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

Official Protocol Title: 
NCT number: 
NCT03692871  
Document Date: 
11-Feb-2019
A Phase 3, Multicenter, Randomized, Double-blind, Active 
Comparator-controlled Study to Evaluate the Safety and Tolerability 
of V114 in Healthy Infants (PNEULINK)

PRODUCT: V114  
1
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety and Tolerability of V114 in Healthy Infants (PNEU-
LINK)
Protocol Number: 031-01
Compound Number: V114
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
EudraCT
14115
2018-003308-38
Approval Date: 11 February 2019
 
 
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PRODUCT: V114  
2
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-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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PRODUCT: V114  
3
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
V114-031-00
06-Sep-2018
Original protocol
V114-031-01
11-Feb-2019
Amendment to add opsonophagocytic activity (OPA) testing to the Premature Infant 
Immunogenicity Substudy
 
 
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PRODUCT: V114  
4
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
The main purpose for this protocol amendment is to add opsonophagocytic activity (OPA) testing to the Premature Infant 
Immunogenicity Substudy.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title page
The EudraCT number was corrected. 
The correct EudraCT number is: 
2018-003308-38.
Updated for accuracy
Section 3: Hypotheses, Objectives, 
and Endpoints
An exploratory objective was added for the 
Premature Infant Immunogenicity Substudy
to evaluate anti-PnPs serotype-specific 
opsonophagocytic activity (OPA) 
geometric mean titers (GMTs)
Updated to align with addition of OPA testing 
to the Premature Infant Immunogenicity 
Substudy
Section 4.2.1.1: Immunogenicity 
Endpoints
Section 8.2: Immunogenicity 
Assessments
Added information on the multiplexed 
opsonophagocytic assay (MOPA).
MOPA is another method for evaluating the 
immune response to pneumococcal conjugate 
vaccines (PCVs). This assay is being added to 
complement the pneumococcal 
electrochemiluminescence (PnECL) assay.
 
 
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PRODUCT: V114  
5
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
Section # and Name
Description of Change 
Brief Rationale 
Section 9.4.1: Immunogenicity 
Endpoints
Section 9.6.1: Statistical Methods 
for Immunogenicity Analyses
Added OPA GMT as exploratory 
immunogenicity endpoint.
Updated to align with addition of OPA 
responses as an exploratory endpoint for the 
Premature Infant Immunogenicity Substudy.
Section 9.9.1: Sample Size and 
Power for Immunogenicity 
Analyses
The sample size assumptions for the 
Premature Infant Immunogenicity Substudy 
were clarified.
The text “prior PD4” was revised to “prior 
to Dose 4”in this section for clarity.
Revised for clarity.
Section 10.3.4: Recording AE and 
SAE, Assessment of intensity
Clarified the reporting period for injection-
site AEs evaluated by maximum size. 
Original Text:
Injection site redness or swelling from the 
day of vaccination through Day 5 
postvaccination will be evaluated by 
maximum size.
Revised Text:
Injection site redness, swelling, or hard 
lump from the day of vaccination through 
Day 14 postvaccination will be evaluated 
by maximum size.
Revised for accuracy and alignment with the
primary objective of the protocol (Section 3).
Section 10.7.1: Country-specific 
request for Malaysia
Added a general safety hypothesis based on 
feedback from Malaysia.
Addition of safety hypothesis is necessary to 
conduct the study in Malaysia.
 
 
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PRODUCT: V114  
6
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
Section # and Name
Description of Change 
Brief Rationale 
Section 10.8: Abbreviations
Added abbreviations for MOPA and OPA.
Revised for completeness.
Throughout
Minor editorial revisions
Changes are minor and have not been 
summarized individually.
 
 
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PRODUCT: V114  
7
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................24
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................24
2.2.1
V114 and Pneumococcal Disease................................................................24
2.2.2
Preclinical and Clinical Studies ...................................................................25
2.2.3
Information on Other Study-related Therapy ..............................................25
2.3
Benefit/Risk Assessment......................................................................................26
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................26
4
STUDY DESIGN............................................................................................................27
4.1
Overall Design......................................................................................................27
4.2
Scientific Rationale for Study Design.................................................................28
4.2.1
Rationale for Endpoints ...............................................................................29
4.2.1.1
Immunogenicity Endpoints................................................................29
4.2.1.2
Safety Endpoints................................................................................30
4.2.1.3
Future Biomedical Research..............................................................30
4.2.2
Rationale for the Use of Comparator...........................................................30
4.3
Justification for Dose...........................................................................................31
4.4
Beginning and End of Study Definition .............................................................31
4.4.1
Clinical Criteria for Early Study Termination .............................................31
5
STUDY POPULATION ................................................................................................31
5.1
Inclusion Criteria.................................................................................................31
5.2
Exclusion Criteria................................................................................................32
5.3
Lifestyle Considerations......................................................................................34
5.4
Screen Failures.....................................................................................................34
5.5
Participant Replacement Strategy......................................................................34
6
STUDY INTERVENTION............................................................................................34
6.1
Study Intervention(s) Administered...................................................................34
6.2
Preparation/Handling/Storage/Accountability .................................................36
6.2.1
Dose Preparation..........................................................................................36
 
 
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PRODUCT: V114  
8
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
6.2.2
Handling, Storage, and Accountability........................................................36
6.3
Measures to Minimize Bias: Randomization and Blinding..............................37
6.3.1
Intervention Assignment..............................................................................37
6.3.2
Stratification.................................................................................................37
6.3.3
Blinding........................................................................................................37
6.4
Study Intervention Compliance..........................................................................38
6.5
Concomitant Therapy..........................................................................................38
6.5.1
Rescue Medications and Supportive Care ...................................................39
6.6
Dose Modification (Escalation/Titration/Other)...............................................39
6.7
Intervention After the End of the Study............................................................39
6.8
Clinical Supplies Disclosure................................................................................39
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................39
7.1
Discontinuation of Study Intervention...............................................................39
7.2
Participant Withdrawal From the Study...........................................................40
7.3
Lost to Follow-up .................................................................................................41
8
STUDY ASSESSMENTS AND PROCEDURES........................................................41
8.1
Administrative and General Procedures ...........................................................42
8.1.1
Informed Consent.........................................................................................42
8.1.1.1
General Informed Consent.................................................................42
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................43
8.1.2
Inclusion/Exclusion Criteria ........................................................................43
8.1.3
Participant Identification Card.....................................................................43
8.1.4
Medical History ...........................................................................................43
8.1.5
Prior and Concomitant Medications Review...............................................44
8.1.5.1
Prior Medications...............................................................................44
8.1.5.2
Concomitant Medications..................................................................44
8.1.6
Assignment of Screening Number...............................................................44
8.1.7
Assignment of Treatment/Randomization Number.....................................44
8.1.8
Study Intervention Administration ..............................................................45
8.1.8.1
Timing of Dose Administration.........................................................46
8.1.9
Electronic Vaccination Report Card ............................................................46
8.1.10
Telephone Contact Guide for Day 15 Post Each Dose................................46
8.1.11
Telephone Contact Questionnaire................................................................47
8.1.12
Discontinuation and Withdrawal .................................................................47
8.1.12.1
Withdrawal From Future Biomedical Research ................................47
8.1.13
Participant Blinding/Unblinding..................................................................47
 
 
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PRODUCT: V114  
9
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
8.1.14
Calibration of Equipment.............................................................................48
8.2
Immunogenicity Assessments .............................................................................48
8.2.1
Pneumococcal Electrochemiluminescence ..................................................49
8.2.2
Multiplex Opsonophagocytic Assay............................................................49
8.3
Safety Assessments...............................................................................................50
8.3.1
Physical Examinations.................................................................................50
8.3.2
Body Temperature Measurements ...............................................................50
8.3.3
Safety Assessment and Use of the eVRC ....................................................51
8.3.4
Clinical Safety Laboratory Assessments .....................................................51
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................51
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................52
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......53
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...53
8.4.4
Regulatory Reporting Requirements for SAE .............................................54
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................54
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................54
8.4.7
Events of Clinical Interest (ECIs) ................................................................54
8.5
Treatment of Overdose........................................................................................54
8.6
Pharmacokinetics.................................................................................................55
8.7
Pharmacodynamics..............................................................................................55
8.8
Future Biomedical Research Sample Collection...............................................55
8.9
Planned Genetic Analysis Sample Collection....................................................55
8.10
Biomarkers ...........................................................................................................55
8.11
Medical Resource Utilization and Health Economics.......................................55
8.12
Visit Requirements...............................................................................................55
8.12.1
Screening......................................................................................................55
8.12.2
Treatment Period/Vaccination Visit ............................................................55
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........56
9
STATISTICAL ANALYSIS PLAN .............................................................................56
9.1
Statistical Analysis Plan Summary.....................................................................56
9.2
Responsibility for Analyses/In-house Blinding .................................................58
9.3
Hypotheses/Estimation ........................................................................................58
9.4
Analysis Endpoints...............................................................................................58
9.4.1
Immunogenicity Endpoints..........................................................................58
9.4.2
Safety Endpoints..........................................................................................59
 
 
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PRODUCT: V114  
10
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
9.5
Analysis Populations............................................................................................59
9.5.1
Immunogenicity Analysis Populations ........................................................59
9.5.2
Safety Analysis Populations ........................................................................60
9.6
Statistical Methods...............................................................................................60
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................61
9.6.2
Statistical Methods for Safety Analyses ......................................................61
9.6.3
Demographic and Baseline Characteristics .................................................63
9.7
Interim Analyses ..................................................................................................64
9.8
Multiplicity ...........................................................................................................64
9.9
Sample Size and Power Calculations .................................................................64
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................64
9.9.2
Sample Size and Power for Safety Analyses ...............................................65
9.10
Subgroup Analyses...............................................................................................66
9.11
Compliance (Medication Adherence).................................................................66
9.12
Extent of Exposure...............................................................................................66
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................67
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........67
10.1.1
Code of Conduct for Clinical Trials.............................................................67
10.1.2
Financial Disclosure.....................................................................................69
10.1.3
Data Protection.............................................................................................69
10.1.3.1
Confidentiality of Data ......................................................................70
10.1.3.2
Confidentiality of Participant Records...............................................70
10.1.3.3
Confidentiality of IRB/IEC Information............................................70
10.1.4
Committees Structure...................................................................................70
10.1.4.1
Scientific Advisory Committee..........................................................70
10.1.4.2
Executive Oversight Committee........................................................70
10.1.4.3
External Data Monitoring Committee ...............................................71
10.1.5
Publication Policy........................................................................................71
10.1.6
Compliance with Study Registration and Results Posting Requirements ...71
10.1.7
Compliance with Law, Audit, and Debarment ............................................72
10.1.8
Data Quality Assurance ...............................................................................72
10.1.9
Source Documents .......................................................................................73
10.1.10
Study and Site Closure.................................................................................74
10.2
Appendix 2: Clinical Laboratory Tests..............................................................75
10.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................76
10.3.1
Definition of AE ..........................................................................................76
 
 
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PRODUCT: V114  
11
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
10.3.2
Definition of SAE ........................................................................................77
10.3.3
Additional Events Reported.........................................................................78
10.3.4
Recording AE and SAE ...............................................................................78
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................82
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical 
Device Incidents: Definitions, Collection, and Documentation .......................84
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................85
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................86
10.7
Appendix 7: Country-specific Requirements....................................................91
10.7.1
Country-specific Request for Malaysia .......................................................91
10.8
Appendix 8: Abbreviations .................................................................................92
11
REFERENCES...............................................................................................................93
 
 
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PRODUCT: V114  
12
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
LIST OF TABLES
Table 1
Study Interventions....................................................................................35
Table 2
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................53
Table 3
Analysis Strategy for Immunogenicity Variables......................................61
Table 4
Analysis Strategy for Safety Parameters....................................................63
Table 5 
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and 
Varying Standard Deviations.....................................................................65
Table 6 
Differences in Incidence of Adverse Event Rates Between the 2 
Vaccination Groups That Can be Detected With an ~80% Probability 
(Assuming 2-sided 5% Alpha Level with 2000 Participants in V114 
Group and 400 Participants in Prevnar 13™ Group).................................66
 
 
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PRODUCT: V114  
13
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
LIST OF FIGURES
Figure 1
V114-031 Study Design.............................................................................18
 
 
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PRODUCT: V114  
14
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety and Tolerability of V114 in Healthy Infants (PNEU-
LINK)
Short Title: Safety and tolerability of V114 in healthy infants
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-031 (PNEU-LINK)
Hypotheses, Objectives, and Endpoints:
There is no formal hypothesis testing in this study.
The following objectives and endpoints will be evaluated in healthy infants enrolled at 
approximately 2 months of age (from 42 to 90 days [inclusive]) administered V114 or 
Prevnar 13™:
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
Secondary Objectives
Secondary Endpoints
- Objective (Premature Infant 
Immunogenicity Substudy only): To evaluate 
the anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
Geometric Mean Concentrations (GMCs) at 
30 days following Dose 3, prior to Dose 4 
and at 30 days following Dose 4 for each 
vaccination group.
- Anti-PnP serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
30 days postdose 3 (PD3), prior to Dose 4 
(Predose 4) and at 30 days postdose 4 
(PD4)
 
 
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PRODUCT: V114  
15
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
- Objective (Premature Infant 
Immunogenicity Substudy only): 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 Dose 3 
for each vaccination group.
- Anti-PnP serotype-specific IgG response 
rates for the 15 serotypes contained in 
V114 at 30 days PD3
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Healthy infants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control without placebo
Study Blinding
Double-blind, with in-house blinding
Masking
Participant or Subject
Care Provider
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 25 months from the time that written 
informed consent is provided for the first participant until 
the last participant’s last study-related telephone call or 
visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result 
or at the time of final contact with the last participant, 
whichever comes last.
 
