A Phase 3, Multicenter, Randomized, Double-blind, Active-comparator-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Healthy Infants (PNEU-PED-EU-1)
Phase: PHASE3
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04031846 
Document Date: 
16-Mar-2021
A Phase 3, Multicenter, Randomized, Double-blind, Active-
comparator-controlled Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of V114 in Healthy Infants (PNEU-PED-EU-1)

PRODUCT: V114  
1
PROTOCOL/AMENDMENT NO.: 025-02 
V114-025-02 FINAL PROTOCOL
16-MAR-2021
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active-comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in 
Healthy Infants (PNEU-PED-EU-1)
Protocol Number: 025-02
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
2018-003787-31
Approval Date: 16 March 2021
 
 
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PRODUCT: V114  
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PROTOCOL/AMENDMENT NO.: 025-02 
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16-MAR-2021
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.: 025-02 
V114-025-02 FINAL PROTOCOL
16-MAR-2021
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
V114-025-02
16-MAR-2021
Amendment to expand the visit windows for Visit 4 (post primary series
blood draw) and Visit 6 (post toddler dose blood draw) to allow inclusion of
more participants in the immunogenicity analysis based on the per-protocol 
population. This change is being made in response to the COVID-19 global 
pandemic which impacted the ability of many participants to attend study 
visits within the prescribed visit windows due to local conditions and travel 
restrictions.
V114-025-01
24-JUL-2019
This country-specific amendment incorporates feedback from the Russian 
Ministry of Health.
V114-025-00
22-FEB-2019
Original protocol
 
 
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PRODUCT: V114  
4
PROTOCOL/AMENDMENT NO.: 025-02 
V114-025-02 FINAL PROTOCOL
16-MAR-2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
The COVID-19 global pandemic impacted the ability of many participants to attend study visits within the prescribed visit windows 
due to local conditions and travel restrictions. The primary purpose of this amendment is to expand the visit windows for Visit 4 (post 
primary series blood draw) and Visit 6 (post toddler dose blood draw) to allow inclusion of more participants in the immunogenicity 
analysis based on the per-protocol population.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities
The visit windows for Visit 4 (post 
primary series blood draw) and Visit 6 
(post toddler dose blood draw) were 
expanded by 18 days.
The expansion of the visit windows will allow inclusion 
of more participants in the immunogenicity analysis
based on the per-protocol population. This change is 
being made in response to the COVID-19 global 
pandemic which impacted the ability of many 
participants to attend study visits within the prescribed 
visit windows due to local conditions and travel 
restrictions.
Section 10.8
Appendix 8: 
Abbreviations
Added COVID-19 to the List of 
Abbreviations.
Revision made for completeness.
Throughout
Editorial revisions
Changes are minor and have not been summarized 
individually.
 
 
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PRODUCT: V114  
5
PROTOCOL/AMENDMENT NO.: 025-02 
V114-025-02 FINAL PROTOCOL
16-MAR-2021
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................26
2.1
Study Rationale....................................................................................................26
2.2
Background ..........................................................................................................27
2.2.1
V114 and Pneumococcal Disease................................................................27
2.2.2
Preclinical and Clinical Studies ...................................................................28
2.2.3
Information on Other Study-related Therapy ..............................................28
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................28
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................34
4.2.1
Rationale for Endpoints ...............................................................................34
4.2.1.1
Immunogenicity Endpoints................................................................34
4.2.1.2
Safety Endpoints................................................................................36
4.2.1.3
Future Biomedical Research..............................................................36
4.2.2
Rationale for the Use of Comparator/Placebo .............................................36
4.3
Justification for Dose...........................................................................................37
4.4
Beginning and End of Study Definition .............................................................37
4.4.1
Clinical Criteria for Early Study Termination .............................................37
5
STUDY POPULATION ................................................................................................37
5.1
Inclusion Criteria.................................................................................................37
5.2
Exclusion Criteria................................................................................................38
5.3
Lifestyle Considerations......................................................................................40
5.4
Screen Failures.....................................................................................................40
5.5
Participant Replacement Strategy......................................................................40
6
STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................41
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
 
 
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PRODUCT: V114  
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6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Rescue Medications and Supportive Care ...................................................46
6.6
Dose Modification (Escalation/Titration/Other)...............................................46
6.7
Intervention After the End of the Study............................................................46
6.8
Clinical Supplies Disclosure................................................................................46
6.9
Standard Policies..................................................................................................46
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................47
7.1
Discontinuation of Study Intervention...............................................................47
7.2
Participant Withdrawal From the Study...........................................................48
7.3
Lost to Follow-up .................................................................................................48
8
STUDY ASSESSMENTS AND PROCEDURES........................................................48
8.1
Administrative and General Procedures ...........................................................49
8.1.1
Informed Consent.........................................................................................49
8.1.1.1
General Informed Consent.................................................................49
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................50
8.1.2
Inclusion/Exclusion Criteria ........................................................................50
8.1.3
Participant Identification Card.....................................................................50
8.1.4
Medical History ...........................................................................................51
8.1.5
Prior and Concomitant Medications Review...............................................51
8.1.5.1
Prior Medications...............................................................................51
8.1.5.2
Concomitant Medications..................................................................51
8.1.6
Assignment of Screening Number...............................................................51
8.1.7
Assignment of Treatment/Randomization Number.....................................52
8.1.8
Study Intervention Administration ..............................................................52
8.1.8.1
Timing of Dose Administration.........................................................53
8.1.9
Electronic Vaccination Report Card ............................................................53
8.1.10
Day 15 Postdose Telephone Contact Guide.................................................54
8.1.11
Telephone Contact Questionnaire................................................................54
8.1.12
Discontinuation and Withdrawal .................................................................54
8.1.12.1
Withdrawal From Future Biomedical Research ................................54
 
 
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16-MAR-2021
8.1.13
Participant Blinding/Unblinding..................................................................55
8.1.14
Calibration of Equipment.............................................................................55
8.2
Immunogenicity Assessments .............................................................................56
8.2.1
Pneumococcal Electrochemiluminescence ..................................................56
8.2.2
Multiplex Opsonophagocytic Assay............................................................57
8.2.3
Anti-Diphtheria Toxoid, Tetanus Toxoid, and Pertussis Antigen 
Serology Assay ............................................................................................57
8.2.4
Haemophilis Influenzae Type B IgG ELISA...............................................57
8.2.5
Hepatitis B Enhanced Chemiluminescence (ECi) Assay.............................58
8.2.6
Micrometabolic Inhibition Test-based Virus Neutralization Assay (Polio 
MIT).............................................................................................................58
8.2.7
Anti-rotavirus IgA Enzyme Immunoassay (EIA)........................................59
8.3
Safety Assessments...............................................................................................59
8.3.1
Physical Examinations.................................................................................59
8.3.2
Body Temperature Measurements ...............................................................60
8.3.3
Safety Assessments and Use of the eVRC...................................................60
8.3.4
Clinical Safety Laboratory Assessments .....................................................61
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................61
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................61
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......63
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...64
8.4.4
Regulatory Reporting Requirements for SAE .............................................64
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................64
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................64
8.4.7
Events of Clinical Interest (ECIs)................................................................64
8.5
Treatment of Overdose........................................................................................64
8.6
Pharmacokinetics.................................................................................................65
8.7
Pharmacodynamics..............................................................................................65
8.8
Biomarkers ...........................................................................................................65
8.9
Planned Genetic Analysis Sample Collection....................................................65
8.10
Future Biomedical Research Sample Collection...............................................65
8.11
Medical Resource Utilization and Health Economics.......................................65
8.12
Visit Requirements...............................................................................................65
8.12.1
Screening......................................................................................................66
8.12.2
Treatment Period/Vaccination Visit ............................................................66
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........66
 
 
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PRODUCT: V114  
8
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16-MAR-2021
9
STATISTICAL ANALYSIS PLAN .............................................................................66
9.1
Statistical Analysis Plan Summary.....................................................................66
9.2
Responsibility for Analyses/In-house Blinding .................................................69
9.3
Hypotheses/Estimation ........................................................................................70
9.4
Analysis Endpoints...............................................................................................70
9.4.1
Immunogenicity Endpoints..........................................................................70
9.4.2
Safety Endpoints..........................................................................................71
9.5
Analysis Populations............................................................................................72
9.5.1
Immunogenicity Analysis Populations ........................................................72
9.5.2
Safety Analysis Populations ........................................................................73
9.6
Statistical Methods...............................................................................................73
9.6.1
Statistical Methods for Immunogenicity......................................................73
9.6.2
Statistical Methods for Safety Analyses ......................................................77
9.6.3
Summaries of Baseline Characteristics........................................................78
9.7
Interim Analyses ..................................................................................................78
9.8
Multiplicity ...........................................................................................................79
9.9
Sample Size and Power Calculations .................................................................79
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................79
9.9.2
Sample Size and Power for Safety Analyses ...............................................81
9.10
Subgroup Analyses...............................................................................................82
9.11
Compliance (Medication Adherence).................................................................82
9.12
Extent of Exposure...............................................................................................82
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................83
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........83
10.1.1
Code of Conduct for Clinical Trials.............................................................83
10.1.2
Financial Disclosure.....................................................................................85
10.1.3
Data Protection.............................................................................................85
10.1.3.1
Confidentiality of Data ......................................................................86
10.1.3.2
Confidentiality of Participant Records...............................................86
10.1.3.3
Confidentiality of IRB/IEC Information............................................86
10.1.4
Committees Structure...................................................................................86
10.1.4.1
Scientific Advisory Committee..........................................................86
10.1.4.2
Executive Oversight Committee........................................................86
10.1.4.3
External Data Monitoring Committee ...............................................87
10.1.5
Publication Policy........................................................................................87
10.1.6
Compliance with Study Registration and Results Posting Requirements ...87
10.1.7
Compliance with Law, Audit, and Debarment ............................................88
 
 
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PRODUCT: V114  
9
PROTOCOL/AMENDMENT NO.: 025-02 
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16-MAR-2021
10.1.8
Data Quality Assurance ...............................................................................88
10.1.9
Source Documents .......................................................................................89
10.1.10
Study and Site Closure.................................................................................90
10.2
Appendix 2: Clinical Laboratory Tests..............................................................91
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................92
10.3.1
Definition of AE ..........................................................................................92
10.3.2
Definition of SAE ........................................................................................93
10.3.3
Additional Events Reported.........................................................................94
10.3.4
Recording AE and SAE ...............................................................................94
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................97
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................99
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................100
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................101
10.7
Appendix 7: Country-specific Requirements..................................................106
10.7.1
Study Design..............................................................................................106
10.7.2
Statistical Analysis Plan.............................................................................108
10.7.2.1
Analysis Endpoints ..........................................................................108
10.7.2.1.1
Immunogenicity Endpoints....................................................108
10.7.2.1.2
Safety Endpoints....................................................................108
10.7.2.2
Analysis Populations and Statistical Methods.................................108
10.7.2.2.1
Immunogenicity Analysis......................................................108
10.7.2.2.2
Safety Analysis ......................................................................108
10.8
Appendix 8: Abbreviations ...............................................................................109
11
REFERENCES.............................................................................................................111
 
 
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PRODUCT: V114  
10
PROTOCOL/AMENDMENT NO.: 025-02 
V114-025-02 FINAL PROTOCOL
16-MAR-2021
LIST OF TABLES
Table 1
Study Interventions..........................................................................................41
Table 2
Concomitant Vaccine Schedule.......................................................................45
Table 3
Recommended Injection-site Location for Study Interventions......................46
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................63
Table 5
Summary of Endpoints for Concomitant Vaccine Antigens............................71
Table 6
Analysis Strategy for Immunogenicity Variables............................................76
Table 7
Analysis Strategy for Safety Parameters..........................................................78
Table 8
Summary of Endpoints and Power for Concomitant Vaccine Antigens..........81
Table 9
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 590 Participants in Each Group) ..82
 
 
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PRODUCT: V114  
11
PROTOCOL/AMENDMENT NO.: 025-02 
V114-025-02 FINAL PROTOCOL
16-MAR-2021
LIST OF FIGURES
Figure 1
V114-025 Study Design...................................................................................18
Figure 2
V114-025-01 Study Design (For Sites in the Russian Federation Only).......107
 
 
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PRODUCT: V114  
12
PROTOCOL/AMENDMENT NO.: 025-02 
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16-MAR-2021
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active-comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in 
Healthy Infants (PNEU-PED-EU-1)
Short Title: Safety, tolerability, and immunogenicity of V114 in healthy infants
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-025 (PNEU-PED-EU-1)
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives and endpoints will be evaluated in healthy infants enrolled at 
approximately 2 months of age (from 42 to 90 days [inclusive]) administered V114 or 
Prevenar 13™. The statistical criteria for the primary hypotheses are provided in the table 
below and for the secondary hypotheses can be found in Section 9.9.1 (Table 8). Information 
on safety and immunogenicity endpoints and planned statistical analyses for participants 
enrolled at sites in the Russian Federation can be found in Appendix 7.
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
Following any vaccination with V114:
- Solicited injection-site AEs from Day 1 
through Day 14 postvaccination
- Solicited systemic AEs from Day 1 through 
Day 14 postvaccination
- Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation
- Objective: To compare the 
anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
response rates (proportion of participants 
meeting serotype-specific IgG threshold 
value of ≥0.35 μg/mL) at 30 days following 
the toddler dose (Postdose 3 for full-term 
infants; Postdose 4 for preterm infants) for 
participants administered V114 versus 
participants administered Prevenar 13™.
- Anti-PnPs serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
30 days following the toddler dose (PTD)
 
 
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Hypothesis (H1): V114 is non-inferior to 
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based on 
response rates at 30 days following the 
toddler dose.
(The statistical criterion for non-inferiority 
requires the lower bound of the 2-sided 
95% CI for the difference in responses rates 
[V114 minus Prevenar 13™] to be greater 
than -0.1).
Hypothesis (H2): V114 is superior to 
Prevenar 13™ for the 2 serotypes unique to 
V114 based on the response rates at 30 days 
following the toddler dose.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 
95% CI for the difference in responses rates 
[V114 minus Prevenar 13™] to be greater 
than 0.1).
- Objective: To compare anti-PnPs 
serotype-specific IgG geometric mean 
concentrations (GMCs) at 30 days following 
the toddler dose for participants administered 
V114 versus participants administered 
Prevenar 13™.
Hypothesis (H3): V114 is non-inferior to 
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based on 
anti-PnPs serotype-specific IgG GMCs at 
30 days following the toddler dose.
(The statistical criterion for non-inferiority 
requires the lower bound of the 2-sided 
95% CI for anti-PnPs serotype-specific IgG 
GMC ratio [V114/ Prevenar 13™] to be 
greater than 0.5.)
Hypothesis (H4): V114 is superior to 
Prevenar 13™ for the 2 serotypes unique to 
V114 based on anti-PnPs serotype-specific 
IgG GMCs at 30 days following the toddler 
dose.
- Anti-PnPs serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
30 days PTD
 
 
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(The statistical criterion for superiority 
requires the lower bound of the 2-sided 95% 
CI for anti-PnPs serotype-specific IgG GMC 
ratio [V114/ Prevenar 13™] to be greater 
than 2.0.)
Secondary Objectives
Secondary Endpoints
- Objective: To compare the antigen-specific 
response rate to each antigen included in 
INFANRIX™ hexa at 30 days following the 
toddler dose for participants administered 
V114 concomitantly with INFANRIX™ 
hexa versus participants administered 
Prevenar 13™ concomitantly with 
INFANRIX™ hexa.
Hypothesis (H5): INFANRIX™ hexa 
administered concomitantly with V114 is 
non-inferior to INFANRIX™ hexa 
administered concomitantly with 
Prevenar 13™ at 30 days following the 
toddler dose for each antigen included in 
INFANRIX™ hexa.
Antibody responses to:
- diphtheria toxoid
- tetanus toxoid
- pertussis toxin (PT)
- pertussis filamentous hemagglutinin (FHA)
- pertussis pertactin (PRN)
- Haemophilus influenzae type b 
polyribosylribitol phosphate (Hib-PRP)
- hepatitis B surface antigen (HBsAg)
- poliovirus serotypes 1, 2, and 3
at 30 days PTD of V114 or Prevenar 13™
- Objective: To compare anti-rotavirus 
immunoglobulin A (IgA) geometric mean 
titers (GMTs) at 30 days after the completion 
of the primary series (Postdose 2 for 
full-term infants; Postdose 3 for preterm 
infants) for participants administered V114 
concomitantly with Rotarix™ versus 
participants administered Prevenar 13™ 
concomitantly with Rotarix™.
Hypothesis (H6): Rotarix™ administered 
concomitantly with V114 is non-inferior to 
Rotarix™ administered concomitantly with 
Prevenar 13™ based on GMTs at 30 days 
after the completion of the primary series.
- Anti-rotavirus IgA response at 30 days post 
primary series (PPS) of V114 or 
Prevenar 13™
- Objective: To evaluate the anti-PnPs 
serotype-specific IgG response rates and 
GMCs at 30 days after the completion of the 
primary series by each vaccination group.
- Anti-PnP serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
30 days PPS
 
 
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PRODUCT: V114  
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- Objective (OPA Subset): To evaluate the 
anti-PnPs serotype-specific 
opsonophagocytic activity (OPA) GMTs and 
response rate at 30 days following the toddler 
dose by each vaccination group.
- Anti-PnPs serotype-specific OPA responses 
for the 15 serotypes contained in V114 at 
30 days PTD
- Objective: To evaluate the anti-PnPs 
serotype-specific IgG response rates to the 
2 unique serotypes in V114 compared with 
the lowest IgG response rate in any of 
13 shared serotypes in Prevenar 13™ at 
30 days following the toddler dose.
- Anti-PnPs serotype-specific IgG responses 
for the 2 unique serotypes contained in V114 
at 30 days PTD
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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Number of Participants:
Approximately 1180 participants will be randomized, with approximately 590 in each 
intervention group.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination 
Regimen a
Use
V114
V114
Refer to 
IB
3 doses
IM
Single dose at 
Visits 1, 3, and 5 
(~2, 4, and 11 to 
15 months of 
age, 
respectively)
Experimental
Prevenar 13™
Prevenar 13™
Refer to 
product 
labelling
3 doses
IM
Single dose at 
Visits 1, 3, and 5 
(~2, 4, and 11 to 
15 months of 
age, 
respectively)
Experimental
Admin. = administration; IB = Investigator’s Brochure; IM = intramuscular.
a Vaccination regimen specified in the table is for full-term infant participants. For preterm infant 
participants (<37 weeks gestational age), the vaccination regimen will be as follows: V114 or 
Prevenar 13™ will be administered at Visits 1, 2, 3, and 5 (~2, 3, 4, and 11 to 15 months of age, 
respectively). Preterm infants will not be enrolled at sites in the Russian Federation (Appendix 7).
Note: All participants will also receive other pediatric vaccines, including Rotarix™ and INFANRIX™ 
hexa, as part of the study design (Table 1 and Table 2). Tradenames for licensed vaccines may vary 
depending on where clinical supplies are sourced by the Sponsor. Rotarix™ will not be administered to 
participants enrolled at sites in the Russian Federation (Appendix 7).
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 14 to 20 months
from the time the participant’s legally acceptable representative signs the 
Informed Consent Form (ICF) through the final contact.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The study design is depicted in Figure 1.
The study design for participants enrolled at sites in the Russian Federation is provided in Figure 2 (Appendix 7).
Figure 1
V114-025 Study Design
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Intervention
Follow-
up
Comments
Visit Number
1 
TC
2
TC
3
TC
4
5
TC
6
TC
Scheduled Time
Age: ~2 
months
Day 15
after 
vaccination
Age: ~3 
months
Day 15 
after 
vaccination
Age: ~4 
months
Day 15 
after 
vaccination
~1 
month 
after 
primary 
series
Age: ~11 to 
15 months
Day 15 after
vaccination
~1 
month 
after 
toddler 
dose
~6 
months
after 
toddler 
dose
Months of age is 
calculated according to 
the participant’s birth 
date.
Visit Window a,b
≥42 days 
of age to 
≤90 days 
of age
Day 15 
to Day 
19 PD
3 months 
of age to 
1 day 
prior to 4 
months of 
age
Day 15 
to Day 
19 PD
4 months 
of age to 
1 day 
prior to 
5 months 
of age
Day 15 
to Day 
19 PD
Day 28 
to 
Day 60 
PPS
11 months 
of age to 
1 day prior 
to 
16 months 
of age
Day 15 to 
Day 19 
PTD
Day 28 
to 
Day 60 
PTD
Day 166 
to 
Day 194 
PTD
Administrative and General Procedures
Screening Procedures
Informed 
Consent/Assent
X
Consent must be 
obtained before any 
study procedures.
Informed 
Consent/Assent for 
Future Biomedical 
Research
X
Participation in future 
biomedical research is 
optional and consent 
must be obtained 
before collection of 
buccal swab DNA
samples.
Assignment of 
Screening Number
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Review of prior 
medications/
vaccinations, a 
complete physical 
examination, and 
temperature 
measurement are 
required at Visit 1 to 
determine eligibility.
 
