A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of Catch-up Vaccination Regimens of V114 in Healthy Infants, Children, and Adolescents (PNEU-PLAN)
Phase: PHASE3
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03885934 
Document Date: 
04-JAN-2019
Phase 3, Multicenter, Randomized, Double-blind, Active Comparator 
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of 
Catch -up Vaccination Regimens of V114 in Healthy Infants, Children, and 
Adolescents (PNEUPLAN)

PRODUCT: V114  
1
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Title Page
THIS PROTOCOL 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 Catch-up 
Vaccination Regimens of V114 in Healthy Infants, Children, and Adolescents (PNEU-
PLAN)
Protocol Number: 024-00
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
14115
2018-003706-88
Approval Date: 4 January 2019
 
 
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PRODUCT: V114  
2
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
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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05PSCV

PRODUCT: V114  
3
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Table of Contents
1
PROTOCOL SUMMARY ............................................................................................10
1.1
Synopsis.................................................................................................................10
1.2
Schema ..................................................................................................................14
1.3
Schedule of Activities (SoA) ................................................................................15
1.3.1
Schedule A: SoA for Participants Enrolled at 7 to 11 Months of Age ........15
1.3.2
Schedule B: SoA for Participants Enrolled at 12 to 23 Months of Age ......19
1.3.3
Schedule C: SoA for Participants Enrolled at 2 to 17 Years of Age 
(Inclusive) ....................................................................................................22
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................26
2.2.1
V114 and Pneumococcal Disease ................................................................26
2.2.2
Preclinical and Clinical Studies ...................................................................27
2.2.3
Information on Other Study-related Therapy ..............................................27
2.3
Benefit/Risk Assessment......................................................................................27
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS ................................................27
4
STUDY DESIGN............................................................................................................29
4.1
Overall Design ......................................................................................................29
4.2
Scientific Rationale for Study Design.................................................................30
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Immunogenicity Endpoints................................................................31
4.2.1.2
Safety Endpoints ................................................................................31
4.2.1.3
Future Biomedical Research..............................................................32
4.2.2
Rationale for the Use of Comparator...........................................................32
4.3
Justification for Dose ...........................................................................................32
4.4
Beginning and End of Study Definition .............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................33
5
STUDY POPULATION ................................................................................................33
5.1
Inclusion Criteria.................................................................................................33
5.2
Exclusion Criteria ................................................................................................34
5.3
Lifestyle Considerations ......................................................................................36
5.4
Screen Failures.....................................................................................................36
5.5
Participant Replacement Strategy......................................................................36
6
STUDY INTERVENTION............................................................................................36
6.1
Study Intervention(s) Administered...................................................................37
6.2
Preparation/Handling/Storage/Accountability .................................................39
 
 
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PRODUCT: V114  
4
PROTOCOL/AMENDMENT NO.: 024-00 
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04-JAN-2019
6.2.1
Dose Preparation..........................................................................................39
6.2.2
Handling, Storage, and Accountability........................................................39
6.3
Measures to Minimize Bias: Randomization and Blinding..............................40
6.3.1
Intervention Assignment..............................................................................40
6.3.2
Stratification.................................................................................................40
6.3.3
Blinding........................................................................................................40
6.4
Study Intervention Compliance..........................................................................41
6.5
Concomitant Therapy..........................................................................................41
6.5.1
Rescue Medications and Supportive Care ...................................................42
6.6
Dose Modification (Escalation/Titration/Other)...............................................42
6.7
Intervention After the End of the Study............................................................42
6.8
Clinical Supplies Disclosure................................................................................42
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................42
7.1
Discontinuation of Study Intervention...............................................................42
7.2
Participant Withdrawal From the Study...........................................................43
7.3
Lost to Follow-up .................................................................................................44
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................44
8.1
Administrative and General Procedures ...........................................................45
8.1.1
Informed Consent.........................................................................................45
8.1.1.1
General Informed Consent.................................................................45
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................46
8.1.2
Inclusion/Exclusion Criteria ........................................................................46
8.1.3
Participant Identification Card.....................................................................46
8.1.4
Medical History ...........................................................................................46
8.1.5
Prior and Concomitant Medications Review ...............................................47
8.1.5.1
Prior Medications...............................................................................47
8.1.5.2
Concomitant Medications ..................................................................47
8.1.6
Assignment of Screening Number...............................................................47
8.1.7
Assignment of Treatment/Randomization Number .....................................47
8.1.8
Study Intervention Administration ..............................................................48
8.1.8.1
Timing of Dose Administration.........................................................49
8.1.9
Electronic Vaccination Report Card ............................................................49
8.1.10
Day 15 Postdose Telephone Contact Guide.................................................49
8.1.11
Telephone Contact Questionnaire................................................................50
8.1.12
Discontinuation and Withdrawal .................................................................50
8.1.12.1
Withdrawal From Future Biomedical Research ................................50
 
 
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PRODUCT: V114  
5
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
8.1.13
Participant Blinding/Unblinding..................................................................51
8.1.14
Calibration of Equipment.............................................................................51
8.2
Immunogenicity Assessments .............................................................................51
8.3
Safety Assessments...............................................................................................52
8.3.1
Physical Examinations.................................................................................53
8.3.2
Pregnancy Test.............................................................................................53
8.3.3
Body Temperature Measurement.................................................................53
8.3.4
Safety Assessments and Use of the eVRC...................................................54
8.3.5
Clinical Laboratory Assessments.................................................................54
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................55
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................55
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......57
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...58
8.4.4
Regulatory Reporting Requirements for SAE .............................................58
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................58
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................59
8.4.7
Events of Clinical Interest (ECIs) ................................................................59
8.5
Treatment of Overdose........................................................................................59
8.6
Pharmacokinetics.................................................................................................59
8.7
Pharmacodynamics..............................................................................................59
8.8
Biomarkers ...........................................................................................................59
8.9
Planned Genetic Analysis Sample Collection ....................................................59
8.10
Future Biomedical Research Sample Collection...............................................60
8.11
Medical Resource Utilization and Health Economics.......................................60
8.12
Visit Requirements...............................................................................................60
8.12.1
Screening......................................................................................................60
8.12.2
Treatment Period/Vaccination Visit ............................................................60
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........60
9
STATISTICAL ANALYSIS PLAN .............................................................................60
9.1
Statistical Analysis Plan Summary.....................................................................61
9.2
Responsibility for Analyses/In-house Blinding .................................................62
9.3
Hypotheses/Estimation ........................................................................................62
9.4
Analysis Endpoints...............................................................................................63
9.4.1
Immunogenicity Endpoints..........................................................................63
9.4.2
Safety Endpoints ..........................................................................................63
 
 
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PRODUCT: V114  
6
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
9.5
Analysis Populations............................................................................................64
9.5.1
Immunogenicity Analysis Populations ........................................................64
9.5.2
Safety Analysis Populations ........................................................................65
9.6
Statistical Methods...............................................................................................65
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................65
9.6.2
Statistical Methods for Safety Analyses ......................................................66
9.6.3
Demographic and Baseline Characteristics .................................................67
9.7
Interim Analyses ..................................................................................................68
9.8
Multiplicity ...........................................................................................................68
9.9
Sample Size and Power Calculations .................................................................68
9.9.1
Sample Size and Power for Immunogenicity Analyses ...............................68
9.9.2
Sample Size and Power for Safety Analyses ...............................................69
9.10
Subgroup Analyses...............................................................................................70
9.11
Compliance (Medication Adherence).................................................................70
9.12
Extent of Exposure...............................................................................................70
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .....................................................................................................71
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........71
10.1.1
Code of Conduct for Clinical Trials.............................................................71
10.1.2
Financial Disclosure.....................................................................................73
10.1.3
Data Protection.............................................................................................73
10.1.3.1
Confidentiality of Data ......................................................................74
10.1.3.2
Confidentiality of Participant Records...............................................74
10.1.3.3
Confidentiality of IRB/IEC Information............................................74
10.1.4
Committees Structure...................................................................................74
10.1.4.1
Scientific Advisory Committee..........................................................74
10.1.4.2
Executive Oversight Committee........................................................74
10.1.4.3
External Data Monitoring Committee ...............................................75
10.1.5
Publication Policy........................................................................................75
10.1.6
Compliance with Study Registration and Results Posting Requirements ...75
10.1.7
Compliance with Law, Audit, and Debarment ............................................76
10.1.8
Data Quality Assurance ...............................................................................76
10.1.9
Source Documents .......................................................................................77
10.1.10
Study and Site Closure.................................................................................78
10.2
Appendix 2: Clinical Laboratory Tests..............................................................79
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................80
10.3.1
Definition of AE ..........................................................................................80
 
 
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PRODUCT: V114  
7
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
10.3.2
Definition of SAE ........................................................................................81
10.3.3
Additional Events Reported.........................................................................82
10.3.4
Recording AE and SAE ...............................................................................82
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................85
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................87
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................88
10.5.1
Definitions....................................................................................................88
10.5.2
Contraception Requirements........................................................................89
10.5.3
Pregnancy Testing........................................................................................90
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................91
10.7
Appendix 7: Country-specific Requirements ....................................................95
10.8
Appendix 8: Abbreviations .................................................................................96
11
REFERENCES...............................................................................................................98
 
 
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PRODUCT: V114  
8
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
LIST OF TABLES
Table 1
Catch-Up Vaccination Schedules in V114-024 .........................................29
Table 2
Study Interventions ....................................................................................38
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................57
Table 4
Analysis Strategy for Immunogenicity Variables......................................66
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination .....67
Table 6
Within-Group 95% CIs for Varying Sample Size with Hypothetical 
IgG GMCs, Standard Deviations and 80% Evaluable Rate.......................69
 
 
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05PSCV

PRODUCT: V114  
9
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
LIST OF FIGURES
Figure 1
V114-024 Study Diagram..........................................................................14
 