 
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PRODUCT: V114  
16
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
Number of Participants:
Approximately 2,400 participants will be randomly assigned to receive either V114 or 
Prevnar 13™ in the following ratios based on gestational age:

Full-term infants (gestational age ≥37 weeks) 5:1 to V114 or Prevnar 13™

Premature infants (gestational age <37 weeks) 1:1 to V114 or Prevnar 13™
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Vaccination 
Regimen
Use
V114
V114
Refer to 
IB
4 doses
IM
Single dose 
at Visits 1, 2, 
3, and 5 (~2, 
4, 6, and 12 
to 15 months 
of age, 
respectively)
Experi
mental
Prevnar 13™
Prevnar 1
3™
Refer to 
product 
labeling
4 doses
IM
Single dose 
at Visits 1, 2, 
3, and 5 (~2, 
4, 6, and 12 
to 15 months 
of age, 
respectively)
Experi
mental
Admin. = administration; IB = Investigator’s Brochure; IM = intramuscular
Total Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 16 to 20 
months from the time the participant’s legally acceptable representative 
signs the Informed Consent Form (ICF) through the final contact.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
 
 
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PRODUCT: V114  
17
PROTOCOL/AMENDMENT NO.: 031-01 
V114-031-01 FINAL PROTOCOL
11-FEB-2019
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
18
PROTOCOL/AMENDMENT NO.: 031-01
V114-031-01 FINAL PROTOCOL
11-FEB-2019
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
V114-031 Study Design
 
 
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PRODUCT: V114
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PROTOCOL/AMENDMENT NO.: 031-01
V114-031-01 FINAL PROTOCOL
11-FEB-2019
1.3
Schedule of Activities (SoA)
Study Period
Intervention
Follow-up
Comments
Months of age is 
calculated according 
to the participant’s 
birth date. 
Visit Number:
1
TC
2
TC
3
TC
4b
5
TC
6
TC
Scheduled Time:
Age: ~2 
months
(Dose 1)
Day 15 
after 
Dose 1
Age: ~4 
months
(Dose 2)
Day 15 
after 
Dose 2
Age: ~6 
months
(Dose 3)
Day 15 
after 
Dose 3
~1 
month 
after 
Dose 3
Age: ~12 
to 15 
months
(Dose 4)
Day 15 
after 
Dose 4
~1 
month 
after 
Dose 4
~6 
months 
after 
Dose 4
Visit Window:a
≥42 
days of 
age to 
≤90 
days of 
age
Day 15 
to 
Day 19 
Post-
dose 1
4 months 
of age to 1 
day prior 
to 
5 months 
of age
Day 15 
to 
Day 19 
Post-
dose2
6 months 
of age to 
1 day 
prior to 7 
months of 
age
Day 15 
to 
Day 19 
Post-
dose 3
Day 28 
to 
Day 42 
Post-
dose 3
12 
months of 
age to 
1 day 
prior to 
16 month
s of age
Day 15 
to Day 
19 
Post-
dose4
Day 28 
to 
Day 42 
Post-
dose 4
Day 166 
to 
Day 194 
Post-
dose 4
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be 
obtained before any 
study procedures.
Informed Consent for Future 
Biomedical Research 
X
Consent for future 
biomedical research 
samples is optional and
must be obtained 
before the collection of 
buccal swab DNA 
samples.
Assignment of Screening 
Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Medical History
X
Post-Enrollment Procedures
Assignment of Randomization 
Number
X
Prior/Concomitant Medication 
and Nonstudy Vaccination 
Review
X
X
X
X
X
X
X
X
X
X
See Section 8.1.5 for 
details.
V114 or Prevnar 13™ 
Administration (Blinded)
X
X
X
X
At these visits, 
participants will 
receive either a single 
dose of V114 or 
Prevnar 13™.
 
 
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PRODUCT: V114
20
PROTOCOL/AMENDMENT NO.: 031-01
V114-031-01 FINAL PROTOCOL
11-FEB-2019
Study Period
Intervention
Follow-up
Comments
Months of age is 
calculated according 
to the participant’s 
birth date. 
Visit Number:
1
TC
2
TC
3
TC
4b
5
TC
6
TC
Scheduled Time:
Age: ~2 
months
(Dose 1)
Day 15 
after 
Dose 1
Age: ~4 
months
(Dose 2)
Day 15 
after 
Dose 2
Age: ~6 
months
(Dose 3)
Day 15 
after 
Dose 3
~1 
month 
after 
Dose 3
Age: ~12 
to 15 
months
(Dose 4)
Day 15 
after 
Dose 4
~1 
month 
after 
Dose 4
~6 
months 
after 
Dose 4
Visit Window:a
≥42 
days of 
age to 
≤90 
days of 
age
Day 15 
to 
Day 19 
Post-
dose 1
4 months 
of age to 1 
day prior 
to 
5 months 
of age
Day 15 
to 
Day 19 
Post-
dose2
6 months 
of age to 
1 day 
prior to 7 
months of 
age
Day 15 
to 
Day 19 
Post-
dose 3
Day 28 
to 
Day 42 
Post-
dose 3
12 
months of 
age to 
1 day 
prior to 
16 month
s of age
Day 15 
to Day 
19 
Post-
dose4
Day 28 
to 
Day 42 
Post-
dose 4
Day 166 
to 
Day 194 
Post-
dose 4
Nonstudy Pediatric Vaccines
X
X
X
X
Nonstudy pediatric 
vaccines are permitted 
and should be 
administered according 
to the local 
recommended 
schedule. If given at a 
study visit, oral 
vaccines should be 
administered prior to 
the study vaccine and 
other injectable 
vaccines. Other
injectable vaccines 
should be given after 
the study vaccine and 
in a separate limb.
Provide eVRC
X
Participants will be 
provided an eVRC at 
Visit 1 to record AEs, 
body temperature 
measurements, 
concomitant 
medications, and 
nonstudy vaccinations. 
Instructions for using 
the eVRC will be 
reviewed with the 
participant’s legally 
acceptable 
representative.
 
 
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Study Period
Intervention
Follow-up
Comments
Months of age is 
calculated according 
to the participant’s 
birth date. 
Visit Number:
1
TC
2
TC
3
TC
4b
5
TC
6
TC
Scheduled Time:
Age: ~2 
months
(Dose 1)
Day 15 
after 
Dose 1
Age: ~4 
months
(Dose 2)
Day 15 
after 
Dose 2
Age: ~6 
months
(Dose 3)
Day 15 
after 
Dose 3
~1 
month 
after 
Dose 3
Age: ~12 
to 15 
months
(Dose 4)
Day 15 
after 
Dose 4
~1 
month 
after 
Dose 4
~6 
months 
after 
Dose 4
Visit Window:a
≥42 
days of 
age to 
≤90 
days of 
age
Day 15 
to 
Day 19 
Post-
dose 1
4 months 
of age to 1 
day prior 
to 
5 months 
of age
Day 15 
to 
Day 19 
Post-
dose2
6 months 
of age to 
1 day 
prior to 7 
months of 
age
Day 15 
to 
Day 19 
Post-
dose 3
Day 28 
to 
Day 42 
Post-
dose 3
12 
months of 
age to 
1 day 
prior to 
16 month
s of age
Day 15 
to Day 
19 
Post-
dose4
Day 28 
to 
Day 42 
Post-
dose 4
Day 166 
to 
Day 194 
Post-
dose 4
Review eVRC Data with 
Participant’s Legally 
Acceptable Representative
X
X
X
X
X
X
X
X
X
See Section 8.1.10 for 
details.
Collect eVRC from Participant
X
Complete the Telephone 
Contact Questionnaire
X
The Telephone Contact 
Questionnaire will be 
provided by the 
Sponsor. 
Safety Procedures
Complete Physical 
Examination
X
To be performed by the 
investigator or 
medically qualified 
designee before 
vaccine is 
administered.
Targeted Physical Examination
X
X
X
To be performed by the 
investigator or 
medically qualified 
designee before 
vaccine is 
administered.
 
 
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Study Period
Intervention
Follow-up
Comments
Months of age is 
calculated according 
to the participant’s 
birth date. 
Visit Number:
1
TC
2
TC
3
TC
4b
5
TC
6
TC
Scheduled Time:
Age: ~2 
months
(Dose 1)
Day 15 
after 
Dose 1
Age: ~4 
months
(Dose 2)
Day 15 
after 
Dose 2
Age: ~6 
months
(Dose 3)
Day 15 
after 
Dose 3
~1 
month 
after 
Dose 3
Age: ~12 
to 15 
months
(Dose 4)
Day 15 
after 
Dose 4
~1 
month 
after 
Dose 4
~6 
months 
after 
Dose 4
Visit Window:a
≥42 
days of 
age to 
≤90 
days of 
age
Day 15 
to 
Day 19 
Post-
dose 1
4 months 
of age to 1 
day prior 
to 
5 months 
of age
Day 15 
to 
Day 19 
Post-
dose2
6 months 
of age to 
1 day 
prior to 7 
months of 
age
Day 15 
to 
Day 19 
Post-
dose 3
Day 28 
to 
Day 42 
Post-
dose 3
12 
months of 
age to 
1 day 
prior to 
16 month
s of age
Day 15 
to Day 
19 
Post-
dose4
Day 28 
to 
Day 42 
Post-
dose 4
Day 166 
to 
Day 194 
Post-
dose 4
Body Temperature 
Measurement
X
X
X
X
Each participant’s body 
temperature must be 
taken before 
vaccination (see 
Section 8.3.2 for details
on the method of 
temperature 
collection). Participants 
who have febrile illness 
occurring at or within 
72 hours of Visit 1 
must be rescheduled 
(see Section 5.2 for 
details). 
30-Minute Postvaccination 
Observation Period
X
X
X
X
To be performed by 
blinded study site 
personnel only.
AE Monitoring
X
X
X
X
X
X
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) (Premature Infant 
Immunogenicity Substudy
Only)
X
X
X
Blood samples must be 
collected before study 
vaccination when 
applicable.
 