 
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Study Period
Intervention
Follow-
up
Comments
Visit Number
1 
TC
2
TC
3
TC
4
5
TC
6
TC
Scheduled Time
Age: ~2 
months
Day 15
after 
vaccination
Age: ~3 
months
Day 15 
after 
vaccination
Age: ~4 
months
Day 15 
after 
vaccination
~1 
month 
after 
primary 
series
Age: ~11 to 
15 months
Day 15 after
vaccination
~1 
month 
after 
toddler 
dose
~6 
months
after 
toddler 
dose
Months of age is 
calculated according to 
the participant’s birth 
date.
Visit Window a,b
≥42 days 
of age to 
≤90 days 
of age
Day 15 
to Day 
19 PD
3 months 
of age to 
1 day 
prior to 4 
months of 
age
Day 15 
to Day 
19 PD
4 months 
of age to 
1 day 
prior to 
5 months 
of age
Day 15 
to Day 
19 PD
Day 28 
to 
Day 60 
PPS
11 months 
of age to 
1 day prior 
to 
16 months 
of age
Day 15 to 
Day 19 
PTD
Day 28 
to 
Day 60 
PTD
Day 166 
to 
Day 194 
PTD
Medical History 
X
Post-Randomization Procedures
Assignment of 
Randomization 
Number
X
Prior/Concomitant 
Medication and 
Nonstudy Vaccination 
Review
X
X
X
X
Preterm 
Infants 
Only c
X
X
X
X
X
X
V114 or Prevenar 
13™Administration 
(Blinded)
X
X
Preterm 
Infants 
Only c
X
X
Before vaccine 
administration, the 
investigator (or 
designee) must review 
medical history to 
ensure the participant 
has no new 
contraindication to the 
vaccine(s) scheduled 
to be given (see 
Section 8.1.8). 
 
 
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Study Period
Intervention
Follow-
up
Comments
Visit Number
1 
TC
2
TC
3
TC
4
5
TC
6
TC
Scheduled Time
Age: ~2 
months
Day 15
after 
vaccination
Age: ~3 
months
Day 15 
after 
vaccination
Age: ~4 
months
Day 15 
after 
vaccination
~1 
month 
after 
primary 
series
Age: ~11 to 
15 months
Day 15 after
vaccination
~1 
month 
after 
toddler 
dose
~6 
months
after 
toddler 
dose
Months of age is 
calculated according to 
the participant’s birth 
date.
Visit Window a,b
≥42 days 
of age to 
≤90 days 
of age
Day 15 
to Day 
19 PD
3 months 
of age to 
1 day 
prior to 4 
months of 
age
Day 15 
to Day 
19 PD
4 months 
of age to 
1 day 
prior to 
5 months 
of age
Day 15 
to Day 
19 PD
Day 28 
to 
Day 60 
PPS
11 months 
of age to 
1 day prior 
to 
16 months 
of age
Day 15 to 
Day 19 
PTD
Day 28 
to 
Day 60 
PTD
Day 166 
to 
Day 194 
PTD
Concomitant Vaccine 
Administration 
(Open-label) d
INFANRIX™
hexa
X
X
X
X
Before vaccine 
administration, the 
investigator (or 
designee) must review 
medical history to 
ensure the participant 
has no new 
contraindication to the 
vaccine(s) scheduled 
to be given (see 
Section 8.1.8). 
See Section 6.5 for 
details on concomitant 
vaccines. 
Rotarix™ is 
administered orally 
and should be given 
before V114 or 
Prevenar 13™ and 
other concomitant 
vaccines.
INFANRIX™ hexa
should be given after 
V114 or 
Prevenar 13™.
Concomitant Vaccine 
Administration 
(Open-label) d
Rotarix™e
X
X
 
 
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Study Period
Intervention
Follow-
up
Comments
Visit Number
1 
TC
2
TC
3
TC
4
5
TC
6
TC
Scheduled Time
Age: ~2 
months
Day 15
after 
vaccination
Age: ~3 
months
Day 15 
after 
vaccination
Age: ~4 
months
Day 15 
after 
vaccination
~1 
month 
after 
primary 
series
Age: ~11 to 
15 months
Day 15 after
vaccination
~1 
month 
after 
toddler 
dose
~6 
months
after 
toddler 
dose
Months of age is 
calculated according to 
the participant’s birth 
date.
Visit Window a,b
≥42 days 
of age to 
≤90 days 
of age
Day 15 
to Day 
19 PD
3 months 
of age to 
1 day 
prior to 4 
months of 
age
Day 15 
to Day 
19 PD
4 months 
of age to 
1 day 
prior to 
5 months 
of age
Day 15 
to Day 
19 PD
Day 28 
to 
Day 60 
PPS
11 months 
of age to 
1 day prior 
to 
16 months 
of age
Day 15 to 
Day 19 
PTD
Day 28 
to 
Day 60 
PTD
Day 166 
to 
Day 194 
PTD
Provide eVRC
X
An eVRC will be 
provided at Visit 1 to 
record AEs, body 
temperature, 
concomitant 
medications, and 
nonstudy vaccinations. 
Instructions for using 
the eVRC will be 
reviewed with the 
participant’s legally 
acceptable 
representative.
Review eVRC data 
with participant’s 
legally acceptable 
representative
X
X
X
Preterm 
Infants 
Only c
X
X
X
X
X
X
See Section 8.1.9 and 
Section 8.3.3 for 
details.
The participant’s 
legally acceptable 
representative will 
complete the eVRC 
only after visits when 
V114 or Prevenar 13™ 
are administered.
Collect eVRC from 
participant’s legally 
acceptable 
representative
X
 
 
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Study Period
Intervention
Follow-
up
Comments
Visit Number
1 
TC
2
TC
3
TC
4
5
TC
6
TC
Scheduled Time
Age: ~2 
months
Day 15
after 
vaccination
Age: ~3 
months
Day 15 
after 
vaccination
Age: ~4 
months
Day 15 
after 
vaccination
~1 
month 
after 
primary 
series
Age: ~11 to 
15 months
Day 15 after
vaccination
~1 
month 
after 
toddler 
dose
~6 
months
after 
toddler 
dose
Months of age is 
calculated according to 
the participant’s birth 
date.
Visit Window a,b
≥42 days 
of age to 
≤90 days 
of age
Day 15 
to Day 
19 PD
3 months 
of age to 
1 day 
prior to 4 
months of 
age
Day 15 
to Day 
19 PD
4 months 
of age to 
1 day 
prior to 
5 months 
of age
Day 15 
to Day 
19 PD
Day 28 
to 
Day 60 
PPS
11 months 
of age to 
1 day prior 
to 
16 months 
of age
Day 15 to 
Day 19 
PTD
Day 28 
to 
Day 60 
PTD
Day 166 
to 
Day 194 
PTD
Complete the 
Telephone Contact 
Questionnaire
X
See Section 8.1.11 for 
details.
Safety Procedures
Complete Physical 
Examination
X
To be performed by 
the investigator or 
medically qualified 
designee to determine 
study eligibility at 
screening and before 
vaccine is 
administered (see
Section 8.3.1).
Targeted Physical 
Examination
X
X
X
To be performed by 
the investigator or 
medically qualified 
designee before 
vaccine is 
administered (see 
Section 8.3.1).
 
 
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Study Period
Intervention
Follow-
up
Comments
Visit Number
1 
TC
2
TC
3
TC
4
5
TC
6
TC
Scheduled Time
Age: ~2 
months
Day 15
after 
vaccination
Age: ~3 
months
Day 15 
after 
vaccination
Age: ~4 
months
Day 15 
after 
vaccination
~1 
month 
after 
primary 
series
Age: ~11 to 
15 months
Day 15 after
vaccination
~1 
month 
after 
toddler 
dose
~6 
months
after 
toddler 
dose
Months of age is 
calculated according to 
the participant’s birth 
date.
Visit Window a,b
≥42 days 
of age to 
≤90 days 
of age
Day 15 
to Day 
19 PD
3 months 
of age to 
1 day 
prior to 4 
months of 
age
Day 15 
to Day 
19 PD
4 months 
of age to 
1 day 
prior to 
5 months 
of age
Day 15 
to Day 
19 PD
Day 28 
to 
Day 60 
PPS
11 months 
of age to 
1 day prior 
to 
16 months 
of age
Day 15 to 
Day 19 
PTD
Day 28 
to 
Day 60 
PTD
Day 166 
to 
Day 194 
PTD
Body Temperature 
Measurement
X
X
X
X
Each participant’s 
body temperature must 
be taken before 
vaccination (see 
Section 8.3.2 for 
method). Participants 
who have febrile 
illness at or within 
72 hours of 
vaccination must be 
rescheduled.
30-minute 
Postvaccination 
Observation Period
X
X
X
X
To be performed by 
blinded study site 
personnel only.
AE Monitoring
X
X
X
X
Preterm 
Infants 
Only c
X
X
X
X
X
X
X
Nonserious AEs are to 
be reported from 
Days 1 through 14 
following each 
vaccination with V114
or Prevenar 13™. 
SAEs and deaths are to 
be reported throughout 
the duration of an 
individual’s study 
participation.
 
 
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Study Period
Intervention
Follow-
up
Comments
Visit Number
1 
TC
2
TC
3
TC
4
5
TC
6
TC
Scheduled Time
Age: ~2 
months
Day 15
after 
vaccination
Age: ~3 
months
Day 15 
after 
vaccination
Age: ~4 
months
Day 15 
after 
vaccination
~1 
month 
after 
primary 
series
Age: ~11 to 
15 months
Day 15 after
vaccination
~1 
month 
after 
toddler 
dose
~6 
months
after 
toddler 
dose
Months of age is 
calculated according to 
the participant’s birth 
date.
Visit Window a,b
≥42 days 
of age to 
≤90 days 
of age
Day 15 
to Day 
19 PD
3 months 
of age to 
1 day 
prior to 4 
months of 
age
Day 15 
to Day 
19 PD
4 months 
of age to 
1 day 
prior to 
5 months 
of age
Day 15 
to Day 
19 PD
Day 28 
to 
Day 60 
PPS
11 months 
of age to 
1 day prior 
to 
16 months 
of age
Day 15 to 
Day 19 
PTD
Day 28 
to 
Day 60 
PTD
Day 166 
to 
Day 194 
PTD
Immunogenicity Procedures
Serum for 
Immunogenicity 
Assays (Including 
Retention Serum)
X
X
X
Blood samples must be 
collected before 
vaccination where 
applicable.
Future Biomedical Research
Collect Buccal Swabs 
for Future Biomedical 
Research
X
Buccal swab DNA 
samples for analysis 
should be obtained 
prior to vaccination at 
Visit 1, on randomized 
and FBR consented 
participants only, or at 
a later date as soon as 
the informed consent 
is obtained.
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic vaccination report card; FBR = Future Biomedical Research; PD = postdose; PPS = post primary series; 
PTD = post toddler dose; SAE = serious adverse event; TC = telephone contact.
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
A minimum of 28 days is required between vaccine doses, in addition to complying with age and visit window requirements described above.
c
Preterm infants will not be enrolled at sites in the Russian Federation (Appendix 7).
d
Tradenames for licensed vaccines may vary depending on where clinical supplies are sourced by the Sponsor.
e
Rotarix™ will not be administered to participants enrolled at sites in the Russian Federation (Appendix 7).
 
 
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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 
Prevenar 13™ (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein], 
Wyeth Pharmaceuticals, a subsidiary of Pfizer, Inc., Philadelphia, PA), plus 2 additional 
serotypes (22F, 33F).
2.1
Study Rationale
Routine PCV immunization of children is effective in preventing vaccine serotype-specific 
pneumococcal disease. Despite the availability of PCVs, pneumococcal disease remains a 
concern as non-vaccine serotypes have emerged in increasing frequency in invasive 
pneumococcal disease (IPD) isolates. Given the high morbidity and mortality of IPD 
worldwide, the evolving serotype distribution, and the value of multiple suppliers to 
strengthen global supply, there is a continued need to develop new PCVs with expanded 
serotype coverage. V114 includes an additional 2 key serotypes compared with 
Prevenar 13™ and will address an unmet medical and public health need for a PCV with 
expanded coverage.
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 Prevenar 13™ 
and the 2 additional serotypes (22F and 33F) in V114.
The purpose of this clinical study is to evaluate the safety and immunogenicity of a PCV 
3-dose schedule (2-dose primary series followed by a toddler dose) in full-term infants, and a 
4-dose schedule (3-dose primary series followed by a toddler dose) in preterm infants as 
currently recommended by the World Health Organization (WHO) Strategic Advisory Group 
of Experts (SAGE) on Immunizations and practiced in many countries including those in the 
European Union (EU). Country-specific routine immunization regimens vary by schedule 
and number of doses. In this study, full-term infant participants will be given 3 doses of 
V114 or Prevenar 13™ at approximately 2, 4, and 11 to 15 months of age; preterm infant 
participants will be given 4 doses of V114 or Prevenar 13™ at approximately 2, 3, 4, and 
11 to 15 months of age. Preterm infants will not be enrolled at sites in the Russian Federation
(Appendix 7).
In most countries, it is recommended that PCVs are to be given at the same time as other 
recommended pediatric vaccines. The concomitant administration of V114 with 
recommended pediatric vaccines will be evaluated as part of the Phase 3 pediatric clinical 
program. This study will evaluate the concomitant administration of V114 and the following 
pediatric vaccines: INFANRIX™hexa and Rotarix™. Rotarix™ will not be administered to 
participants enrolled at sites in the Russian Federation (Appendix 7). In addition to 
 
 
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concomitant vaccines being provided in the study, other nonstudy pediatric vaccines may be 
permitted according to local, regional, and/or country guidelines (Section 6.5).
Countries participating in this study must follow the vaccination schedule being evaluated in 
the study with respect to PCV and the concomitant vaccines.
2.2
Background
2.2.1
V114 and Pneumococcal Disease
Refer to the Investigator’s Brochure (IB) for detailed background information on V114,
including information on pneumococcal disease burden.
Streptococcus pneumoniae remains a significant cause of disease worldwide, with clinical 
manifestations including meningitis, sepsis, pneumonia, sinusitis and otitis media. Currently, 
many countries worldwide have incorporated licensed PCVs (eg, Prevenar 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 Prevenar 13™ in 2009 (EU) and 
Prevnar 13™in 2010 (United States, US). Synflorix™ was licensed in the EU in 2009. 
Although Prevenar 13™ is indicated for children and adults; Synflorix™ is only indicated for 
children up to 5 years of age. Widespread use of PCVs has 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 Prevenar 13™ plus 2 additional 
serotypes (22F and 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 Prevenar™ and 
Prevenar 13™. Approximately 4 years after inclusion of Prevenar™ in the US infant 
immunization schedule, serotypes 22F and 33F accounted for approximately 13% of IPD 
cases in children <5 years of age (incidence rate of IPD due to 22F and 33F combined of 
3.1 cases per 100,000 person-years), in contrast to 1.3% of IPD cases in the pre-PCV7 era 
(incidence rate of 22F and 33F IPD of 1.2 cases per 100,000 person-years) [Hicks, L. A., et 
al 2007]. By 2013, both 22F and 33F were among the leading serotypes causing IPD beyond 
those already included in Prevenar 13™, accounting for approximately 21% of all IPD in 
children <5 years of age in the US [Moore, M. R., et al 2015]. Data from 2014 reported in the 
2016 annual epidemiological report on IPD by the European Centre for Disease Prevention 
and Control showed that both serotypes 22F and 33F are among the most common serotypes 
causing IPD [European Centre for Disease Prevention and Control 2016]. In a systematic 
review and meta-analysis of serotype distribution of S pneumoniae causing invasive disease 
 
 
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in children conducted across geographical regions, including Europe, serotypes 22F and 33F 
were identified among the overall predominant non-Prevenar 13™serotype [Balsells, E., et 
al 2017].
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 Prevenar 13™ and other 
licensed pediatric vaccines administered concomitantly.
Prevenar 13™ contains the 7 pneumococcal serotypes included in Prevenar™ (4, 6B, 9V, 14, 
18C, 19F, and 23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A).
Prevenar™ and Prevenar 13™ are also known as Prevnar™ and Prevnar 13™ in the US; 
these vaccines will be referred to as Prevenar™ and Prevenar 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 effectiveness of an investigational medicine.
Approximately 50% of participants will receive Prevenar 13™, the standard of care, as the 
active comparator in this study. V114 is expected to provide comparable immune responses 
and a comparable safety profile to Prevenar 13™ for the shared pneumococcal serotypes 
while providing additional coverage for the 2 serotypes (22F and 33F) unique to V114. It is 
unknown if the investigational V114 will have the same benefit/risk profile as Prevenar 13™.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
 