 
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PRODUCT: V114  
10
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
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 Catch-up 
Vaccination Regimens of V114 in Healthy Infants, Children, and Adolescents (PNEU-
PLAN)
Short Title: Safety and Immunogenicity of Catch-up Vaccination Regimens of V114
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-024 (PNEU-PLAN)
Hypotheses, Objectives, and Endpoints:
There is no formal hypothesis testing in this study.
The following objectives and endpoints will be evaluated in participants enrolled from 7 
months to 17 years of age (inclusive) who are either pneumococcal vaccine-naïve or who 
previously received a partial or full regimen of pneumococcal conjugate vaccine (PCV) 
(Table 1). Immunogenicity and safety objectives will be evaluated by age at randomization 
(ie, 7 to 11 months of age, 12 to 23 months of age, and 2 to 17 years of age).
Primary Objectives
Primary Endpoints
- Objective: 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 
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: To evaluate the 
anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
Geometric Mean Concentrations (GMCs) at 
30 days following the last dose for each 
vaccination group.
- Anti-PnPs serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 30 
days after the last dose of study vaccine
 
 
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PRODUCT: V114  
11
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate 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 the last dose for each 
vaccination group.
- Anti-PnPs serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 30 
days after the last dose of study vaccine
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Healthy children 7 months to 17 years of age (inclusive)
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
Masking
Participant or Subject
Care Provider
Investigator
Sponsor
 
 
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PRODUCT: V114  
12
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 17 months from the time the first participant 
signs the informed consent 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 600 participants will be randomized, with approximately 300 participants in 
each intervention group.
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
1 to 3
doses, 
depending 
on age at 
enrollment
IM
Schedule A:
7 to 11 months of 
age: Single dose at 
Visits 1, 2A, and 3A
Schedule B:
12 to 23 months of 
age: Single dose at 
Visits 1 and 2B
Schedule C:
2 to 17 years of age
(inclusive): Single 
dose at Visit 1
Experimental
Prevnar 13™Prevnar
13™
Refer to 
product 
labeling
1 to 3 
doses, 
depending 
on age at 
enrollment
IM
Schedule A:
7 to 11 months of 
age: Single dose at 
Visits 1, 2A, and 3A
Schedule B:
12 to 23 months of 
age: Single dose at 
Visits 1 and 2B
Schedule C:
2 to 17 years of age
(inclusive): Single 
dose at Visit 1
Experimental
Abbreviations: Admin. = administration; IB = Investigator’s Brochure; IM = intramuscular.
 
 
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PRODUCT: V114  
13
PROTOCOL/AMENDMENT NO.: 024-00 
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04-JAN-2019
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 6 months to 12 
months from the time the participant or 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
Yes
Data Monitoring Committee
Yes
Clinical Adjudication 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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PRODUCT: V114  
14
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
1.2
Schema
The key components of the study design are depicted in Figure 1.
Figure 1
V114-024 Study Diagram
 
 
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PRODUCT: V114  
15
PROTOCOL/AMENDMENT NO.: 024-00 
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule A: SoA for Participants Enrolled at 7 to 11 Months of Age
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2A
TC
3A
TC
4
TC
Scheduled Time
Day 1 
(Dose
1)
Day 15 
after 
Visit 1
Week 4
(Dose 2)
Day 15 
after 
Visit 2A
Age: at 
least ~12 
months
(Dose 3)
Day 15 
after 
Visit 3A
~1 month 
after 
Dose 3
~6 months 
after 
Dose 3
Visit Windows
Day 15 to 
Day 19 
after 
Visit 1
Day 28 to 
Day 56
after 
Visit 1a
Day 15 to 
Day 19 
after 
Visit 2A
Day 56 to 
Day 84
after 
Visit 2Ab
Day 15 to 
Day 19 
after 
Visit 3A
Day 28 to 
Day 42 
after 
Visit 3A
Day 166 to 
Day 194 
Visit 3A
Months of age is calculated 
according to the 
participant’s birth date.
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained 
before any study procedures.
Informed Consent for Future 
Biomedical Research 
X
Participation in future 
biomedical research 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
 
 
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PRODUCT: V114  
16
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2A
TC
3A
TC
4
TC
Scheduled Time
Day 1 
(Dose
1)
Day 15 
after 
Visit 1
Week 4
(Dose 2)
Day 15 
after 
Visit 2A
Age: at 
least ~12 
months
(Dose 3)
Day 15 
after 
Visit 3A
~1 month 
after 
Dose 3
~6 months 
after 
Dose 3
Visit Windows
Day 15 to 
Day 19 
after 
Visit 1
Day 28 to 
Day 56
after 
Visit 1a
Day 15 to 
Day 19 
after 
Visit 2A
Day 56 to 
Day 84
after 
Visit 2Ab
Day 15 to 
Day 19 
after 
Visit 3A
Day 28 to 
Day 42 
after 
Visit 3A
Day 166 to 
Day 194 
Visit 3A
Months of age is calculated 
according to the 
participant’s birth date.
Post-Randomization Procedures
Assignment of Randomization 
Number
X
Prior/Concomitant Medication and 
Nonstudy Vaccination Review
X
X
X
X
X
X
X
See Section 8.1.5 for details.
V114 or Prevnar 13™ 
Administration (Blinded)
X
X
X
Participants will receive 
either a single dose of V114 
or Prevnar 13™ at scheduled 
visits.
Provide eVRC
X
An eVRC will be provided at 
Visit 1 to record AEs, body 
temperature, concomitant 
medications, and non-study 
vaccinations. Instructions for 
using the eVRC will be 
reviewed with the 
participant’s legally 
acceptable representative.
Review eVRC data with 
participant’s legally acceptable 
representative
X
X
X
X
X
X
See Section 8.1.10 for 
details.
Collect eVRC from participant’s 
legally acceptable representative
X
Complete the Telephone Contact 
Questionnaire
X
See Section 8.1.11 for 
details.
 
 
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PRODUCT: V114  
17
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2A
TC
3A
TC
4
TC
Scheduled Time
Day 1 
(Dose
1)
Day 15 
after 
Visit 1
Week 4
(Dose 2)
Day 15 
after 
Visit 2A
Age: at 
least ~12 
months
(Dose 3)
Day 15 
after 
Visit 3A
~1 month 
after 
Dose 3
~6 months 
after 
Dose 3
Visit Windows
Day 15 to 
Day 19 
after 
Visit 1
Day 28 to 
Day 56
after 
Visit 1a
Day 15 to 
Day 19 
after 
Visit 2A
Day 56 to 
Day 84
after 
Visit 2Ab
Day 15 to 
Day 19 
after 
Visit 3A
Day 28 to 
Day 42 
after 
Visit 3A
Day 166 to 
Day 194 
Visit 3A
Months of age is calculated 
according to the 
participant’s birth date.
Safety Procedures
Complete Physical Examination
X
To be performed by the 
investigator or medically 
qualified designee before 
vaccine is administered (see
Section 8.3.1).
Targeted Physical Examination
X
X
To be performed by the 
investigator or medically 
qualified designee before 
vaccine is administered (see
Section 8.3.1).
Body Temperature Measurement
X
X
X
Each participant’s body 
temperature must be taken 
before vaccination (see 
Section 8.3.3 for method). 
Participants who have febrile 
illness at or within 72 hours 
of vaccination must be 
rescheduled.
30-Minute Postvaccination 
Observation Period
X
X
X
To be performed by blinded 
study site personnel only.
 
