the VRC (Section 8.3.3) and appropriate eCRF.
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 randomization. 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 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
 
 
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A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Before each vaccine administration, the investigator must review medical history to ensure 
that the participant has no new contraindication to the vaccine(s) scheduled to be given. This 
information should be documented in the participant’s chart. 
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer the study vaccine. Study vaccines should be administered by appropriately 
qualified members of the study personnel (physician or nurse). Procedures for handling, 
preparing, and administering the unblinded vaccines are provided in the Investigator Trial 
File Binder. Unblinded study personnel should follow the preparation and administration 
instructions for Prevenar 13™as specified in the product label.
Study vaccines should be removed from the refrigerator no more than 1 hour before 
vaccination. The time of removal and time of vaccination should be documented in the 
participant’s chart.
The V114 is provided as a single dose pre-filled syringe. Prior to administration of study 
vaccine, the unblinded study personnel should shake vigorously to obtain a homogenous 
white suspension. If white colored insoluble particle appears, the unblinded study personnel
should use rapid, horizontal hand-shaking for 5 to 10 seconds while holding the syringe in 
between the thumb and index finger until complete resuspension. This action should be 
repeated, as necessary. If appearance is otherwise, the vaccine should not be administered.
The vaccine should not be used if the vaccine cannot be resuspended.
Prevenar 13™will be supplied as a pre-filled syringe.
A 0.5-mL subcutaneous administration of study vaccine will be administered to healthy
Japanese infants at Visit 1, 2, 3 and 5. The study vaccines are administered in the either arm.
If an abnormality (ie, rash) is observed at the site where the previous dose of the study 
vaccine was administered, it is permissible to use the anterolateral muscle of the other limb to 
administer the following dose of the study vaccine. 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].
Unblinded study personnel should not have contact with participants for any study-related 
procedures/assessments after administration of study vaccines, which includes all safety 
follow-up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant and participant’s parent/guardian will be blinded to the 
study vaccine received by the participant during the study. Vaccination information, such as 
Component Identification Number and time of vaccination, must be recorded on the 
appropriate eCRF as per the data entry guidelines.
 
 
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8.1.8.1
Timing of Dose Administration
V114 or Prevenar 13™will be administered as indicated in Section 1.3. All participants will 
be observed for at least 30 minutes following each vaccination for any immediate reactions. 
This observation must be performed by blinded site personnel for V114 and Prevenar 13™
(Section 1.3 and Section 6.3.3).
Participants must be afebrile (axillary temperature <37.5°C) for at least 72 hours prior to 
each vaccine administration (Section 1.3 and Section 8.3.2). 
Blood samples at Visit 5 must be collected before study vaccination.
8.1.9
Vaccination Report Card
The investigator or delegate will train the participant’s legally acceptable representative 
(parent/guardian) in the use of the paper VRC as indicated in Section 1.3.
Body temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or non-study vaccinations will be recorded on the 
VRC as described in Section 1.3 and Section 8.3.3. The investigator or delegate will review 
the data captured on the VRC with the participant’s parent/guardian.
For the AEs outlined above, the investigator will use the information provided by the 
participant’s parent/guardian on the VRC, and verbally at the time of VRC review, to apply 
the appropriate assessment of intensity as described in Appendix 3.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the protocol-specified 
vaccinations should be encouraged to continue to be followed for all remaining study visits
as outlined in Section 1.3 and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit (Visit 6) 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 8.4.
8.1.10.1
Withdrawal From Future Biomedical Research
Consent for future biomedical research may be withdrawn by the participant’s legally 
acceptable representative. Consent may be withdrawn by the legally acceptable 
representative 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’s legally acceptable representative 
of completion of withdrawal. Any analyses in progress at the time of request for withdrawal 
 
 
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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.
8.1.11
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee needs to 
identify the intervention used by a participant and/or the dosage administered, he/she will 
contact the emergency unblinding call center by telephone and make a request for emergency 
unblinding. As requested by the investigator or medically qualified designee, the emergency 
unblinding call center will provide the information to him/her promptly and report unblinding 
to the Sponsor. Prior to contacting the emergency unblinding call center to request 
unblinding of a participant’s intervention assignment, the investigator who is a qualified 
physician should make reasonable attempts to enter the intensity of the AEs observed, the 
relation to study intervention, the reason thereof, etc., in the medical chart. If it is not 
possible to record this assessment in the chart prior to the unblinding, the unblinding should 
not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding that is part of the study design has taken place, the
investigator, site personnel, and Sponsor personnel may be unblinded so that the appropriate
follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or non-study treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.12
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 are reliable and/or reproducible. 
 