 
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Study Period
Intervention
Follow-up
Comments
Months of age is 
calculated according 
to the participant’s 
birth date. 
Visit Number:
1
TC
2
TC
3
TC
4b
5
TC
6
TC
Scheduled Time:
Age: ~2 
months
(Dose 1)
Day 15 
after 
Dose 1
Age: ~4 
months
(Dose 2)
Day 15 
after 
Dose 2
Age: ~6 
months
(Dose 3)
Day 15 
after 
Dose 3
~1 
month 
after 
Dose 3
Age: ~12 
to 15 
months
(Dose 4)
Day 15 
after 
Dose 4
~1 
month 
after 
Dose 4
~6 
months 
after 
Dose 4
Visit Window:a
≥42 
days of 
age to 
≤90 
days of 
age
Day 15 
to 
Day 19 
Post-
dose 1
4 months 
of age to 1 
day prior 
to 
5 months 
of age
Day 15 
to 
Day 19 
Post-
dose2
6 months 
of age to 
1 day 
prior to 7 
months of 
age
Day 15 
to 
Day 19 
Post-
dose 3
Day 28 
to 
Day 42 
Post-
dose 3
12 
months of 
age to 
1 day 
prior to 
16 month
s of age
Day 15 
to Day 
19 
Post-
dose4
Day 28 
to 
Day 42 
Post-
dose 4
Day 166 
to 
Day 194 
Post-
dose 4
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 
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; SAE = serious adverse event
a
For calculating the visit windows, the day of vaccination is considered Day 1. To calculate visit windows for subsequent vaccinations, confirm participant date of birth and 
ensure the age of the participant will fall within the appropriate age range for each study visit.
b
Visit 4 is applicable to the Premature Infant Immunogenicity Substudy
 
 
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2
INTRODUCTION
Merck Sharp & Dohme Corp. (MSD) is developing an investigational 15-valent 
pneumococcal conjugate vaccine (PCV) (referred to as V114) for the prevention of 
pneumococcal disease caused by the serotypes in the vaccine. V114 contains the 13 serotypes 
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 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
Despite the availability of PCVs, pneumococcal disease remains a concern as non-vaccine 
serotypes began to appear in increasing frequency in invasive pneumococcal disease (IPD)
isolates. Given the importance of pneumococcal disease 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. 
This clinical study, to be conducted in healthy infants approximately 2 months of age (42 to 
90 days of age), is part of a Phase 3 pediatric clinical program to support an initial 
registration of V114 for use in healthy infants and children for the prevention of 
pneumococcal disease caused by the 13 pneumococcal serotypes contained in Prevnar 13™ 
and 2 additional unique serotypes (22F and 33F) in V114.
The primary purpose of this study is to evaluate the safety and tolerability of a 4-dose 
schedule (3 doses in the infant primary series followed by 1 toddler dose) of V114 as 
compared to Prevnar 13™. The study sample size was selected to complement other studies 
in the V114 pediatric clinical development program to create a robust safety database to 
characterize the safety profile of V114. Immunogenicity of V114 in full-term infants will be 
evaluated in other studies within the V114 clinical development program. In this study, 
premature infants (gestational age <37 weeks) will be included in the Premature Infant 
Immunogenicity Substudy, which will include immunogenicity and safety assessments 
following administration of V114 or Prevnar 13™. Immunogenicity and safety data from 
premature infants will be pooled across the V114 clinical program to evaluate the safety and 
immunogenicity of V114 in this population.
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.
 
 
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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 [PY]), 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 PY) [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.
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.
 
 
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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 17% of participants will receive 4 doses of 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 healthy infants enrolled at 
approximately 2 months of age (from 42 to 90 days [inclusive]) administered V114 or 
Prevnar 13™:
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
 
 
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Objectives
Endpoints
Secondary
•
Objective (Premature Infant 
Immunogenicity Substudy only): To 
evaluate the anti-pneumococcal 
polysaccharide (PnPs) serotype-specific 
Immunoglobulin G (IgG) Geometric 
Mean Concentrations (GMCs) at 30 days 
following Dose 3, prior to Dose 4 and at 
30 days following Dose 4 for each 
vaccination group.
•
Anti-PnP serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 30 days postdose 
3 (PD3), prior to Dose 4 (Predose 4) 
and at 30 days postdose 4 (PD4)

Objective (Premature Infant 
Immunogenicity Substudy only): 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 Dose 3 for each 
vaccination group.

Anti-PnP serotype-specific IgG 
response rates for the 15 serotypes 
contained in V114 at 30 days PD3
Exploratory

Objective (Premature Infant 
Immunogenicity Substudy only): To 
evaluate the anti-PnPs serotype-specific 
opsonophagocytic activity (OPA) GMTs 
at 30 days following Dose 3, prior to 
Dose 4 and at 30 days following Dose 4
for each vaccination group. 

Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes 
contained in V114 at 30 days PD3, 
Predose 4 and at 30 days PD4
4
STUDY DESIGN
4.1
Overall Design
Approximately 2,400 healthy infants will be randomly assigned to receive V114 (n=~2,000) 
or Prevnar 13™(n=~400) at Visits 1, 2, 3, and 5 (approximately 2, 4, 6, and 12 to 15 months 
of age, respectively) in the following ratios based on gestational age:

Full-term infants (gestational age ≥37 weeks) 5:1 to V114 or Prevnar 13™

Premature infants (gestational age <37 weeks) 1:1 to V114 or Prevnar 13™
 
 
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It is estimated that approximately 1 to 2% of the overall study population will have a 
gestational age <37 weeks and will be eligible for inclusion in the Premature Infant 
Immunogenicity Substudy. There is no prespecified number of premature infants targeted for 
enrollment in the substudy.
Participants will be followed for local 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 to be 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 for the V114 Phase 3 pediatric program. A description of the structure, function, and 
guidelines for decision making by 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.
In addition to the safety assessments, participants in the Premature Infant Immunogenicity 
Substudy, will also have blood samples for immunogenicity assays drawn at 3 timepoints: (1) 
30 days Postdose 3 (PD3), (2) immediately prior to Dose 4, and (3) 30 days Postdose 4
(PD4).
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 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 be conducted in healthy infants 
approximately 2 months of age (42 to 90 days of age), with premature infants (gestational 
age <37 weeks) comprising approximately 1 to 2% of the overall study population. This will
allow assessment of the safety and tolerability of V114 in a population that is representative 
of children receiving licensed PCVs in many countries throughout the world. Safety data 
collected this study will be pooled with safety data from similar studies in the V114 pediatric 
clinical development program to create a comprehensive V114 safety database. 
Premature infants enrolled in the study will be stratified into the Premature Infant Substudy, 
which includes immunogenicity assessments at the completion of the primary series (after 
Dose 3 of V114 or Prevnar 13™), as well as before and after Dose 4 of V114 or 
Prevnar 13™. Previous studies have shown that premature infants demonstrate a reduced 
response to conjugate vaccines [Esposito, S., et al 2005] [Moss, S. J., et al 2010] and that 
gestational age may affect the ability of preterm infants to generate a protective immune 
 
 
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response against S. pneumoniae following receipt of PCVs [Shinefield, H., et al 2002]. These 
data, together with the increased risk of IPD in premature infants [Hausdorff, W. P., et al 
2000], highlight the importance of evaluating PCV immune responses in this population. 
Immunogenicity and safety data from these infants will be pooled with similar data from 
other studies in the V114 clinical development program to characterize the safety and 
immunogenicity of V114 in premature infants.
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 in an infant population. This study will also contribute to the overall safety database 
and immunogenicity profile of V114 to support initial licensure in infants.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Sera from participants in the Premature Infant Immunogenicity Substudy will be used to 
measure vaccine-induced anti-PnPs serotype-specific immune responses for all 15 serotypes 
included in V114. The pneumococcal electrochemiluminescence (PnECL) assay and the 
multiplexed opsonophagocytic assay (MOPA) will be used to evaluate immune responses in 
the Premature Infant Immunogenicity Substudy. PnECL measures serotype-specific IgG 
GMCs (secondary endpoint), and MOPA measures serotype-specific OPA GMTs
(exploratory endpoint). OPA GMTs represent functional antibodies capable of inhibiting 
growth of S. pneumoniae in culture. Additional information on the immunogenicity assays 
can be found in Section 8.2.
It is anticipated that not all participants in the Premature Infant Immunogenicity Substudy 
will have sufficient serum to conduct both PnECL and MOPA; therefore, priority will be 
given to the PnECL assessment, and the PnECL assay will be used to test the secondary 
immunogenicity hypotheses in this study.
The use of the serotype-specific IgG antibody level of ≥0.35 µg/mL has been recommended 
by a World Health Organization (WHO) expert panel as an acceptable threshold value for 
evaluating the clinical performance of PCVs following a routine childhood vaccination 
regimen [World Health Organization 2008] [World Health Organization 2005]. The response 
rate (ie, the proportion of participants meeting the serotype-specific IgG threshold value of 
≥0.35 μg/mL) is a secondary endpoint in the Premature Infant Immunogenicity Substudy.
Anti-PnPs serotype-specific IgG and OPA responses will be measured at 3 time points:

Approximately 30 days following Dose 3 to evaluate the immune response to the 
primary vaccination series in premature infants (IgG GMCs, IgG response rates, and 
OPA GMTs) 

Immediately prior to Dose 4 to evaluate the persistence of protective immunity in 
premature infants (IgG GMCs and OPA GMTs) 
 
 
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
Approximately 30 days following Dose 4 to evaluate anamnestic antibody responses
in premature infants (IgG GMCs and OPA GMTs) 
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 feedback 
received 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].
Details on the safety endpoints evaluated in this study can be found in Section 8.3.3 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of 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™.
 
 
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4.3
Justification for Dose
The dose and dosing schedule of V114 is similar to that used in previous pediatric V114 
clinical studies, which demonstrated safety and comparable immune responses to those of 
Prevnar 13™. Refer to V114 IB for details on dosing schedule.
In order to support initial licensure in countries that use either the 3+1 Prevnar 13™dosing 
schedule (3 doses in the infant primary series followed by 1 toddler dose) or the 2+1 
Prevnar 13™dosing schedule (2 doses in infant primary series followed by 1 toddler dose), 
this study will use the currently approved dose and United States Advisory Committee on 
Immunization Practices recommended 3+1 dosing schedule of Prevnar 13™.
4.4
Beginning and End of Study Definition
The overall study begins when written informed consent is provided for the first participant. 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.
5
STUDY POPULATION
Healthy male and female infants approximately 2 months of age, from 42 and 90 days
(inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Be healthy (based on a review of medical history and physical examination) based on the 
clinical judgement of the investigator.
 
 
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Demographics
2. Be male or female approximately 2 months of age, from 42 days to 90 days inclusive, at 
the time of obtaining the informed consent.
Informed Consent
3. Have a legally acceptable representative who understands the study procedures, alternate 
treatments available, and risks involved with the study and voluntarily agrees to 
participate by giving written informed consent. The legally acceptable representative may
also provide consent for future biomedical research. However, the participant may 
participate in the main study without participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or other 
sterile site) or known history of other culture positive pneumococcal disease.
2. Has a known hypersensitivity to any component of the PCV or any diphtheria toxoid-
containing vaccine.
3. *Had a recent febrile illness (rectal temperature ≥38.1°C [≥100.5°F] or axillary 
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.
8. Has failure to thrive based on the clinical judgement of the investigator.
9. Has a known coagulation 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).
 
 
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11. Has a known neurologic or cognitive behavioral disorder, including encephalitis/myelitis, 
acute disseminating encephalomyelitis, pervasive development disorder, and related 
disorders.
Prior/Concomitant Therapy
12. Has received a dose of any pneumococcal vaccine prior to study entry.
13. *Meets one or more of the following systemic corticosteroid exclusion criteria:
a.
Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/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 systemic corticosteroids within 14 days prior to the first dose of study 
vaccine at randomization.
c.
Is expected to require systemic corticosteroids within 30 days after each vaccination 
during conduct of the study.
Note: Topical, ophthalmic and inhaled steroids are permitted.
14. *Has received other licensed non-live vaccines within the 14 days before receipt of first 
dose of study vaccine.
15. *Has received a licensed live virus vaccine within the 30 days before receipt of first dose 
of study vaccine.
16. Has received a blood transfusion or blood products, including immunoglobulins, before 
receipt of first dose of study vaccine.
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.
 