 
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PRODUCT: V114  
18
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2A
TC
3A
TC
4
TC
Scheduled Time
Day 1 
(Dose
1)
Day 15 
after 
Visit 1
Week 4
(Dose 2)
Day 15 
after 
Visit 2A
Age: at 
least ~12 
months
(Dose 3)
Day 15 
after 
Visit 3A
~1 month 
after 
Dose 3
~6 months 
after 
Dose 3
Visit Windows
Day 15 to 
Day 19 
after 
Visit 1
Day 28 to 
Day 56
after 
Visit 1a
Day 15 to 
Day 19 
after 
Visit 2A
Day 56 to 
Day 84
after 
Visit 2Ab
Day 15 to 
Day 19 
after 
Visit 3A
Day 28 to 
Day 42 
after 
Visit 3A
Day 166 to 
Day 194 
Visit 3A
Months of age is calculated 
according to the 
participant’s birth date.
AE Monitoring
X
X
X
X
X
X
X
X
Nonserious AEs are to be 
reported from Days 1 
through 14 following each 
vaccination. SAEs and 
deaths are to be reported 
throughout the duration of an 
individual’s study 
participation.
Immunogenicity Procedures
Serum for Immunogenicity Assays 
(Including Retention Serum)
X
Blood samples must be 
collected before study 
vaccination when applicable
Future Biomedical Research
Collect Buccal Swabs for Future
Biomedical Research
X
Buccal swab DNA samples 
for analysis should be 
obtained prior to the 
vaccination on Visit 1, on 
randomized and FBR 
consented participants only, 
or at a later date as soon as 
the informed consent is 
obtained.
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic vaccination report card; FBR = future biomedical research;SAE = serious adverse event.
a Visit 2A should be scheduled at least 4 weeks but no more than 8 weeks after Visit 1. For calculating the visit windows, the day of vaccination is considered Day 1.
b Visit 3A should be scheduled at least 8 weeks but no more than 12 weeks after Visit 2A except for participants who are ≤12 months of age during this visit window. Participants 
who need to wait until they are 12 months of age before receiving their third dose at Visit 3A or participants whose first birthday falls within the 8- to 12-week visit window for 
Visit 3A (Dose 3) have 28 days from their first birthday to receive the third dose of study vaccine.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
19
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
1.3.2
Schedule B: SoA for Participants Enrolled at 12 to 23 Months of Age
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2B
TC
3B
TC
Scheduled Time
Day 1 
(Dose 1)
Day 15 
after 
Visit 1
Week 8
(Dose 2)
Day 15 
after 
Visit 2B
~1 month 
after 
Dose 2
~6 
months 
after 
Dose 2
Visit Window
Day 15 to 
Day 19 
after 
Visit 1
Day 56 to 
Day 84
after 
Visit 1
Day 15 to 
Day 19 
after 
Visit 2B
Day 28 to 
Day 42 
after 
Visit 2B
Day 166 
to 
Day 194 
after 
Visit 2B
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study 
procedures.
Informed Consent for Future Biomedical 
Research 
X
Participation in future biomedical research 
is optional and consent must be obtained 
before the 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 Nonstudy 
Vaccination Review
X
X
X
X
X
See Section 8.1.5 for details.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
20
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2B
TC
3B
TC
Scheduled Time
Day 1 
(Dose 1)
Day 15 
after 
Visit 1
Week 8
(Dose 2)
Day 15 
after 
Visit 2B
~1 month 
after 
Dose 2
~6 
months 
after 
Dose 2
Visit Window
Day 15 to 
Day 19 
after 
Visit 1
Day 56 to 
Day 84
after 
Visit 1
Day 15 to 
Day 19 
after 
Visit 2B
Day 28 to 
Day 42 
after 
Visit 2B
Day 166 
to 
Day 194 
after 
Visit 2B
V114 or Prevnar 13™ Administration (Blinded)
X
X
Participants will receive either a single dose 
of V114 or Prevnar 13™ at scheduled 
visits.
Provide eVRC
X
An eVRC will be provided at Visit 1 to 
record AEs, body temperature, concomitant 
medications, and non-study vaccinations. 
Instructions for using the eVRC will be 
reviewed with the participant or the 
participant’s legally acceptable 
representative.
Review eVRC data with participant’s legally 
acceptable representative
X
X
X
X
X
See Section 8.1.10 for details.
Collect eVRC from participant’s legally 
acceptable representative
X
Complete the Telephone Contact Questionnaire
X
See Section 8.1.11 for details.
Safety Procedures
Complete Physical Examination
X
To be performed by the investigator or 
medically qualified designee before vaccine 
is administered. See Section 8.3.1 for 
details.
Targeted Physical Examination
X
To be performed by the investigator or 
medically qualified designee before vaccine 
is administered. See Section 8.3.1 for 
details.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
21
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2B
TC
3B
TC
Scheduled Time
Day 1 
(Dose 1)
Day 15 
after 
Visit 1
Week 8
(Dose 2)
Day 15 
after 
Visit 2B
~1 month 
after 
Dose 2
~6 
months 
after 
Dose 2
Visit Window
Day 15 to 
Day 19 
after 
Visit 1
Day 56 to 
Day 84
after 
Visit 1
Day 15 to 
Day 19 
after 
Visit 2B
Day 28 to 
Day 42 
after 
Visit 2B
Day 166 
to 
Day 194 
after 
Visit 2B
Body Temperature Measurement
X
X
Each participant’s body temperature must 
be taken before vaccination (see 
Section 8.3.3 for method). Participants who 
have febrile illness at or within 72 hours of 
vaccination must be rescheduled.
30-Minute Postvaccination Observation Period
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 and deaths are to be 
reported throughout the duration of an 
individual’s study participation.
Immunogenicity Procedures
Serum for Immunogenicity Assays (Including 
Retention Serum)
X
Blood samples must be collected before 
study vaccination when applicable
Future Biomedical Research
Collect Buccal Swabs for Future Biomedical 
Research
X
Buccal swab DNA samples for analysis 
should be obtained prior to the vaccination 
on Visit 1, on randomized and FBR 
consented participants only, or at a later 
date as soon as the informed consent is 
obtained.
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic vaccination report card; FBR = future biomedical research; SAE = serious adverse event.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
22
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
1.3.3
Schedule C: SoA for Participants Enrolled at 2 to 17 Years of Age (Inclusive)
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2C
TC
Scheduled Time
Day 1 
(Dose 1)
Day 15 
after Visit 1
~1 month 
after Dose 1
~6 months 
after Dose 1
Visit Window
Day 15 to 
Day 19 
after Visit 1
Day 28 to 
Day 42 
after Visit 1
Day 166 to 
Day 194 
after Visit 1
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study procedures.
Informed Consent for Future Biomedical Research 
X
Participation in future biomedical research is optional 
and consent must be obtained before the collection of 
buccal swab DNA samples in participants ≥2 to <5 
years of age and saliva DNA samples in participants ≥5 
years of age.
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Review of prior medications/vaccinations, a complete 
physical examination, temperature measurement, and 
pregnancy testing are required at Visit 1 to determine 
eligibility.
Medical History
X
Post-Randomization Procedures
Assignment of Randomization Number
X
Prior/Concomitant Medication and Nonstudy 
Vaccination Review
X
X
X
See Section 8.1.5 for details.
V114 or Prevnar 13™ Administration (Blinded)
X
Participants will receive either a single dose of V114 or 
Prevnar 13™ at scheduled visits.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
23
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2C
TC
Scheduled Time
Day 1 
(Dose 1)
Day 15 
after Visit 1
~1 month 
after Dose 1
~6 months 
after Dose 1
Visit Window
Day 15 to 
Day 19 
after Visit 1
Day 28 to 
Day 42 
after Visit 1
Day 166 to 
Day 194 
after Visit 1
Provide eVRC
X
An eVRC will be provided at Visit 1 to record AEs, 
body temperature, concomitant medications, and non-
study vaccinations. Instructions for using the eVRC will 
be reviewed with the participant or the participant’s 
legally acceptable representative.
Review eVRC data with participant or participant’s 
legally acceptable representative
X
X
X
See Section 8.1.10 for details.
Collect eVRC from participant or participant’s legally 
acceptable representative
X
Complete the Telephone Contact Questionnaire
X
See Section 8.1.11 for details.
Safety Procedures
Complete Physical Examination
X
To be performed by the investigator or medically 
qualified designee before vaccine is administered. See 
Section 8.3.1 for details.
Pregnancy Test – if applicable
X
A pregnancy test consistent with local requirements 
must be performed before administration of the study 
vaccine in women of child-bearing potential. Urine or 
serum tests can be used, and results must be negative 
before vaccination can occur.
Body Temperature Measurement
X
Each participant’s body temperature must be taken 
before vaccination (see Section 8.3.3 for method). 
Participants who have febrile illness at or within 72 
hours of vaccination must be rescheduled.
30-Minute Postvaccination Observation Period
X
To be performed by blinded study site personnel only.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
24
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Study Period
Intervention
Follow-up
Comments
Visit Number
1
TC
2C
TC
Scheduled Time
Day 1 
(Dose 1)
Day 15 
after Visit 1
~1 month 
after Dose 1
~6 months 
after Dose 1
Visit Window
Day 15 to 
Day 19 
after Visit 1
Day 28 to 
Day 42 
after Visit 1
Day 166 to 
Day 194 
after Visit 1
AE Monitoring
X
X
X
X
Nonserious AEs are to be reported from Days 1 through 
14 following each vaccination. SAEs and deaths are to 
be reported throughout the duration of an individual’s 
study participation.
Immunogenicity Procedures
Serum for Immunogenicity Assays (Including 
Retention Serum)
X
X
Blood samples must be collected before study 
vaccination when applicable
Future Biomedical Research
Collect Samples for Future Biomedical Research
X
Buccal swab DNA samples for analysis should be 
obtained prior to the vaccination on Visit 1, on 
randomized and FBR consented participants only, or at 
a later date as soon as the informed consent is obtained. 
Buccal swab DNA samples will be collected in 
participants ≥2 to <5 years of age; saliva DNA samples 
will be collected in participants ≥5 years of age.
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic vaccination report card; FBR = future biomedical research; SAE = serious adverse event.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
25
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
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, 23F) present in the licensed vaccine 
Prevnar 13™ (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein], 
Wyeth Pharmaceuticals, a subsidiary of Pfizer, Inc., Philadelphia, PA), plus 2 additional 
serotypes (22F, 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 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 expanded 
serotype coverage. V114 includes 2 key additional serotypes compared with Prevnar 13™ 
and will address an unmet medical and public health need for a PCV with expanded 
coverage. 
The World Health Organization (WHO) and the United States Advisory Committee for 
Immunization Practices (ACIP) recommend all infants be vaccinated with PCV. Country-
specific routine immunization regimens vary by schedule and number of doses. The ACIP 
recommends a 4-dose schedule: 3 primary infant doses (at 2, 4, and 6 months of age) and a 
booster dose (at 12 to15 months of age). The WHO and ACIP also recommend catch-up PCV 
vaccination for healthy children who fall behind or start late with their recommended PCV 
immunization schedule. This study will enroll children who have not started their PCV 
vaccination regimen (PCV-naïve), as well as children partially or fully vaccinated with lower 
valency PCVs as these participants are naïve to the additional serotypes included in V114 or 
Prevnar 13™and are expected to benefit from the immunity conferred to the additional 
serotypes.
Despite high coverage rates in the United States, there are still a substantial number of 
children who are behind the recommended PCV schedule. In 2017, 8.1% of children 19 to 35 
months of age had not received 3 doses of PCV and 17.6% had not received 4 doses of PCV
[Hill, H. A., et al 2018]. Poverty, race/ethnicity, and health insurance status have been 
associated with low coverage rates [Hill, H. A., et al 2016]. Similarly, a substantial number 
of children in other countries do not receive the recommended doses of PCV on schedule
[Global Health Observatory 2018]. The evaluation of safety and immunogenicity of catch-up 
vaccination may inform the development of new PCVs. 
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
26
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
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 including meningitis, sepsis, pneumonia, sinusitis and otitis media. Currently, 
many countries worldwide have incorporated licensed PCVs (eg, Prevnar 13™ and/or 
Synflorix™ (pneumococcal polysaccharide conjugate vaccine [adsorbed], GlaxoSmithKline 
Biologicals S.A, Rixensart, Belgium) into their infant immunization programs. Prevnar™ 
was first licensed in 2000 and later replaced by Prevnar 13™ in 2009 (European Union) and 
2010 (United States). Synflorix™ was licensed in the European Union in 2009. Although 
Prevnar 13™ is indicated for children and adults, Synflorix™ is only indicated for children 
up to 5 years of age. Widespread use of PCVs have reduced the burden of pneumococcal 
disease caused by the serotypes contained in the vaccines in children who received the 
vaccines, as well as unvaccinated individuals through herd protection [Centers for Disease 
Control and Prevention 2008] [Ruckinger, S., et al 2009] [Farrell, D. J, et al 2007] [Pilishvili, 
Tamara, et al 2010] [Lexau, C. A., et al 2005] [Metlay, J. P., et al 2006] [Whitney, Cynthia 
G., et al 2003] [Moore, M. R., et al 2015] [Lepoutre, A., et al 2015] [Weiss, S., et al 2015] 
[Martinelli, D., et al 2014] [Guevara, M., et al 2016] [Waight, P. A., et al 2015] [Jokinen, J., 
et al 2015] [Palmu, A. A., et al 2015] [Wagenvoort, G. H., et al 2016]. Despite this, an 
increase in the burden of IPD caused by serotypes not contained in currently available 
vaccines has been observed.
V114 contains all the pneumococcal serotypes contained in Prevnar 13™ plus 2 additional 
serotypes (22F, 33F). The selection of 22F and 33F was primarily based on the emergence of 
these 2 serotypes as important causes of IPD in the era of Prevnar™ and Prevnar 13™. 
Approximately 4 years after inclusion of Prevnar™ in the United States infant immunization 
schedule, serotypes 22F and 33F accounted for approximately 13% of IPD cases in children 
<5 years of age (incidence rate of IPD due to 22F and 33F combined of 3.1 cases per 100,000 
person-years), in contrast to 1.3% of IPD cases in the pre-PCV7 era (incidence rate of 22F 
and 33F IPD of 1.2 cases per 100,000 person-years) [Hicks, L. A., et al 2007]. By 2013, both 
22F and 33F were among the leading serotypes causing IPD beyond those already included 
in Prevnar 13™, accounting for approximately 21% of all IPD in children <5 years of age in 
the United States [Moore, M. R., et al 2015]. 
The additional serotypes contained in V114 will provide broader coverage against the leading 
serotypes associated with pneumococcal disease worldwide. V114 is designed to meet 
continuing medical and public health needs for PCVs globally, as well as address the 
emergence of pneumococcal disease caused by serotypes not contained in currently licensed 
PCVs.
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
27
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
V114.
2.2.3
Information on Other Study-related Therapy
Refer to approved labeling for detailed background information on Prevnar 13™ and other 
licensed pediatric vaccines administered concomitantly.
Prevnar 13™ contains the 7 pneumococcal serotypes included in Prevnar™ (4, 6B, 9V, 14, 
18C, 19F, 23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A).
Prevnar™ and Prevnar 13™ are also known as Prevenar™ and Prevenar 13™ in many 
countries outside of the United States; these vaccines will be referred to as Prevnar™ and 
Prevnar 13™ throughout this document.
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 efficacy of an investigational medicine.
Approximately 50% of participants will receive Prevnar 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 Prevnar 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 Prevnar 13™.
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
There is no formal hypothesis testing in this study.
The following objectives and endpoints will be evaluated in participants enrolled from 7 
months to 17 years of age (inclusive) who are either pneumococcal vaccine-naïve or who 
previously received a partial or full regimen of pneumococcal conjugate vaccine (PCV) 
(Table 1). Immunogenicity and safety objectives will be evaluated by age at randomization 
(ie, 7 to 11 months of age, 12 to 23 months of age, and 2 to 17 years of age).
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
28
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
Objectives
Endpoints
Primary