 
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Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Two immunogenicity assays (PnECL and MOPA) will be used to measure vaccineinduced, 
anti-PnPs serotype-specific immune responses for all 15 serotypes included in V114. 
Blood collection, storage and shipment instructions for serum samples will be provided in the 
operations/laboratory manual.
8.2.1
Pneumococcal Electrochemiluminescence
The Sponsor has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 PnPs serotypes contained in V114. 
The PnECL assay is based on the Meso Scale Discovery technology, which employs 
disposable multi-spot microtiter plates. The benefits of the ECL multiplex technology over 
the prior enzyme-linked immunosorbent assay (ELISA) methodology include speed, 
equivalent or better sensitivity, increased dynamic range, the ability to multiplex, and 
reduction in required serum sample and reagent volumes. The measurement of immune 
responses to the 15 serotypes included in V114 is performed using an assay format consisting 
of 2 groups of 7 and 8 serotypes each. The PnECL v2.0 assay for all 15 serotypes has 
undergone validation. The validation study evaluated various performance parameters of the 
assay including precision, ruggedness, relative accuracy, dilutional linearity, selectivity, and 
specificity. The validation results were evaluated against pre-specified acceptance criteria for 
each of the parameters.
The WHO Expert Committee on Biological Standardization has recommended that in-house 
assays used in immunogenicity studies designed to evaluate protection against IPD be 
bridged to the WHO reference assay to maintain the link between immune responses to 
vaccination and the clinical demonstration of protective efficacy against IPD conferred by the 
7 conjugated polysaccharides in Prevenar™. In 2012 and 2014, the Sponsor formally bridged 
the original PnECL assay (v1.0) to the WHO IgG ELISA in order to determine the PnECL 
threshold values that correspond to 0.35 µg/mL in the WHO ELISA for each of the 7 
Prevenar™ serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and for each of the additional 6 
serotypes (1, 3, 5, 6A, 7F, and 19A) in Prevenar 13™.
A confirmatory study was also performed to formally bridge the optimized PnECL assay 
(v2.0) to the WHO reference ELISA, and to assess the PnECL threshold values that 
correspond to 0.35 µg/mL measured using the WHO ELISA for each of the serotypes in 
V114, including the Prevenar 13™ serotypes and serotypes 22F and 33F, which were not 
previously assessed. The bridging of the PnECL v2.0 to the WHO ELISA has been 
completed, and the data showed concordance between the PnECL and WHO ELISA around 
the 0.35 μg/mL threshold value for all 15 serotypes. Thus, it is recommended that a single 
PnECL threshold value of 0.35 µg/mL be applied to each of the 15 serotypes.
 
 
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8.2.2
Multiplex Opsonophagocytic Assay
The MOPA, developed by the laboratory of Professor Moon Nahm at University of Alabama 
(World Health Organization Pneumococcal Serology Reference Laboratory), is a multiplexed 
OPA assay capable of measuring 4 serotypes at a time, against a total of 16 serotypes of 
pneumococci [Burton, Robert L. and Nahm, Moon H. 2006]. The OPA is an antibody-
mediated killing assay that measures the ability of human serum to kill S. pneumoniae
serotypes with the help of complement and phagocytic effector cells. The ability of the assay 
to simultaneously test 4 serotypes/run reduces the amount of serum needed for testing. The 
assay readout is the opsonization index, which is the reciprocal of the highest dilution that 
gives ≥50% bacterial killing, as determined by comparison to assay background controls. The 
Sponsor has developed and optimized the MOPA in a high throughput micro-colony 
platform. The MOPA assay for all 15 V114 serotypes has undergone validation. The 
validation study evaluated various performance parameters of the assay including precision, 
relative accuracy/dilutional linearity, and specificity. The validation results were evaluated 
against pre-specified acceptance criteria for each of the parameters.
8.3
Safety Assessments
The total amount of blood to be drawn over the course of the study (from prestudy to 
poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in study assessments and procedures in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator at Visit 1 for all 
participants. A targeted physical examination will be performed at subsequent vaccination 
visits (Visit 2, 3, and 5). Any clinically significant abnormality will be recorded on the 
appropriate eCRF.
The complete and targeted physical examination procedures both include obtaining vital 
signs (eg, heart rate, respiratory rate, and axillary temperature), auscultation of the heart and 
lung, and examination of the abdomen. In addition, a complete physical examination will 
include an assessment of the head, eyes, ears, nose and throat, skin, lymph nodes, 
neurological system, and musculoskeletal system. 
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Body Temperature Measurements
Pre-vaccination axillary temperatures will be taken by study personnel as indicated in Section 
1.3. Participants who have febrile illness (axillary temperature ≥37.5°C) at or within 72 hours 
of Visit 1, 2, 3, and 5 must be rescheduled. 
 
 
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Temperature readings should be taken at approximately the same time each day if possible. 
Use of temporal or tympanic thermometers to collect temperature for this study is prohibited. 
The participant’s parent/guardian will be asked to record the participant’s temperature 
reading on the VRC from Day 1 through Day 7 following each vaccination. Temperature 
measurement must be recorded in the VRC if fever is suspected during Day 8 through Day 
14.
8.3.3
Safety Assessment and Use of the VRC
All participants will be observed for 30 minutes after each vaccination for any immediate
reactions. If any immediate AEs are observed during this period, the time at which the event
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event, must be recorded on the appropriate eCRF.
Participant’s parent/guardian will use the VRC (Section 8.1.9) to document the following
information:
•
Axillary temperatures measured Day 1 (day of vaccination) through Day 7 following 
each vaccination; Day 8 through Day 14 following each vaccination if fever is suspected
•
Solicited injection-site AEs (swelling, redness, pain or tenderness, and hard lump) Day 1 
through Day 14 postvaccination
•
Solicited systemic AEs (irritability, drowsiness, appetite lost, and hives or welts) Day 1 
through Day 14 postvaccination
•
Any other unsolicited injection-site or systemic AEs Day 1 through Day 14 
postvaccination
•
Concomitant medications and non-study vaccinations Day 1 to Day 14 postvaccination
8.3.4
Clinical Safety Laboratory Assessments
There are no laboratory safety evaluations required by the protocol.
8.4
Adverse Events, Serious Adverse Events, 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.
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).
 