 
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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 
Prevenar 13™. The statistical criteria for the primary hypotheses are provided in the table 
below and for the secondary hypotheses can be found in Section 9.9.1 (Table 8). Information 
on safety and immunogenicity endpoints and planned statistical analyses for participants 
enrolled at sites in the Russian Federation can be found in Appendix 7.
Objectives
Endpoints
Primary
•
Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
Following any vaccination with V114:
•
Solicited injection-site AEs from Day 1 
through Day 14 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 14 postvaccination
•
Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation
•
Objective: To compare the 
anti-pneumococcal polysaccharide 
(PnPs) serotype-specific 
Immunoglobulin G (IgG) response rates 
(proportion of participants meeting 
serotype-specific IgG threshold value of 
≥0.35 μg/mL) at 30 days following the 
toddler dose (Postdose 3 for full-term 
infants; Postdose 4 for preterm infants) 
for participants administered V114 
versus participants administered 
Prevenar 13™.
Hypothesis (H1): V114 is non-inferior 
to Prevenar 13™ for the 13 shared 
serotypes between V114 and 
Prevenar 13™ based on response rates
at 30 days following the toddler dose.
(The statistical criterion for 
non-inferiority requires the lower bound 
of the 2-sided 95% CI for the difference 
in responses rates [V114 minus 
Prevenar 13™] to be greater than -0.1).
•
Anti-PnPs serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
30 days following the toddler dose (PTD)
 
 
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Objectives
Endpoints
Hypothesis (H2): V114 is superior to 
Prevenar 13™ for the 2 serotypes 
unique to V114 based on the response 
rates at 30 days following the toddler 
dose.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 
95% CI for the difference in responses 
rates [V114 minus Prevenar 13™] to be 
greater than 0.1).
•
Objective: To compare anti-PnPs 
serotype-specific IgG geometric mean 
concentrations (GMCs) at 30 days 
following the toddler dose for 
participants administered V114 versus 
participants administered 
Prevenar 13™.
Hypothesis (H3): V114 is non-inferior 
to Prevenar 13™ for the 13 shared 
serotypes between V114 and 
Prevenar 13™ based on anti-PnPs 
serotype-specific IgG GMCs at 30 days 
following the toddler dose.
(The statistical criterion for 
non-inferiority requires the lower bound 
of the 2-sided 95% CI for anti-PnPs 
serotype-specific IgG GMC ratio 
[V114/ Prevenar 13™] to be greater 
than 0.5.)
Hypothesis (H4): V114 is superior to 
Prevenar 13™ for the 2 serotypes 
unique to V114 based on anti-PnPs 
serotype-specific IgG GMCs at 30 days 
following the toddler dose.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 
95% CI for anti-PnPs serotype-specific 
IgG GMC ratio [V114/ Prevenar 13™]
to be greater than 2.0.)
•
Anti-PnPs serotype-specific IgG responses
for the 15 serotypes contained in V114 at 
30 days PTD
 
 
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Objectives
Endpoints
Secondary
•
Objective: To compare the 
antigen-specific response rate to each 
antigen included in INFANRIX™ hexa 
at 30 days following the toddler dose 
for participants administered V114 
concomitantly with INFANRIX™ hexa 
versus participants administered 
Prevenar 13™ concomitantly with 
INFANRIX™ hexa.
Hypothesis (H5): INFANRIX™ hexa 
administered concomitantly with V114 
is non-inferior to INFANRIX™ hexa 
administered concomitantly with 
Prevenar 13™ at 30 days following the 
toddler dose for each antigen included 
in INFANRIX™ hexa.
Antibody responses to:
•
diphtheria toxoid
•
tetanus toxoid
•
pertussis toxin (PT)
•
pertussis filamentous hemagglutinin 
(FHA)
•
pertussis pertactin (PRN)
• Haemophilus influenzae type b 
polyribosylribitol phosphate (Hib-PRP)
•
hepatitis B surface antigen (HBsAg)
•
poliovirus serotypes 1, 2, and 3
at 30 days PTD of V114 or Prevenar 13™
•
Objective: To compare anti-rotavirus 
immunoglobulin A (IgA) geometric 
mean titers (GMTs) at 30 days after the 
completion of the primary series
(Postdose 2 for full-term infants; 
Postdose 3 for preterm infants) for 
participants administered V114 
concomitantly with Rotarix™ versus 
participants administered Prevenar 13™ 
concomitantly with Rotarix™.
Hypothesis (H6): Rotarix™ 
administered concomitantly with V114 
is non-inferior to Rotarix™ 
administered concomitantly with 
Prevenar 13™ based on GMTs at 
30 days after the completion of the 
primary series.
•
Anti-rotavirus IgA response at 30 days post 
primary series (PPS) of V114 or 
Prevenar 13™
•
Objective: To evaluate the anti-PnPs 
serotype-specific IgG response rates 
and GMCs at 30 days after the 
completion of the primary series by 
each vaccination group.
•
Anti-PnP serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
30 days PPS
 
 
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Objectives
Endpoints
•
Objective (OPA Subset): To evaluate 
the anti-PnPs serotype-specific 
opsonophagocytic activity (OPA) 
GMTs and response rate at 30 days 
following the toddler dose by each 
vaccination group.
•
Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes contained in 
V114 at 30 days PTD
•
Objective: To evaluate the anti-PnPs 
serotype-specific IgG response rates to 
the 2 unique serotypes in V114 
compared with the lowest IgG response 
rate in any of 13 shared serotypes in 
Prevenar 13™ at 30 days following the 
toddler dose.
•
Anti-PnPs serotype-specific IgG responses 
for the 2 unique serotypes contained in 
V114 at 30 days PTD
Tertiary/Exploratory
•
Objective: To evaluate the anti PnPs 
serotype specific IgG GMCs 
immediately prior to the toddler dose by 
each vaccination group.
•
Anti-PnP serotype-specific IgG responses 
for the 15 serotypes contained in V114 
immediately prior to the toddler dose 
(Pretoddler Dose)
•
Objective: To evaluate the antigen-
specific response rate to each antigen 
included in INFANRIX™ hexa at 
30 days after the completion of the 
primary series for participants
administered V114 concomitantly with 
INFANRIX™ hexa versus participants 
administered Prevenar 13™ 
concomitantly with INFANRIX™ 
hexa.
Antibody responses to:
•
diphtheria toxoid 
•
tetanus toxoid 
•
PT
•
FHA
•
PRN
•
Hib-PRP
•
HBsAg
•
poliovirus serotypes 1, 2, and 3
at 30 days PPS of V114 or Prevenar 13™
•
Objective (OPA Subset): To evaluate 
the anti-PnPs serotype-specific OPA 
GMTs and response rate at 30 days 
after the completion of the primary 
series and immediately prior to the 
toddler dose by each vaccination group.
•
Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes contained in 
V114 at 30 days PPS and Pretoddler Dose
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multi-site, double-blind
(with in-house blinding) study of V114 in healthy infants enrolled at approximately 2 months 
of age (from 42 to 90 days [inclusive]). Randomization will be stratified according to the 
gestational age (≥37 weeks or <37 weeks). Approximately 1180 healthy infant participants 
will be randomly assigned, in a 1:1 ratio, to receive either V114 (590 participants) or 
Prevenar 13™ (590 participants). It is estimated that approximately 15 preterm infants
(<37 weeks gestational age) will be enrolled in this study. Preterm infants will not be 
enrolled at sites in the Russian Federation (Appendix 7).
A 0.5-mL intramuscular dose of V114 or Prevenar 13™will be administered (blinded) to 
healthy full-term infants at approximately 2, 4, and 11 to 15 months of age and administered 
to healthy preterm infants at approximately 2, 3, 4, and 11 to 15 months of age. All 
participants will also be administered concomitant pediatric vaccines (ie, INFANRIX™ hexa
and Rotarix™) during the study (Section 1.3). Rotarix™ will not be administered to 
participants enrolled at sites in the Russian Federation (Appendix 7). These vaccines will be
administered open label.
Participants will be followed for injection-site and systemic AEs through Day 14 following 
each vaccination with V114 or Prevenar 13™. Information for SAEs and deaths, regardless 
of whether the events are considered vaccine related by the investigator, will be collected 
from the time consent is signed through completion of participation in the study. 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 and function of
the DMC, along with the timing and content of the safety reviews, will be outlined in the 
DMC charter. Information regarding the composition of the DMC is provided in Appendix 1.
Blood samples (approximately 5 mL) for immunogenicity assays will be drawn at 3 time 
points: (1) 30 days after the completion of the primary series of V114 or Prevenar 13™(PPS; 
Postdose 2 for full-term infants; Postdose 3 for preterm infants), (2) immediately prior to the 
toddler dose of V114 or Prevenar 13™administered at Visit 5 (Pretoddler Dose), and 
(3) 30 days following the toddler dose of V114 or Prevenar 13™(PTD; Postdose 3 for 
full-term infants; Postdose 4 for preterm infants).
After completion of immunogenicity testing to evaluate the study objectives and hypotheses,
serum samples will be stored to conduct any additional study-related testing as required by 
regulatory agencies or the Sponsor. For randomized study participants who provided consent 
for Future Biomedical Research, leftover sera from the study may be used for other purposes,
such as the development and/or validation of pneumococcal assays after completion of all 
study-related immunogenicity testing.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
 
 
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4.2
Scientific Rationale for Study Design
This study will be conducted in healthy infants approximately 2 months of age (42 to 90 days 
of age) at enrollment. These infants are at increased risk for pneumococcal disease and its 
associated morbidity and mortality [Drijkoningen, J. J 2014]. The study will assess safety, 
tolerability, and immunogenicity of the PCV vaccination schedule (2+1 for full-term infant 
participants and 3+1 for preterm infant participants) and concomitant use with other pediatric 
vaccines recommended in many countries worldwide. These vaccination schedules are 
currently recommended by the WHO SAGE on Immunizations and practiced in many 
countries, including those in the EU. The immune response to INFANRIX™hexa and
Rotarix™when administered concomitantly with V114 will also be evaluated in this study.
Rotarix™ will not be administered to participants enrolled at sites in the Russian Federation
(Appendix 7).
The study allows enrollment of children who were born preterm (<37 weeks gestational age). 
To ensure a balanced distribution of preterm infants across the vaccination groups, 
enrollment will be stratified by gestational age. Preterm infants will not be enrolled at sites in
the Russian Federation (Appendix 7).
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints are consistent with previous studies evaluating PCVs and the 
concomitantly administered pediatric vaccines in this study.
The pneumococcal electrochemiluminescence (PnECL) assay and the multiplexed 
opsonophagocytic assay (MOPA) will be used to measure vaccine-induced, anti-PnPs 
serotype-specific immune responses for all 15 serotypes included in V114. PnECL measures 
serotype-specific IgG concentrations (primary endpoint based on GMCs), and MOPA
measures serotype-specific OPA titers (secondary endpoint based on GMTs). OPA GMTs 
represent functional antibodies capable of inhibiting growth of S pneumoniae in culture. 
Additional information on the immunogenicity assays can be found in Section 8.2.
Several studies have shown a positive correlation between serotype-specific IgG antibody 
concentrations and OPA titers in children and adults [Centers for Disease Control and 
Prevention 2010] [Anttila, M., et al 1999] [Romero-Steiner, S., et al 1997]. Since the MOPA 
requires more serum than the PnECL assay, the PnECL will be used to test the primary 
immunogenicity hypotheses in this study
The use of the serotype-specific IgG antibody level of ≥0.35 µg/mL has been recommended 
by a WHO expert panel as an acceptable threshold value for evaluating the clinical 
performance of PCVs following a routine childhood vaccination regimen [World Health 
Organization 2008] [World Health Organization 2005]. The response rate (ie, the proportion 
of participants meeting the serotype-specific IgG threshold value of ≥0.35 μg/mL) is a
primary endpoint in this study.
 
 
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Anti-PnPs serotype-specific IgG and OPA responses will be measured at 3 time points:
•
Approximately 30 days following the primary series to evaluate the immune response to 
the primary vaccination series (IgG GMCs, IgG response rates, OPA GMTs, and OPA 
response rates) 
•
Immediately prior to the toddler dose to evaluate the persistence of protective immunity 
(IgG GMCs, OPA GMTs, and OPA response rates) 
•
Approximately 30 days following the toddler dose to evaluate anamnestic antibody 
responses (IgG GMCs, Ig G response rates, OPA GMTs, and OPA response rates) 
Measurement at 30 days following the toddler dose (PTD) was selected for the primary 
endpoint, as the PTD is considered the completion of the PCV series, where immune memory 
is boosted.
Due to the larger serum requirements of the MOPA assay, functional antibody activity (as 
measured by the OPA GMTs) will be assessed in the first 20% of all participants with 
sufficient serum volume at PPS to evaluate OPA responses (OPA Subset). Additionally, 
evaluation of OPA responses will be conducted at the Pretoddler Dose and PTD for all 
participants who had OPA performed at PPS and for whom there is sufficient volume.
In addition, sera from study participants will be used to measure the immune responses to the 
following antigens contained in the pediatric vaccines administered concomitantly with either 
V114 or Prevenar 13™:
•
Diphtheria toxoid, tetanus toxoid, pertussis (PT, FHA, and PRN), PRP-Hib, HBsAg, 
poliovirus (serotypes 1, 2, and 3), and rotavirus at 30 days PPS
•
Diphtheria toxoid, tetanus toxoid, pertussis (PT, FHA, and PRN), PRP-Hib, HBsAg, and 
poliovirus (serotypes 1, 2, and 3) at 30 days PTD
The endpoints used to evaluate the immune responses to the concomitantly administered 
pediatric vaccines are consistent with established protective and acceptable antibody levels 
[Plotkin, S. A. 2010] [Andrews, Nick, et al 2003]. For rotavirus and pertussis, there are no
benchmark antibody concentrations that are widely accepted as correlates of protection.
Following rotavirus vaccination, IgA GMT ratios are used because of the correlation between 
serum anti-rotavirus and protective immunity at the population level [Liu, G. F., et al 2017]. 
For pertussis, the pertussis antigen endpoints are based on previously published standards
that are also above assay lower limit of quantitation [Edwards, K. M. 2014].
Rotarix™ will not be administered to participants enrolled at sites in the Russian Federation;
therefore, the evaluation of concomitant administration of PCV and rotavirus vaccine will not 
be conducted in these participants (Appendix 7).
 
 
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Results from clinical studies with Prevenar 13™indicate that Prevenar 13™can be 
administered concomitantly with the pediatric vaccines being administered in this study
[Bryant, K. A., et al 2013]. Interference between V114 and these vaccines is not anticipated.
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in previous studies, published data from marketed PCVs, and guidance
from regulatory agencies during product development. Data from this study will also 
contribute to the overall safety database of V114 to support initial licensure in infants. 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 (FDA) Guidance for Industry: Patient-Reported Outcome Measures 
[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
Placebo-controlled clinical studies for new PCVs are no longer acceptable given the proven 
clinical efficacy, public health impact, and widespread use of licensed PCVs worldwide. 
Prevenar 13™ is currently the 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 Prevenar 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 
Prevenar 13™. Refer to the V114 IB for details on dosing schedule.
This study will support initial licensure of V114 in countries that use the approved 2+1 
Prevenar 13™ dosing schedule (2 doses in infant primary series followed by 1 toddler dose)
for full-term infants and 3+1 Prevenar 13™dosing schedule (3 doses in infant primary series 
followed by 1 toddler dose) for preterm infants (<37 weeks gestational age).These schedules 
have also been recommended by WHO SAGE on Immunizations and implemented in many 
countries, including those in the EU.
4.4
Beginning and End of Study Definition
The overall study begins when written informed consent is provided for the first participant. 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy male and female infants approximately 2 months of age, from 42 to 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
A participant will be eligible for inclusion in the study if the participant:
1. Is healthy (based on review of medical history and physical examination) based on the 
clinical judgement of the investigator.
 
 
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Demographics
2. Is male or female, approximately 2 months of age, from 42 days to 90 days inclusive, at 
the time of signing the informed consent.
Informed Consent
3. Has a legally acceptable representative who understands the study procedures, alternate 
treatments available, and risks involved with the study and voluntarily agrees to 
participate by giving written informed consent. The legally acceptable representative may 
also provide consent for future biomedical research. However, the participant may 
participate in the main study without participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or other 
sterile site) or known history of other culture positive pneumococcal disease.
2. Has a known hypersensitivity to any component of the PCV, any component of the 
licensed pediatric vaccines to be administered concomitantly in the study, or any 
diphtheria toxoid-containing vaccine.
3. Has any contraindication to the concomitant study vaccines being administered in the 
study (concomitant vaccine contraindication details provided in the Investigator Trial File 
Binder).
4. *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.
5. Has a known or suspected impairment of immunological function.
6. Has a history of congenital or acquired immunodeficiency.
7. Has, or his/her mother has, a documented human immunodeficiency virus (HIV) 
infection.
8. Has, or his/her mother has, a documented hepatitis B surface antigen – positive test.
9. Has known or history of functional or anatomic asplenia.
10. Has failure to thrive based on the clinical judgement of the investigator.
11. Has a bleeding disorder contraindicating intramuscular vaccination.
 
 
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12. 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).
13. Has a known neurologic or cognitive behavioral disorder, including encephalitis/myelitis, 
acute disseminating encephalomyelitis, pervasive development disorder, and related 
disorders.
Prior/Concomitant Therapy
14. Has received a dose of any pneumococcal vaccine prior to study entry.
15. Has received >1 dose of monovalent hepatitis B vaccine or hepatitis B-based combination 
vaccine prior to study entry.
16. Has received a dose of any acellular pertussis- or whole cell pertussis-based combination 
vaccines, Haemophilus influenzae type b conjugate vaccine, poliovirus vaccine, rotavirus 
vaccine, or any other combination thereof, prior to study entry. Note: Prior receipt of 
rotavirus vaccine is not exclusionary for participants enrolled at sites in the Russian 
Federation.
17. *Meets one or more of the following systemic corticosteroid exclusion criteria:
a.
Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/day for persons weighing >10 kg) for ≥14 consecutive days 
and has not completed this course of treatment at least 30 days prior to the first dose 
of study vaccine at randomization.
b. Has received or is expected to receive systemic corticosteroids within 14 days prior to 
any dose of study vaccine.
c.
Is expected to require systemic corticosteroids within 30 days after any study 
vaccination during conduct of the study.
Note: Topical, ophthalmic, and inhaled steroids are permitted.
18. *Has received other licensed non-live vaccines within 14 days before receipt of the first 
dose of study vaccines.
19. *Has received a licensed live vaccine within 30 days before receipt of the first dose of 
study vaccines.
20. Has received a blood transfusion or blood products, including immunoglobulins.
 