Objective: 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 
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: To evaluate the 
anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G 
(IgG) Geometric Mean Concentrations 
(GMCs) at 30 days following the last 
dose for each vaccination group.

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes contained 
in V114 at 30 days after the last dose of 
study vaccine
Secondary

Objective: To evaluate 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 the 
last dose for each vaccination group.

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes contained 
in V114 at 30 days after the last dose of 
study vaccine
Tertiary/Exploratory

Objective (Participants ≥2 years of age
only): To evaluate the serotype-specific 
Geometric Mean Fold Rises (GMFRs) in 
IgG responses from prevaccination (Day 
1) to 30 days following the last dose for 
each vaccination group. 

Serotype-specific IgG responses for the 
15 serotypes in V114 at Day 1 and 30 
days after the last dose of study vaccine
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
29
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active comparator-controlled, parallel-group, multi-site, double-blind 
(with in-house blinding) study of V114 in healthy children who are either pneumococcal 
vaccine-naïve or who previously received a partial or full regimen of PCV (Table 1).
Approximately 600 individuals will be randomly assigned, in a 1:1 ratio, to receive either 
V114 (300 participants) or Prevnar 13™ (300 participants). Randomization will be stratified 
by age (7 months to 11 months, 12 months to 23 months [<2 years], ≥2 years to <6 years, and 
≥6 years to 17 years [inclusive]). A maximum of 300 participants will be ≥6 years of age. 
Participants ≥2 years of age will be further stratified based on the history of prior PCV 
vaccination status (Yes and No) (see Section 6.3.2 for details on stratification).
Approximately 300 participants will be PCV-naïve.
Table 1
Catch-Up Vaccination Schedules in V114-024
Age at 
Randomization
PCV Status
Number of 
Doses of V114 
or Prevnar 13™
Dose Schedule
7 to 11 months
Naïve
3 doses
Dose 1: At randomization
Dose 2: 4 to 8 weeks after Dose 1
Dose 3: 8 to 12 weeks after Dose 2 
AND ≥12 months of age
12 to 23 months
Naïve
2 doses
Dose 1: At randomization
Dose 2: 8 to 12 weeks after Dose 1
2 to 17 years
(inclusive)
Naïve
1 dose
Dose 1: At randomization
Partial regimen of 
Prevnar™, 
Synflorix™, or 
Prevnar 13™
1 dose
Dose 1: At randomization (at least 
8 weeks after previous dose of 
PCV)
Complete regimen of 
Prevnar™ or 
Synflorix™
1 dose
Dose 1: At randomization (at least 
8 weeks after previous dose of 
PCV)
Participants will be followed for injection-site and systemic AEs through Day 14 following 
each vaccination with V114 or Prevnar 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. An external Data 
Monitoring Committee (DMC) will conduct a periodic review of safety and tolerability data 
 
 
054BCT
 
 
05PSCV

PRODUCT: V114  
30
PROTOCOL/AMENDMENT NO.: 024-00 
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
for the V114 Phase 3 pediatric program. A description of the structure and function of the 
DMC, along with the timing and content of the safety reviews will be outlined in the DMC 
charter. Information regarding the composition of the DMC is provided in Appendix 1.
Blood samples for immunogenicity assays will be collected at 1 month (28 to 42 days) after 
the last scheduled dose of study vaccine. For participants ≥2 years at enrollment, a blood 
sample will be collected immediately before vaccination and at 1 month following 
vaccination.
After completion of immunogenicity testing, 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 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
Healthy infants are at increased risk for pneumococcal disease and its associated morbidity 
and mortality [Drijkoningen, J. J 2014]. This study will assess the safety and immunogenicity 
of V114 when given as a catch-up vaccination using recommended age-appropriate catch-up 
vaccination [Nuorti, J. P. and Whitney, C. G. 2010] [Centers for Disease Control and 
Prevention (CDC) 2013]. Children 2 years and older who have completed a full regimen of 
Prevnar™ or Synflorix™ are included in this study because the extended serotype coverage 
of the study intervention (V114 or Prevnar 13™) is expected to confer additional therapeutic 
benefit against the serotypes not contained in these lower valency vaccines.
Healthy infants and toddlers represent an immunologically-naïve population whereas school-
aged children are more likely to have circulating serotype-specific pneumococcal antibodies 
due to prior exposure (eg, history of carriage, acute otitis media) [Anttila, M., et al 1999] 
[Rodriguez, M. E., et al 1999] [Vidarsson, G., et al 1998]; therefore, randomization will be 
stratified by age. Stratification will assure similar distribution of participants between V114 
and Prevnar 13™across the age groups. Additional age-appropriate vaccination is permitted 
during the study to ensure that participants receive other recommended vaccines.
The immunogenicity and safety endpoints, including the duration of the safety follow-up 
period, are consistent with previous studies evaluating the immunogenicity and safety of 
PCVs. Data collected from this study will be added also to the larger safety database of V114 
to support initial licensure in infants, children, and adolescents.  
 
 
054BCT
 
 
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PRODUCT: V114  
31
PROTOCOL/AMENDMENT NO.: 024-00 
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04-JAN-2019
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints are consistent with previous studies evaluating the 
immunogenicity of investigational PCVs. Serotype-specific IgG GMC is the primary 
immunogenicity endpoint and the response rate (ie, the proportion of participants meeting the 
serotype-specific IgG threshold value of ≥0.35 μg/mL) is the secondary endpoint in this 
study. The use of the serotype-specific IgG antibody level of ≥0.35 µg/mL has been 
recommended by a WHO expert panel as an acceptable threshold value for evaluating the 
clinical performance of PCVs following a routine childhood vaccination regimen [World 
Health Organization 2008] [World Health Organization 2005].
The pneumococcal electrochemiluminescence (PnECL) assay will be used to measure the 
primary and secondary immunogenicity endpoints. Additional information on the 
immunogenicity assay can be found in Section 8.2.
Anti-PnPs serotype-specific IgG GMCs and response rates will be measured at 30 days 
following the last dose of study vaccine to evaluate the immune response to the catch-up 
vaccination. In participants ≥2 years of age, the immune response will be measured 
prevaccination and postvaccination to evaluate the fold-rise from baseline levels as older 
children may have circulating anti-pneumococcal antibodies due to either prior exposure or 
PCV vaccination.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1.
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, and guidance
from regulatory agencies during product development.
The electronic Vaccination Report Card (eVRC) used to record AEs during the 
postvaccination periods, as defined in Section 8.1.9, was structured as recommended in the 
final Food and Drug Administration Patient Reported Outcome Guidance [U.S. Food and 
Drug Administration 2009]. This study will utilize 2 eVRCs (1 for participants <3 years of 
age and 1 for participants ≥3 years of age) that are designed and validated to collect AEs
using terms that are developmentally appropriate for infants and children of different ages.
Solicited systemic AE terms used by the 2 eVRCs align with expected developmental 
language capabilities of each age-group (<3 and ≥3 years). Infants and toddlers (<3 years 
old) have limited language development and are not expected to be able to communicate 
organ-specific systemic AE terms that are used for older children and adults (eg, muscle pain, 
joint pain and headache). The systemic AE terms used for infants and toddlers (irritability, 
drowsiness, appetite lost) allow the participant’s legally acceptable representative to describe 
 
 
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the participant’s general behavior rather than attempt to identify a specific symptom. Because 
hives and welts are visual signs that do not require communication by the participant, these 
AE terms are solicited across all age groups.
Details on the safety endpoints evaluated in this study can be found in Section 8.3.4 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 this future biomedical research substudy are presented in Appendix 6.
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. 
Prevnar 13™ is currently the most widely recommended vaccine for the prevention of 
pneumococcal disease in infants in many countries worldwide, includes the largest number of 
serotypes, and will be used as the active comparator in this study.
Refer to approved labeling for detailed background information on Prevnar 13™.
4.3
Justification for Dose
The dose of V114 is similar to that used in previous pediatric V114 clinical studies, which 
demonstrated safety and comparable immune responses to those of Prevnar 13™. The dosing 
schedule is consistent with the ACIP recommendation for Prevnar 13™ catch-up vaccination. 
Refer to the V114 IB for details on doses evaluated in previous pediatric V114 clinical 
studies.
 