 
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For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants whose legally acceptable representative provides 
consent to participate in the clinical study but are not subsequently randomized in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the 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.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
 
 
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Table 1
Study Interventions
Arm 
Name
Arm Type
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
Single dose at 
Visits 1, 2, 3, and 
5 (~2, 4, 6, and 12 
to 15 months of 
age, respectively)
Experi
mental
IMP
Central
Prevnar 
13™
Active 
Comparator
Prevnar 13™
Biological
/Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single dose at 
Visits 1, 2, 3, and 
5 (~2, 4, 6, and 12 
to 15 months of 
age, respectively)
Experi
mental
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 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
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. 
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. Full-term infant participants 
(gestational age ≥37 weeks) will be assigned randomly in a 5:1 ratio to receive V114 or 
Prevnar 13™. Premature infant participants (gestational age <37 weeks) in the 
immunogenicity substudy 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:

Gestational age <37 weeks (yes/no)
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 located in the Investigator Trial File Binder.
In order 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. 
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.
 
 
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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’s legally acceptable representative.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate electronic Case Report Form (eCRF). It is important to record the use of any 
analgesic or antipyretic use that occurs on the day of vaccination on the eVRC and 
appropriate eCRF.
During influenza season, it is anticipated that participants 6 months of age and older may be 
given an influenza vaccine. Influenza vaccine should be administered either 7 days prior to or 
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. If given 
at a study visit, oral vaccines should be administered prior to the study vaccine and other 
injectable vaccines. Precautions must be taken to prevent choking during the administration 
of oral vaccines. Other injectable vaccines should be given after the study vaccine. These 
vaccinations should be recorded on the appropriate eCRF.
V114 or Prevnar 13™should be administered in the right thigh. To avoid any confounding 
results, nonstudy 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 appropriate eCRF. As the study is reporting 
injection-site AEs for V114 or Prevnar 13™ (and not from the nonstudy pediatric vaccines), 
this information should also be recorded on the eVRC to inform the parent or legally 
acceptable representative of the appropriate limb to monitor for AEs related to the V114 or 
Prevnar 13™. 
No other investigational compound or device may be administered at any time during this 
study without prior approval by the Sponsor.
 
 
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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
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 
regimen will still continue to participate in the study as specified in Section 1.3 and 
Section 8.12.3 unless the consent is withdrawn for the participant (Section 7.2). A participant 
may discontinue from study intervention (including receipt of V114 or Prevnar 13™) but 
continue to participate in protocol-specified, AE-monitoring activities (see Section 8.12.3 for 
details).
 
 
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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.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment is unblinded by the investigator or through the 
emergency unblinding call center.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, 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.
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 
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.
 
 
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant’s legally acceptable representative and 
reschedule the missed visit. If the participant’s legally acceptable representative is 
contacted, the participant’s legally acceptable representative should be counseled on the 
importance of maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the 
participant’s legally acceptable representative at each missed visit (eg, telephone calls 
and/or a certified letter to the legally acceptable representative last known mailing 
address or locally equivalent methods). These contact attempts should be documented in 
the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified 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.
For participants in the Premature Infant Immunogenicity Substudy only, approximately 5 mL
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 15 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each 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 is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant’s legally 
acceptable representative before the individual’s participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant’s legally acceptable representative must receive the Institutional Review 
Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable opinion in advance 
of use. The participant’s legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the willingness for the 
participant to continue participation in the study. The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the dated signature of the participant’s legally acceptable representative.
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.
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 to the participant’s legally acceptable representative, answer all of his/her questions, 
and obtain written informed consent before performing any procedure related to the future 
biomedical research substudy. A copy of the informed consent will be given to the 
participant’s legally acceptable representative.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study. The investigator should 
consult with the Sponsor’s Clinical Director for any questions about participant eligibility.
If the participant meets any of the exclusion criteria with an asterisk (*), Visit 1 may be 
rescheduled for a time when these criteria are not met.
8.1.3
Participant Identification Card
The legally acceptable representative for each participant will be given a Participant 
Identification Card identifying the individual as a participant in a research study. The card 
will contain study site contact information (including direct telephone numbers) to be utilized 
in the event of an emergency. The investigator or qualified designee will provide the legally 
acceptable representative for each participant with a Participant Identification Card 
immediately after written informed consent is provided. At the time of treatment 
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. Note: birth weight (kg) and gestational age will be documented in the 
participant’s medical history.
 
 
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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.
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 prohibitive steroid regimen, immunoglobulin, 
blood, or blood products during a participant’s participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate eCRF. 
It is important to record any analgesic or antipyretic use that occurs on the day of vaccination 
on the 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 8.3.3.
Nonstudy pediatric vaccines administered during the study should be recorded on the 
appropriate eCRF. Injectable vaccines should not be administered in the same limb as V114 
or Prevnar 13™. Documentation of which limb was used for the administration of V114 or 
Prevnar 13™ must be recorded on the eVRC (Section 8.3.3) and appropriate eCRF. 
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.12.1.
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 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
 
 
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A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
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.
A 0.5-mL intramuscular dose of study vaccine will be administered to healthy infants at 
approximately 2, 4, 6, and 12 to 15 months of age. Prevnar 13™will be supplied as a 
pre-filled syringe. The study vaccines are to be administered at the locations recommended in 
Section 6.5. If an abnormality (ie, rash) is observed at the site where the previous dose of the 
study vaccine was administered, it is permissible to use the anterolateral muscle of the other 
limb to administer the following dose of the study vaccine. Adequate treatment provision, 
including epinephrine and equipment for maintaining an airway, should be available for 
immediate use should an anaphylactic or anaphylactoid reaction occur [Centers for Disease 
Control and Prevention 2015].
Unblinded study personnel should not have contact with participants for any study-related 
procedures/assessments after administration of study vaccines, which includes all safety 
follow-up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant or participant’s parent/guardian will be blinded to the 
study vaccine received by the participant. Vaccination information, such as Component 
 
 
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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 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 for participants in the Premature Infant Immunogenicity Substudy 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’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 nonstudy vaccinations will be recorded on the 
eVRC as described in Section 1.3 and Section 8.3.3. The investigator or delegate will review 
the data captured on the eVRC with the 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’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
Telephone Contact Guide for Day 15 Post Each Dose
Site personnel will contact study participants on Day 15 post each dose to review eVRC data 
with the participant’s legally acceptable representative. The Day 15 Postdose Telephone 
Contact Guide will be provided by the Sponsor. This guide is designed to assist site 
personnel to collect any updates or edits to data previously entered on the eVRC from 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).
 
 
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8.1.11
Telephone Contact Questionnaire
Site personnel will contact 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 the 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 (Visit 6) 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
Consent for future biomedical research may be withdrawn by the participant’s legally 
acceptable representative. Consent may be withdrawn by the legally acceptable 
representative at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant’s legally acceptable representative 
of completion of withdrawal. Any analyses in progress at the time of request for withdrawal 
or already performed prior to the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.13 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 
 
 
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dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding that is part of the study design has taken place, the principal 
investigator, site personnel, and Sponsor personnel may be unblinded so that the appropriate 
follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or 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 is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Two immunogenicity assays (PnECL and MOPA) will be used to measure vaccine-induced, 
anti-PnPs serotype-specific immune responses for all 15 serotypes included in V114 in the 
Premature Infant Immunogenicity Substudy. 
Blood collection, storage and shipment instructions for serum samples will be provided in the 
operations/laboratory manual.
 
 
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8.2.1
Pneumococcal Electrochemiluminescence
The Sponsor has developed and optimized a multiplex, electrochemiluminescence 
(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
(ELISA) methodology include speed, equivalent or better sensitivity, increased dynamic 
range, the ability to multiplex, and reduction in required serum sample and reagent volumes. 
The measurement of immune responses to the 15 serotypes included in V114 is performed 
using an assay format consisting of 2 groups of 7 and 8 serotypes each. The PnECL v2.0 
assay for all 15 serotypes has undergone validation. The validation study evaluated various 
performance parameters of the assay including precision, ruggedness, relative accuracy, 
dilutional linearity, selectivity, and specificity. The validation results were evaluated against 
pre-specified acceptance criteria for each of the parameters.
The WHO Expert Committee on Biological Standardization has recommended that in-house 
assays used in immunogenicity studies designed to evaluate protection against IPD be 
bridged to the WHO reference assay in order 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 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 
0.35 µg/mL be applied to each of the 15 serotypes.
8.2.2
Multiplex Opsonophagocytic Assay
The MOPA, developed and published by Professor Moon Nahm (Director of the United 
States World Health Organization pneumococcal serology reference laboratory and National 
Institutes of Health pneumococcal reference laboratories), is a multiplexed OPA assay 
capable of measuring 4 serotypes at a time, against a total of 16 serotypes of pneumococci 
[Burton, Robert L. and Nahm, Moon H. 2006]. The OPA is an antibody-mediated killing 
assay that measures the ability of human serum to kill S. pneumoniae serotypes with the help
of complement and phagocytic effector cells. The ability of the assay to simultaneously test 
4 serotypes/run reduces the amount of serum needed for testing. The assay readout is the 
opsonization index, which is the reciprocal of the highest dilution that gives ≥50% bacterial 
 
 
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killing, as determined by comparison to assay background controls. The Sponsor has 
developed and optimized the MOPA in a high throughput micro-colony platform. The 
MOPA assay for all 15 V114 serotypes has undergone validation. The validation study 
evaluated various performance parameters of the assay including precision, relative 
accuracy/dilutional linearity, and specificity. The validation results were evaluated against 
pre-specified acceptance criteria for each of the parameters.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. 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.
8.3.1
Physical Examinations
A complete physical examination will be performed at Visit 1. A targeted physical 
examination will be performed at subsequent vaccination visits (Visits 2, 3, and 5). Any 
clinically significant abnormality will be recorded on the appropriate eCRF.
The full and targeted physical examination procedures both 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 full physical examination will include an 
assessment of the head, eyes, ears, nose and throat, skin, lymph nodes, neurological system, 
and musculoskeletal system.
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Body Temperature Measurements
Pre-vaccination rectal temperatures will be taken by study staff as indicated in Section 1.3. 
Participants who have febrile illness (rectal temperature ≥38.1°C [≥100.5°F] or axillary 
temperature ≥37.8°C [≥100.0°F]) occurring at or within 72 hours of Visits 1, 2, 3, and 5 must 
be rescheduled. 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. 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.
The participant’s legally acceptable representative will be asked to record the participant’s
temperature reading on the eVRC from Day 1 through Day 7 following each vaccination. 
 
 
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Temperature measurement must be recorded in the eVRC if fever is suspected during Day 8 
through Day 14.
8.3.3
Safety Assessment and Use of the eVRC
All participants will be observed for 30 minutes after each vaccination for any immediate 
reactions. If any immediate AEs are observed during this period, the time at which the event 
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event, must be recorded on the appropriate eCRF.
Participant’s legally acceptable representative will use the eVRC (Section 8.1.9) to document 
the following information:
•
Rectal temperatures measured Day 1 (day of vaccination) through Day 7 following each 
vaccination; Day 8 through Day 14 following each vaccination if fever is suspected
•
Solicited injection-site AEs (swelling, redness, pain or tenderness, and hard lump) Day 1 
through Day 14 postvaccination
•
Solicited systemic AEs (irritability, drowsiness, appetite lost, and hives or welts) Day 1 
through Day 14 postvaccination
•
Any other unsolicited injection-site or systemic AEs Day 1 through Day 14 
postvaccination
•
The limb that was used for the administration of V114 or Prevnar 13™ (Note: the study 
will report injection-site AEs from V114 or Prevnar 13™ and not from concomitant 
injectable vaccines; the location of V114 or Prevnar 13™ administration can be used by 
the participant’s legally acceptable representative to monitor the appropriate limb for 
injection-site AEs related to V114 or Prevnar 13™)
•
Use of any analgesic or antipyretic on the day of vaccination
•
Concomitant medications and nonstudy vaccinations Day 1 to Day 14 postvaccination
8.3.4
Clinical Safety Laboratory Assessments
There are no laboratory safety evaluations required by the protocol.
8.4
Adverse Events (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.
 
 
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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.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
a.
A death that occurs prior to the participant completing the study.
OR
b. 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 2.
 
 
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Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report
Event and 
Follow-up 
Information 
to Sponsor:
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
Not applicable since participants are infants.
Event of Clinical 
Interest 
There are no ECIs 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.
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 
 
 
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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
Information in this section is not applicable since participants are infants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest (ECIs)
There are no events of clinical interest in 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.
 