 
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Prior/Concurrent Clinical Study Experience
21. 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
22. 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.
23. Is or has an immediate family member (eg, parent/legal guardian or sibling) who is 
investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants whose legally acceptable representative provides
consent to participate in the clinical study, but are not subsequently randomized in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the 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, Prevenar 13™, and concomitant vaccines listed in Table 2) will be 
packaged to support enrollment. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
 
 
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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 a
Use
IMP/
NIMP
Sourcing
V114
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension
Refer to IB
0.5 mL
IM
Single dose at 
Visits 1, 3, 
and 5
Experimental
IMP
Central
V114
Experimental
Rotarix™ b
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
1.5 mL
Oral
Single dose at 
Visits 1 and 3
Experimental
IMP
Central
V114
Experimental
INFANRIX™ 
hexa
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single dose at 
Visits 1, 2, 3,
and 5
Experimental
IMP
Central
Prevenar 
13™
Active 
Comparator
Prevenar 13™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single dose at 
Visits 1, 3, 
and 5
Experimental
IMP
Central
Prevenar 
13™
Active 
Comparator
Rotarix™ b
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
1.5 mL
Oral
Single dose at 
Visits 1 and 3
Experimental
IMP
Central
Prevenar 
13™
Active 
Comparator
INFANRIX™ 
hexa
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single dose at 
Visits 1, 2, 3,
and 5
Experimental
IMP
Central
Admin. = administration; IB = Investigator’s Brochure; IM = intramuscular; IMP = investigational medicinal product; NIMP = non-investigational medicinal product.
Definition of IMP and 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.
a
Vaccination regimen specified in the table is for full-term infant participants. For preterm infant participants (<37 weeks gestational age), the vaccination regimen will be as 
follows: V114 or Prevenar 13™ will be administered at Visits 1, 2, 3, and 5.
b
Rotarix™ will not be administered to participants enrolled at sites in the Russian Federation (Appendix 7).
 
 
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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. Information on preparation and administration of 
study vaccines is provided in Section 6.3.3 and Section 8.1.8.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to V114 study intervention or Prevenar 13™.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
•
Gestational age <37 weeks (yes/no)
Preterm infants will not be enrolled at sites in the Russian Federation; therefore, there will be 
no stratification for these participants (Appendix 7).
Stratification will be monitored by IRT.
6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevenar 13™ will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study site personnel. The 
participant and the investigator who are involved in the clinical evaluation of the participants 
will remain blinded to the group assignments.
Because V114 and Prevenar 13™ have a different appearance, a member of the study site 
staff will be unblinded for the purposes of receiving, maintaining, preparing, and 
administering these study vaccines. The pediatric vaccines being provided in the study 
(ie, Rotarix™and INFANRIX™ hexa) will also be prepared and administered by unblinded 
study site staff for consistency even though these vaccines are being provided open label for 
this study. Rotarix™ will not be provided to clinical study sites in the Russian Federation or 
administered to participants enrolled at sites in the Russian Federation (Appendix 7).
Procedures for handling, preparing, and administering the unblinded vaccines are in the 
Investigator Trial File Binder.
To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel will not be present in the examination room when study vaccines are administered. 
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 
 
 
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directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified plan for V114, Prevenar 13™, and all concomitant
vaccinations, as indicated in Section 1.3, require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the study (see Section 5.2 for details). Although there are restrictions on licensed 
vaccines in the Exclusion Criteria before administration of the first dose of study vaccines, 
other nonstudy pediatric vaccines (such as measles, mumps, rubella, varicella, and influenza 
vaccines) are permitted during the study according to local, regional, and/or country 
guidelines. 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 prohibited steroid regimen, immunoglobulin, 
blood, or blood products during a subject's participation in this study, one of the individuals 
listed on the Sponsor Contact Information page must be notified as soon as possible. Any 
concurrent medication or medical treatment must be recorded on the appropriate electronic 
case report form (eCRF). It is important to record the use of any analgesic or antipyretic 
medication that occurs on the day of vaccination on the eVRC and appropriate eCRF.
All participants will receive licensed pediatric vaccines according to the recommended 
schedule (Table 2). Countries participating in this study must follow the vaccination schedule 
being evaluated in the study with respect to PCV and the concomitant vaccines.
Administration of meningococcal vaccine is permitted; however, administration of a 
meningococcal vaccine with a CRM197 or other diphtheria toxoid carrier protein (details 
provided in the Investigator Trial File Binder) should be given after the final blood draw of 
the study (Visit 6). Meningococcal B vaccine must not be given within 14 days before or 
after receipt of V114 or Prevenar 13™, or within 30 days before any scheduled blood draw. 
During influenza season, it is possible that participants 6 months of age and older could 
receive an inactivated influenza vaccine. Influenza vaccine should be administered at least
7 days prior to or at least 15 days after the administration of V114 or Prevenar 13™.
 
 
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If the participant is scheduled to receive any other nonstudy pediatric vaccine (except for 
measles, mumps, rubella, varicella, meningococcal, and influenza vaccines), the investigator 
should discuss this with the Sponsor Clinical Director as soon as possible. All nonstudy
vaccinations should be recorded on the appropriate eCRF.
Concomitant vaccines (oral or injectable) should be administered on the same day as V114 or
Prevenar 13™. Rotarix™ is administered orally and should be given before V114 or
Prevenar 13™ and other injectable concomitant vaccines. Precautions must be taken to 
prevent choking during the administration of oral vaccines. Rotarix™ will not be 
administered to participants enrolled at sites in the Russian Federation (Appendix 7). Other 
pediatric injectable vaccines administered concomitantly should be given after V114 or 
Prevenar 13™. To avoid any confounding results, concomitant injectable vaccines and other 
nonstudy pediatric vaccines should not be administered in the same limb as V114 or 
Prevenar 13™. Recommended injection-site locations for V114 or Prevenar 13™ and 
concomitant injectable vaccines being provided in the study are listed in Table 3.
Injection-site AEs for the licensed, concomitantly administered vaccines will not be 
collected.
No other investigational compound or device may be administered at any time during this 
study without prior approval by the Sponsor.
Table 2
Concomitant Vaccine Schedule 
Vaccine Tradename a
(Generic Name)
Indication
Visit 1
(~2 months 
of age)
Visit 2
(~3 months 
of age)
Visit 3
(~4 months 
of age)
Visit 5
(~11 to 
15 months 
of age)
Rotarix™b
(Rotavirus vaccine, live)
Prevention of 
rotavirus 
gastroenteritis
X
X
INFANRIX™ hexa
(Diphtheria, tetanus, 
pertussis (acellular, 
component), hepatitis B 
(rDNA), poliomyelitis 
(inactivated) and 
Haemophilus influenzae 
type b conjugate vaccine 
(adsorbed))
Prevention of 
diphtheria, tetanus, 
pertussis, hepatitis B,
poliomyelitis, and 
invasive disease due 
to Haemophilus 
influenzae type b
X
X
X
X
rDNA = ribosomal deoxyribonucleic acid.
a
Tradenames for licensed vaccines may vary depending on where clinical supplies are sourced by the Sponsor.
b
Rotarix™ is administered orally and should be given before V114 or Prevenar 13™ and other concomitant vaccines. 
INFANRIX™ hexa should be given after V114 or Prevenar 13™. Rotarix™ will not be administered to participants 
enrolled at sites in the Russian Federation (Appendix 7).
 
 
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Table 3
Recommended Injection-site Location for Study Interventions
Vaccine
Recommended Injection Site
V114 or Prevenar 13™
Right thigh
INFANRIX™ hexa
Left thigh
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 open label; therefore, an unblinded 
pharmacist or unblinded qualified study site personnel will be used to maintain the blinding 
of the study staff who are directly involved in the clinical evaluation of participants in the 
study. 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.
6.9
Standard Policies
Not applicable.
 
 
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccination 
regimen will still continue to participate in the study as specified in Section 1.3, unless the 
consent is withdrawn for the participant (Section 7.2). A participant may discontinue from 
study intervention (including receipt of V114, Prevenar 13™, and concomitant vaccines 
provided in the study) but continue to participate in the protocol-specified, AE-monitoring 
activities (see Section 8.12.3 for details).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.12 and 
Section 8.12.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant’s legally acceptable representative requests to discontinue study 
intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study vaccination.
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.
 
 
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant’s legally acceptable 
representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.12. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant’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 participant’s 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.
 
 
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant’s legally 
acceptable representative. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
Approximately 5 mL of blood will be drawn at each of Visits 4, 5, and 6 for immunogenicity 
assays. The maximum amount of blood collected from each participant over the duration of 
the study will not exceed approximately 15 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant’s legally acceptable 
representative prior to participating in a clinical study or future biomedical research.If there 
are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented on the consent form by the dated signature of the participant’s 
legally acceptable representative along with the dated signature of the person conducting the 
consent discussion. 
A copy of the signed and dated consent form should be given to the participant’s legally 
acceptable representative before the individual’s participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant’s legally acceptable representative must receive the Institutional Review 
Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable opinion in advance 
 
 
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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.
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 participation eligibility.
If the participant meets any of the Exclusion Criteria with and 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.
 
 
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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.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations and 
medications taken by the participant within 30 days before the first dose of study vaccine at 
Visit 1. The receipt of hepatitis B vaccine at birth must be reviewed and documented in the 
participant’s chart and recorded in the study database.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
If a medical condition requires the use of a 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.
The administration of pediatric vaccines listed in Table 2 will be recorded on the appropriate 
eCRF. To avoid any confounding results, concomitant injectable vaccines should not be 
administered in the same limb as V114 or Prevenar 13™. Documentation of which limb was 
used for the administration of V114 or Prevenar 13™ must be recorded on the eVRC 
(Section 8.3.3) and appropriate eCRF. Documentation of injection-site location for the 
concomitant injectable vaccines must be recorded on the 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.
 
 
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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.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Before each vaccine administration, the investigator (or designee) must review medical 
history to ensure that the participant has no new contraindication to the vaccine(s) scheduled 
to be given. This information should be documented in the participant’s chart. 
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer the study vaccine. Study vaccines should be 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 Prevenar 13™ as 
specified in the product label.
Study vaccines should be removed from the refrigerator no more than 1 hour before 
vaccination. The time of removal and time of vaccination should be documented in the 
participant’s chart. 
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.
Prevenar 13™ will be supplied as a pre-filled syringe.
 
 
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A 0.5-mL intramuscular dose of study vaccine will be administered to healthy full-term 
infants at approximately 2, 4, and 11 to 15 months of age and healthy preterm infants at 
approximately 2, 3, 4, and 11 to 15 months of age. The study vaccines are to be administered 
at the locations recommended in Table 3 (Section 6.5). Documentation of which limb was 
used for the administration of V114 or Prevenar 13™ should be recorded on the appropriate 
eCRF. This information should also be recorded on the eVRC to inform the participant’s 
legally acceptable representative of the appropriate limb to monitor for AEs related to the 
V114 or Prevenar 13™.
If an abnormality (ie, rash) is observed at the site where the previous dose of the study 
vaccine was administered, it is permissible to use the anterolateral muscle of the other limb to 
administer the following dose of the study vaccine. Adequate treatment provision, including 
epinephrine and equipment for maintaining an airway, should be available for immediate use 
should an anaphylactic or anaphylactoid reaction occur [Centers for Disease Control and 
Prevention 2015].
Unblinded study personnel should not have contact with participants for any study-related 
procedures/assessments after administration of study vaccines, which includes all safety 
follow-up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant or participant’s parent/guardian will be blinded to the 
study vaccine received by the participant. Vaccination information, such as Component 
Identification Number and time of vaccination, must be recorded on the appropriate eCRF as
per the data entry guidelines.
8.1.8.1
Timing of Dose Administration
V114 or Prevenar 13™ will be administered as indicated in Section 1.3. All participants will 
be observed for at least 30 minutes following each vaccination for any immediate reactions. 
This observation must be performed by blinded site personnel for V114 and Prevenar 13™ 
(Section 1.3 and Section 6.3.3).
Participants must be afebrile for at least 72 hours prior to vaccination (Section 1.3 and 
Section 8.3.2).
Blood samples must be collected before study vaccination.
8.1.9
Electronic Vaccination Report Card
The eVRC was developed to be administered electronically via a hand-held device. This item 
was structured as recommended in the final FDA Guidance for Industry: Patient-Reported 
Outcome Measures [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 
 
 
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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
Day 15 Postdose Telephone Contact Guide
Site personnel will contact the participant’s legally acceptable representative on Day 15 after 
each vaccination dose to review eVRC data. The Day 15 Postdose Telephone Contact Guide 
will be provided by the Sponsor. This guide is designed 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).
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 
vaccination regimen should be encouraged to continue to be followed for all remaining study 
visits as outlined in Section 1.3 and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (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 
 
 
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or already performed prior to the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.13
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
 
 
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calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
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.
Blood collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
8.2.1
Pneumococcal Electrochemiluminescence
The Sponsor has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 PnPs serotypes contained in V114. 
The PnECL 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 prespecified acceptance criteria for 
each of the parameters.
The WHO Expert Committee on Biological Standardization has recommended that inhouse 
assays used in immunogenicity studies designed to evaluate protection against IPD be 
bridged to the WHO reference assay to maintain the link between immune responses to 
vaccination and the clinical demonstration of protective efficacy against IPD conferred by the 
7 conjugated polysaccharides in Prevenar™. In 2012 and 2014, the Sponsor formally bridged 
the original PnECL assay to the WHO IgG ELISA in order to determine the PnECL 
threshold values that correspond to 0.35 µg/mL in the WHO ELISA for each of the 
7 Prevenar™ serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and for each of the additional 
6 serotypes (1, 3, 5, 6A, 7F, and 19A) in Prevenar 13™.
A confirmatory study was performed to formally bridge the optimized PnECL assay (v2.0) to 
the WHO reference ELISA and to assess the PnECL threshold values that correspond to 
0.35 µg/mL measured using the WHO ELISA for each of the serotypes in V114, including 
the Prevenar 13™ serotypes and serotypes 22F and 33F, which were not previously assessed. 
The bridging of the 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.
 
 
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8.2.2
Multiplex Opsonophagocytic Assay
The MOPA, developed and published by Professor Moon Nahm (Director of the US WHO 
Pneumococcal Serology Reference Laboratory and National Institutes of Health 
Pneumococcal Reference Laboratory), is a multiplexed OPA assay capable of measuring 
4 serotypes at a time, against a total of 16 serotypes of pneumococci [Burton, Robert L. and 
Nahm, Moon H. 2006]. The OPA is an antibody-mediated killing assay that measures the 
ability of human serum to kill S pneumoniae serotypes with the help of complement and 
phagocytic effector cells. The ability of the assay to simultaneously test 4 serotypes/run 
reduces the amount of serum needed for testing. The assay readout is the opsonization index, 
which is the reciprocal of the highest dilution that gives ≥50% bacterial killing, as 
determined by comparison to assay background controls. The Sponsor has developed and 
optimized the MOPA in a high throughput micro-colony platform. The MOPA assay for all 
15 V114 serotypes has undergone validation. The validation study evaluated various 
performance parameters of the assay, including precision, relative accuracy/dilutional 
linearity, and specificity. The validation results were evaluated against prespecified 
acceptance criteria for each of the parameters.
8.2.3
Anti-Diphtheria Toxoid, Tetanus Toxoid, and Pertussis Antigen Serology 
Assay
The diphtheria, tetanus, and pertussis 6-valent IgG (DTP-6 IgG) assay measures total IgG 
antibodies specific to the following antigens: pertussis toxin (PT), filamentous hemagglutinin 
(FHA), pertactin (PRN), fimbriae types 2/3 (FIM 2/3), diphtheria toxoid, and tetanus toxoid.
Antigen-specific immunoglobulin serum antibodies bind directly to the epitopes on antigens 
covalently conjugated to 6 distinct Luminex microspheres. The measured fluorescent signal 
of the phycoerythrin-labeled detection antibody is directly proportional to the amount of 
antigen-specific IgG antibodies present in a serum sample. Samples are read on a Luminex 
200 instrument, which identifies the specific Luminex microspheres by their distinct red and 
infrared fluorescent dye spectral properties. Quantitation of the human IgG antibodies to 
DTP-6 antigens, or titer, is determined by comparison of the resulting test fluorescence 
measurement to the reference standard serum, which was calibrated to 06/140 for PT, FHA, 
and PRN, FDA Lot 3 for FIM 2/3, to TE-3 for tetanus toxoid and to 00/496 for diphtheria 
toxoid.
8.2.4
Haemophilis Influenzae Type B IgG ELISA
The Haemophilis influenzae type b (Hib) IgG ELISA for the in-vitro measurement of specific 
IgG antibodies against Hib capsular polysaccharide in human serum uses the Vacczyme™ 
Human Anti-Haemophilus influenzae type b Enzyme Immunoassay Kit purchased from The 
Binding Site (catalog # MK016), which was further validated for use in clinical trials. The kit 
contains microtiter wells pre-coated with Hib polysaccharide antigen conjugated to human 
serum albumin. Diluted serum is added to the microtiter wells and allowed to incubate. After 
incubation and washing to remove non-bound serum proteins, horseradish peroxidase 
(HRP)-conjugated rabbit anti-human IgG is added, which binds to any captured Hib-specific 
IgG molecules. After another wash step, tetramethylbenzidine substrate is added; the ensuing 
 