 
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. 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.
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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 male or female, from 7 months to 17 years of age (inclusive), at the time of obtaining
the informed consent/assent.
 
 
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Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
3. Not be pregnant (Appendix 5) or breastfeeding, and at least 1 of the following conditions 
applies:
a.
Not be a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP must agree to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 6 weeks after the last dose of study intervention.
Informed Consent
4. 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. As appropriate based on local guidelines,
the participant will also provide written informed assent for the study. The participant or 
the participant’s legally acceptable representative may also provide assent/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 (defined as rectal, oral or tympanic temperature ≥38.1°C 
[≥100.5°F] or axillary or temporal temperature ≥37.8°C [≥100.0°F]) 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 known or history of functional or anatomic asplenia.
 
 
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8. Has failure to thrive based on the clinical judgement of the investigator.
9. Has a bleeding disorder contraindicating intramuscular vaccination.
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. Is 7 to 23 months of age and has received a dose of a pneumococcal vaccine prior to 
study entry based on medical record. Participants ≥2 years of age could have received a 
PCV at least 8 weeks prior to study entry as follows: a partial regimen of Prevnar™, 
Synflorix™, or Prevnar 13™ or a full regimen of Prevnar™ or Synflorix™based on 
local guidelines. Participants should not have received any dose of a pneumococcal 
polysaccharide vaccine.
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/day 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 exceeding 
physiologic replacement doses (approximately 5 mg/day prednisone equivalent) 
within 14 days prior to any dose of study vaccine.
c.
Is expected to require systemic corticosteroids within 30 days after any study 
vaccination during conduct of the study.
Note: Topical, ophthalmic and inhaled steroids are permitted.
14. *Has received other licensed non-live vaccines within 14 days before receipt of study 
vaccine. Exception: Inactivated influenza vaccine may be administered but must be 
given at least 7 days before receipt of study vaccine or at least 15 days after receipt of 
study vaccine.
15. *Has received a licensed live vaccine within 30 days before receipt of study vaccine.
16. Has received a blood transfusion or blood products, including immunoglobulins, within 
6 months before receipt of study vaccine.
 
 
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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.
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 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 who 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 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who 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 Prevnar 13™) will be packaged to support enrollment . Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
 
 
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6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
 
 
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
V114
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension
Refer to IB
0.5 mL
IM
Schedule A:
7 to 11 months 
of age: Single 
dose at Visits 1, 
2A, and 3A
Schedule B:
12 to 23 months 
of age: Single 
dose at Visits 1 
and 2B
Schedule C:
2 to 17 years of 
age (inclusive): 
Single dose at 
Visit 1 
Experimental
IMP
Central
Prevnar 
13™
Active 
Comparator
Prevnar 13™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Schedule A:
7 to 11 months 
of age: Single 
dose at Visits 1, 
2A, and 3A
Schedule B:
12 to 23 months 
of age: Single 
dose at Visits 1 
and 2B
Schedule C:
2 to 17 years of 
age (inclusive): 
Single dose at 
Visit 1
Experimental
IMP
Central
Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; 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.
 
 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
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.
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.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to receive V114 or Prevnar 13™.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:

Age at time of randomization

PCV-naïve or receipt of prior PCV
The stratification levels are shown below:
1. 7 to 11 months of age
2. 12 to 23 months of age (<2 years of age)
3. ≥2 years to <6 years of age
3a. No (PCV-naïve)
3b. Yes (Receipt of prior PCV)
4. ≥6 years to 17 years of age (inclusive) (maximum of 300 participants)
4a. No (PCV-naïve)
4b. Yes (Receipt of prior PCV)
Approximately 300 participants will be PCV- naïve.
Stratification will be managed by the IRT system.
6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevnar 13™ will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study site personnel. The 
participant and the investigator who are involved in the clinical evaluation of the participants 
will remain blinded to the group assignments.
Because V114 and Prevnar 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 will not be present in the examination room when study vaccines are administered. 
 
 
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Contact between participants and unblinded study 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) and Merck Research Laboratories employees 
directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
See Section 8.1.13 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 or Prevnar 13™vaccination 
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 the ongoing study (see Section 5.2 for details). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
If a medical condition requires the use of a prohibited 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 use that occurs on the day of vaccination on the eVRC and 
appropriate eCRF. 
During influenza season, it is anticipated that participants may be given an influenza vaccine. 
Influenza vaccine should be administered at least 7 days prior to or at least 15 days after the 
administration of the study vaccine. Other nonstudy pediatric vaccines are permitted and 
should be administered according to the local recommended schedule. Other injectable 
vaccines should be given after the study vaccine and should not be administered in the same 
limb as V114 or Prevnar 13™. These vaccinations should be recorded on the appropriate 
eCRF.
 
 
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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/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 8.1.13). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.13 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
For participants enrolled at 7 to 23 months of age:
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccination 
 
 
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regimen will still continue to participate in the study as specified in Section 1.3 and 
Section 8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.12 and 
Section 8.12.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
1. The participant or participant’s legally acceptable representative requests to 
discontinue study intervention.
2. The participant’s treatment assignment is unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
3. The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, places the participant at unnecessary risk 
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 8.12.3 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.
For participants enrolled at 24 months through 17 years of age: 
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or 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 
 
 
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outlined in Section 8.1.12. The procedures to be performed should a participant repeatedly 
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 and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
The investigator or designee must make every effort to regain contact with the participant at 
each missed visit (eg, telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified or trained staff. Delegation of study site personnel responsibilities will be 
documented in the Investigator Trial File Binder (or equivalent).
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
 
 
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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. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
Approximately 5mL of blood will be drawn at the visits indicated in Section 1.3. The 
maximum amount of blood collected from each participant over the duration of the study 
during planned study visits will not exceed 10mL.
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, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical study or 
future biomedical research. If there are changes to the participant’s status during the study 
(eg, health or age of majority requirements), the investigator or medically qualified designee 
must ensure the appropriate consent/assent is in place.
8.1.1.1
General Informed Consent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form, and any written information provided to the participant must receive the 
Institutional Review Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable 
opinion in advance of use. The participant or his/her legally acceptable representative should 
be informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent/assent form or 
addendum to the original consent form that captures the participant’s dated signature or by 
the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
 
 
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant, answer all of his/her questions, and obtain written informed 
consent/assent before performing any procedure related to the future biomedical research 
substudy. A copy of the informed consent/assent will be given to the participant.
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 (Day 1) may 
be rescheduled for a time when these criteria are not met.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. 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. 
The participant’s medical history for up to 5 years prior to Visit 1 will be obtained to ensure 
that the participant satisfies the inclusion and exclusion criteria of the study.
 
 
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations and
medications taken by the participant within 30 days before the first dose of study vaccine at 
Visit 1. The receipt of a pneumococcal vaccine needs to be reviewed and documented in the 
participant’s chart and recorded in the study database.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
If a medical condition requires the use of a prohibited 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 the use of any analgesic or antipyretic use that occurs on the day of 
vaccination on the eVRC and appropriate eCRF. Concomitant medications taken after Visit 1 
and nonstudy vaccines received since Visit 1 will be recorded with the eVRC as specified in 
Section 8.3.4.
Other vaccinations administered during the study should be recorded on the appropriate 
eCRF. Injectable vaccines should not be administered in the same limb as V114 or 
Prevnar 13™. Documentation of which limb was used for the administration of V114 or 
Prevnar 13™ should be recorded on the eVRC (Section 8.3.4) 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 8.12.1.
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 
 
 
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treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer the study vaccine. Study vaccines should be prepared and administered by 
appropriately qualified members of the study personnel (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacist or medical assistant) as allowed by local/state, 
country and institutional guidance. 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 Prevnar 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.
If the V114 is provided as a syringe: Prior to administration of study vaccine, the unblinded 
pharmacist should shake vigorously to obtain a homogenous white suspension. If 
white-colored insoluble particle appears, the unblinded pharmacist 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. 
If V114 is provided as a vial: Prior to administration of study vaccine, the unblinded 
pharmacist should use rapid, horizontal hand-shaking for up to 5 seconds while holding the 
vial in between the thumb and index finger to obtain a homogenous white suspension. 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.
Prevnar 13™ will be supplied as a pre-filled syringe.
A 0.5-mL intramuscular dose of study vaccine will be administered as stated in Section 1.3.
Documentation of which limb was used for the administration of V114 or Prevnar 13™ 
should be recorded on the appropriate eCRF. This information should also be recorded on the 
eVRC to inform the participant or participant’s legally acceptable representative of the 
appropriate limb to monitor for AEs related to the V114 or Prevnar 13™. 
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 
 