 
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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, or a procedure.
From the time of allocation/randomization through 14 days (42 days for live attenuated 
vaccines) following the first vaccination(s) and from the time of any subsequent 
vaccination(s) through 14 days (42 days for live attenuated vaccines) thereafter, all AEs, 
SAEs, and other reportable safety events must be reported by the investigator.
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.
SAEs must also be reported throughout the duration of the individual's participation in the 
study, regardless of whether or not related to the Sponsor's product.
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 2.
 
 
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Table 2
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:
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
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
ECI
There are no ECI for this study.
Not applicable
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
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
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 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
 
 
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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 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
Information in this section is not applicable since participants are infants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest
There are no events of clinical interest in this study.
8.4.8
Combination Products – Medical Device Incident
The procedure for documenting and reporting for medical device incident in combination 
products is shown below and in Appendix 4.
In order to fulfill Japan regulatory reporting obligations, medical device incident (as defined 
in Section 10.4.1) will be collected and reported to the sponsor in the same time frame as 
serious adverse events as per Section 8.4.1 via CRF (paper or electronic) and as per data 
entry guidelines. The paper CRF is to be used only when electronic CRF system is down. All 
medical device incidents will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant or associated person is lost to follow-up (as defined in 
Section 7.3).
 
 
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Sponsor shall review reported events by the investigator to fulfill the legal responsibility of 
notifying appropriate regulatory authorities and other entities as needed about certain safety 
information relating to medical devices being used in clinical studies.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the adverse event 
and the medical device.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study
vaccine in any 24-hour period.
No specific information is available on the treatment of overdose. 
All reports of overdose 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 electronic data collection (EDC) data entry guidelines. Paper reporting procedures can be
found in the Investigator Trial File Binder (or equivalent).
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
Biomarkers
Biomarkers are not evaluated in this study.
8.8.1
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.9
Future Biomedical Research Sample Collection
If the participant’s legally acceptable representative signs the future biomedical research 
consent, the following specimens will be obtained as part of future biomedical research:

Buccal swab DNA for future research

Leftover main study serum from immunogenicity assay stored for future research
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
 
 
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Screening procedures will be conducted at Visit 1 as outlined in Section 1.3.
8.11.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
If the participant develops a new clinical condition during the study that makes him/her 
ineligible for the study, the investigator should discuss with the Sponsor Clinical Director as 
soon as possible. The decision to continue the participant on study intervention requires the 
mutual agreement of the investigator, the Sponsor, and the participant’s legally acceptable 
representative.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
A participant may discontinue from study intervention (including receipt of V114, 
Prevenar 13™) but continue to participate in protocol-specified, AE-monitoring activities as 
outlined in Section 1.3, as long as the participant’s legally acceptable representative does not 
withdraw consent. Blood draws for immunogenicity testing could occur if agreed to by the 
participant’s legally acceptable representative at the discretion of the investigator.
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 unblinding, changes are made to primary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to unblinding, will be documented in a 
supplemental statistical analysis plan (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study. Post hoc exploratory analyses will be clearly identified in the CSR.
 
 
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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
A Phase 3, Multicenter, Randomized, Double-blind, Active-Comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of 
V114 in Healthy Japanese Infants
Treatment Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 or Prevenar 13™, 
stratified by age category (2 months, 3 months, 4 to 6 months of age).
Analysis Population
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:

Anti-PnPs serotype-specific IgG response rates (proportion of participants 
with anti-PnPs serotype-specific IgG ≥0.35 µg/mL) at 30 days PD3

Anti-PnPs serotype-specific IgG GMCs at 30 days PD3 for the 13 shared 
serotypes contained in V114 and Prevenar 13™
Safety:

Proportion of participants with solicited injection-site AEs (swelling, 
redness/erythema, tenderness/pain, and hard lump/induration) from Day 1 
through Day 14 following any vaccination with V114 or Prevenar 13™

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, appetite lost/decreased appetite, and hives or 
welts/urticaria) from Day 1 through Day 14 following any vaccination with 
V114 or Prevenar 13™