 
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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 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
Future Biomedical Research Sample Collection
If the participant’s legally acceptable representative signs the future biomedical research 
consent, the following specimens will be obtained as part of future biomedical research:
•
Buccal swab DNA for future research
•
Leftover study serum at the central laboratory stored for future research after aliquoting 
samples for completion of immunogenicity
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10 Biomarkers
Biomarkers are not evaluated in this study.
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 as outlined in Section 1.3.
8.12.2 Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
 
 
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If the participant develops a new clinical condition during the study that makes him/her 
ineligible for the study, the investigator should discuss with the Sponsor Clinical Director as 
soon as possible. The decision to continue the participant on study intervention requires the 
mutual agreement of the investigator, the Sponsor, and the participant’s legally acceptable 
representative.
8.12.3 Discontinued Participants Continuing to be Monitored in the Study
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’s legally acceptable representative does not 
withdraw consent. Blood draws for immunogenicity testing in the Premature Infant 
Immunogenicity Substudy could occur if agreed to by the participant’s legally acceptable 
representative at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report for 
the study. Post hoc exploratory analyses will be clearly identified in the Clinical Study 
Report.
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 to Section 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active 
Comparator-controlled Study to Evaluate the Safety and Tolerability 
of V114 in Healthy Infants (PNEU-LINK)
Treatment Assignment
Approximately 2400 healthy infants approximately 2 months of age
will be enrolled.

Full-term infants (gestational age ≥37 weeks) will be randomly 
assigned in a 5:1 ratio to a complete dosing schedule of V114 or 
Prevnar 13™. 

Premature infants (gestational age <37 weeks) will be randomly 
assigned in a 1:1 ratio to a complete dosing schedule of V114 or 
Prevnar 13™
Analysis Populations
Safety: All Participants as Treated (APaT)
Immunogenicity: Per-Protocol (PP) and Full Analysis Set (FAS) 
population for the Premature Infant Immunogenicity Substudy
 
 
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Primary Endpoint(s)

Proportion of participants with solicited injection-site AEs 
(swelling, redness/erythema, tenderness/pain, and hard 
lump/induration) from Day 1 through Day 14 following any 
vaccination with V114 or Prevnar 13™

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, appetite lost/decreased appetite, and 
hives or welts/urticaria) from Day 1 through Day 14 following any 
vaccination with V114 or Prevnar 13™

Proportion of participants with vaccine-related SAEs from Day 1 
through completion of study participation
Key Secondary Endpoints
Premature Infant Immunogenicity Substudy only:

Anti-pneumococcal polysaccharide (PnPs) serotype-specific 
Immunoglobulin G (IgG) Geometric Mean Concentrations 
(GMCs) for the 15 serotypes contained in V114 at 30 days 
PD3, prior to Dose 4 and at 30 days PD4

Anti-PnPs serotype-specific IgG response rates (proportion of 
participants meeting serotype-specific IgG threshold value of 
≥0.35 μg/mL) for the 15 serotypes contained in V114 at 30 
days PD3 
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes contained in V114 separately. To address the 
immunogenicity objectives, evaluation of the IgG GMCs and anti-PnPs 
serotype-specific IgG response rates will be summarized descriptively.
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 endpoints) and 95% CIs (Tier 1 and Tier 2 endpoints) 
will be provided for between-vaccination group differences in the 
percentage of participants with events; these analyses will be 
performed using the M&N method [Miettinen, O. and Nurminen, M. 
1985].
Interim Analyses
To support the periodic review of safety and tolerability data across the   
V114 Phase 3 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 immunogenicity objectives for this study are descriptive 
secondary objectives for the Premature Infant Immunogenicity 
Substudy only. The study will randomize premature infant participants 
in a 1:1 ratio to either V114 or Prevnar 13™ vaccination group. The 
sample size of the Premature Infant Immunogenicity Substudy will be 
approximately 1% to 2% of overall participants. There is no hypothesis 
to be evaluated for immunogenicity objectives. Section 9.9.1 provides 
information about the expected variability of the IgG GMC given the 
sample size.
Safety:
Section 9.9.2 provides information about the ability of this study to 
estimate the incidence of AEs within and between the vaccination 
groups.
 
 
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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 in 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. There is no hypothesis to be evaluated in this 
study. 
9.4
Analysis Endpoints
Safety endpoints for all participants and immunogenicity endpoints for the Premature Infant 
Immunogenicity Substudy that will be evaluated for within- and/or between-treatment 
differences are listed below.
9.4.1
Immunogenicity Endpoints
The immunogenicity analyses are for the Premature Infant Immunogenicity Substudy only. 
A description of immunogenicity assessments for the Premature Infant Immunogenicity 
Substudy is contained in Section 8.2. Immune responses will be measured for the 15 
serotypes contained in V114 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and
33F).
The secondary immunogenicity analysis endpoints include:

Anti- PnPs serotype-specific Immunoglobulin G (IgG) Geometric Mean 
Concentrations (GMCs) for the 15 serotypes contained in V114 at 30 days PD3, prior 
to Dose 4 and at 30 days PD4

Anti-PnPs serotype-specific IgG response rates (proportion of participants meeting 
serotype-specific IgG threshold value of ≥0.35 μg/mL) for the 15 serotypes contained 
in V114 at 30 days PD3
The exploratory immunogenicity analysis endpoint includes:

Anti-PnPs serotype-specific OPA GMTs for the 15 serotypes contained in V114 at 30 
days PD3, prior to Dose 4 and at 30 days PD4
 
 
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9.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 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 
with V114 or Prevnar 13™.
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (swelling, 
redness/erythema, tenderness/pain, and hard lump/induration) from Day 1 through 
Day 14 following any vaccination with V114 or Prevnar 13™

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, hives or welts/urticaria, and appetite loss/decreased appetite) 
from Day 1 through Day 14 following any vaccination with V114 or Prevnar 13™

Proportions of participants with the broad AE categories consisting of any AE, a 
vaccine-related AE, an SAE, an AE which is both vaccine-related and serious, and 
discontinuation due to an AE, and the proportion of participants who died

Participants body temperature measured Day 1 (day of vaccination) through Day 7 
following any vaccination with V114 or Prevnar 13™
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The immunogenicity analyses will be performed for the Premature Infant Immunogenicity 
Substudy only. The Per-Protocol (PP) population will serve as the primary population for the 
analysis of immunogenicity data in this study. The PP population consists of all randomized 
participants in the Premature Infant Immunogenicity Substudy without deviations from the 
protocol that may substantially affect the results of the immunogenicity endpoint(s). Potential 
deviations that may result in the exclusion of a participant from the PP population for all 
immunogenicity analyses include:

Failure to receive primary infant series vaccination (V114 or Prevnar 13™ Doses 1, 
2, and 3) as per randomization schedule

Receipt of prohibited medication or prohibited vaccine prior to study vaccination
 
 
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Additional potential deviations that may result in the exclusion of a participant from the PP
population for specific immunogenicity analyses (depending on the time point for analysis) 
include:

Failure to receive study vaccine (V114, Prevnar 13™) according to vaccination 
schedule required at the time point for the analysis

Failure to receive the scheduled doses of V114 or Prevnar 13™(at least 28 days 
between Doses 1 and 2 and between Doses 2 and 3 [for PD3 and pre-dose 4 analysis], 
12 months to 1 day prior to 16 months of age for Dose 4 [for PD4 PP analyses])

Receipt of prohibited medication or prohibited vaccine prior to a blood sample 
collection

Collection of blood sample at the time point for the analysis outside of the 
pre-specified window (as described in Section 1.3)
The final determination on protocol deviations, and thereby the composition of the PP
population, will be made prior to the final unblinding of the database. Participants will be 
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 immunogenicity endpoints. The FAS population consists of all randomized 
participants who received all study vaccinations required at the time point for the analysis 
and have serology result. Participants will be included in the vaccination group to which they 
are randomized for the analysis of immunogenicity data 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 one dose of study 
vaccination. Participants will be included in the group corresponding to the study vaccination 
they actually received for the analysis of safety data using the APaT population. This will be 
the group to which they are randomized except for participants who take incorrect study 
vaccination; such participants will be included in the vaccination group corresponding to the 
study vaccination actually received.
At least 1 temperature measurement obtained subsequent to study intervention is required for 
inclusion in the analysis of temperature.
9.6
Statistical Methods
Statistical testing and inference for safety and immunogenicity analyses are described in 
Section 9.6.1 and Section 9.6.2, respectively. Unless otherwise stated, all statistical tests will 
be conducted at the α=0.05 (2-sided) level.
 
 
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9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the secondary and exploratory 
objectives about the immunogenicity analyses to be performed for the Premature Infant 
Immunogenicity Substudy.
For the Premature Infant Immunogenicity Substudy, evaluation of secondary and exploratory 
endpoints regarding anti-PnPs serotype-specific IgG GMCs and OPA GMTs at 30 days PD3, 
prior to Dose 4 and at 30 days PD4 for the 15 serotypes contained in the V114 group will be 
performed within each vaccination group separately. The point estimates will be calculated 
by exponentiating the estimates of the mean of the natural log values and the confidence 
intervals (CIs) will be derived by exponentiating the CIs of the mean of the natural log values 
based on the 1-sample t-distribution. For the secondary endpoints regarding anti-PnPs 
serotype-specific IgG response rates at 30 days PD3 for the 15 serotypes contained in the 
V114 group, 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].
A detailed analysis strategy for immunogenicity endpoints is listed in Table 3.
Table 3
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Anti-PnPs IgG GMCs at 30 days 
PD3
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Anti-PnPs IgG GMCs prior to 
Dose 4
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Anti-PnPs IgG GMCs at 30 days 
PD4
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Proportion of participants with 
anti-PnPs IgG ≥0.35 µg/mL at 
30 days PD3
P
Descriptive Statistics
(estimate, 95% CIǁ)
PP
Missing data 
will not be 
imputed
S
FAS
S
FAS
† P = Primary approach; S = Supportive approach. 
ǁ Within group summaries provided using exact method proposed by Clopper and Pearson.
CI = confidence interval; FAS = Full Analysis Set; GMC = Geometric Mean Concentration; 
IgG = Immunoglobulin G; PD = postdose; PnPs = pneumococcal polysaccharide; PP = Per-Protocol
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.
 
 
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The analysis of safety results will follow a tiered approach (Table 4). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) are either pre-specified as “Tier 1” endpoints, or will be classified 
as belonging to “Tier 2” or “Tier 3” based on the number of events observed. 
Tier 1 Events
Safety parameters or AEs of special interest that are identified constitute “Tier 1” safety 
endpoints that will be subject to inferential testing for statistical significance with p-values 
and 95% CIs to be provided for between-treatment differences in the proportion of 
participants with events; these analyses will be performed using the Miettinen and Nurminen 
(M&N) method (1985), an unconditional, asymptotic method. However, these p-values and 
CIs should be regarded as helpful descriptive measures to be used in review, not formal 
methods for assessing the statistical significance of the between-treatment differences in AEs 
and safety parameters. For this protocol, solicited injection-site AEs (redness, swelling, hard 
lump, and tenderness/pain) from Day 1 through Day 14 postvaccination and solicited 
systemic AEs (irritability, drowsiness, hives or welts, and appetite loss) from Day 1 through 
Day 14 postvaccination are considered Tier 1 events.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the M&N method [1985]) [Miettinen, 
O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 1% of the participants in either treatment group 
exhibit the event. The threshold of at least 1% was chosen because when less than 1% of 
participants report AEs in both groups with more events in the V114 group, the 95% CI for 
the between-group difference in percent incidence will always include zero. Note that when 
less than 1% of participants report AEs in both groups but with more events in the 
Prevnar 13™ group or equal in both groups, the 95% CI for the between-group difference 
may exclude zero. However, the clinical significance of these differences is unknown given 
the small number of participants who report AEs in this situation (fewer the 4 subjects in
each group) and; therefore, these AEs will be categorized as Tier 3 events. Because many 
95% CIs for Tier 2 events may be provided without adjustment for multiplicity, the CIs 
should be regarded as a helpful descriptive measure to be used in review, not a formal 
method for assessing the statistical significance of the between-group differences in AEs and 
safety parameters that meet predefined limits of change.
In addition to individual events that occur in at least 1% of participants in any treatment 
group, the broad AE categories consisting of the proportion of participants with any AE, a 
vaccine-related AE, an SAE, a vaccine-related SAE, discontinuation due to an AE, and the 
proportion of participants who died will be considered Tier 2 endpoints. 
 