 
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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 or participant’s parent/guardian will be blinded to the 
study vaccine received by the participant. Vaccination information, such as Component 
Identification Number and time of vaccination, must be recorded on the appropriate eCRF as 
per the Data Entry Guidelines.
8.1.8.1
Timing of Dose Administration
V114 or Prevnar 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 Prevnar 13™ 
(Section 1.3 and Section 6.3.3).
Participants must be afebrile for at least 72 hours prior to vaccination. 
Blood samples must be collected before study vaccination.
8.1.9
Electronic Vaccination Report Card
The eVRC was developed to be administered electronically via a hand-held device. This item 
was structured as recommended in the final Food and Drug Administration Patient Reported 
Outcome Guidance [U.S. Food and Drug Administration 2009]. The investigator or delegate 
will train the participant or participant’s legally acceptable representative in the use of the 
eVRC 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 
eVRC as described in Section 1.3 and Section 8.3.4. The investigator or delegate will review 
the data captured on the eVRC with the participant or participant’s legally acceptable 
representative as indicated in Section 1.3.
For the AEs outlined above, the investigator will use the information provided by the 
participant or participant’s legally acceptable representative, both on the eVRC and verbally 
at the time of eVRC review, to apply the appropriate assessment of intensity as described in 
Appendix 3.
8.1.10
Day 15 Postdose Telephone Contact Guide
Site personnel will contact the participant or the participant’s legally acceptable 
representative on Day 15 after each vaccination dose to review eVRC data. The Day 15 
Postdose Telephone Contact Guide will be provided by the Sponsor. This guide is designed 
 
 
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to assist site personnel to collect any updates or edits to data previously entered on the eVRC 
from the participant or the participant’s legally acceptable representative. Any differences 
between eVRC data and the clinical database must be clearly explained in the participant’s 
source documentation with an indication of where the information was obtained (eg, from the 
Day 15 Postdose Telephone Contact with the participant’s legally acceptable representative).
8.1.11
Telephone Contact Questionnaire
Site personnel will contact the participant or the participant’s legally acceptable 
representative approximately 6 months after the last dose of study vaccine to collect 
additional information based on a Telephone Contact Questionnaire provided by the Sponsor. 
Data to be reported from this discussion will include SAEs and/or any updates to previously 
reported safety information.
8.1.12
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 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.12.1
Withdrawal From Future Biomedical Research
A participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate). A participant’s consent 
may be withdrawn at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
 
 
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8.1.13
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 (consistent 
with local requirements) 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.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.14
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. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced anti-PnPs serotype-specific 
IgG for all the 15 serotypes contained in V114 using PnECL v2.0 assay.
 
 
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Blood collection, storage and shipment instructions for serum samples will be provided in the 
operations/laboratory manual.
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 v2.0 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 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 prespecified 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 Prevnar™. In 2012 and 2014, the Sponsor formally bridged 
the original PnECL assay to the WHO IgG enzyme-linked immunosorbent assay (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 Prevnar™ 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 Prevnar 13™.
A confirmatory study was 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 Prevnar 13™ serotypes and serotypes 22F and 33F, which were not previously assessed. 
The bridging of the optimized PnECL to the WHO ELISA is complete, and the data showed 
good concordance between the PnECL and WHO ELISA around the 0.35 μg/mL threshold 
value for all 15 serotypes. It is recommended that a single PnECL threshold value of 
0.35µg/mL be applied to each of the 15 serotypes.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
 
 
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) at Visit 1 for all participants. A targeted 
physical examination will be performed at subsequent vaccination visits as indicated in 
Section 1.3. Any clinically significant abnormality will be recorded on the appropriate eCRF.
Complete and targeted physical examination procedures include obtaining vital signs (heart 
rate, respiratory rate, and rectal 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, 
musculoskeletal system, and other organ systems as clinically indicated. 
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Pregnancy Test
A pregnancy test consistent with local requirements (sensitive to at least 25 IU beta human
chorionic gonadotropin must be performed before vaccination in WOCBP as described in 
Section 1.3. Urine or serum tests can be used, and results must be negative before vaccination 
can occur.
8.3.3
Body Temperature Measurement
Prevaccination body temperature will be taken by study staff as indicated in Section 1.3. 
Participants who have febrile illness (defined as rectal, oral or tympanic temperature 
≥38.1°C [≥100.5°F] or axillary or temporal temperature ≥37.8°C [≥100.0°F]) within 72 
hours of Visit 1 must be rescheduled.
The participant or the participant’s legally acceptable representative will be asked to record a 
body temperature reading on the eVRC from Day 1 through Day 7 postvaccination. 
Temperature measurement must be recorded in the eVRC if fever is suspected during Day 8 
through Day 14 postvaccination.
Temperature readings should be taken at approximately the same time each day. Use of 
temporal or tympanic thermometers to collect temperature for this study is prohibited.

For participants 7 months to <3 years of age, rectal is the preferred method of obtaining 
participant’s temperature. Axillary (underarm) is an acceptable method but temperature 
needs to be confirmed by rectal measurement if fever is detected. If an axillary 
temperature is reported to be ≥37.8°C (≥100.0°F), a rectal temperature must be taken. In 
this case, both axillary and rectal temperatures must be recorded on the eVRC.

For participants ≥3 years of age, oral is the preferred method of obtaining participant’s 
temperature. Axillary (underarm) is an acceptable method but temperature needs to be 
 
 
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confirmed by oral measurement if fever is detected. If an axillary temperature is reported 
to be ≥37.8°C (≥100.0°F), an oral temperature must be taken. In this case, both axillary 
and oral temperatures must be recorded on the eVRC.
8.3.4
Safety Assessments and Use of the eVRC
All participants will be observed for at least 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.
The limb that was used for the administration of V114 or Prevnar 13™ will be recorded in 
the eVRC (Note: the study will report injection-site AEs from V114 or Prevnar 13™; the 
location of V114 or Prevnar 13™ administration can be used by the participant or 
participant’s legally acceptable representative to monitor the appropriate limb for injection-
site AEs related to V114 or Prevnar 13™).
The participant or the participant’s legally acceptable representative will use the eVRC 
(Section 8.1.9) to document the following information:

Body temperatures measured Day 1 (day of vaccination) through Day 7 
postvaccination; Day 8 through Day 14 postvaccination if fever is suspected

Solicited injection-site AEs (redness, swelling, tenderness, and hard lump) Day 1 
through Day 14 postvaccination

For participant 7 months to <3 years of age at enrollment, solicited systemic AEs 
(irritability, drowsiness, appetite lost, and hives or welts) Day 1 through Day 14 
postvaccination

For participant ≥3 years of age at enrollment, solicited systemic AEs (muscle pain, 
joint pain, headache, tiredness, and hives or welts) Day 1 through Day 14 
postvaccination

Any other injection-site or systemic AEs Day 1 through Day 14 postvaccination

Use of any analgesic or antipyretic on the day of vaccination

Concomitant medications and nonstudy vaccinations Day 1 to Day 14 postvaccination
8.3.5
Clinical Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and Section 1.3.
 
 
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If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the results must be recorded in the appropriate CRF (eg, SLAB).
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study, every attempt should be made to perform repeat assessments until 
the values return to normal or baseline or if a new baseline is established as determined by 
the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the day of allocation/randomization to the first vaccination and from the day of each 
vaccination through 14 days postvaccination. 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.
 
 
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Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
1. A death that occurs prior to the participant completing the study.
OR
2. An SAE that is considered by an investigator who is a qualified physician to be 
vaccine-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
 
 
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion of 
study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest
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
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.
 
 
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
 
 
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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 (ECIs)
There are no events of clinical interest for this study.
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.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
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
PK 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.
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
 
 
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8.10
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Buccal swab DNA (participants <5 years of age) or saliva DNA (participants ≥5years 
of age) for future research

Leftover study serum after completion of immunogenicity testing stored for future 
research
8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Screening procedures will be conducted at Visit 1 (Day 1) as outlined in Section 1.3.
8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
This section is applicable to participants 7 months to 23 months of age at enrollment and who 
receive more than 1 dose of study vaccine. A participant may discontinue from study 
intervention (including receipt of V114 or Prevnar 13™) but continue to participate in 
protocol-specified, AE-monitoring activities as outlined in Section 1.3, as long as the
participant or participant’s legally acceptable representative does not withdraw consent.
Blood draws for immunogenicity testing could occur if agreed to by the participant or 
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. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental Statistical Analysis Plan 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 Section 9.2 through Section 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of Catch-up Vaccination Regimens of V114 in Healthy 
Infants, Children, and Adolescents (PNEU-PLAN)
Intervention Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 or
Prevnar 13™, respectively. Randomization will be stratified according to 
the participant’s age (7 to 11 months of age, 12 to 23 months of age, 2 to 
5 years of age, and 6 to 17 years of age); participants ≥ 2 years of age 
will be further stratified by the history of prior PCV vaccination (Yes and 
No) at the time of randomization as described in Section 6.3.2.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)

Primary Endpoint(s)
Immunogenicity:

Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes 
contained in V114 at 30 days after the last dose
Safety:

Proportion of participants with solicited injection-site AEs
(redness/erythema, swelling, tenderness/pain, and hard 
lump/induration) from Day 1 through Day 14 postvaccination

Proportion of participants with solicited systemic AEs (Details are in 
Section 9.4.2) from Day 1 through Day 14 postvaccination

Proportion of participants with vaccine-related SAEs through 
completion of study participation
Key Secondary Endpoints
Immunogenicity:

Anti-PnPs serotype-specific IgG response rates (proportion of 
participants with IgG ≥0.35 µg/mL) at 30 days following the last 
dose.
Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes contained in V114 separately by age group (7 to 
11 months of age, 12 to 23 months of age, and 2 to 17 years of age) at the 
time of randomization. 
To address the primary immunogenicity objective, evaluation of the IgG 
GMCs at 30 days following the last dose with V114 or Prevnar 13™ will 
include descriptive summaries. The point estimates will be calculated by 
exponentiating the estimates of the mean of the natural log values and the 
within-group confidence intervals (CIs) will be derived by 
exponentiating the upper and lower bounds of the CI for the mean of the 
natural log values based on the t-distribution. For the dichotomous 
endpoints that immune responses meet threshold value as defined in the 
objectives, the within-group CIs will be calculated based on the exact 
method proposed by Clopper and Pearson [CLOPPER, C. J. and 
PEARSON, E. S. 1934].
 