Proportion of participants with vaccine-related SAEs from Day 1 through 
completion of study participation
Statistical Methods for 
Key Immunogenicity 
Analyses
The between-group differences (V114 minus Prevenar 13™) in the response 
rates of anti-PnPs serotype-specific IgG at 30 days PD3, along with 
corresponding 95% CIs based on the method of Miettinen and Nurminen
[Miettinen, O. and Nurminen, M. 1985] stratified by age category (2 months of 
age, ≥3 months of age), will be estimated. The Cochran-Mantel-Haenszel weight 
will be used to obtain stratum-adjusted proportion difference. The lower bound 
of the 95% CIs will be compared against the pre-specified margin of -0.1 to test 
the non-inferiority hypotheses.
Anti-PnPs serotype-specific IgG concentrations at 30 days PD3 for the 13 shared 
serotypes in V114 and Prevenar 13™ will be natural log-transformed and 
analyzed using a linear model with factors for vaccination group and age 
category. Between-group differences (V114 minus Prevenar 13™) and 
corresponding 95% CIs will be estimated on the log scale using the model above, 
and the results will be transformed back to the original scale to obtain the IgG 
GMC ratios (V114/Prevenar 13™). The lower bound of the 95% CIs will be 
compared against the pre-specified margin of 0.5 to test the non-inferiority 
hypotheses.
Statistical Methods for 
Key Safety Analyses
The analysis of safety endpoints will follow a tiered approach. p-Values (Tier 1 
endpoints) for between-group comparisons and 95% CIs (Tier 1 and Tier 2 
endpoints) for between-group differences in the percentage of participants with 
the respective events will be provided. These analyses will be performed using 
the unstratified Miettinen and Nurminen method.
Interim Analysis
No interim analysis is planned.
 
 
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Multiplicity
The study will be considered to have met its primary immunogenicity objectives 
if non-inferiority is demonstrated in the IgG response rates for the 15 serotypes 
and in the IgG GMCs for the 13 shared serotypes, both at 30 days PD3.
Successful achievement of the primary immunogenicity objective requires that 
all individual serotypes within the hypotheses satisfy the pre-specified non-
inferiority criteria at a 1-sided α level of 0.025. This approach will control the 1-
sided type I error rate at 0.025, thus no multiplicity adjustment will be required.
No multiplicity adjustments will be made for the safety objective.
Sample Size and Power
A total of 660 participants will be randomized in a 1:1 ratio to V114 or Prevenar
13™ to have 300 participants per arm in the PP population at 30 days PD3. The 
study will have an overall power of ~83% for all the primary hypotheses at a 1-
sided α level of 0.025, with the underlying serotype-specific IgG response rates 
as observed in V114 Protocol 008, as well as the true IgG GMC ratios of 1.0 and 
the true standard deviation of natural log IgG concentration of 1.1 for all shared 
serotypes.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IRT (or equivalent).
9.3
Hypotheses/Estimation
The primary immunogenicity objectives are described below.
Primary endpoints/hypotheses (H1 and H2)
The first primary objective is to compare the response rates of anti-PnPs serotype-specific 
IgG between V114 and Prevenar 13™ at 30 days PD3. The response rate is defined as the 
proportion of participants with anti-PnPs serotype-specific IgG responses achieving the 
threshold value of 0.35 μg/mL. The objective will be assessed via the following non-
inferiority hypotheses:
H0: p1-p2 ≤-0.1 versus
H1: p1-p2 >-0.1.
For the 13 shared serotypes contained in V114 and Prevenar 13™, p1 is the response rate for 
the V114 group and p2 is the response rate for the Prevenar 13™ group. The 2 unique 
serotypes in V114 will be compared with the shared serotype with the lowest response rate in 
the Prevenar 13™ group. For the 2 serotypes unique to V114, p1 is the response rate of the 2 
 
 
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unique serotypes for the V114 group and p2 is the lowest response rate among all 13 shared 
serotypes for the Prevenar 13™ group. V114 is non-inferior to Prevenar 13™ if the lower 
bound of the 2-sided 95% CI for the between-group differences (V114 minus Prevenar 13™) 
is greater than -0.1.
Primary endpoints/hypotheses (H3)
The second primary objective is to compare the anti-PnPs serotype-specific IgG GMCs 
between V114 and Prevenar 13™ at 30 days PD3 for the 13 shared serotypes contained in 
V114 and Prevenar 13™. The objective will be assessed via the following non-inferiority 
hypotheses:
H0: GMC1/GMC2 ≤0.5 versus
H1: GMC1/GMC2 >0.5,
where GMC1 is the anti-PnPs serotype-specific IgG GMCs for the V114 group and GMC2 is 
the anti-PnPs serotype-specific IgG GMCs for the Prevenar 13™ group. A ratio of 0.5 
corresponds to a 2.0-fold decrease of anti-PnPs serotype-specific IgG GMCs in the V114 
group as compared with the Prevenar 13™ group. V114 is non-inferior to Prevenar 13™ if 
the lower bound of the 2-sided 95% CI for the GMC ratios (V114/Prevenar 13™) is greater 
than 0.5. 
9.4
Analysis Endpoints
9.4.1
Immunogenicity Endpoints
The primary immunogenicity endpoints include:

Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL 
(response rate) at 30 days PD3 for the 13 shared serotypes in V114 and Prevenar 
13™, and for the 2 serotypes unique to V114