 
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Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Table 4
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
p-Value
95% CI for 
Between-
Group 
Comparison
Descriptive
Statistics
Tier 1
Injection-site redness/erythema (Days 1 to 14)
X
X
X
Injection-site swelling (Days 1 to 14)
X
X
X
Injection-site tenderness/pain (Days 1 to 14)
X
X
X
Injection-site hard lump/induration (Days 1 to 
14)
X
X
X
Irritability (Days 1 to 14)
X
X
X
Drowsiness/somnolence (Days 1 to 14)
X
X
X
Hives or welts/urticaria (Days 1 to 14)
X
X
X
Appetite loss/decreased appetite (Days 1 to 14)
X
X
X
Tier 2
Any AE†
X
X
Any Vaccine-Related AE†
X
X
Any SAE†
X
X
Any Vaccine-Related SAE†
X
X
Discontinuation due to AE†
X
X
Death†
X
X
Maximum temperature measurements meeting 
the Brighton Collaboration cut points (Days 1 
to 7) 
X
X
Specific AEs by SOC and PT‡ (incidence ≥4 of 
participants in one of the vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PT‡ (incidence <4 of 
participants in all of the vaccination groups)
X
† These endpoints are broad adverse event categories. For example, descriptive statistics for the safety 
endpoint of “Any AE” will provide the number and percentage of participants with at least one AE.
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
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 the use of summary tables. No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (e.g., age, race, and gender, birth weight [kg], 
gestational age), baseline characteristics, prior and concomitant vaccinations and therapies 
will be summarized by vaccination group either by descriptive statistics or categorical tables.
Demographic variables and baseline characteristics will also be summarized for the 
Premature Infant Immunogenicity Substudy. 
 
 
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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, function, and guidelines for decision-making by 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. There are no plans to conduct an 
interim analysis of unblinded immunogenicity data in this study. However, unblinded 
immunogenicity data from this study and other ongoing V114 clinical studies will be made 
available to the DMC upon request to enable a benefit-risk assessment.
Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
intervention assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician performing 
interim analyses.
The DMC will serve as the primary reviewer of the results of the safety interim analyses 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 in order to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the external 
unblinded statistician. Additional logistical details will be provided in the DMC Charter.
Intervention-level results from the safety interim analysis 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 
interim analyses.
9.8
Multiplicity
No multiplicity adjustment is planned as there is no formal hypothesis testing.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
Immunogenicity analyses are for Premature Infant Immunogenicity Substudy only and 
considered as secondary objectives in this study. All immunogenicity objectives are 
descriptive endpoints. The study will randomize premature infants in a 1:1 ratio to either 
V114 or Prevnar 13™ vaccination group. The sample size of Premature Infant 
Immunogenicity Substudy will be approximately 1% to 2% of the total enrolled participants. 
The width of the within-group 95% CIs for the serotype-specific IgG GMCs depends on the 
 
 
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sample size, variability of the natural log concentrations, and the magnitude of the IgG GMC. 
For demonstration, it is assumed that 25 participants in each vaccination group will be 
enrolled and 22 participants will be evaluable for PP immunogenicity analyses at 30 days 
PD3, prior to Dose 4, and 30 days PD4 (based on the 90% evaluability rate). The 95% CIs 
based on the assumed number of evaluable subjects for various hypothetical IgG GMCs at 30
days PD3, prior to Dose 4, and 30 days PD4 and various hypothetical standard deviation 
estimates for the natural log titers are displayed in Table 5.
Table 5
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying 
Standard Deviations 
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™
1.0
(0.64, 1.56)
(3.21, 7.79)
(6.42, 15.58)
1.5
(0.51, 1.94)
(2.57, 9.72)
(5.14, 19.45)
2.0
(0.41, 2.43)
(2.06, 12.14)
(4.12, 24.27)
Based on 22 evaluable participants 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 
2,000 participants in V114 group if the underlying incidence of an SAE is 0.08% (1 of every 
1243 participants receiving the vaccine). There is a 50% chance of observing at least one 
SAE among 2,000 participants in V114 group if the underlying incidence of an SAE is 
0.03% (1 of every 2,886 participants receiving the vaccine). If no SAEs are observed among 
2,000 participants, this study will provide 97.5% confidence that the underlying percentage 
of participants with an SAE is <0.18% (one in every 543 participants).
Table 6 summarizes the percentage point differences between the 2 vaccination groups that 
could be detected with 80% probability for a variety of hypothetical underlying incidences of 
an AE. These calculations assume 2,000 participants in V114 group and 400 participants in 
Prevnar 13™ group, and are based on a 2-sided 5% alpha level. The calculations are based 
on an asymptotic method proposed by Farrington and Manning (1990) [Farrington, C. P. 
1990]; no multiplicity adjustments were made.
 
 
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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 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
 
 
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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.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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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 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
 
 
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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.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
 
 
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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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10.1.10Study 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
Not applicable.
 
 
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10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1 Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are 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.”
   
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
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:
1.
Results in death
2.
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.
3.
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.
4.
Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
5.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
6.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
10.3.3 Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4 Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
 
 
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
•
Injection site redness, swelling, or hard lump from the day of vaccination through Day 14
postvaccination will be evaluated by maximum size.
 
 
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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.
(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.
 
 
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-
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).
 
 
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4 Appendix 4: 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
Not applicable.
 
 
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10.6 Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 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
 
 
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International 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
10.7.1 Country-specific Request for Malaysia
In addition to the safety objectives presented in Section 3, the following safety hypothesis 
will be added. This hypothesis corresponds to the primary safety objective of the study.
Hypothesis:
V114 is well tolerated in healthy infants.
The safety endpoints, safety analysis populations, and statistical methods for safety analyses 
used to evaluate this hypothesis are described in Section 9.4.2, Section 9.5.2, and 
Section 9.6.2, respectively, and are the same as those being conducted for all participants in 
the study.
 
 
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10.8 Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
APaT
all participants as treated
CRF
case report form
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
eVRC
electronic Vaccination Report Card
FAS
full analysis set
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice 
GMC
geometric mean concentration
HIV
human immunodeficiency virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IPD
invasive pneumococcal disease
IRB
Institutional Review Board 
IRT
Interactive response technology
M&N
Miettinen and Nurminen
MOPA
Multiplex Opsonophagocytic Assay
MSD
Merck Sharp & Dohme Corp.
OPA
Opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PD3
postdose 3
PD4
postdose 4
PnECL
pneumococcal electrochemiluminescence
PnPs
pneumococcal polysaccharide 
PP
Per-protocol
PY
person-years
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SoA
schedule of activities
sSAP
supplemental statistical analysis plan
WHO
World Health Organization
 
 
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11
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Guevara M, Barricarte A, Torroba L, Herranz 
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Hausdorff WP, Bryant J, Kloek C, Paradiso 
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03QT0G
[Jokinen, J., et al 2015]
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Lepoutre A, Varon E, Georges S, Dorleans F, 
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03RBPW
[Martinelli, D., et al 2014]
Martinelli D, Pedalino B, Cappelli MG,
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04KW8B
[Metlay, J. P., et al 2006]
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[Moss, S. J., et al 2010]
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[Wagenvoort, G. H., et al 
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[Waight, P. A., et al 2015]
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04KTFC
[Whitney, Cynthia G., et al 
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03R0JC
 
 
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Supplemental Statistical Analysis Plan (sSAP)
 
 
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Table of Contents
1. INTRODUCTION ..........................................................................................4
2. SUMMARY OF CHANGES..........................................................................4
2.1 SUMMARY OF CHANGES FROM PROTOCOL SAP...............................4
2.2 SUMMARY OF CHANGES FROM PREVIOUS VERSIONS OF THE 
SSAP...............................................................................................................5
3. ANALYTICAL AND METHODOLOGICAL DETAILS.............................6
3.1 STATISTICAL ANALYSIS PLAN SUMMARY .........................................6
3.2 RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING .................7
3.3 HYPOTHESES/ESTIMATION .....................................................................7
3.4 ANALYSIS ENDPOINTS .............................................................................7
3.4.1
Immunogenicity Endpoints...........................................................7
3.4.2
Safety Endpoints...........................................................................8
3.5 ANALYSIS POPULATIONS ........................................................................8
3.5.1
Immunogenicity Analysis Populations.........................................8
3.5.2
Safety Analysis Populations .........................................................9
3.6 STATISTICAL METHODS.........................................................................10
3.6.1
Statistical Methods for Immunogenicity Analyses.....................10
3.6.2
Statistical Methods for Safety Analyses.....................................12
3.6.3
Demographic and Baseline Characteristics ................................14
3.7 INTERIM ANALYSES................................................................................15
3.8 MULTIPLICITY ..........................................................................................15
3.9 SAMPLE SIZE AND POWER CALCULATIONS.....................................15
3.9.1
Sample Size and Power for Immunogenicity Analyses..............15
3.9.2
Sample Size and Power for Safety Analyses..............................16
3.10
SUBGROUP ANALYSES .....................................................................18
3.11
COMPLIANCE (MEDICATION ADHERENCE) ................................18
3.12
EXTENT OF EXPOSURE.....................................................................18
4. LIST OF REFERENCES..............................................................................19
 
 
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List of Tables
Table 1
Analysis Strategy for Immunogenicity Variables................................................................ 11
Table 2 Limits of Quantitation for OPA and IgG Serotype-specific Responses ...................................... 12
Table 3
Analysis Strategy for Safety Parameters ............................................................................. 14
Table 4
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying Standard 
Deviations ......................................................................................................................................... 16
Table 5
Differences in Incidence of Adverse Event Rates Between the 2 Vaccination Groups That 
Can be Detected With an ~80% Probability (Assuming 2-sided 5% Alpha Level with 2000 
Participants in V114 Group and 400 Participants in Prevnar 13™ Group)...................................... 18
 
 
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1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the information 
presented in the protocol SAP which provides the principal features of confirmatory analyses for this trial, 
this sSAP provides additional statistical analysis details/data derivations and documents modifications or 
additions to the analysis plan that are not “principal” in nature and result from information that was not 
available at the time of protocol finalization.
2. SUMMARY OF CHANGES 
2.1
Summary of Changes from Protocol SAP
A summary of changes is provided in the table below:
Section 
Description of Change
Rationale
Section 3.4.2 Safety 
Endpoints
Added a paragraph to specify the timeframe 
associated with the reporting of AEs. 
Revisions made for clarity. 
Section 3.5.1 Immunogenicity 
Analysis Populations
Updated one sentence in this section from 
“The FAS population consists of all 
randomized participants who received all 
study vaccinations required at the time point 
for the analysis and have serology result” to 
“The FAS population consists of all 
randomized participants who received all 
study vaccinations required at the time point 
for the analysis and have at least one
serology result at the time point for the 
analysis.”
Revisions made to clarify the criteria for
inclusion in the FAS population.
Section 3.5.2 Safety Analysis 
Population
Updated one sentence in this section from 
“Safety analyses will be conducted in the All 
Participants as Treated (APaT) population,
which consists of all randomized participants 
who received at least one dose of study
vaccination” to “Safety analyses will be 
conducted in the All Participants as Treated 
(APaT) population, which consists of all 
randomized participants who received at 
least one dose of study vaccination for the 
time point of interest. For safety analyses 
following any dose of PCV, participants
vaccinated with PCV at any time point will 
be included. For safety analyses following 
each dose of PCV, participants vaccinated 
with PCV at that dose will be included.
Participants who inadvertently received both 
V114 and Prevnar 13™ during the study will 
be excluded from the analyses and will only 
be included in a separate AE listing.”
Revisions made to clarify the criteria for 
inclusion in the APaT population. 
Section 3.6 Statistical 
Methods
Added a sentence to clarify that the correct 
stratum will be used for analyses when mis-
stratification happens.
Added to provide additional statistical 
analysis details/data derivations.
 