 
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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 intervention assignment. Randomization will be implemented using an IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study, and no formal 
hypothesis testing will be performed.
Statistical Methods for Key 
Safety Analyses
The analysis strategy for safety parameters following vaccination is 
described in Section 9.6.2. Safety analyses will be conducted by age (7 to 
11 months of age, 12 to 23 months of age, and 2 to 17 years of age) at the 
time of randomization. Safety parameters will be summarized via 
descriptive statistics. In addition, for select safety parameters, 95% 
within-group CIs will be provided.
Interim Analyses
To support the periodic review of safety and tolerability data across the      
V114 Phase 3 pediatric program, an external unblinded statistician will 
provide unblinded interim safety summaries to an independent DMC for 
their review. There are no plans to conduct an interim analysis of 
unblinded immunogenicity data in this study. However, unblinded 
immunogenicity data will be made available to the DMC upon request to 
enable a benefit-risk assessment.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
Immunogenicity:
The planned sample size is 600 participants. Participants are to be 
randomly assigned in 1:1 ratio to V114 or Prevnar 13™, respectively. It 
is assumed that approximately 240 participants in the V114 group and 
240 in the Prevnar 13™ group will be evaluable for the PP 
immunogenicity analyses at 30 days following the last dose (80% 
evaluability rate). There are no hypotheses to be evaluated for primary 
objectives. Section 9.9.1 provides information about the expected
variability of IgG GMCs given the sample size.  
Safety:
Section 9.9.2 provides information about the ability of this study to 
estimate the incidence of AEs within the V114 group.
 
 
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9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be summarized are listed below.
9.4.1
Immunogenicity Endpoints
A description of immunogenicity assessments is presented in Section 8.2. Immune responses 
will be measured for each of the following serotypes contained in V114: 1, 3, 4, 5, 6A, 6B, 
7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F.
The primary immunogenicity analysis endpoint is:

Anti-PnPs serotype-specific IgG GMCs at 30 days following the last dose.
The secondary immunogenicity analysis endpoint is:

Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL at 30 
days following the last dose.
The exploratory immunogenicity analysis endpoint (for participants ≥2 years of age only) is: 

Anti-PnPs serotype-specific GMFRs from Prevaccination (Day 1) to 30 days 
following the last dose for IgG responses. 
9.4.2
Safety Endpoints
A description of safety measures is contained in Section 8.3 and Section 8.4. The analysis of 
safety results is described in Section 9.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events and postvaccination temperature measurements following any vaccination 
following V114 or Prevnar 13™.
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration) from Day 1 through Day 14 
following any vaccination with V114 or Prevnar 13™

Proportion of participants with solicited systemic AEs from Day 1 through Day 14 
following any vaccination with V114 or Prevnar 13™
o
For participants 7 months to <3 years of age at enrollment, solicited systemic 
AEs include irritability, drowsiness/somnolence, appetite lost/decreased 
appetite, and hives or welts/urticaria
 
 
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o
For participant ≥3 years to of age at enrollment, solicited systemic AEs 
include muscle pain/ myalgia, joint pain/arthralgia, headache, 
tiredness/fatigue, and hives or welts/urticaria

Proportions of participants with the broad AE categories consisting of any AE, a 
vaccine-related AE from Day 1 through Day 14 following any vaccination with V114
or Prevnar 13™

Proportion of participants with the broad AE categories consisting of an SAE, a 
vaccine-related SAE, a death, and discontinuation due to an AE through completion 
of study participation

Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 7 following any 
vaccination with V114 or Prevnar 13™
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The Per-Protocol (PP) population will serve as the primary population for the analysis of 
immunogenicity data in this study. All the immunogenicity analyses will be conducted by 
age (7 to 11 months of age, 12 to 23 months of age, and 2 to 17 years of age) at the time of 
randomization.
The PP population consists of all randomized participants without deviations from the 
protocol that may substantially affect the results of the immunogenicity endpoint. Potential 
deviations that may result in the exclusion of a participant from the PP population for all 
immunogenicity analyses include:

Failure to receive study vaccine (V114, Prevnar 13™) as per randomization schedule

Failure to receive correct clinical material as per randomization schedule (ie, 
participants who were cross-treated)

Receipt of a prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion from the PP immunogenicity 
analyses at a particular timepoint include:

Receipt of a prohibited medication or prohibited vaccine prior to a blood sample 
collection 

Collection of a blood sample outside of the prespecified 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 final unblinding of the database. Participants will be 
 
 
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included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the PP population.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed 
for the primary immunogenicity endpoint(s). The FAS population consists of all randomized 
participants who received the study vaccination and have at least 1 serology result. 
Participants will be included in the vaccination group to which they are randomized for the 
analysis of immunogenicity data using the FAS population.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 1 dose of study 
vaccination. Safety analyses will be conducted by age (7 to 11 months of age, 12 to 23 
months of age, and 2 to 17 years of age) at the time of randomization. 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 treatment group corresponding to the study vaccination actually 
received.
At least 1 temperature measurement obtained after study intervention is required for 
inclusion in the analyses of temperature.  
9.6
Statistical Methods
Statistical testing and inference for immunogenicity and safety analyses are described in 
Section 9.6.1 and Section 9.6.2, respectively. Section 9.6.3 describes how demographic and 
baseline characteristics will be summarized.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives. Methods related to exploratory objectives will be further 
described in the supplemental statistical analysis plan. All the immunogenicity analyses will 
be conducted by age (7 to 11 months of age, 12 to 23 months of age, and 2 to 17 years of 
age) at the time of randomization.
To address the primary immunogenicity objective, anti-PnPs serotype-specific IgG GMCs at 
30 days after the last dose will be evaluated for each of the 15 pneumococcal serotypes 
contained in V114. Point estimates for the IgG GMCs will be calculated by exponentiating 
the estimates of the mean of the natural log values. The within-group CIs will be derived by 
exponentiating the upper and lower bounds of the CI for the mean of the natural log values
based on the 1-sample t-distribution. For the secondary endpoints that immune responses 
meet threshold value as defined in the objectives, the within-group CIs will be calculated 
 
 
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based on the exact method proposed by Clopper and Pearson [CLOPPER, C. J. and 
PEARSON, E. S. 1934].
Reverse cumulative distribution curves for IgG concentrations will be graphically displayed 
by serotype at 30 days after the last dose. 
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 4.
Table 4
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs 
Supportive 
Approach†
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Anti-PnPs IgG GMCs at 30 days following
the last dose
P
Descriptive 
Statistics
(estimate, 95%
CI)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoints
Proportion of participants with anti-PnPs IgG 
≥0.35 µg/mL at 30 days following the last 
dose
P
Descriptive 
Statistics
(estimate, 95% 
CI)
PP
Missing data 
will not be 
imputed
CI = confidence interval; FAS = full analysis set; GMC = geometric mean concentration; IgG = 
immunoglobulin G; PnPs = pneumococcal polysaccharide; PP = per-protocol.
†
P = primary approach; S = supportive approach.
All the immunogenicity analyses will be conducted by age (7 to 11 months of age, 12 to 23 months of age, and 
2 to 17 years of age) at the time of randomization.
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. Safety analyses will be conducted by 
age (7 to 11 months of age, 12 to 23 months of age, and 2 to 17 years of age) at the time of 
randomization. Descriptive summaries of AEs following administration of V114 or 
Prevnar 13™ will include nonserious adverse events within 14 days of vaccination and SAEs 
occurring Day 1 through completion of study participation (end of the study). Additional 
summaries on key safety parameters will also be provided following each vaccination. 
The analysis strategy for safety parameters following each vaccination is summarized in 
Table 5. The proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration Day 1 to Day 14 postvaccination) and 
solicited systemic AEs from Day 1 to Day 14 postvaccination will be provided along with the 
corresponding within-group 95% CIs based on the exact binomial method proposed by 
Clopper and Pearson [CLOPPER, C. J. and PEARSON, E. S. 1934]. Of note, as solicited 
systemic AEs will be collected differently for participants <3 and ≥3 years of age (Section 
4.2.1.2 and Section 9.4.2), additional analyses may be provided. Details will be documented 
in the supplemental Statistical Analysis Plan.
 
 
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In addition, the broad AE categories consisting of the proportion of participants with any AE, 
a vaccine-related AE, a SAE, an AE which is both vaccine-related and serious, 
discontinuation due to an AE, and death will be summarized in the same manner. The 
proportion of participants with maximum temperature measurements meeting the Brighton 
Collaboration cut points (from Day 1 through Day 7) will also will be provided along with 
the corresponding within-group 95% CIs. Point estimates by vaccination group will be 
provided for all other safety parameters (specific AE terms and system organ class terms).
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination
Safety Endpoint
95% CI for Within-Group 
Descriptive Statistics
Injection-site redness/erythema (Days 1 to 14)†
X
X
Injection-site swelling (Days 1 to 14)†
X
X
Injection-site tenderness/pain (Days 1 to 14)†
X
X
Injection-site hard lump/induration (Days 1 to 14) †
X
X
Irritability (Days 1 to 14)‡
X
X
Drowsiness/somnolence (Days 1 to 14)‡
X
X
Appetite loss/decreased appetite (Days 1 to 14)‡
X
X
Hives or welts/urticaria (Days 1 to 14) ‡§
X
X
Muscle pain/myalgia (Days 1 to 14)§
X
X
Joint pain/arthralgia (Days 1 to 14)§
X
X
Headache (Days 1 to 14)§
X
X
Tiredness/fatigue (Days 1 to 14)§
X
X
Any AEǁ
X
X
Any vaccine-related AEǁ
X
X
Any SAEǁ
X
X
Any vaccine-related SAEǁ
X
X
Discontinuation due to AEǁ
X
X
Deathǁ
X
X
Maximum temperature measurements meeting the 
Brighton Collaboration cut points (Days 1 to 7)
X
X
Specific AEs by SOCs and PT
X
† Includes solicited injection-site AEs only.
‡ Solicited systemic-site AEs that apply to <3 years of age.
§ Solicited systemic-site AEs that apply to ≥3 years of age.
ǁ 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 1 AE.
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = system organ class; 
X = results will be provided.
9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed by using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
 