Anti-PnPs serotype-specific IgG GMCs at 30 days PD3 for the 13 shared serotypes in 
V114 and Prevenar 13™
The secondary immunogenicity endpoints include:

Anti-PnPs serotype-specific IgG GMCs at 30 days PD3 for the 2 serotypes unique to 
V114

Anti-PnPs serotype-specific IgG response rates at 30 days PD4

Anti-PnPs serotype-specific IgG GMCs at 30 days PD4

Anti-PnPs serotype-specific OPA GMTs at 30 days PD3

Anti-PnPs serotype-specific OPA GMTs at 30 days PD4
 
 
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
Anti-PnPs serotype-specific OPA response rates at 30 days PD3

Anti-PnPs serotype-specific OPA response rates at 30 days PD4
The exploratory endpoints include:

Anti-PnPs serotype-specific IgG response rates at Predose 4

Anti-PnPs serotype-specific IgG GMCs at Predose 4

Anti-PnPs serotype-specific OPA GMTs at Predose 4

Anti-PnPs serotype-specific OPA response rates at Predose 4
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements following any vaccination with V114 or 
Prevenar 13™.
The safety endpoints include:

Proportion of participants with solicited injection-site AEs (swelling, 
redness/erythema, tenderness/pain, and hard lump/induration) from Day 1 through 
Day 14 following any vaccination with V114 or Prevenar 13™

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, hives or welts/urticaria, and appetite loss/decreased appetite) 
from Day 1 through Day 14 following any vaccination with V114 or Prevenar 13™

Proportions of participants with the broad AE categories consisting of any AE and a 
vaccine-related AE from Day 1 through Day 14 following any vaccination with V114 
or Prevenar 13™

Proportions of participants with an SAE, a vaccine-related SAE, and discontinuation 
due to an AE, and death from Day 1 (day of Dose 1) through completion of study 
participation

Participants body temperature measured from Day 1 (day of vaccination) through 
Day 7 following any vaccination with V114 or Prevenar 13™
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Population
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this study. The PP population consists of all randomized participants without 
deviations from the protocol that may substantially affect the results of the immunogenicity 
 
 
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endpoint(s). Potential deviations that may result in the exclusion of a participant from the PP 
population for all immunogenicity analyses include:

Failure to receive primary infant series vaccination (V114 or Prevenar 13™ Doses 1, 
2, and 3) as per randomization schedule

Receipt of prohibited medication or prohibited vaccine prior to the first study 
vaccination
Additional potential deviations that may result in the exclusion from the PP immunogenicity 
analyses at a particular timepoint include:

Failure to receive Dose 4 of V114 or Prevenar 13™ according to vaccination 
schedule required at the timepoint for the analysis 

Failure to receive the scheduled doses of V114 or Prevenar 13™ with the specified 
intervals / time window (at least 28 days between Doses 1 and 2 and between Doses 2 
and 3 [for PD3 and Predose 4 analysis], 12 months to 1 day prior to 16 months of age 
for Dose 4 [for PD4 analyses])

Receipt of prohibited medication or prohibited vaccine prior to a blood sample 
collection

Collection of blood sample at the timepoint for the analysis outside of the pre 
specified window (as described in Section 1.3)
The final determination on protocol deviations, and thereby the composition of the PP 
population, will be made prior to the unblinding of the database.
A supportive analysis using the Full Analysis Set (FAS) population may also be performed 
for the primary immunogenicity endpoints. The FAS population consists of all randomized 
participants who received all study vaccinations required at the timepoint for the analysis and 
have serology result.
Participants will be included in the vaccination group to which they are randomized for the 
analysis of immunogenicity data.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study vaccination. Participants will be included 
in the group corresponding to the study vaccination they actually received for the analysis of 
safety data using the APaT population. This will be the group to which they are randomized 
except for participants who take incorrect study vaccination; such participants will be 
included in the vaccination group corresponding to the study vaccination actually received. 
Safety parameters for cross-treated participants (ie, those who received vaccinations of both 
V114 and Prevenar 13™) will be summarized separately.
 
 
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At least 1 temperature measurement obtained after study intervention is required for 
inclusion in the analysis of temperature.
9.6
Statistical Methods
Unless otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives. Further details will be described in the sSAP. The analyses will 
be conducted for each of the 15 pneumococcal serotypes in V114 separately.
The between-group differences (V114 minus Prevenar 13™) in the response rates of anti-
PnPs serotype-specific IgG at 30 days PD3, along with corresponding 95% CIs based on the 
method of Miettinen and Nurminen stratified by age category (2 months of age, ≥3 months of 
age), will be estimated. The Cochran-Mantel-Haenszel weight will be used to obtain stratum-
adjusted proportion difference. The lower bound of the 95% CIs will be compared against the 
pre-specified margin of -0.1 to test the non-inferiority hypotheses. Other response rate 
analyses in immunogenicity endpoints will be performed using the same model as above.
Note that the strata of 3 months of age and 4 to 6 months of age will be combined into a 
single stratum for the purpose of statistical analysis as the number of participants in the 4 to 6 
months of age is anticipated to be very small.
Anti-PnPs serotype-specific IgG concentrations at 30 days PD3 for the 13 shared serotypes in 
V114 and Prevenar 13™ will be natural log-transformed and analyzed using a linear model 
with factors for vaccination group and age category. Between-group differences (V114 minus 
Prevenar 13™) and corresponding 95% CIs will be estimated on the log scale using the 
model above, and the results will be transformed back to the original scale to obtain the IgG 
GMC ratios (V114/Prevenar 13™). The lower bound of the 95% CIs will be compared 
against the pre-specified margin of 0.5 to test the non-inferiority hypotheses. The same 
model will be used to analyze IgG concentrations at 30 days PD3 for the 2 serotypes unique 
to V114, IgG concentrations at other timepoints, as well as OPA titers.
Table 3 Summarizes key immunogenicity analyses.
 