 
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Section 3.6.1 Statistical 
Methods for Immunogenicity 
Analyses
Added a paragraph and a table (Table 2) to 
explain how values below the LLOQ or
above the ULOQ should be treated in 
various analyses.
Added to provide additional statistical 
analysis details/data derivations.
Section 3.6.1 Statistical 
Methods for Immunogenicity 
Analyses
Added a paragraph to provide Reverse 
Cumulative Distribution Curves for IgG 
concentrations and OPA Titers at 30 Days 
Postdose 3 and 30 Days Postdose 4.
Added to provide additional statistical 
analysis details/data derivations.
Section 3.6.2 Statistical 
Methods for Safety Analyses
Added a paragraph to explain the rationale 
for not including vaccination-site AEs in the 
summary tables.
Added to provide additional statistical 
analysis details/data derivations.
Section 3.6.2 Statistical 
Methods for Safety Analyses
Added a paragraph to explain the rationale 
for not including laboratory AEs in the 
summary tables.
Added to provide additional statistical 
analysis details/data derivations.
Section 3.6.2 Statistical 
Methods for Safety Analyses
Added a paragraph to describe an additional 
supportive analysis of the proportion of 
participants with solicited complaints using 
the data collected directly from participants 
via the VRC.
Added to provide additional statistical 
analysis details/data derivations.
Section 3.6.3 Summaries of 
Demographic and Baseline 
Characteristics
Added a sentence to specify the age variable 
used for the analyses.
Added to provide additional statistical 
analysis details/data derivations.
Section 3.10 Subgroup 
Analyses 
Added details of subgroup analyses.
Added to provide additional statistical 
analysis details/data derivations.
Throughout
Corrected minor typographical and 
grammatical errors.
Revisions made for accuracy. 
2.2
Summary of Changes from Previous Versions of the sSAP
Previous 
Version 
Current 
Version
Section
Description 
of 
Change
Rationale
None
17 Mar 2021
Not Applicable
Not Applicable
This is the first version of the sSAP.
 
 
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3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is provided 
in Sections 3.2 through 3.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety and Tolerability of V114 in 
Healthy Infants (PNEU-LINK)
Intervention Assignment
Approximately 2400 healthy infants approximately 2 months of age will 
be enrolled.

Full-term infants (gestational age ≥37 weeks) will be randomly 
assigned in a 5:1 ratio to a complete dosing schedule of V114 or 
Prevnar 13™. 

Premature infants (gestational age <37 weeks) will be randomly 
assigned in a 1:1 ratio to a complete dosing schedule of V114 or 
Prevnar 13™
Analysis Populations
Safety:  All Participants as Treated (APaT)
Immunogenicity: Per-Protocol (PP) and Full Analysis Set (FAS) 
population for the Premature Infant Immunogenicity Substudy
Primary Endpoint(s)

Proportion of participants with solicited injection-site AEs 
(swelling, redness/erythema, tenderness/pain, and hard 
lump/induration) from Day 1 through Day 14 following any 
vaccination with V114 or Prevnar 13™

Proportion of participants with solicited systemic AEs 
(irritability, drowsiness/somnolence, appetite lost/decreased 
appetite, and hives or welts/urticaria) from Day 1 through Day 14 
following any vaccination with V114 or Prevnar 13™

Proportion of participants with vaccine-related SAEs from Day 1 
through completion of study participation
Key Secondary Endpoint(s)
Premature Infant Immunogenicity Substudy only:

Anti-pneumococcal polysaccharide (PnPs) serotype-specific 
Immunoglobulin G (IgG) Geometric Mean Concentrations 
(GMCs) for the 15 serotypes contained in V114 at 30 days PD3, 
prior to Dose 4 and at 30 days PD4

Anti-PnPs serotype-specific IgG response rates (proportion of 
participants meeting serotype-specific IgG threshold value of 
≥0.35 μg/mL) for the 15 serotypes contained in V114 at 30 days 
PD3
Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes contained in V114 separately. To address the 
immunogenicity objectives, evaluation of the anti-PnPs serotype-specific 
IgG GMCs and response rates will be summarized descriptively. 
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 endpoints) and 95% CIs (Tier 1 and Tier 2 endpoints) will 
be provided for between-vaccination group differences in the percentage 
of participants with events; these analyses will be performed using the 
M&N method [Ref. 5.4: 03QCDT].
Interim Analyses
To support the periodic review of safety and tolerability data across the   
V114 Phase 3 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 
 
 
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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 immunogenicity objectives for this study are descriptive secondary 
objectives for the Premature Infant Immunogenicity Substudy only. The 
study will randomize premature infant participants in a 1:1 ratio to either 
the V114 or Prevnar 13™ vaccination group. The sample size of the 
Premature Infant Immunogenicity Substudy will be approximately 1% 
to 2% of overall participants. There is no hypothesis to be evaluated for 
the immunogenicity objectives. Section 3.9.1 provides information 
about the expected variability of the IgG GMC given the sample size.
Safety:
Section 3.9.2 provides information about the ability of this study to 
estimate the incidence of AEs within and between the vaccination 
groups.
3.2
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 in an IRT.
Blinding issues related to the planned interim analyses are described in Section 3.7. 
3.3
HYPOTHESES/ESTIMATION
Objectives of the study are stated in Section 3 of the protocol. There is no hypothesis to be evaluated in 
this study. 
3.4
ANALYSIS ENDPOINTS
Safety endpoints for all participants and immunogenicity endpoints for the Premature Infant 
Immunogenicity Substudy that will be evaluated for within- and/or between-treatment differences are 
listed below.
3.4.1
Immunogenicity Endpoints
The immunogenicity analyses are for the Premature Infant Immunogenicity Substudy only.  A 
description of immunogenicity assessments for the Premature Infant Immunogenicity Substudy is 
contained in Section 8.2 of the protocol. Immune responses will be measured for the 15 serotypes 
contained in V114 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).
 
 
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The secondary immunogenicity analysis endpoints include:

Anti-PnPs serotype-specific Immunoglobulin G (IgG) Geometric Mean Concentrations (GMCs)
for the 15 serotypes contained in V114 at 30 days PD3, prior to Dose 4 and at 30 days PD4

Anti-PnPs serotype-specific IgG response rates (proportion of participants meeting serotype-
specific IgG threshold value of ≥0.35 μg/mL) for the 15 serotypes contained in V114 at 30 days 
PD3
The exploratory immunogenicity analysis endpoint includes:

Anti-PnPs serotype-specific OPA GMTs for the 15 serotypes contained in V114 at 30 days PD3, 
prior to Dose 4 and at 30 days PD4
3.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 8.4 of the protocol. The analysis of 
safety results is described in Section 3.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including adverse 
events and postvaccination temperature measurements following any vaccination with V114 or 
Prevnar 13™.
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (swelling, redness/erythema, 
tenderness/pain, and hard lump/induration) from Day 1 through Day 14 following any 
vaccination with V114 or Prevnar 13™

Proportion of participants with solicited systemic AEs (irritability, drowsiness/somnolence, hives 
or welts/urticaria, and appetite loss/decreased appetite) from Day 1 through Day 14 following 
any vaccination with V114 or Prevnar 13™

Proportions of participants with the broad AE categories consisting of any AE, a vaccine-related 
AE, an SAE, an AE which is both vaccine-related and serious, and discontinuation due to an AE, 
and the proportion of participants who died

Participants body temperature measured Day 1 (day of vaccination) through Day 7 following 
any vaccination with V114 or Prevnar 13™
The timeframe associated with the reporting of AEs is consistent with the collection. Nonserious adverse 
events (NSAEs) are reported from Day 1 through Day 14 following each vaccination. SAEs are reported 
from Day 1 through completion of study participation.
3.5
ANALYSIS POPULATIONS
3.5.1
Immunogenicity Analysis Populations
 
 
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The immunogenicity analyses will be performed for the Premature Infant Immunogenicity Substudy 
only. The Per-Protocol (PP) population will serve as the primary population for the analysis of 
immunogenicity data in this study. The PP population consists of all randomized participants in the 
Premature Infant Immunogenicity Substudy without deviations from the protocol that may substantially 
affect the results of the immunogenicity endpoint(s). Potential deviations that may result in the exclusion 
of a participant from the PP population for all immunogenicity analyses include:

Failure to receive primary infant series vaccination (V114 or Prevnar 13™ for Doses 1, 2, and 3) 
as per randomization schedule

Receipt of prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant from the PP population 
for specific immunogenicity analyses (depending on the time point for analysis) include:

Failure to receive required study vaccine (V114, Prevnar 13™) according to vaccination 
schedule at the time point for the analysis

Failure to receive the scheduled doses of V114 or Prevnar 13™ (at least 28 days between Doses 
1 and 2 and between Doses 2 and 3 [for PD3 and pre-dose 4 analysis], 12 months to 1 day prior 
to 16 months of age for Dose 4 [for PD4 PP analyses])

Receipt of prohibited medication or prohibited vaccine prior to a blood sample collection

Collection of blood sample at the time point for the analysis outside of the pre-specified window 
(as described in Section 1.3 of the protocol)
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 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 
immunogenicity endpoints. The FAS population consists of all randomized participants who received all 
study vaccinations required at the time point for the analysis and have at least one serology result at the 
time point for the analysis. Participants will be included in the vaccination group to which they are 
randomized for the analysis of immunogenicity data using the FAS population.
3.5.2
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 one dose of study vaccination for the time point of 
interest. For safety analyses following any dose of PCV, participants vaccinated with PCV at any time
point will be included. For safety analyses following each dose of PCV, participants vaccinated with 
PCV at that dose will be included. Participants who inadvertently received both V114 and Prevnar 13™ 
during the study will be excluded from the analyses and will only be included in a separate AE listing. 
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 
 
 
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randomized except for participants who take incorrect study vaccination; such participants will be 
included in the vaccination group corresponding to the study vaccination actually received.
At least 1 temperature measurement obtained subsequent to study intervention is required for inclusion 
in the analysis of temperature.
3.6 
STATISTICAL METHODS
Statistical testing and inference for safety and immunogenicity analyses are described in Section 3.6.1 
and Section 3.6.2, respectively. Unless otherwise stated, all statistical tests will be conducted at the 
α=0.05 (2-sided) level.
The correct stratum will be used for analysis regardless of the assigned stratum at randomization (ie, 
stratification errors will be corrected for the purposes of analysis).
3.6.1 Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the secondary and exploratory objectives 
about the immunogenicity analyses to be performed for the Premature Infant Immunogenicity Substudy. 
For the Premature Infant Immunogenicity Substudy, evaluation of secondary and exploratory endpoints 
regarding anti-PnPs serotype-specific IgG GMCs and OPA GMTs at 30 days PD3, prior to Dose 4 and 
at 30 days PD4 for the 15 serotypes contained in the V114 group will be performed within each 
vaccination group separately. The point estimates will be calculated by exponentiating the estimates of 
the mean of the natural log values and the confidence intervals (CIs) will be derived by exponentiating 
the CIs of the mean of the natural log values based on the 1-sample t-distribution. For the secondary 
endpoints regarding anti-PnPs serotype-specific IgG response rates at 30 days PD3 for the 15 serotypes 
contained in the V114 group, the within-group CIs will be calculated based on the exact method 
proposed by Clopper and Pearson [Ref. 5.4: 03RRVC].
A detailed analysis strategy for immunogenicity endpoints is listed in Table 1.
 
 
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Table 1
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Anti-PnPs IgG GMCs at 30 days PD3
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Anti-PnPs IgG GMCs prior to Dose 4
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Anti-PnPs IgG GMCs at 30 days PD4
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Proportion of participants with anti-PnPs 
IgG ≥0.35 µg/mL at 30 days PD3
P
Descriptive Statistics
(estimate, 95% CIǁ)
PP
Missing data 
will not be 
imputed
S
FAS
† P = Primary approach; S = Supportive approach.
ǁ Within group summaries provided using exact method proposed by Clopper and Pearson.
CI = confidence interval; FAS = Full Analysis Set; GMC = Geometric Mean Concentration; IgG = Immunoglobulin G;
PD = postdose; PnPs = pneumococcal polysaccharide; PP = Per-Protocol
The detectable ranges for OPA and IgG responses differ across serotypes. The limits of quantitation define 
the range of responses over which the assay provides precise and accurate measurements. Table 2 gives 
the limits of quantitation defined for each serotype for OPA and IgG responses. For responses smaller 
than the lower limit of quantitation (LLOQ), half of the LLOQ is used for analysis when calculating the 
OPA GMTs and IgG GMCs. For OPA and IgG responses that are larger than the upper limit of quantitation 
(ULOQ), a value equal to ULOQ + 1 is used for analysis.
 