 
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color development reaction is then stopped at a defined time point by the addition of a dilute 
acid solution. The optical density (OD) is measured at 450 nm and is directly proportional to 
the amount of anti-Hib IgG present in the serum specimen. Levels of anti-Hib IgG are 
quantified by interpolation from a standard curve that has been calibrated to the FDA 
Lot 1983 reference serum.
8.2.5
Hepatitis B Enhanced Chemiluminescence (ECi) Assay
The purpose of the hepatitis B ECi assay is to detect total antibody to human plasma-derived 
hepatitis B surface antigen (HBsAg) subtypes ad and ay after vaccination with 
HBsAg-containing vaccine(s). This is the primary assay used to evaluate the serological 
response to the vaccine(s). The assay is a solid phase sandwich enzyme-labeled 
immunoassay. Results for the assay are reported in mIU/mL.
This assay involves the reaction of anti-HBs in a test sample with HBsAg (ad and ay 
subtypes) coated onto the wells. An HRP-labeled HBsAg conjugate (ad and ay subtypes) 
then forms a complex with the bound anti-HBs, forming an “antigen sandwich”. Unbound 
materials are removed by washing. A reagent that contains luminogenic substrates (a luminol 
derivative and a peracid salt) and an electron transfer agent will be added to the wells. The 
HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing 
light. The electron transfer agent will increase the level and duration of the light produced. 
The amount of HRP conjugate bound and subsequent light produced is indicative of the 
concentration of anti-HBs present in the sample.
Three internally prepared control serum pools, consisting of a high-positive, low-positive, 
and negative control, will be used to monitor the performance of the assay. These pools will
each be prepared from 4 individual human immune sera obtained from an external vendor. 
Additionally, there will be anti-HBs positive and negative manufacturer-supplied controls, 
which will be prepared from freeze-dried recalcified human plasma. The hepatitis B WHO 
International reference standard at 10 mIU/mL will also run as a control in every assay. The 
lower limit of quantification of the assay is 5 mIU/mL.
8.2.6
Micrometabolic Inhibition Test-based Virus Neutralization Assay (Polio MIT)
The Polio method quantifies neutralizing (functional) antibodies to poliovirus serotypes 1, 2,
and 3 in serial dilutions of serum using a micrometabolic inhibition test (MIT)-based virus 
neutralization assay (Polio MIT). The Polio MIT assay quantifies the level of neutralizing 
antibodies to Poliovirus type 1, type 2, and type 3 in human sera. The process that was 
validated is an assay method involving challenging serial diluted sera with Poliovirus type 1, 
type 2, or type 3. Tissue culture cells are then added to the serum-virus mixture, incubated 
for 6 to 8 days, and the ability of the sera to neutralize the cytotoxic effects of a particular 
type of Poliovirus is determined. Poliovirus exerts a profound shutdown of normal cell 
function. Metabolism and CO2 production are stopped in mammalian cells infected with 
virus; consequently, the pH remains at 7.4 or higher as indicated by the red color of the 
phenol red indicator in the cell culture medium. Control cells that are incubated with 
antibody that neutralizes the virus, metabolize and produce CO2 in normal amounts, lowering 
the pH of the cell culture medium to <7.0 and changing the color of the pH indicator to 
 
 
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yellow. Therefore, Poliovirus neutralizing antibody titers correlate with the ability of the 
serum to neutralize viral infectivity, which prevents the metabolic effects of infection on 
mammalian cells. Results are determined by the inverse serum dilution where the change in 
pH occurs, ranging from a titer of 4.0 to 65,536.0.
8.2.7
Anti-rotavirus IgA Enzyme Immunoassay (EIA)
The anti-rotavirus IgA EIA assay is used to detect and quantify rotavirus IgA antibody 
response in human serum. The assay is performed at the Laboratory for Specialized Clinical 
Studies, Division of Infectious Diseases of Cincinnati Children's Hospital Medical Center. 
This assay is run in a standard EIA format. Microtiter plates are coated with a rabbit 
anti-rotavirus polyclonal antibody. Rotavirus lysate (positive wells) from the WC3 strain of 
the virus and Mock Infected lysate (negative wells) from the MA104 cell line are added to 
the coated microtiter plates along with standards, controls, and serum dilutions. The negative 
wells allow for measurement of rotavirus specific response, by correcting each sample, 
control and standard curve serum OD for non-specific antibody binding. IgA antibody 
detection occurs by first adding a biotinylated anti-human IgA to the wells, followed by an 
avidin-biotin-peroxidase complex and substrate. The quantity of anti-rotavirus IgA is 
determined by comparison of the delta optical density (DOD) from sample wells to the 
standard curve. The DOD is defined as the average of the positive well ODs minus the 
average of the negative well ODs. All serum samples are run in duplicate at 2 dilutions. A 
cut-off of 7.5 units/mL was derived during the assay validation.
Rotarix™ will not be administered to participants enrolled at sites in the Russian Federation; 
therefore, this testing will not be conducted on these participants (Appendix 7).
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) at Visit 1 for all participants. A targeted 
physical examination will be performed at subsequent vaccination visits as indicated in 
Section 1.3. Any clinically significant abnormality will be recorded on the appropriate eCRF.
Complete and targeted physical examination procedures include obtaining vital signs (heart 
rate, respiratory rate, and rectal temperature), auscultation of the heart and lung, and 
examination of the abdomen. In addition, a complete physical examination will include an 
assessment of the head, eyes, ears, nose and throat, skin, lymph nodes, neurological system, 
and musculoskeletal system.
 
 
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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]) within 72 hours of vaccination must be rescheduled.
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. 
Temperature measurement must be recorded in the eVRC if fever is suspected during Day 8 
through Day 14.
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.
8.3.3
Safety Assessments and Use of the eVRC
All participants will be observed for at least 30 minutes after each vaccination for any 
immediate reactions. If any immediate AEs are observed during this period, the time at which 
the event occurred within this timeframe, as well as the event itself, any concomitant 
medications that were administered, and resolution of the event, must be recorded on the 
appropriate eCRF.
The limb that was used for the administration of V114 or Prevenar 13™ will be recorded in 
the eVRC (Note: the study will report injection-site AEs from V114 or Prevenar 13™only; 
the location of V114 or Prevenar 13™ administration can be used by the participant or 
participant’s legally acceptable representative to monitor the appropriate limb for 
injection-site AEs related to V114 or Prevenar 13™).
Participant’s legally acceptable representative will use the eVRC (Section 8.1.9) to document 
the following information after visits when V114 or Prevenar 13™ are administered:
•
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.
 
 
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•
Any other unsolicited injection-site or systemic AEs Day 1 through Day 14 
postvaccination.
•
Use of any analgesic or antipyretic on the day of vaccination.
•
Concomitant medications and nonstudy vaccinations Day 1 to Day 14 postvaccination.
8.3.4
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.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the day of allocation/randomization to the first vaccination and from the day of each 
vaccination through 14 days postvaccination. SAEs must also be reported throughout the 
duration of the individual's participation in the study, regardless of whether or not related to 
the Sponsor's product.
 
 
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Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
1. A death that occurs prior to the participant completing the study.
OR
2. An SAE that is considered by an investigator who is a qualified physician to be 
vaccine-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
 
 
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Table 4
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.
 
 
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including cancer, and overdose will be followed until resolution, stabilization, until the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
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 for this study.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study 
vaccine in a 24-hour period.
 
 
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No specific information is available on the treatment of overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
All reports of overdose must be reported by the investigator within 5 calendar days to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in 
the electronic data collection (EDC) data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
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 testing
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.
 
 
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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.
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, 
Prevenar 13™, and concomitant vaccines provided in the study) but continue to participate in 
protocol-specified, AE-monitoring activities as outlined in Section 1.3, as long as the 
participant’s legally acceptable representative does not withdraw consent. Blood draws for 
immunogenicity testing could occur if agreed to by the participant’s legally acceptable 
representative at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with International Council for Harmonisation [ICH]
Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, but prior to unblinding, will be documented in a supplemental 
Statistical Analysis Plan and referenced in the clinical study report (CSR) for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
 
 
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Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active-
comparator-controlled Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of V114 in Healthy Infants 
(PNEU-PED-EU-1)
Treatment Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 or 
Prevenar 13™, respectively.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:

Anti-PnP serotype-specific IgG response rates (proportion of 
participants meeting serotype-specific IgG threshold value 
of ≥0.35 μg/mL) at 30 days PTD

Anti-PnPs serotype-specific IgG GMCs at 30 days PTD
Safety:

Proportion of participants with solicited injection-site AEs 
(swelling, redness/erythema, tenderness/pain, and hard 
lump/induration) from Day 1 through Day 14 following any 
vaccination with V114 or Prevenar 13™

Proportion of participants with solicited systemic AEs 
(irritability, drowsiness/somnolence, appetite lost/decreased 
appetite, and hives or welts/urticaria) from Day 1 through 
Day 14 following any vaccination with V114 or 
Prevenar 13™

Proportion of participants with vaccine-related SAEs from 
Day 1 through completion of study participation
Key Secondary Endpoints

Antigen-specific responses for all antigens included in 
INFANRIX™ hexa at 30 days PTD of V114 or 
Prevenar 13™ for participants administered V114 
concomitantly with INFANRIX™ hexa versus participants 
administered Prevenar 13™ concomitantly with 
INFANRIX™ hexa

Anti-rotavirus IgA GMT at 30 days PPS of V114 or 
Prevenar 13™ for participants administered V114 
concomitantly with Rotarix™ versus participants 
administered Prevenar 13™ concomitantly with Rotarix™.

Anti-PnPs serotype-specific IgG response rates (proportion 
of participants meeting serotype-specific IgG threshold 
value of ≥0.35 μg/mL) and GMCs for the 15 serotypes 
contained in V114 at 30 days PPS
 
 
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Statistical Methods for Key 
Immunogenicity
To address the primary immunogenicity non-
inferiority/superiority objectives (H1 and H2), the comparison 
between groups will be made based on the proportion of anti-
PnPs serotype-specific IgG ≥0.35 μg/mL at 30 days PTD 
(Postdose 3 for full-term infants; Postdose 4 for preterm infants) 
for 15 serotypes contained in V114 at 30 days PTD. The 
between-treatment difference (V114 minus Prevenar 13™) and 
its 95% confidence interval (CI) will be calculated using 
unstratified Miettinen and Nurminen (M&N) method [Miettinen, 
O. and Nurminen, M. 1985].
To address the primary immunogenicity non-
inferiority/superiority objectives (H3 and H4), the comparison 
between groups will be made based on serotype-specific IgG 
GMCs for 15 serotypes contained in V114 at 30 days PTD. The 
estimation of the IgG GMC ratios and computation of the
corresponding 95% CIs will be calculated using t-distribution 
with the variance estimate from a linear model utilizing the 
log-transformed antibody concentration as the response and a 
single term for vaccination group.
To address the secondary objectives regarding the non-inferiority 
evaluation of concomitant antigens contained in INFANRIX™ 
hexa at 30 days PTD, the comparison between groups will be 
made based on the proportion of participants achieving the 
antigen-specific antibody threshold value described in 
Section 9.4.1. The between-treatment difference (V114 minus
Prevenar 13™) and the corresponding 95% CIs will be calculated 
using the M&N method [Miettinen, O. and Nurminen, M. 1985].
To address the secondary objectives regarding the non-inferiority 
evaluation of anti-rotavirus IgA response contained in Rotarix™, 
the comparison between groups will be made based on 
anti-rotavirus IgA GMT at 30 days PPS. The estimation of the 
IgA GMT ratios and its corresponding 95% CI will be calculated 
using t-distribution with the variance estimate from a linear model 
utilizing the log-transformed antibody titers as the response and a 
single term for vaccination group.
All hypothesis testing, including both non-inferiority and 
superiority, will be based on the lower bound of the 2-sided 95% 
CI to be greater than the prespecified margins listed in 
Section 9.9.1.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. 
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].
 
 
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Interim Analyses
To support the periodic review of safety and tolerability data 
across the V114 Phase 3 pediatric program, an external 
unblinded statistician will provide unblinded interim safety 
summaries to an independent external Data Monitoring 
Committee (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
The study will be considered to have met its primary 
immunogenicity objective if non-inferiority is demonstrated with 
respect to IgG GMCs and response rates for the 13 shared 
serotypes and superiority is demonstrated respect to IgG GMCs 
and response rates for the 2 unique serotypes at 30 days PTD. All 
hypotheses will be tested individually for each serotype at a 
1-sided 0.025 alpha level. This approach controls the 1-sided 
type-I error rate at 0.025; thus, no multiplicity adjustment is 
required. The study will be considered to have met its secondary 
objective for a specific concomitant vaccine if non-inferiority is 
demonstrated for all the antigens included in that concomitant 
vaccine.
No multiplicity adjustments will be made for the safety 
comparisons.
Sample Size and Power 
The study will randomize participants in a 1:1 ratio to V114 or 
Prevenar 13™, respectively. The overall sample size will be 
approximately 1180, with 590 participants into each vaccination 
group. For primary objectives/hypotheses, the study has >95%
power. The overall power for all the secondary hypotheses 
regarding concomitant vaccines (INFANRIX™ hexa and
Rotarix™) is ~90%. Details are provided in Section 9.9.1.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
 
 
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9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be evaluated for within- and/or 
between-treatment differences are listed below.
9.4.1
Immunogenicity Endpoints
The primary immunogenicity analysis endpoints include:
•
Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL at 30 days 
PTD
•
Anti-PnPs IgG GMCs at 30 days PTD
The secondary immunogenicity analysis endpoints include:
•
Antigen-specific response rates at 30 days PTD for all antigens included in INFANRIX™ 
hexa when administered concomitantly with V114 or Prevenar 13™(Table 5)
•
Anti-rotavirus IgA GMTs at 30 days PPS for Rotarix™when administered 
concomitantly with V114 or Prevenar 13™
•
Anti-PnPs serotype-specific IgG response rates (proportion of participants meeting 
serotype-specific IgG threshold value of ≥0.35 μg/mL) and GMCs at 30 days PPS
•
Anti-PnPs serotype-specific OPA GMTs and response rates at 30 days PTD
•
Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL for the 
2 unique serotypes contained in V114 at 30 days PTD
The exploratory immunogenicity analysis endpoints include:
•
Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes contained in V114 at 
Pretoddler Dose
•
Antigen-specific response rates for all antigens included in INFANRIX™ hexa of V114 
or Prevenar 13™at 30 days PPS
•
Anti-PnPs serotype-specific OPA GMTs and response rates at 30 days PPS and
Pretoddler Dose
Detailed immunogenicity endpoints for concomitant vaccines are listed in Table 5.
 
 
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Table 5
Summary of Endpoints for Concomitant Vaccine Antigens
Vaccine
Antigen
Endpoint
Time Point
INFANRIX™ hexa
Diphtheria toxoid
% ≥0.1 IU/mL
PTD/PPS
Tetanus toxoid
% ≥0.1 IU/mL
PTD/PPS
Pertussis – PT
% ≥5 EU/mL
PTD/PPS
Pertussis – FHA
% ≥5 EU/mL
PTD/PPS
Pertussis – PRN
% ≥5 EU/mL
PTD/PPS
Hib-PRP
% ≥0.15 µg/mL
PTD/PPS
HBsAg
% ≥10 mIU/mL
PTD/PPS
Poliovirus 1
% with Nab ≥1:8 dilution
PTD/PPS
Poliovirus 2
% with Nab ≥1:8 dilution
PTD/PPS
Poliovirus 3
% with Nab ≥1:8 dilution
PTD/PPS
Rotarix™
Rotavirus
GMT Ratio
PPS
EU = endotoxin unit; FHA = filamentous hemagglutinin; GMT = geometric mean titers; Hib = Haemophilus influenzae type 
b; HBsAg = hepatitis B surface antigen; IU = international unit; Nab = neutralizing antibodies; NI = non-inferiority; 
PPS = post primary series; PTD = post toddler dose; PRN = pertactin; PRP = polyribosylribitol phosphate; PT = pertussis 
toxin.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs and postvaccination temperature measurements following any vaccination 
with V114 or Prevenar 13™.
The safety 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 Prevenar 13™
•
Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, hives or welts/urticaria, and appetite loss/decreased appetite) 
from Day 1 through Day 14 following any vaccination with V114 or Prevenar 13™
•
Proportions of participants with the broad AE categories consisting of any AE and a 
vaccine-related AE from Day 1 through Day 14 following any vaccination with V114 or 
Prevenar 13™
•
Proportions of participants with an SAE, a vaccine-related SAE, and discontinuation due 
to an AE, and death from Day 1 through 6 months PTD with V114 or Prevenar 13™
•
Participants body temperature measured Day 1 (day of vaccination) through Day 7 
following any vaccination with V114 or Prevenar 13™
 
 
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9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The Per-Protocol (PP) population will serve as the primary population for the analysis of 
immunogenicity data in this study. The PP population consists of all randomized participants 
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 series vaccination (V114/Prevenar 13™Doses 1 and 2 for 
full-term infants; Doses 1, 2, and 3 for preterm infants) as per randomization schedule
•
Receipt of prohibited medication or prohibited vaccine prior to the first study vaccination
Additional potential deviations that may result in the exclusion from the PP population 
immunogenicity analyses at a particular time point include:
•
Failure to receive the toddler dose of V114 or Prevenar 13™according to vaccination 
schedule required at the time point for the analysis
•
Failure to receive INFANRIX™hexa or Rotarix™according to vaccination schedule 
required at the time point for the analysis
•
Failure to receive the scheduled doses of V114 or Prevenar 13™ (at least 28 days 
between doses during primary series vaccination [for PPS and Pretoddler Dose analysis], 
11 months to 1 day prior to 16 months of age for the toddler dose [for PTD 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 prespecified 
window (as described in Section 1.3)
The final determination on protocol deviations, and thereby the composition of the PP 
population, will be made prior to the final unblinding of the database. Participants will be 
included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the PP population.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed 
for the primary immunogenicity endpoints and secondary immunogenicity endpoints that are 
associated with a hypothesis test. The FAS population consists of all randomized participants 
who received at least one PCV vaccination and have a serology result relevant to the 
immunogenicity endpoint and time point being analyzed. Participants will be included in the 
vaccination group to which they are randomized for the analysis of immunogenicity data 
using the FAS population. Participants enrolled at sites in the Russian Federation will be 
included in the FAS population (Appendix 7)
 
 
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9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 1 dose of study 
vaccination. Participants will be included in the group corresponding to the study vaccination 
they actually received for the analysis of safety data using the APaT population. This will be 
the group to which they are randomized except for participants who take incorrect study 
vaccination; such participants will be included in the vaccination group corresponding to the 
study vaccination actually received. Safety parameters for cross-treated participants (ie, those 
who received vaccinations of both V114 and Prevenar 13™) will be summarized separately.
At least 1 temperature measurement obtained after study intervention is required for 
inclusion in the analysis of temperature.
9.6
Statistical Methods
Statistical testing and inference for immunogenicity and safety analyses are described in
Section 9.6.1 and Section 9.6.2, respectively. Unless otherwise stated, all statistical tests will 
be conducted at the α=0.05 (2-sided) level. Section 9.6.3 describes how demographic and 
baseline characteristics will be summarized.
9.6.1
Statistical Methods for Immunogenicity
This section describes the statistical methods that address the primary, secondary, and 
exploratory immunogenicity objectives.
Primary Endpoint
Primary Endpoint #2/Hypothesis (H1 and H2)
The primary endpoint, anti-PnPs serotype-specific IgG responses at or above the threshold 
value of 0.35 μg/mL for 13 shared serotypes contained in V114 and Prevenar 13™at 30 days 
PTD, will be assessed via the following non-inferiority hypotheses:
H0: p1-p2 ≤-0.1 versus
H1: p1-p2 >-0.1
and for the 2 unique serotypes contained in V114, the primary endpoint, anti-PnP IgG 
responses, will be assessed via the following superiority hypotheses:
H0: p1-p2 ≤0.1 versus
H1: p1-p2 >0.1,
where p1 is the response rate for the V114 group and p2 is the response rate for the 
Prevenar 13™group. V114 is non-inferior to Prevenar 13TM if the lower bound of the 
2-sided 95% CI for the between-treatment differences (V114 minus Prevenar 13™) is greater 
than -0.1 for the 13 shared serotypes, and superior to Prevenar 13TM if the lower bound of the 
2-sided 95% CI for the between-treatment differences (V114 minus Prevenar 13™) is greater 
than 0.1 for the 2 unique serotypes contained in V114. The Miettinen and Nurminen (M&N) 
 