 
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Table 3
Analysis Strategy for Key Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary
Anti-PnPs serotype-specific 
IgG response rates at 30 days 
PD3
P
Stratified Miettinen 
and Nurminen
(estimate, 95% CI,
p-value)
PP
Missing data will 
not be imputed
S
FAS
Anti-PnPs serotype-specific 
IgG GMCs at 30 days PD3
for the 13 shared serotypes
P
Linear model
(estimate, 95% CI)
PP
Missing data will 
not be imputed
S
FAS
Secondary
Anti-PnPs serotype-specific 
IgG GMCs at 30 days PD3
for the 2 unique serotypes
P
Linear model
(estimate, 95% CI)
PP
Missing data will 
not be imputed
Anti-PnPs serotype-specific 
IgG response rates at 30 days 
PD4
P
Stratified Miettinen 
and Nurminen
(estimate, 95% CI)
PP
Missing data will 
not be imputed
Anti-PnPs serotype-specific 
IgG GMCs at 30 days PD4
P
Linear model
(estimate, 95% CI)
PP
Missing data will 
not be imputed
Anti-PnPs serotype-specific 
OPA GMTs at:

30 days PD3

30 days PD4
P
Linear model
(estimate, 95% CI)
PP
Missing data will 
not be imputed
Anti-PnPs serotype-specific 
OPA response rates at:

30 days PD3

30 days PD4
P
Stratified Miettinen 
and Nurminen
(estimate, 95% CI)
PP
Missing data will 
not be imputed
PnPs = pneumococcal polysaccharide, IgG = immunoglobulin G, PD = postdose, PP = Per-Protocol, FAS = 
Full Analysis Set, CI = confidence interval, OPA = opsonophagocytic activity
† P = primary approach, S = supportive approach
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements. Additional summaries on key safety 
parameters will also be provided following each vaccination.
The analysis of safety results will follow a tiered approach (Table 4). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and other safety parameters are either pre-specified as “Tier 1” endpoints or will 
 
 
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be classified as belonging to “Tier 2” or “Tier 3” based on the number of participants with 
events.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance with p-
values and 95% CIs to be provided for between-group differences in the proportion of 
participants with events. These analyses will be performed using the unstratified Miettinen 
and Nurminen method. These p-values and CIs should be regarded as helpful descriptive 
measures to be used in review, not formal methods for assessing the statistical significance of 
the between-group differences. For this protocol, solicited injection-site AEs 
(redness/erythema, swelling, hard lump/induration, and tenderness/pain) from Day 1 through 
Day 14 postvaccination and solicited systemic AEs (irritability, drowsiness/somnolence, 
hives or welts/urticaria, and appetite loss/decreased appetite) from Day 1 through Day 14 
postvaccination are considered Tier 1 events.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the unstratified Miettinen and 
Nurminen method).
In this study, membership in Tier 2 requires that at least 4 participants in any vaccination
group exhibit the event. The threshold of at least 4 participants was chosen because the 95% 
CI for the between-group difference in percent incidence will always include zero when 
treatment groups of equal size each have less than 4 participants with events and thus would 
add little to the interpretation of potentially meaningful differences. Because many 95% CIs 
for Tier 2 events may be provided without adjustment for multiplicity, the CIs should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences.
In addition to individual events that occur in at least 4 participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a vaccine-
related AE, an SAE, a vaccine-related SAE, discontinuation due to an AE, and death will be 
considered Tier 2 endpoints. The proportion of participants with maximum temperature 
measurements meeting particular points (≥37.5 °C, ≥38.0 °C, ≥39.0 °C, ≥40.0 °C) will also 
be considered Tier 2 endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Medical device incidents due to syringe, if any, will be listed.
 