 
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Table 2 Limits of Quantitation for OPA and IgG Serotype-specific Responses
OPA
IgG
Serotype
LLOQ (1/dil)
ULOQ (1/dil)
LLOQ (µg/mL)
ULOQ (µg/mL)
1
9
30,213
0.05
850
3
19
30,564
0.05
145
4
34
137,160
0.05
173
5
27
119,016
0.10
368
6A
232
210,600
0.05
393
6B
40
105,840
0.05
341
7F
61
251,235
0.05
830
9V
151
224,316
0.05
644
14
62
281,637
0.05
1,520
18C
115
445,230
0.05
730
19A
31
128,304
0.05
1,387
19F
113
158,841
0.05
1,461
22F
15
229,338
0.05
1,054
23F
55
251,829
0.05
595
33F
20
399,600
0.05
833
IgG = immunoglobulin G; LLOQ = lower limit of quantitation; OPA= opsonophagocytic activity; ULOQ = upper 
limit of quantitation.
Reverse Cumulative Distribution Curves for IgG concentrations and OPA Titers at 30 Days Postdose 3
and 30 Days Postdose 4 will be graphically displayed by serotype.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs and 
postvaccination temperature measurements.
The analysis of safety results will follow a tiered approach (Table 3). The tiers differ with respect to the 
analyses that will be performed. Adverse events (specific terms as well as system organ class terms) are 
either pre-specified as “Tier 1” endpoints, or will be classified as belonging to “Tier 2” or “Tier 3” based 
on the number of events observed. 
Tier 1 Events
Safety parameters or AEs of special interest that are identified constitute “Tier 1” safety endpoints that 
will be subject to inferential testing for statistical significance with p-values and 95% CIs to be provided 
for between-treatment differences in the proportion of participants with events; these analyses will be 
 
 
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performed using the Miettinen and Nurminen (M&N) method (1985), an unconditional, asymptotic 
method. However, these p-values and CIs should be regarded as helpful descriptive measures to be used 
in review, not formal methods for assessing the statistical significance of the between-treatment 
differences in AEs and safety parameters. For this protocol, solicited injection-site AEs (redness, 
swelling, hard lump, and tenderness/pain) from Day 1 through Day 14 postvaccination and solicited 
systemic AEs (irritability, drowsiness, hives or welts, and appetite loss) from Day 1 through Day 14 
postvaccination are considered Tier 1 events.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences in the 
proportion of participants with events (also via the M&N method [1985]) [Ref. 5.4: 03QCDT].
Membership in Tier 2 requires that at least 1% of the participants in either treatment group exhibit the 
event. The threshold of at least 1% was chosen because when less than 1% of participants report AEs in 
both groups with more events in the V114 group, the 95% CI for the between-group difference in 
percent incidence will always include zero. Note that when less than 1% of participants report AEs in 
both groups but with more events in the Prevnar 13™ group or equal in both groups, the 95% CI for the 
between-group difference may exclude zero. However, the clinical significance of these differences is 
unknown given the small number of participants who report AEs in this situation (1% of the participants 
in either treatment group) and; therefore, these AEs will be categorized as Tier 3 events. Because many 
95% CIs for Tier 2 events may be provided without adjustment for multiplicity, the CIs should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for assessing the 
statistical significance of the between-group differences in AEs and safety parameters that meet 
predefined limits of change.
In addition to individual events that occur in at least 1% of participants in any treatment group, the broad 
AE categories consisting of the proportion of participants with any AE, a vaccine-related AE, an SAE, a 
vaccine-related SAE, discontinuation due to an AE, and the proportion of participants who died will be 
considered Tier 2 endpoints. 
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point estimates by 
treatment group are provided for Tier 3 safety parameters.
 
 
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Table 3
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
p-Value
95% CI for 
Between-
Group 
Comparison
Descriptive
Statistics
Tier 1
Injection-site redness/erythema (Days 1 to 14)
X
X
X
Injection-site swelling (Days 1 to 14)
X
X
X
Injection-site tenderness/pain (Days 1 to 14)
X
X
X
Injection-site hard lump/induration (Days 1 to 
14)
X
X
X
Irritability (Days 1 to 14)
X
X
X
Drowsiness/somnolence (Days 1 to 14)
X
X
X
Hives or welts/urticaria (Days 1 to 14)
X
X
X
Appetite loss/decreased appetite (Days 1 to 14)
X
X
X
Tier 2
Any AE†
X
X
Any Vaccine-Related AE†
X
X
Any SAE†
X
X
Any Vaccine-Related SAE†
X
X
Discontinuation due to AE†
X
X
Death†
X
X
Maximum temperature measurements meeting 
the Brighton Collaboration cut points (Days 1 to 
7) 
X
X
Specific AEs by SOC and PT‡ (incidence ≥1%
of participants in one of the vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PT‡ (incidence <1%
of participants in all of the vaccination groups)
X
† These endpoints are broad adverse event categories. For example, descriptive statistics for the safety 
endpoint of “Any AE” will provide the number and percentage of participants with at least one AE.
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; 
SOC = system organ class; X = results will be provided
Laboratory AEs will not be reported in summary tables as laboratory testing is not performed as part of 
the study and thus such AEs would only be reported spontaneously. A listing of laboratory AEs will be 
provided.
A supportive analysis comparing the proportion of participants reporting each of the solicited complaints 
on the VRC will be conducted in support of the primary safety analyses that are based on solicited AEs. 
This supportive analysis will use the methodology specified in Table 3 for solicited AEs. The analysis 
will be conducted on the subset of the APaT population who entered solicited complaints data on the 
VRC.
3.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline characteristic 
will be assessed by the use of summary tables. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened and randomized and the primary 
reasons for screening failure and discontinuation will be displayed. Demographic variables (e.g., age, 
race, gender, and gestational age), baseline characteristics, prior and concomitant vaccinations and 
therapies will be summarized by vaccination group either by descriptive statistics or categorical tables. 
 
 
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Demographic variables and baseline characteristics will also be summarized for the Premature Infant 
Immunogenicity Substudy. 
Calculated age based on the difference in months between the birthdate and randomization date will be 
used for summaries of age. 
3.7
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, function, and 
guidelines for decision-making by 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. There are no plans to conduct an interim analysis of unblinded immunogenicity data in this 
study. However, unblinded immunogenicity data from this study and other ongoing V114 clinical 
studies will be made available to the DMC upon request to enable a benefit-risk assessment.
Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to intervention 
assignment will be maintained at all investigational sites. The results of interim analyses will not be 
shared with the investigators prior to the completion of the study. Participant-level unblinding will be 
restricted to an external unblinded statistician performing interim analyses.
The DMC will serve as the primary reviewer of the results of the safety interim analyses 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 in order to act on these recommendations. The extent to 
which individuals are unblinded with respect to results of interim analyses will be documented by the 
external unblinded statistician. Additional logistical details will be provided in the DMC Charter.
Intervention-level results from the safety interim analysis 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 interim analyses.
3.8
MULTIPLICITY
No multiplicity adjustment is planned as there is no formal hypothesis testing.
3.9
SAMPLE SIZE AND POWER CALCULATIONS
3.9.1
Sample Size and Power for Immunogenicity Analyses
Immunogenicity analyses are for Premature Infant Immunogenicity Substudy only and considered as 
secondary objectives in this study. All immunogenicity objectives are descriptive endpoints. The study 
will randomize premature infants in a 1:1 ratio to either V114 or Prevnar 13™ vaccination group. The 
sample size of Premature Infant Immunogenicity Substudy will be approximately 1% to 2% of the total 
 
 
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enrolled participants. The width of the within-group 95% CIs for the serotype-specific IgG GMCs depends 
on the sample size, variability of the natural log concentrations, and the magnitude of the IgG GMC. For 
demonstration, it is assumed that 25 participants in each vaccination group will be enrolled and 22 
participants will be evaluable for PP immunogenicity analyses at 30 days PD3, prior to Dose 4, and 30 
days PD4 (based on the 90% evaluability rate). The 95% CIs based on the assumed number of evaluable 
participants for various hypothetical IgG GMCs at 30 days PD3, prior to Dose 4, and 30 days PD4 and 
various hypothetical standard deviation estimates for the natural log titers are displayed in Table 4.
Table 4
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying Standard 
Deviations 
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™
1.0
(0.64, 1.56)
(3.21, 7.79)
(6.42, 15.58)
1.5
(0.51, 1.94)
(2.57, 9.72)
(5.14, 19.45)
2.0
(0.41, 2.43)
(2.06, 12.14)
(4.12, 24.27)
Based on 22 evaluable participants 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.
3.9.2
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 2,000 participants in V114 
group if the underlying incidence of an SAE is 0.08% (1 of every 1243 participants receiving the 
vaccine). There is a 50% chance of observing at least one SAE among 2,000 participants in V114 group 
if the underlying incidence of an SAE is 0.03% (1 of every 2,886 participants receiving the vaccine). If 
no SAEs are observed among 2,000 participants, this study will provide 97.5% confidence that the 
underlying percentage of participants with an SAE is <0.18% (one in every 543 participants).
 
 
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Table 5 summarizes the percentage point differences between the 2 vaccination groups that could be 
detected with 80% probability for a variety of hypothetical underlying incidences of an AE. These 
calculations assume 2,000 participants in V114 group and 400 participants in Prevnar 13™ group, and 
are based on a 2-sided 5% alpha level. The calculations are based on an asymptotic method proposed by 
Farrington and Manning (1990) [Ref. 5.4: 04FS6L]; no multiplicity adjustments were made.
 
 
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Table 5
Differences in Incidence of Adverse Event Rates Between the 2 Vaccination Groups That 
Can be Detected With an ~80% Probability (Assuming 2-sided 5% Alpha Level with 2000 Participants 
in V114 Group and 400 Participants in Prevnar 13™ Group)
Incidence of Adverse Event
Risk Difference
V114 (%)
Prevnar 13™ (%)
Percentage Points
1.6
0.1
1.5
4.9
2
2.9
9.0
5
4.0
15.2
10
5.2
21.0
15
6.0
26.6
20
6.6
37.3
30
7.3
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
Based on an asymptotic method proposed by Farrington and Manning (1990) [Ref. 5.4: 04FS6L]
3.10
SUBGROUP ANALYSES
An overall summary of AEs and a summary of solicited AEs following any vaccination will be provided 
for each subgroup (point estimates only) with ≥5% of the total number of randomized participants in 
each vaccination group (except subgroups based on gestational age, which will be provided regardless of 
the percentage of the total number of randomized participants in each vaccination group).
The following subgroups are planned for evaluation:

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Race (American Indian or Alaska Native, Asian, Black or African American, Multiple, Native 
Hawaiian or Other Pacific Islander, White)

Sex (Female, Male)

Gestational age < 37 weeks (yes/no)
3.11
COMPLIANCE (MEDICATION ADHERENCE)
The number and proportion of randomized participants receiving each vaccination will be summarized 
(Section 3.12).
3.12
EXTENT OF EXPOSURE
The extent of exposure will be summarized by the number and proportion of randomized participants 
administered V114 or Prevnar 13™ at each vaccination schedule.
 
 
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4. LIST OF REFERENCES 
[Ref. 5.4: 03QCDT]
Miettinen O, Nurminen M. Comparative Analysis 
of Two Rates. Stat Med 1985;4:213-26.
[Ref. 5.4: 03RRVC]
Clopper CJ, Pearson ES. The use of confidence of 
fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26(4):404-13.
[Ref. 5.4: 04FS6L]
Farrington CP, Manning G. Test Statistics and 
Sample Size Formulae for Comparative Binomial 
Trials with Null Hypothesis of Non-Zero Risk 
Difference or Non-Unity Relative Risk. Stat Med 
Vol. 9,1447-1454 (1990)
 
 
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