 
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method (1985), an unconditional, asymptotic method, will be used for this analysis
[Miettinen, O. and Nurminen, M. 1985].
Primary Endpoint #2/Hypothesis (H3 and H4)
The primary endpoint, anti-PnPs serotype-specific IgG GMCs for 13 shared serotypes 
contained in V114 and Prevenar 13™at 30 days PTD, will be assessed via the following 
non-inferiority hypotheses:
H0: GMC1/GMC2 ≤0.5 versus
H1: GMC1/GMC2 >0.5,
and for the 2 unique serotypes contained in V114, the primary endpoint, anti-PnP IgG 
GMCs, will be assessed via the following superiority hypotheses:
H0: GMC1/GMC2 ≤2.0 versus
H1: GMC1/GMC2 >2.0
where GMC1 is the anti-PnPs serotype-specific IgG GMCs for V114 group and GMC2 is the 
anti-PnPs serotype-specific IgG GMCs for the Prevenar 13™. For the 13 shared serotypes,
V114 is non-inferior to Prevenar 13™if the lower bound of the 2-sided 95% CI for the GMC
ratios (V114/Prevenar 13™) is greater than 0.5; for the 2 unique serotypes, V114 is superior 
to Prevenar 13™if the lower bound of the 2-sided 95% CI for the GMC ratios
(V114/Prevenar 13™) is greater than 2.0. Estimation of the IgG GMC ratios and computation 
of the corresponding 95% CIs will be calculated using t-distribution with the variance 
estimate from a linear model utilizing the natural log-transformed antibody concentrations as 
the response and a single term for vaccination group.
Secondary Endpoints
Secondary Endpoint #1/Hypothesis (H5)
For this hypothesis (H5), the antigen-specific response rates (listed in Table 8) for
participants administered V114 concomitantly with INFANRIX™ hexa will be compared 
with participants administered Prevenar 13™ concomitantly with INFANRIX™ hexa at 
30 days PTD via the following non-inferiority hypotheses:
H0: p1-p2 ≤δ versus
H1: p1-p2 >δ
where p1 is the response rate for the V114 group, p2 is the response rate for the 
Prevenar 13™group, and δ is the prespecified non-inferiority margin and the values of δ are 
listed in Table 8. INFANRIX™ hexa administered concomitantly with V114 is non-inferior 
to INFANRIX™ hexa administered concomitantly with Prevenar 13TM if the lower bound of 
the 2-sided 95% CI for the between-treatment difference between V114 vs Prevenar 13™
greater than δ. The M&N method will be used for this analysis. 
 
 
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Secondary Endpoint #2/Hypothesis (H6)
For this hypothesis (H6), the anti-rotavirus IgA GMTs between participants administered 
V114 concomitantly with Rotarix™ versus participants administered Prevenar 13™ 
concomitantly with Rotarix™ at 30 days PPS of V114 or Prevenar 13™ will be assessed via 
the following non-inferiority hypotheses:
H0: GMT1/GMT2 ≤0.5 versus
H1: GMT1/GMT2 >0.5
where GMT1 is the anti-rotavirus IgA GMT for the V114 group and GMT2 is the
anti-rotavirus IgA GMT for the Prevenar 13™ group. A ratio of 0.5 corresponds to a 2.0-fold 
decrease of anti-rotavirus IgA GMT in the V114 as compared with the Prevenar 13™. 
Rotarix™administered concomitantly with V114 is non-inferior to Rotarix™administered 
concomitantly with Prevenar 13TM if the lower bound of the 2-sided 95% CI for the GMT 
ratio (V114/Prevenar 13™) >0.5. Estimation of the IgG GMC ratios and computation of the 
corresponding 95% CIs will be calculated using t-distribution with the variance estimate 
from a linear model utilizing the log-transformed antibody titers as the response and a single 
term for vaccination group.
Other Secondary Endpoints/Exploratory Endpoints
Other secondary/exploratory objectives include the evaluation of anti-PnPs serotype-specific 
IgG GMCs at 30 days PPS and Pretoddler Dose, anti-PnPs serotype-specific IgG response 
rates at 30 days PPS, antigen-specific response rates for all antigens included in 
INFANRIX™hexa at 30 days PPS, and anti-PnPs serotype-specific OPA GMTs and 
response rates at 30 days PPS, Pretoddler Dose, and 30 days PTD. The evaluations of these 
objectives will be performed within each vaccination group separately. Descriptive statistics 
with point estimates and within-group 95% CIs will be provided. For the continuous 
endpoints, the point estimates will be calculated by exponentiating the estimates of the mean 
of the natural log values and the within-group CIs will be derived by exponentiating the 
bounds of CIs of the mean of the natural log values based on the 1-sample t-distribution. For 
the dichotomous endpoints, 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].
For the secondary objective regarding anti-PnPs serotype-specific IgG response rates for the 
2 unique serotypes contained in V114, the response rates obtained from the 2 unique 
serotypes in V114 group will be compared to the lowest IgG response rate among the 
13 shared serotypes in Prevenar 13™ vaccination group at 30 days PTD. Comparisons will 
be made through the estimation of difference between serotype-specific response rate and 
lowest response rate among 13 shared serotypes observed in Prevenar 13™vaccination 
group. Estimation of the proportion difference and 95% CI will be calculated using the M&N 
method (1985); an unconditional, asymptotic method, will be used for this analysis
[Miettinen, O. and Nurminen, M. 1985].
Reverse Cumulative Distribution Curves for IgG concentrations at 30 days PTD will be 
graphically displayed by serotype.
 
 
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A detailed analysis strategy for immunogenicity endpoints is listed in Table 6.
Table 6
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing 
Data 
Approach
Primary Endpoint (H1 – H2)
Anti-PnPs serotype-specific IgG 
response rates at 30 days PTD
P
Miettinen and 
Nurminen
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Primary Endpoint (H3 – H4)
Anti-PnPs serotype-specific IgG GMCs 
at 30 days PTD
P
t-distribution with the 
variance estimate from 
a linear model‡
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Secondary Endpoint (H5)
Antigen-specific response rates for all 
antigens included in INFANRIX™ 
hexa at 30 days PTD of V114 or 
Prevenar 13™
P
Miettinen and 
Nurminen
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Secondary Endpoint (H6)
Anti-rotavirus IgA GMT at 30 days 
PPS of V114 or Prevenar 13™
P
t-distribution with the 
variance estimate from 
a linear model‡
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Other Secondary Endpoints
Anti-PnPs serotype-specific IgG 
response rates and GMCs for the 15 
serotypes contained in V114 at 30 days 
PPS
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed.
Anti-PnPs serotype-specific OPA 
GMTs and response rates at 30 days 
PTD 
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed.
Anti-PnPs serotype-specific IgG 
response rates for the 2 unique 
serotypes in V114 at 30 days PTD
P
Miettinen and 
Nurminen
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed.
CI = confidence interval; FAS = Full Analysis Set; GMC = geometric mean concentration; GMT = geometric mean titer; 
H = hypothesis; IgA = Immunoglobulin A; IgG = Immunoglobulin G; OPA = opsonophagocytic activity; PD = postdose; 
PnPs = pneumococcal polysaccharide; PP = Per-Protocol; PPS = post primary series; PTD = post toddler dose.
†
P = Primary approach; S = Supportive approach.
‡
Estimation of the IgG GMC ratios and computation of the corresponding 95% CIs will be calculated using t-distribution 
with the variance estimate from a linear model utilizing the log-transformed antibody titers as the response and a single 
term for vaccination group.
 
 
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs and postvaccination temperature measurements. Additional summaries on key 
safety parameters will also be provided following each vaccination.
The analysis of safety results will follow a tiered approach (Table 7). 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 prespecified 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 M&N method (1985), an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985]. 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. For this protocol, solicited injection-site AEs (redness/erythema, swelling, hard 
lump/induration, and tenderness/pain) from Day 1 through Day 14 postvaccination and 
solicited systemic AEs (irritability, drowsiness, 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 4 participants in any treatment group exhibit the 
event. The threshold of at least 4 events was chosen because the 95% CI for the 
between-group difference in percentage incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% CIs for Tier 2 events 
may be provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in AEs.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a 
vaccine-related AE, an SAE, a vaccine-related SAE, discontinuation due to an AE, and death 
will be considered Tier 2 endpoints. The proportion of participants with maximum 
temperature measurements meeting the Brighton Collaboration cut points (Days 1 to 7) will 
also 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 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint a
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 
participants in one of the vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PT‡ (incidence <4 
participants in all of the vaccination groups)
X
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = system organ 
class; X = results will be provided.
†
These endpoints are broad AE 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 prespecified as Tier 1 or not already prespecified as Tier 2 endpoints.
9.6.3
Summaries of Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (eg, age, race, gender, birth weight, and gestational age), 
baseline characteristics, and prior and concomitant vaccinations and therapies will be 
summarized by vaccination group either by descriptive statistics or categorical tables. 
9.7
Interim Analyses
A periodic review of safety and tolerability data across the V114 Phase 3 pediatric program 
will be conducted by an independent, unblinded, external DMC. A description of the 
 
 
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structure and function of the DMC, along with the timing and content of the safety review,
will be outlined in the DMC charter. Information regarding the composition of the DMC is 
provided in Appendix 1. There are no plans to conduct an interim analysis of unblinded 
immunogenicity data in this study. However, unblinded immunogenicity data will be made 
available to the DMC upon request to enable a benefit-risk assessment.
The DMC will serve as the primary reviewer of the results of ongoing safety reviews and will 
make recommendations for discontinuation of the study or protocol modifications to an 
executive committee of the Sponsor (see Appendix 1 for details on the Committees Structure 
for this study). If the DMC recommends modifications to the design of the protocol or 
discontinuation of the study, this Executive Oversight Committee (EOC) of the Sponsor (and 
potentially other limited Sponsor personnel) may be unblinded to results at the intervention 
level to act on these recommendations. The extent to which individuals are unblinded with 
respect to ongoing safety reviews will be documented by the external unblinded statistician. 
Additional logistical details will be provided in the DMC charter.
Study enrollment is likely to be ongoing at the time of external DMC review. Blinding to 
intervention assignment will be maintained at all investigational sites. Participant-level 
unblinding will be restricted to an external unblinded statistician performing ongoing safety 
reviews. Intervention-level ongoing safety reviews will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
safety reviews.
9.8
Multiplicity
The study will be considered to have met its primary immunogenicity objective if 
non-inferiority is demonstrated with respect to IgG GMCs and response rates for the 
13 shared serotypes and superiority is demonstrated respect to IgG GMCs and response rates
for the 2 unique serotypes at 30 days PTD. All hypotheses will be tested individually for each 
serotype at a 1-sided 0.025 alpha level. This approach controls the 1-sided type-I error rate at 
0.025; thus, no multiplicity adjustment is required. The study will be considered to have met 
its secondary objective for a specific concomitant vaccine if non-inferiority is demonstrated 
for all the antigens included in that concomitant vaccine.
No multiplicity adjustments will be made for the safety comparisons.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
The study will randomize participants in a 1:1 ratio to the 2 vaccination groups. The overall 
sample size will be approximately 1180, with 590 participants in each vaccination group. The 
sample size was chosen to ensure sufficient power for the multiple endpoints across both 
primary and secondary hypotheses. It is assumed that approximately 472 participants per 
vaccination group will be evaluable for PP immunogenicity analyses at 30 days PPS (based 
 
 
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on an 80% evaluability rate), and approximately 443 participants per vaccination group will 
be evaluable for PP immunogenicity analyses at 30 days PTD (based on a 75% evaluability 
rate).
With this study sample size and the assumptions listed below, the overall power for the 
primary hypotheses is >95% for demonstrating non-inferiority of V114 to Prevenar 13™ for 
the 13 shared serotypes and superiority for the 2 unique serotypes for V114 formulations. 
The overall power for the secondary hypotheses for concomitant antigens evaluation is 
approximately 90%. Details of individual hypothesis component are provided below.
For the primary immunogenicity endpoint/hypothesis (H1), the study has >95% power at 
a 1-sided 2.5% alpha level to demonstrate V114 is non-inferior to Prevenar 13™at 30 days 
PTD for anti-PnP serotype-specific IgG responses at or above the threshold value of 
≥0.35 μg/mL for the 13 shared serotypes between V114 and Prevenar 13™ based on the 
following assumptions: (1) an approximately 75% evaluability rate at PTD as observed in 
previous Phase 2 V114 pediatric studies; (2) a non-inferiority margins of -0.1 for the 
difference (V114-Prevenar 13™); and (3) underlying serotype-specific IgG response rates 
(proportion of participants meeting serotype-specific IgG threshold value of ≥0.35 μg/mL at 
30 days PTD of V114 or Prevenar 13™) are 95% at 30 days PTD.
For the primary immunogenicity endpoint/hypothesis (H2), the study has >95% power at 
a 1-sided 2.5% alpha level to demonstrate V114 is superior to Prevenar 13™at 30 days PTD
for anti-PnP serotype-specific IgG responses at or above the threshold value of ≥0.35 μg/mL 
for the 2 unique serotypes contained in V114 based on the following assumptions: (1) an 
approximately 75% evaluability rate at 30 days PTD as observed in previous V114 pediatric 
Phase 2 studies; (2) a superiority margin of 0.1 for the difference (V114-Prevenar 13™); and 
(3) underlying serotype-specific IgG response rates (proportion of participants meeting 
serotype-specific IgG threshold value of ≥0.35 μg/mL at 30 days PTD of V114 or 
Prevenar 13™) are 95% in V114 group and 2% in Prevenar 13™ group at 30 days PTD.
For the primary immunogenicity endpoint/hypothesis (H3), the study has >95% power at 
a 1-sided 2.5% alpha level to demonstrate V114 is non-inferior to Prevenar 13™at 30 days 
PTD for anti-PnP serotype-specific IgG GMCs at 30 days PTD based on the following 
assumptions: (1) an approximately 75% evaluability rate at 30 days PTD as observed in 
previous V114 pediatric Phase 2 studies; (2) a non-inferiority margin of 
0.5 (V114/Prevenar 13™); (3) Standard Deviation (SD) of anti-PnP serotype-specific IgG
GMCs in log scale is 1.1 as those observed in previous MSD studies; and (4) the true GMT 
ratio (V114/Prevenar 13™) for anti-PnP serotype-specific IgG GMCs is 1.0.
For the primary immunogenicity endpoint/hypothesis (H4), the study has >95% power at 
a 1-sided 2.5% alpha level to demonstrate V114 is superior to Prevenar 13™at 30 days PTD
for anti-PnP serotype-specific IgG GMCs for the 2 unique serotypes contained in V114 based 
on the following assumptions: (1) an approximately 75% evaluability rate at PTD as 
observed in previous Phase 2 V114 pediatric studies; (2) a superiority margins of 
2.0 (V114/Prevenar 13™); and (3) SD of anti-PnP serotype-specific IgG GMCs in log scale 
is 1.1 as those observed in previous MSD studies; and (4) the true GMT ratio 
(V114/Prevenar 13™) for anti-PnP serotype-specific IgG GMCs is 10.0.
 
 
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The study is considered to have met its primary objective if V114 is non-inferior to 
Prevenar 13™for the 13 shared serotypes and superior to Prevenar 13™for the 2 unique
serotypes contained in V114.
For the hypotheses driven secondary endpoints, the power is 90.9% and >95% for each of the 
2 non-inferiority hypotheses when INFANRIX™ hexa and Rotarix™ administered 
concomitantly with V114 or Prevenar 13™, respectively. This is based on the assumptions of
approximately 80% evaluability rate at PPS for Rotarix™ and 75% evaluability rate at PTD 
for INFANRIX™ hexa. The assumed response rates, GMT, and non-inferiority margins are 
listed in Table 8.
Table 8
Summary of Endpoints and Power for Concomitant Vaccine Antigens
Antigen
Endpoint
Time
Point
Assumed 
Response 
Rate or 
Standard 
Deviation
NI 
Margin
Power
INFANRIX™ 
hexa
Diphtheria
toxoid
% ≥0.1 IU/mL
PTD
95%
-10%
90.9%
Tetanus toxoid
% ≥0.1 IU/mL
PTD
97%
-5%
Pertussis – PT 
% ≥5 EU/mL 
PTD
90%
-10%
Pertussis – FHA 
% ≥5 EU/mL 
PTD
90%
-10%
Pertussis – PRN 
% ≥5 EU/mL 
PTD
90%
-10%
Hib-PRP
% ≥0.15 µg/mL
PTD
90%
-10%
HBsAg
% ≥10 mIU/mL
PTD
95%
-10%
Poliovirus 1
% with Nab ≥1:8 
dilution
PTD
97%
-5%
Poliovirus 2
% with Nab ≥1:8 
dilution
PTD
97%
-5%
Poliovirus 3
% with Nab ≥1:8 
dilution
PTD
97%
-5%
Rotarix™
Rotavirus
GMT Ratio
PPS
SD = 1.7
2-Fold
>95%
EU = endotoxin unit; FHA = filamentous hemagglutinin; GMT = geometric mean titer; HBsAg = hepatitis B surface 
antigen; Hib = Haemophilus influenzae type b; IU = international unit; Nab = neutralizing antibodies; NI = non-inferiority; 
PPS = post primary series; PRN = pertactin; PRP = polyribosylribitol phosphate; PT = pertussis toxin; PTD = post-toddler
dose; SD = standard deviation (in log scale).
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE among 
590 participants in each of the V114 group and Prevenar 13™group if the underlying 
incidence of an SAE is 0.27% (1 of every 368 participants receiving the vaccine). There is a 
50% chance of observing at least 1 SAE among 590 participants in each of the V114 group 
and Prevenar 13™group if the underlying incidence of an SAE is 0.12% (1 of every 
861 participants receiving the vaccine). If no SAEs are observed among 590 participants in 
each of the V114 group and Prevenar 13™group, this study will provide 97.5% confidence 
 
 
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that the underlying percentage of participants with an SAE is <0.62% (1 in every 
160 participants).
Table 9 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 590 participants in each group and are based on a 2-sided 
5% alpha level. The calculations are based on an asymptotic method proposed by Farrington 
and Manning (1990) [Farrington, C. P. 1990]; no multiplicity adjustments were made.
Table 9
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 590 Participants in Each Group)
Incidence of Adverse Event
Risk Difference
V114 (%)
N=590
Prevenar 13™ (%)
N=590
Percentage Points
1.6
0.1
1.5
5.0
2
3.0
9.2
5
4.2
15.4
10
5.4
21.3
15
6.3
26.9
20
6.9
37.7
30
7.7
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) [Farrington, C. P. 1990].
9.10
Subgroup Analyses
Subgroup analyses based on gestational age (≥37 weeks, <37 weeks), sex (female vs male),
and race will be performed for the primary immunogenicity endpoint and selected safety 
endpoints (summary of AEs). Details of subgroup analyses will be documented in the 
supplemental Statistical Analysis Plan. 
9.11
Compliance (Medication Adherence)
The number and proportion of randomized participants receiving each vaccination will be 
summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V114 or Prevenar 13™, INFANRIX™ hexa, and Rotarix™at each 
vaccination schedule.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
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) 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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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
Not applicable.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
b.   Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.   Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.   Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.   Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.   Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
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.
 