 
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Table 4
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
p-Value
95% CI for 
Between-
Group 
Comparison
Descriptive
Statistics
Tier 1
Injection-site redness/erythema (Days 1 to 14)
X
X
X
Injection-site swelling (Days 1 to 14)
Injection-site tenderness/pain (Days 1 to 14)
Injection-site hard lump/induration (Days 1 to 14)
Irritability (Days 1 to 14)
Drowsiness/somnolence (Days 1 to 14)
Hives or welts/urticaria (Days 1 to 14)
Appetite loss/decreased appetite (Days 1 to 14)
Tier 2
Any AE†
X
X
Any Vaccine-related AE†
Any SAE†
Any Vaccine-related SAE†
Discontinuation due to AE†
Death†
Maximum temperature measurements meeting cut 
points (≥37.5 °C, ≥38.0 °C, ≥39.0 °C, ≥40.0 °C; 
Days 1 to 7) 
Specific AEs by SOC and PT‡ (incidence ≥4 
participants in at least one of the vaccination 
groups)
Tier 3
Specific AEs by SOC and PT‡ (incidence <4 
participants in all of the vaccination groups)
X
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; 
SOC = system organ class; X = results will be provided.
† These endpoints are broad adverse event categories. For example, descriptive statistics for the safety 
endpoint of “Any AE” will provide the number and percentage of participants with at least one AE.
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
 
 
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9.6.3
Summary of Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (eg, age, gender, birth weight, and gestational age), 
baseline characteristics, prior and concomitant vaccinations and therapies will be 
summarized by vaccination group either by descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analysis is planned for the study.
9.8
Multiplicity
The study will be considered to have met its primary immunogenicity objective if non-
inferiority is demonstrated in the IgG response rates for the 15 serotypes and in the IgG 
GMCs for the 13 shared serotypes, both at 30 days PD3. Successful achievement of the
primary immunogenicity objective requires that all individual serotypes within the 
hypotheses satisfy the pre-specified non-inferiority criteria at a 1-sided α level of 0.025. This 
approach will control the 1-sided type I error rate at 0.025, thus no multiplicity adjustment 
will be required.
No multiplicity adjustments will be made for the safety objective.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
A total of 660 participants will be randomized in a 1:1 ratio to V114 or Prevenar 13™ to 
have 300 participants per arm in the PP population at 30 days PD3 (~90% evaluability rate). 
The study will have an overall power of ~83% for all the primary hypotheses at a 1-sided α 
level of 0.025. The power calculations for the individual hypotheses are provided below.
Primary endpoints/hypotheses (H1 and H2)
The study will have a power of ~83% at a 1-sided α level of 0.025 to demonstrate that V114 
is non-inferior to Prevenar 13™ for the 13 shared serotypes and the 2 unique serotypes in the 
anti-PnP serotype-specific IgG responses rates at 30 days PD3. The underlying serotype-
specific response rates are based on the results from V114 Protocol 008 (safety and 
immunogenicity of two different lots of V114 were evaluated; Lot 1 and Lot 2 pooled for 
V114), as listed in Table 5 below.
 
 
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Table 5
Assumptions of the True Response Rates at 30 Days PD3
Serotype
True Response Rate
V114
Prevenar 13™
Prevenar 13™ Types 
1
0.972
0.969
3
0.951
0.718
4
0.976
0.951
5
0.960
0.966
6A
0.931
0.962
6B
0.914
0.914
7F
0.995
0.990
9V
0.975
0.958
14
0.984
0.972
18C
0.975
0.955
19A
0.987
0.986
19F
0.995
0.997
23F
0.936
0.907
Non-Prevenar 13™ Types
22F
0.987
0.907†
33F
0.889
0.907†
† Serotype 23F; Based on Phase 2 data, serotype 3 had the lowest response rate for PCV13, however, for the 
purpose of power calculation, the serotype with the next lowest response rate, 23F, was used.
Primary endpoints/hypotheses (H3)
This study will have a power of >99% at a 1-sided α level of 0.025 to demonstrate V114 is 
noninferior to Prevenar 13™ for the 13 shared serotypes based on the anti-PnP serotype-
specific IgG GMCs at 30 days PD3. The power calculations are based on the true IgG GMC 
ratio of 1.0 and the true standard deviation of natural log IgG concentration of 1.1 for all 
shared serotypes.
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. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. There is an 80% chance of observing at least one SAE among 
330 participants in each of the V114 group and Prevenar 13™ group if the underlying 
incidence of an SAE is approximately 0.49% (1 of every 206 participants receiving the 
vaccine). There is a 50% chance of observing at least one SAE among 330 participants in 
each of the V114 group and Prevenar 13™ group if the underlying incidence of an SAE is 
approximately 0.21% (1 of every 477 participants receiving the vaccine). If no SAEs are 
observed among 330 participants in each of the V114 group and Prevenar 13™ group, this 
study will provide 97.5% confidence that the underlying percentage of participants with an 
SAE is approximately <1.1% (one in every 90 participants).
 