 
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randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (eg, age, race, and gender, birth weight, 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
A periodic review of safety and tolerability data across the V114 Phase 3 pediatric program 
will be conducted by an independent, unblinded, external DMC. A description of the 
structure and function of the DMC, along with the timing and content of the safety review 
will be outlined in the DMC charter. Information regarding the composition of the DMC is 
provided in Appendix 1. There are no plans to conduct an interim analysis of unblinded 
immunogenicity data in this study. However, unblinded immunogenicity data will be made 
available to the DMC upon request to enable a benefit-risk assessment.
The DMC will serve as the primary reviewer of the results of ongoing safety reviews and will 
make recommendations for discontinuation of the study or protocol modifications to an 
executive committee of the Sponsor (see Appendix 1 for details on the Committees Structure 
for this study). If the DMC recommends modifications to the design of the protocol or 
discontinuation of the study, this Executive Oversight Committee (EOC) of the Sponsor (and 
potentially other limited Sponsor personnel) may be unblinded to results at the intervention 
level to act on these recommendations. The extent to which individuals are unblinded with 
respect to ongoing safety reviews will be documented by the external unblinded statistician. 
Additional logistical details will be provided in the DMC Charter.
Study enrollment is likely to be ongoing at the time of external DMC review. Blinding to 
intervention assignment will be maintained at all investigational sites. Participant-level 
unblinding will be restricted to an external unblinded statistician performing ongoing safety 
reviews. Intervention-level ongoing safety reviews will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
safety reviews.
9.8
Multiplicity
No adjustment will be made for multiplicity.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. The planned sample size is 600 participants. Participants are to be 
randomly assigned in 1:1 ratio to V114 (300 participants) or Prevnar 13™(300 participants). 
It is assumed that approximately 240 participants in the V114 group and 240 in the 
Prevnar 13™group will be evaluable for PP immunogenicity analyses at Day 30 after the 
 
 
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last dose (based on an 80% evaluability rate). The immunogenicity objectives will be 
evaluated by age at randomization (ie, 7 to 11 months of age, 12 to 24 months of age, and 2 
to 17 years of age).The precision of the serotype-specific IgG GMCs (Table 6) are estimated 
based on a range of sample size in each age group for analyses after accounting for 
variability of the natural log concentrations, and the magnitude of the IgG GMC. The 95% 
CIs for various hypothetical IgG GMCs at 30 days postvaccination and various hypothetical 
standard deviation estimates for the natural log titers are displayed (Table 6).
Table 6
Within-Group 95% CIs for Varying Sample Size with Hypothetical IgG GMCs,
Standard Deviations and 80% Evaluable Rate
Sample Size 
for Each 
Age 
Subgroup†
Standard 
Deviation of 
Natural Log 
Titers‡
Serotype-specific IgG GMCs‡
1
5
10
V114 or Prevnar 13™
V114 or Prevnar 13™
V114 or Prevnar 13™
20
1.0
(0.63, 1.60)
(3.13, 7.98)
(6.26, 15.97)
1.5
(0.50, 2.02)
(2.48, 10.09)
(4.96, 20.18)
2.0
(0.39, 2.55)
(1.96, 12.75)
(3.92, 25.50)
40
1.0
(0.73, 1.38)
(3.63, 6.88)
(7.26, 13.77)
1.5
(0.62, 1.62)
(3.09, 8.08)
(6.19, 16.16)
2.0
(0.53, 1.90)
(2.64, 9.48)
(5.27, 18.96)
80
1.0
(0.80, 1.25)
(4.00, 6.25)
(8.00, 12.49)
1.5
(0.72, 1.40)
(3.58, 6.98)
(7.16, 13.96)
2.0
(0.64, 1.56)
(3.20, 7.80)
(6.41, 15.61)
160
1.0
(0.86, 1.17)
(4.28, 5.84)
(8.55, 11.69)
1.5
(0.79, 1.26)
(3.96, 6.32)
(7.91, 12.64)
2.0
(0.73, 1.37)
(3.66, 6.83)
(7.32, 13.67)
200
1.0
(0.87, 1.15)
(4.35, 5.75)
(8.70, 11.50)
1.5
(0.81, 1.23)
(4.06, 6.16)
(8.11, 12.33)
2.0
(0.76, 1.32)
(3.78, 6.61)
(7.57, 13.22)
† Sample sizes listed in the table are a range of hypothetical number in either V114 group or Prevnar 13™ group
‡ The estimates of the standard deviation and IgG GMCs are representative of those observed in previous MSD 
study.
CI = confidence interval; GMC = geometric mean concentration; IgG=Immunoglobulin G.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least one 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 
300 participants in the V114 group if the underlying incidence of an SAE is 0.5% (1 of every 
187 participants receiving the vaccine). There is a 50% chance of observing at least one SAE 
among 300 participants in the V114 group if the underlying incidence of an SAE is 0.2% (1 
 
 
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of every 439 participants receiving the vaccine). If no SAEs are observed among 300
participants, this study will provide 97.5% confidence that the underlying percentage of 
participants with an SAE is <1.2% (one in every 82 participants).
9.10
Subgroup Analyses
Subgroup analyses (eg, sex = (female, male)) will be performed for the primary 
immunogenicity endpoint and selected safety endpoints (summary of AEs). Details of 
subgroup analyses will be documented in the supplemental Statistical Analysis Plan.
9.11
Compliance (Medication Adherence)
The number and proportion of randomized participants receiving each vaccination will be 
summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V114 or Prevnar 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 of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
 
 
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC is comprised of both Sponsor and non-Sponsor scientific experts who provide input 
with respect to study design, interpretation of study results, and subsequent peer-reviewed 
scientific publications.
10.1.4.2
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
external DMC regarding the study.
 
 
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10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
 
 
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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.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
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.
 
 
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
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.
 
 
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
Pregnancy testing requirements for study inclusion are described in Section 5.1.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
 
 
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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.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
 
 
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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
 
 
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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.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
 
 
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
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category 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.

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.
 
 
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(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:
-
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.
 
 
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.

Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.

Reference Section 8.4.1 for reporting time requirements.

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.
 
 
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
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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen- only contraceptive implantc,

Intrauterine hormone-releasing system (IUS)c. IUS is a progestin releasing IUD.

Intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraception
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraception
-
Oral
-
Injectable
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.

Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)d
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
 
 
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c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation
d.
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
-
Male and female condom should not be used together (due to risk of failure with friction).
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways drugs/vaccines may interact with
-
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 the 
future biomedical research substudy
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
 
 
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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.
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
 
 
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6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
 
 
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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.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACIP
Advisory Committee on Immunization Practices
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
CTFG
Clinical Trial Facilitation Group 
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
ELISA
enzyme-linked immunosorbent assay
EOC
Executive Oversight Committee 
eVRC
electronic Vaccination Report Card
FAS
full analysis set
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GMC
geometric mean concentration
GMFR
geometric mean fold rise
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IM
intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug 
IPD
invasive pneumococcal disease
IRB
Institutional Review Board 
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MSD
Merck Sharp & Dohme Corp.
NDA
New Drug Application 
NIMP
non-investigational medicinal product
NSAE
nonserious adverse event
PCV
pneumococcal conjugate vaccine
PD
postdose
PK
pharmacokinetic
PnECL
pneumococcal electrochemiluminescence
 
 
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Abbreviation
Expanded Term
PnPs
pneumococcal polysaccharide
PP
per protocol
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
siDMC
Standing Internal Data Monitoring Committee
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
 
 
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11
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03QY70
[Centers for Disease Control 
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043QRD
[Centers for Disease Control 
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Centers for Disease Control and Prevention 
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04KW8S
[Centers for Disease Control 
and Prevention 2015]
Centers for Disease Control and Prevention. 
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0508PV
[CLOPPER, C. J. and 
PEARSON, E. S. 1934]
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03RRVC
[Drijkoningen, J. J 2014]
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Microbiol Infect. 2014 May;20 Suppl 5:45-51.
04NFHN
 
 
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[Farrell, D. J, et al 2007]
Farrell DJ, Klugman KP, Pichichero M. 
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04KWD9
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052HHD
[Guevara, M., et al 2016]
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04KSQ3
[Hicks, L. A., et al 2007]
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03QT0G
[Hill, H. A., et al 2016]
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Singleton JA, Kang Y. Vaccination coverage 
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052F6Z
[Hill, H. A., et al 2018]
Hill HA, Elam-Evans LD, Yankey D, 
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052X2R
 
 
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[Jokinen, J., et al 2015]
Jokinen J, Rinta-Kokko H, Siira L, Palmu AA, 
Virtanen MJ, Nohynek H, et al. Impact of ten-
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04KW7F
[Lepoutre, A., et al 2015]
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04KW88
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03RBPW
[Martinelli, D., et al 2014]
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04KW8B
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03RC46
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043MRP
 
 
054BCT
 
 
05PSCV

PRODUCT:  V114  
101
PROTOCOL/AMENDMENT NO.:  024-00  
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
[Nuorti, J. P. and Whitney, C. 
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03QYQQ
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04MG9J
 
 
054BCT
 
 
05PSCV

PRODUCT:  V114  
102
PROTOCOL/AMENDMENT NO.:  024-00  
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
[Vidarsson, G., et al 1998]
Vidarsson G, Sigurdardottir ST, Gudnason T, 
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05336F
[Wagenvoort, G. H., et al 
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04KTDB
[Waight, P. A., et al 2015]
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04KTF2
[Weiss, S., et al 2015]
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[Whitney, Cynthia G., et al 
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03QT0D
[World Health Organization 
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03QTCN
 
 
054BCT
 
 
05PSCV

PRODUCT:  V114  
103
PROTOCOL/AMENDMENT NO.:  024-00  
V114-024-00 FINAL  PROTOCOL
04-JAN-2019
[World Health Organization 
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World Health Organization. WHO/Health 
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03R0JC
 
 
054BCT
 
 
05PSCV