 
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Table 6 summarizes the percentage point differences between the 2 vaccination groups that 
could be detected with ~80% probability for a variety of hypothetical underlying incidences 
of an adverse event. These calculations assume 330 participants in each group and are based 
on a 2-sided 5% alpha level. The calculations are based on an asymptotic method proposed 
by Farrington and Manning [Farrington, C. P. 1990]; no multiplicity adjustments were made.
Table 6
Differences in Incidence of Adverse Events Between the 2 Vaccination Groups
That Can be Detected With an ~80% Probability (Assuming 2-sided 5% Alpha Level With 
330 Participants in Each Group)
Incidence of Adverse Event
Risk Difference
V114 (%)
N=330
Prevenar 13™ (%)
N=330
Percentage Points
2.6
0.1
2.5
6.4
2.0
4.4
10.9
5.0
5.9
17.5
10.0
7.5
23.6
15.0
8.6
29.4
20.0
9.4
40.4
30.0
10.4
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
Based on an asymptotic method proposed by Farrington and Manning [Farrington, C. P. 1990]
9.10
Subgroup Analyses
The IgG response rates and IgG GMCs at 30 days PD3 will be analyzed separately by age 
category (2 months of age, ≥3 months of age; 2 months of age, 3 months of age, 4 to 6 
months of age). The IgG response rates will be analyzed using the unstratified Miettinen and 
Nurminen method, and IgG GMCs will be analyzed using a linear model with a term for 
vaccination group. Additional subgroup analyses, if any, will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
The number and proportion of randomized participants receiving each vaccination will be 
summarized.
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V114 or Prevenar 13™.
 
 
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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 and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 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 (e.g., 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 (i.e., 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 (or individuals acting on behalf of MSD) 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 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, 
 
 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues 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 the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified 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. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
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 individuals acting on behalf of MSD), 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.
 
 
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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.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation 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 (e.g., 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
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
 
 
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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.
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 
 
 
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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.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the 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 Council on Harmonisation 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 Trials.
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.
 
 
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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 
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 
 
 
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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, 
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 or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
Not applicable.
 
 
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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.

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.
 
 
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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.

Congenital disorders (eg, present from birth) that are detected/diagnosed in an infant 
participant.

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.
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.
 
 
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•
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.
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.
 
 
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
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.
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 utilized 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 14 
postvaccination will be evaluated by maximum size.
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 worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
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.
 
 
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•
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 (diary, 
etc.), seroconversion or identification of vaccine virus 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 vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the 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 vaccine 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:
 
 
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-
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.)
•
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.
 
 
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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 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.
·
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).
 
 
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10.4
Appendix 4: Combination Products: Medical Device Incident: Definitions, 
Recording and Follow-up
The recording and follow-up procedures described in the protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol, that are manufactured by the Sponsor or for the Sponsor by a third party, 
procured by the Sponsor for human use and/or combination products, regardless of 
investigational or marketed product.
10.4.1
Definition of Medical Device Incident
Combination product is a product comprised of two or more regulated components, i.e., a 
drug and a device; a device and a cellular and tissue-based products; a cellular and tissue-
based products and a drug; or a drug, a device, and a cellular and tissue-based products 
according to Japan regulations.
Malfunction – Failure of quality, safety and performance, etc. of investigational device in a 
broad sense such as damage or operational failure.
Medical Device Incident is any malfunction in the characteristics and/or performance of a 
device (this study is a pre-filled syringe) as well as any inadequacy in the labeling or the 
instructions for use which might lead to or might have led to the death of a participant and/or 
the associated person or to a serious deterioration in his/her state of health. A medical device 
incident also includes events that did not actually cause anything to a participant and/or the 
associated person.
10.4.2
Recording, Assessment and Follow-up of Medical Device Incident Recording

When medical device incident occurs, it is the responsibility of the investigator to review 
all documentation (e.g. Hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

Any medical device incident occurring during the study will be recorded in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate CRF (paper or electronic) as per instructions provided in 
the EDC data entry guidelines (or equivalent). The paper CRF is to be used only when 
electronic CRF system is down.

It is important that the investigator provides his/her assessment of causality (relationship 
to the medical device) at the time of the initial report.
 
 
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Assessment of Causality

The investigator will consider a reasonable possibility and use clinical judgment to 
determine the causality.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 

Alternative causes should also be considered and investigated.
Follow-up

The investigator will 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 event as fully as possible.
 
 
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10.5
Appendix 5: Contraceptive Guidance
Not applicable.
 
 
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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 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
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.
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 future 
biomedical research
 
 
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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.
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.
 
 
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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 future biomedical research protocol and consent. 
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 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.
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 
 
 
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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 Council on Harmonisation [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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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
CI
Confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
Clinical Study Report
DNA
deoxyribonucleic acid 
eCRF
electronic Case Report Form
ECL
Electrochemiluminescence
ECG
Electrocardiogram 
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice
GMC
Geometric Mean Concentration
GMT
Geometric Mean Titer
HIV
human immunodeficiency virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IPD
invasive pneumococcal disease
IRB
Institutional Review Board
IRT
interactive response technology
MOPA
Multiplexed Opsonophagocytic activity
NIP
National Immunization Program
OPA
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PD3
Postdose 3
PD4
Postdose 4
PnECL
pneumococcal electrochemiluminescence
PnPs
pneumococcal polysaccharide
PP
Per-Protocol
RNA
ribonucleic acid
SAE
serious adverse event 
SoA
schedule of activities
sSAP
supplemental statistical analysis plan 
SUSAR
suspected unexpected serious adverse reaction
VRC
Vaccination Report Card
WHO
World Health Organization
 
 
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11
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