 
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
•
Injection site redness, swelling, or hard lump from the day of vaccination through Day 14 
postvaccination will be evaluated by maximum size.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
 
 
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
 
 
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-
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.
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.
 
 
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•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: 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 8.10 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
This section contains country-specific requirements for conducting the study in the Russian 
Federation. The requirement for the administration of Rotarix™ has been removed for sites 
and participants enrolled in the Russian Federation. Rotarix™ is not registered in the Russian 
Federation and, therefore, will not be administered as part of the study for participants 
enrolled at sites in the Russian Federation.
10.7.1
Study Design
The study design for study sites in the Russian Federation is depicted in Figure 2. Preterm 
infants will not be enrolled at these study sites.
 
 
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Figure 2
V114-025-01 Study Design (For Sites in the Russian Federation Only)
 
 
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10.7.2
Statistical Analysis Plan
10.7.2.1
Analysis Endpoints
10.7.2.1.1
Immunogenicity Endpoints
For participants enrolled at study sites in the Russian Federation, the primary 
immunogenicity analysis endpoints include:
•
Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL at 30 days 
PTD
•
Anti-PnPs IgG GMCs at 30 days PTD
For participants enrolled at study sites in the Russian Federation, the secondary 
immunogenicity analysis endpoints include:

Antigen-specific response rates at 30 days PTD for all antigens included in INFANRIX™ 
hexa when administered concomitantly with V114 or Prevenar 13™ (Table 5)
10.7.2.1.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and postvaccination temperature measurements following any vaccination 
with V114 or Prevenar 13™.
The safety analysis endpoints are outlined in Section 9.4.2.
10.7.2.2
Analysis Populations and Statistical Methods
10.7.2.2.1
Immunogenicity Analysis 
Participants enrolled at sites in the Russian Federation will be included in the FAS population
(Section 9.5.1). Immunogenicity analyses will be conducted using the FAS population for the 
primary immunogenicity endpoints and the secondary endpoints for the evaluation of 
concomitant vaccines (except for Rotarix™). 
The FAS population consists of all randomized participants who received at least one PCV 
vaccination and have a serology result relevant to the immunogenicity endpoint and time 
point being analyzed. Participants will be included in the vaccination group to which they are 
randomized for the analysis of immunogenicity data using the FAS population.
The statistical methods for immunogenicity are provided in Section 9.6.1.
10.7.2.2.2
Safety Analysis
Safety analyses will be conducted as detailed in Section 9.5.2 and Section 9.6.2.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event
APaT
All Participants as Treated
CI
confidence interval
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CRF
case report form
CSR
clinical study report
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DTP-6
diphtheria, tetanus, and pertussis 6-valent
ECG
electrocardiogram
ECi
enhanced chemiluminescence
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic case report form
EDC
electronic data collection
EIA
enzyme immunoassay
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EU
European Union
eVRC
electronic vaccination report card
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FHA
filamentous hemagglutinin
FIM 2/3
fimbriae types 2/3
GCP
Good Clinical Practice
GMC
geometric mean concentration
GMT
geometric mean titer
H
hypothesis
HBsAg
hepatitis B surface antigen
Hib
Haemophilus influenzae type b
HIV
human immunodeficiency virus
HRP
horseradish peroxidase
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IgA
immunoglobulin A
IgG
immunoglobulin G
IPD
invasive pneumococcal disease
IRB
Institutional Review Board 
IRT
interactive response technology
M&N
Miettinen and Nurminen
MIT
micrometabolic inhibition test
MOPA
multiplexed opsonophagocytic activity
MSD
Merck Sharp & Dohme
OD
optical density
OPA
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
 
 
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Abbreviation
Expanded Term
PD
postdose
PnECL
pneumococcal electrochemiluminescence
PnP
pneumococcal polysaccharide
PP
Per-Protocol
PPS
post primary series
PRN
pertactin
PRP
polyribosylribitol phosphate
PT
pertussis toxin
PTD
post toddler dose
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAGE
Strategic Advisory Group of Experts
SD
standard deviation
SoA
schedule of activities
US
United States
WHO
World Health Organization
 
 
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11
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2007]
Farrell DJ, Klugman KP, Pichichero M. Increased antimicrobial 
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Farrington CP, Manning G. Test Statistics and Sample Size 
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[Hicks, L. A., et al 
2007]
Hicks LA, Harrison LH, Flannery B, Hadler JL, Schaffner W, 
Craig AS, et al. Incidence of Pneumococcal Disease Due to 
Non-Pneumococcal Conjugate Vaccine (PCV7) Serotypes in the 
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[Jokinen, J., et al 
2015]
Jokinen J, Rinta-Kokko H, Siira L, Palmu AA, Virtanen MJ, 
Nohynek H, et al. Impact of ten-valent pneumococcal conjugate 
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children a population-based study. PLoS One. 2015 Mar 
17;10(3):e0120290.
[04KW7F]
[Lepoutre, A., et al 
2015]
Lepoutre A, Varon E, Georges S, Dorleans F, Janoir C, 
Gutmann L, et al. Impact of the pneumococcal conjugate 
vaccines on invasive pneumococcal disease in France, 2001-
2012. Vaccine. 2015 Jan 3;33(2):359-66.
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16-MAR-2021
[Lexau, C. A., et al 
2005]
Lexau CA, Lynfield R, Danila R, Pilishvili T, Facklam R, Farley 
MM, et al. Changing epidemiology of invasive pneumococcal 
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[03RBPW]
[Liu, G. F., et al 
2017]
Liu GF, Hille D, Kaplan SS, Goveia MG. Postdose 3 G1 serum 
neutralizing antibody as correlate of protection for pentavalent 
rotavirus vaccine. Hum Vaccin Immunother. 2017;13(10):2357-
63.
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[Martinelli, D., et al 
2014]
Martinelli D, Pedalino B, Cappelli MG, Caputi G, Sallustio A, 
Fortunato F, et al Towards the 13-valent pneumococcal 
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era between PCV7 and PCV13 in Italy, 2010-2013. Hum Vaccin 
Immunother. 2014;10(1):33-9.
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[Metlay, J. P., et al 
2006]
Metlay JP, Fishman NO, Joffe M, Edelstein PH. Impact of 
pediatric vaccination with pneumococcal conjugate vaccine on 
the risk of bacteremic pneumococcal pneumonia in adults. 
Vaccine 2006;24:468-75.
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[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative Analysis of Two Rates. 
Stat Med 1985;4:213-26.
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[Moore, M. R., et al 
2015]
Moore MR, Link-Gelles R, Schaffner W, Lynfield R, Lexau C, 
Bennett NM, et al. Effect of use of 13-valent pneumococcal 
conjugate vaccine in children on invasive pneumococcal disease 
in children and adults in the USA: analysis of multisite, 
population-based surveillance. Lancet Infect Dis. 2015 Feb 3. 
[Epub ahead of print].
[043MRP]
[Palmu, A. A., et al 
2015]
Palmu AA, Kilpi TM, Rinta-Kokko H, Nohynek H, Toropainen 
M, Nuorti JP, et al. Pneumococcal conjugate vaccine and 
clinically suspected invasive pneumococcal disease. Pediatrics. 
2015 Jul;136(1):e22-7.
[04KVRL]
[Pilishvili, Tamara, 
et al 2010]
Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, 
Bennett NM, et al. Sustained reductions in invasive 
pneumococcal disease in the era of conjugate vaccine. J Infect 
Dis 2010;201(1):32-41.
[03R5S4]
[Plotkin, S. A. 2010]
Plotkin SA. Correlates of protection induced by vaccination. 
Clin Vaccine Immunol 2010;17(7):1055-65.
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[Romero-Steiner, S., 
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Romero-Steiner S, Libutti D, Pais LB, Dykes J, Anderson P, 
Whitin JC, et al. Standardization of an opsonophagocytic assay 
for the measurement of functional antibody activity against 
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PROTOCOL/AMENDMENT NO.: 025-02 
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16-MAR-2021
[Ruckinger, S., et al 
2009]
Ruckinger S, van der Linden M, Reinert RR, von Kries R, 
Burckhardt F, Siedler A. Reduction in the incidence of invasive 
pneumococcal disease after general vaccination with 7-valent 
pneumococcal conjugate vaccine in Germany. Vaccine 
2009;27:4136-41.
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Guidance for industry patient-reported outcome measures: use in 
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Wagenvoort GH, Knol MJ, de Melker HE, Vlaminckx BJ, van 
der Ende A, Rozenbaum  MH, et al.  Risk and outcomes of 
invasive pneumococcal disease in adults with underlying 
conditions in the post-PCV7 era, The Netherlands. Vaccine. 
2016 Jan 12;34(3):334-40.
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[Waight, P. A., et al 
2015]
Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MP, 
Miller E. Effect of the 13-valent pneumococcal conjugate 
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Weiss S, Falkenhorst G, van der Linden M, Imohl M, von Kries 
R. Impact of 10-  and 13-valent pneumococcal conjugate 
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Surveill. 2015 Mar 12;20(10):21057.
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Supplemental SAP
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Supplemental Statistical Analysis Plan (sSAP)
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Supplemental SAP
                      AMENDMENT # 1 - 20 AUG 2021
TABLE OF CONTENTS
TABLE OF CONTENTS.....................................................................................................2
LIST OF TABLES...............................................................................................................3
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.............................................8
3.3 HYPOTHESES/ESTIMATION .....................................................................8
3.4 ANALYSIS ENDPOINTS .............................................................................8
3.4.1
Immunogenicity Endpoints...........................................................8
3.4.2
Safety Endpoints.........................................................................10
3.5 ANALYSIS POPULATIONS ......................................................................11
3.5.1
Immunogenicity Analysis Populations.......................................11
3.5.2
Safety Analysis Populations .......................................................15
3.6 STATISTICAL METHODS.........................................................................15
3.6.1
Statistical Methods for Immunogenicity Analyses.....................15
3.6.2
Statistical Methods for Safety Analyses.....................................20
3.6.3
Demographic and Baseline Characteristics ................................22
3.7 INTERIM ANALYSES................................................................................23
3.8 MULTIPLICITY ..........................................................................................23
3.9 SAMPLE SIZE AND POWER CALCULATIONS.....................................24
3.9.1
Sample Size and Power for Immunogenicity Analyses..............24
3.9.2
Sample Size and Power for Safety Analyses..............................26
3.10
SUBGROUP ANALYSES .....................................................................27
3.11
COMPLIANCE (MEDICATION ADHERENCE) ................................27
3.12
EXTENT OF EXPOSURE.....................................................................27
4. LIST OF REFERENCES..............................................................................27
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LIST OF TABLES
Table 1
Summary of Endpoints for Concomitant Vaccine Antigens ................................... 10
Table 2
Effect of Dosing Deviations on the Per-Protocol Population.................................. 13
Table 3
Analysis Strategy for Immunogenicity Variables.................................................... 19
Table 4
Limits of Quantitation for OPA and IgG Serotype-specific Responses .................. 20
Table 5
Analysis Strategy for Safety Parameters ................................................................. 22
Table 6
Summary of Endpoints and Power for Concomitant Vaccine Antigens ................. 25
Table 7
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 
590 Participants in Each Group)........................................................................................... 26
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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
Added Table 2 to display the effect of 
dosing deviations on the PP population.
Added to clarify the criteria for
exclusion in the PP 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 Prevenar 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. 
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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.
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 the 
Pretoddler Dose and 30 Days Post
Toddler Dose.
Added to provide additional statistical 
analysis details/data derivations.
Section 3.6.1 Statistical 
Methods for 
Immunogenicity Analyses
Added a paragraph and a table (Table 4) 
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 3.6.2 Statistical 
Methods for Safety 
Analyses
Added a paragraph to explain that AEs 
related to the concomitant vaccines 
administered as part of the protocol-
specified regimen will be provided. 
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 3.6.3 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
02 Aug 2021
20 Aug 2021
Section 3.6.2 
Statistical 
Methods for 
Safety Analyses
Deleted the 
paragraph that 
described an 
additional 
supportive analysis 
of the proportion 
of participants 
with solicited 
complaints using 
the data collected 
directly from 
participants via the 
VRC.
This analysis is not required by the 
EMA.
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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, Tolerability, and Immunogenicity of 
V114 in Healthy Infants (PNEU-PED-EU-1)
Intervention Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 or Prevenar 
13™, respectively.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:

Anti-PnP serotype-specific IgG response rates (proportion of 
participants meeting serotype-specific IgG threshold value of ≥0.35 
μg/mL) at 30 days PTD 

Anti-PnPs serotype-specific IgG GMCs at 30 days PTD
Safety:

Proportion of participants with solicited injection-site AEs (swelling, 
redness/erythema, tenderness/pain, and hard lump/induration) from 
Day 1 through Day 14 following any vaccination with V114 or 
Prevenar 13™

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, appetite lost/decreased appetite, and hives or 
welts/urticaria) from Day 1 through Day 14 following any 
vaccination with V114 or Prevenar 13™

Proportion of participants with vaccine-related SAEs from Day 1 
through completion of study participation
Key Secondary Endpoint(s)

Antigen-specific responses for all antigens included in INFANRIX™
hexa at 30 days PTD of V114 or Prevenar 13™ for participants 
administered V114 concomitantly with INFANRIX™ hexa versus
participants administered Prevenar 13™ concomitantly with 
INFANRIX™ hexa

Anti-rotavirus IgA GMT at 30 days PPS of V114 or Prevenar 13™ 
for participants administered V114 concomitantly with Rotarix™ 
versus participants administered Prevenar 13™ concomitantly with 
Rotarix™.

Anti-PnPs serotype-specific IgG response rates (proportion of 
participants meeting serotype-specific IgG threshold value of ≥0.35 
μg/mL) and GMCs for the 15 serotypes contained in V114 at 30 days 
PPS
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Statistical Methods for Key 
Immunogenicity Analyses
To address the primary immunogenicity non-inferiority/superiority 
objectives (H1 and H2), the comparison between groups will be made based 
on the proportion of anti-PnPs serotype-specific IgG ≥0.35 μg/mL at 
30 days PTD (Postdose 3 for full-term infants; Postdose 4 for preterm 
infants) for 15 serotypes contained in V114 at 30 days PTD. The 
between-treatment difference (V114 minus Prevenar 13™) and its 95% 
confidence interval (CI) will be calculated using unstratified Miettinen and 
Nurminen (M&N) method [Ref. 5.4: 03QCDT].
To address the primary immunogenicity non-inferiority/superiority 
objectives (H3 and H4), the comparison between groups will be made based 
on serotype-specific IgG GMCs for 15 serotypes contained in V114 at 
30 days PTD. The estimation of the IgG GMC ratios and computation of the
corresponding 95% CIs will be calculated using the t-distribution with the 
variance estimate from a linear model utilizing the log-transformed antibody 
concentration as the response and a single term for vaccination group.
To address the secondary objectives regarding the non-inferiority evaluation 
of concomitant antigens contained in INFANRIX™ hexa at 30 days PTD, 
the comparison between groups will be made based on the proportion of 
participants achieving the antigen-specific antibody threshold value
described in Section 9.4.1. The between-treatment difference (V114 minus 
Prevenar 13™) and the corresponding 95% CIs will be calculated using the 
M&N method [Ref. 5.4: 03QCDT].
To address the secondary objectives regarding the non-inferiority evaluation 
of Anti-rotavirus IgA response contained in Rotarix™, the comparison 
between groups will be made based on anti-rotavirus IgA GMT at 30 days 
PPS. The estimation of the IgA GMT ratios and its corresponding 95% CI 
will be calculated using the t-distribution with the variance estimate from a 
linear model utilizing the log-transformed antibody titers as the response 
and a single term for vaccination group.
All hypothesis testing, including both non-inferiority and superiority, will 
be based on the lower bound of the 2-sided 95% CI to be greater than the 
prespecified margins listed in Section 9.9.1.
Statistical Methods for Key Safety 
Analyses
The analysis of safety results will follow a tiered approach. 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 pediatric program, an external unblinded statistician will 
provide unblinded interim safety summaries to an independent external Data 
Monitoring Committee (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.
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Multiplicity
The study will be considered to have met its primary immunogenicity 
objective if non-inferiority is demonstrated with respect to IgG GMCs and 
response rates for the 13 shared serotypes and superiority is demonstrated 
respect to IgG GMCs and response rates for the 2 unique serotypes at 
30 days PTD. All hypotheses will be tested individually for each serotype at 
a 1-sided 0.025 alpha level. This approach controls the 1-sided type-I error 
rate at 0.025; thus, no multiplicity adjustment is required. The study will be 
considered to have met its secondary objective for a specific concomitant 
vaccine if non-inferiority is demonstrated for all the antigens included in 
that concomitant vaccine.
No multiplicity adjustments will be made for the safety comparisons.
Sample Size and Power
The study will randomize participants in a 1:1 ratio to V114 or 
Prevenar 13™, respectively. The overall sample size will be approximately 
1180, with 590 participants into each vaccination group. For primary 
objectives/hypotheses, the study has >95% power. The overall power for all 
the secondary hypotheses regarding concomitant vaccines (INFANRIX™ 
hexa and Rotarix™) is ~90%. Details are provided in Section 9.9.1.
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 treatment 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.  
3.4
ANALYSIS ENDPOINTS
Immunogenicity and safety analysis endpoints that will be evaluated for within- and/or 
between-treatment differences are listed below.
3.4.1
Immunogenicity Endpoints
The primary immunogenicity analysis endpoints include:

Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL at 30 days 
PTD

Anti-PnPs IgG GMCs at 30 days PTD
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The secondary immunogenicity analysis endpoints include:

Antigen-specific response rates at 30 days PTD for all antigens included in INFANRIX™ 
hexa when administered concomitantly with V114 or Prevenar 13™ (Table 1)

Anti-Rotavirus IgA GMTs at 30 days PPS for Rotarix™when administered 
concomitantly with V114 or Prevenar 13™

Anti-PnPs serotype-specific IgG response rates (proportion of participants meeting 
serotype-specific IgG threshold value of ≥0.35 μg/mL) and GMCs at 30 days PPS

Anti-PnPs serotype-specific OPA GMTs and response rates at 30 days PTD

Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL for the 
2 unique serotypes contained in V114 at 30 days PTD
The exploratory immunogenicity analysis endpoints include:

Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes contained in V114 at 
Pretoddler Dose

Antigen-specific response rates for all antigens included in INFANRIX™ hexa of V114 
or Prevenar 13™ at 30 days PPS

Anti-PnPs serotype-specific OPA GMTs and response rates at 30 days PPS and 
Pretoddler Dose
Detailed immunogenicity endpoints for concomitant vaccines are listed in Table 1.
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Table 1
Summary of Endpoints for Concomitant Vaccine Antigens
Vaccine
Antigen
Endpoint
Time Point
INFANRIX™ hexa
Diphtheria toxoid
% ≥0.1 IU/mL
PTD/PPS
Tetanus toxoid
% ≥0.1 IU/mL
PTD/PPS
Pertussis – PT
% ≥5 EU/mL
PTD/PPS
Pertussis – FHA
% ≥5 EU/mL
PTD/PPS
Pertussis – PRN
% ≥5 EU/mL
PTD/PPS
Hib-PRP
% ≥0.15 µg/mL
PTD/PPS
HBsAg
% ≥10 mIU/mL
PTD/PPS
Poliovirus 1
% with Nab ≥1:8 dilution
PTD/PPS
Poliovirus 2
% with Nab ≥1:8 dilution
PTD/PPS
Poliovirus 3
% with Nab ≥1:8 dilution
PTD/PPS
Rotarix™
Rotavirus
GMT Ratio
PPS
EU = endotoxin unit; FHA = filamentous hemagglutinin; GMT = geometric mean titers; Hib = Haemophilus influenzae type b; 
HBsAg = hepatitis B surface antigen; IU = international unit; Nab = neutralizing antibodies; NI = non-inferiority; PPS = post 
primary series; PTD = post toddler dose; PRN = pertactin; PRP = polyribosylribitol phosphate; PT = pertussis toxin.
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 Prevenar 13™.
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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 Prevenar 13™

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, hives or welts/urticaria, and appetite loss/decreased appetite) 
from Day 1 through Day 14 following any vaccination with V114 or Prevenar 13™

Proportions of participants with the broad AE categories consisting of any AE and a 
vaccine-related AE from Day 1 through Day 14 following any vaccination with V114 or 
Prevenar 13™

Proportions of participants with an SAE, a vaccine-related SAE, and discontinuation due 
to an AE, and death from Day 1 through 6 months PTD with V114 or Prevenar 13™

Participants body temperature measured Day 1 (day of vaccination) through Day 7 
following any vaccination with V114 or Prevenar 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
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 
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 series vaccination (V114/Prevenar 13™Doses 1 and 2 for 
full-term infants; Doses 1, 2, and 3 for preterm infants) as per randomization schedule

Receipt of prohibited medication or prohibited vaccine prior to the first 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 correct study vaccine (V114, Prevnar 13™) according to vaccination 
schedule at the time point for the analysis

Failure to receive INFANRIX™hexa or Rotarix™according to vaccination schedule 
required at the time point for the analysis

Failure to receive the scheduled doses of V114 or Prevenar 13™ (at least 28 days 
between doses during primary series vaccination [for PPS and Pretoddler Dose analysis], 
11 months to 1 day prior to 16 months of age for the toddler dose [for PTD 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 prespecified 
window (as described in Section 1.3 of the protocol)
Table 2 displays the effect of dosing deviations (ie, missed dose, out-of-window dose and extra 
dose) on the PP population.
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Table 2
Effect of Dosing Deviations on the Per-Protocol Population
Vaccine
Dosing
Deviation
Immunogenicity
Analysis
Effect on Per-Protocol Population
PCV
(V114 or 
Prevenar 13™)
Missed
Dose
IgG
Participant will be excluded from the Per-Protocol population at all time points after the 
occurrence of the missed dose
Concomitant
Vaccines
Out-of-Window
Dose
IgG
Participant will be excluded from the Per-Protocol population at the time point 
immediately following the occurrence of the out-of-window dose (only applies to the last 
dose of the primary series and the toddler dose)
Concomitant
Vaccines
Extra
Dose
IgG
Participant will be excluded from the Per-Protocol population at all time points after the 
occurrence of the extra dose
Concomitant
Vaccines
Concomitant Vaccines 
(INFANRIX™ hexa 
and Rotarix™)
Missed
Dose
IgG
Participant will be excluded from the Per-Protocol population at the time point 
immediately following the occurrence of the missed dose (only applies to the last dose of 
the primary series and the toddler dose)
Specified
Concomitant
Vaccine†
Other
Concomitant
Vaccine‡
Missed dose does not affect the immunogenicity analysis of other concomitant vaccine
Out-of-Window
Dose
IgG
Participant will be excluded from the Per-Protocol population at the time point 
immediately following the occurrence of the out-of-window dose (only applies to the last 
dose of the primary series and the toddler dose)
Specified
Concomitant
Vaccine
Other
Concomitant
Vaccine
Out-of-window dose does not affect the immunogenicity analysis of other concomitant 
vaccine
Extra
Dose
IgG
Participant will be excluded from the Per-Protocol population at the time point 
immediately following the occurrence of the extra dose if received within the 14 days 
before receipt of PCV for non-live vaccines or within the 30 days before receipt of PCV 
for live virus vaccines
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Vaccine
Dosing
Deviation
Immunogenicity
Analysis
Effect on Per-Protocol Population
Specified
Concomitant
Vaccine
Participant will be excluded from the Per-Protocol population for all time points following 
the occurrence of the extra dose
Other
Concomitant
Vaccine
Extra dose does not affect the immunogenicity analysis of other concomitant vaccines
† Specific concomitant vaccine pertains to the concomitant vaccine with the dosing deviation.
‡ Other concomitant vaccine pertains to the concomitant vaccine other than the one with the dosing deviation.
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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.
Due to the larger serum requirements of the MOPA assay, functional antibody activity (as measured by 
the OPA GMTs) will be assessed in the first 20% of all participants with sufficient serum volume at PPS 
to evaluate OPA responses (OPA Subset). Additionally, evaluation of OPA responses will be conducted 
at the Pretoddler Dose and PTD for all participants who had OPA performed at PPS and for whom there 
is sufficient volume.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed for the 
primary immunogenicity endpoints and secondary immunogenicity endpoints that are associated with a 
hypothesis test. The FAS population consists of all randomized participants who received at least one 
PCV vaccination and have a serology result relevant to the immunogenicity endpoint and time point 
being analyzed. Participants will be included in the vaccination group to which they are randomized for 
the analysis of immunogenicity data using the FAS population. Participants enrolled at sites in the 
Russian Federation will be included in the FAS population (Appendix 7 of the protocol).
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 Prevenar
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 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 primary, secondary, and exploratory
immunogenicity objectives.
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Primary Endpoint
Primary Endpoint #2/Hypothesis (H1 and H2)
The primary endpoint, anti-PnPs serotype-specific IgG responses at or above the threshold value of 
0.35 μg/mL for 13 shared serotypes contained in V114 and Prevenar 13™at 30 days PTD, will be 
assessed via the following non-inferiority hypotheses:
H0: p1-p2 ≤-0.1 versus
H1: p1-p2 >-0.1
and for the 2 unique serotypes contained in V114, the primary endpoint, anti-PnP IgG responses, will be 
assessed via the following superiority hypotheses:
H0: p1-p2 ≤0.1 versus
H1: p1-p2 >0.1,
where p1 is the response rate for the V114 group and p2 is the response rate for the Prevenar 13™group. 
V114 is non-inferior to Prevenar 13TM if the lower bound of the 2-sided 95% CI for the between-
treatment differences (V114 minus Prevenar 13™) is greater than -0.1 for the 13 shared serotypes, and 
superior to Prevenar 13TM if the lower bound of the 2-sided 95% CI for the between-treatment 
differences (V114 minus Prevenar 13™) is greater than 0.1 for the 2 unique serotypes contained in 
V114. The Miettinen and Nurminen (M&N) method (1985), an unconditional, asymptotic method, will 
be used for this analysis [Ref. 5.4: 03QCDT].
Primary Endpoint #2/Hypothesis (H3 and H4)
The primary endpoint, anti-PnPs serotype-specific IgG GMCs for 13 shared serotypes contained in 
V114 and Prevenar 13™at 30 days PTD, will be assessed via the following non-inferiority hypotheses:
H0: GMC1/GMC2 ≤0.5 versus
H1: GMC1/GMC2 >0.5,
and for the 2 unique serotypes contained in V114, the primary endpoint, anti-PnP IgG GMCs, will be 
assessed via the following superiority hypotheses:
H0: GMC1/GMC2 ≤2.0 versus
H1: GMC1/GMC2 >2.0
where GMC1 is the anti-PnPs serotype-specific IgG GMCs for V114 group and GMC2 is the anti-PnPs 
serotype-specific IgG GMCs for the Prevenar 13™. For the 13 shared serotypes, V114 is non-inferior to 
Prevenar 13™if the lower bound of the 2-sided 95% CI for the GMC ratios (V114/Prevenar 13™) is 
greater than 0.5; for the 2 unique serotypes, V114 is superior to Prevenar 13™if the lower bound of the 
2-sided 95% CI for the GMC ratios (V114/Prevenar 13™) is greater than 2.0. Estimation of the IgG 
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GMC ratios and computation of the corresponding 95% CIs will be calculated using the t-distribution 
with the variance estimate from a linear model utilizing the natural log-transformed antibody 
concentrations as the response and a single term for vaccination group.
Secondary Endpoints
Secondary Endpoint #1/Hypothesis (H5)
For this hypothesis (H5), the antigen-specific response rates (listed in Table 6) for participants 
administered V114 concomitantly with INFANRIX™ hexa will be compared to participants 
administered Prevenar 13™ concomitantly with INFANRIX™ hexa at 30 days PTD via the following 
non-inferiority hypotheses:
H0: p1-p2 ≤δ versus
H1: p1-p2 >δ
where p1 is the response rate for the V114 group, p2 is the response rate for the Prevenar 13™group, and 
δ is the prespecified non-inferiority margin and the values of δ are listed in Table 6. INFANRIX™ hexa 
administered concomitantly with V114 is non-inferior to INFANRIX™ hexa administered 
concomitantly with Prevenar 13TM if the lower bound of the 2-sided 95% CI for the between-treatment 
difference between V114 vs Prevenar 13™greater than δ. The M&N method will be used for this
analysis. 
Secondary Endpoint #2/Hypothesis (H6)
For this hypothesis (H6), the anti-rotavirus IgA GMTs between participants administered V114 
concomitantly with Rotarix™ versus participants administered Prevenar 13™ concomitantly with 
Rotarix™ at 30 days PPS of V114 or Prevenar 13™ will be assessed via the following non-inferiority 
hypotheses:
H0: GMT1/GMT2 ≤0.5 versus
H1: GMT1/GMT2 >0.5
where GMT1 is the anti-rotavirus IgA GMT for the V114 group and GMT2 is the anti-rotavirus IgA 
GMT for the Prevenar 13™ group. A ratio of 0.5 corresponds to a 2.0-fold decrease of anti-rotavirus 
IgA GMT in the V114 as compared with the Prevenar 13™. Rotarix™administered concomitantly with 
V114 is non-inferior to Rotarix™administered concomitantly with Prevenar 13TM if the lower bound of 
the 2-sided 95% CI for the GMT ratio (V114/Prevenar 13™) >0.5. Estimation of the IgG GMC ratios 
and computation of the corresponding 95% CIs will be calculated using the t-distribution with the 
variance estimate from a linear model utilizing the log-transformed antibody titers as the response and a 
single term for vaccination group.
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Other Secondary Endpoints/Exploratory Endpoints
Other secondary/exploratory objectives include the evaluation of anti-PnPs serotype-specific IgG GMCs 
at 30 days PPS and Pretoddler Dose, anti-PnPs serotype-specific IgG response rates at 30 days PPS, 
antigen-specific response rates for all antigens included in INFANRIX™hexa at 30 days PPS, and 
anti-PnPs serotype-specific OPA GMTs and response rates at 30 days PPS, Pretoddler Dose, and 
30 days PTD. The evaluations of these objectives will be performed within each vaccination group 
separately. Descriptive statistics with point estimates and within-group 95% CIs will be provided. For 
the continuous endpoints, the point estimates will be calculated by exponentiating the estimates of the 
mean of the natural log values and the within-group CIs will be derived by exponentiating the bounds of
CIs of the mean of the natural log values based on the 1-sample t-distribution. For the dichotomous 
endpoints, the within-group CIs will be calculated based on the exact method proposed by Clopper and 
Pearson [Ref. 5.4: 03RRVC].
For the secondary objective regarding anti-PnPs serotype-specific IgG response rates for the 2 unique 
serotypes contained in V114, the response rates obtained from the 2 unique serotypes in V114 group 
will be compared to the lowest IgG response rate among the 13 shared serotypes in Prevenar 13™ 
vaccination group at 30 days PTD. Comparisons will be made through the estimation of difference 
between serotype-specific response rate and lowest response rate among 13 shared serotypes observed in 
Prevenar 13™ vaccination group. Estimation of the proportion difference and 95% CI will be calculated 
using the M&N method (1985); an unconditional, asymptotic method, will be used for this analysis
[Ref. 5.4: 03QCDT].
Reverse Cumulative Distribution Curves for IgG concentrations at 30 days PTD, and IgG concentrations 
and OPA titers at the Pretoddler Dose and 30 days PTD, will be graphically displayed by serotype.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 3.
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Table 3
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint (H1 – H2)
Anti-PnPs serotype-specific IgG response 
rates at 30 days PTD
P
Miettinen and Nurminen
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Primary Endpoint (H3 – H4)
Anti-PnPs serotype-specific IgG GMCs at 
30 days PTD
P
t-distribution with the 
variance estimate from a 
linear model‡
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Secondary Endpoint (H5)
Antigen-specific response rates for all 
antigens included in INFANRIX™ hexa at 
30 days PTD of V114 or Prevenar 13™
P
Miettinen and Nurminen
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Secondary Endpoint (H6)
Anti-rotavirus IgA GMT at 30 days PPS of 
V114 or Prevenar 13™
P
t-distribution with the 
variance estimate from a 
linear model‡
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed.
S
FAS
Other Secondary Endpoints
Anti-PnPs serotype-specific IgG response 
rates and GMCs for the 15 serotypes 
contained in V114 at 30 days PPS
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed.
Anti-PnPs serotype-specific OPA GMTs 
and response rates at 30 days PTD 
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed.
Anti-PnPs serotype-specific IgG response 
rates for the 2 unique serotypes in V114 at 
30 days PTD
P
Miettinen and Nurminen
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed.
CI = confidence interval; FAS = Full Analysis Set; GMC = geometric mean concentration; GMT = geometric mean titer; H = hypothesis;
IgA = Immunoglobulin A; IgG = Immunoglobulin G; OPA = opsonophagocytic activity; PD = postdose; PnPs = pneumococcal 
polysaccharide; PP = Per-Protocol; PPS = post primary series; PTD = post toddler dose.
†
P = Primary approach; S = Supportive approach.
‡
Estimation of the IgG GMC ratios and computation of the corresponding 95% CIs will be calculated using t-distribution with the 
variance estimate from a linear model utilizing the log-transformed antibody titers as the response and a single term for vaccination 
group.
The detectable ranges for OPA and IgG responses differ across serotypes. The limits of quantitation 
define the range of responses over which the assays provide precise and accurate measurements. Table 4
gives the limits of quantitation defined for each serotype for OPA and IgG responses. For responses 
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smaller than the lower limit of quantitation (LLOQ), half of the LLOQ is used for analysis when 
calculating the OPA GMTs and IgG GMCs, and in the graphical displays of the Reverse Cumulative 
Distribution Curves for OPA titers and IgG concentrations. 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.
Table 4
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.
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. Additional summaries on key safety parameters will also be 
provided following each vaccination.
The analysis of safety results will follow a tiered approach (Table 5). 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 prespecified as “Tier 1” endpoints or will be classified as belonging to “Tier 2” or “Tier 3” based 
on the number of events observed. 
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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 M&N method (1985), an unconditional, asymptotic method [Ref. 5.4: 03QCDT]. 
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. For this protocol, solicited injection-site AEs (redness/erythema, swelling, hard lump/induration, 
and tenderness/pain) from Day 1 through Day 14 postvaccination and solicited systemic AEs 
(irritability, drowsiness, 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 4 participants in any treatment group exhibit the event. The 
threshold of at least 4 events was chosen because the 95% CI for the between-group difference in 
percentage incidence will always include zero when treatment groups of equal size each have less than 
4 events and thus would add little to the interpretation of potentially meaningful differences. Because 
many 95% CIs for Tier 2 events may be provided without adjustment for multiplicity, the CIs should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for assessing the 
statistical significance of the between-group differences in AEs.
In addition to individual events that occur in 4 or more participants in any treatment group, the broad AE 
categories consisting of the proportion of participants with any AE, a vaccine-related AE, an SAE, a 
vaccine-related SAE, discontinuation due to an AE, and death will be considered Tier 2 endpoints. The 
proportion of participants with maximum temperature measurements meeting the Brighton 
Collaboration cut points (Days 1 to 7) will also be considered Tier 2 endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point estimates by 
treatment group are provided for Tier 3 safety parameters.
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Table 5
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint a
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 
participants in one of the vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PT‡
(incidence <4 
participants in all of the vaccination groups)
X
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = system organ class; X = results 
will be provided.
†
These endpoints are broad AE 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 prespecified as Tier 1 or not already prespecified as Tier 2 endpoints.
Summary tables for AEs related to the concomitant vaccines administered as part of the protocol-
specified regimen will be provided. 
Laboratory AEs will not be reported in summary tables as laboratory testing is not performed as part of 
the study and, as such, AEs would only be reported spontaneously. A listing of laboratory AEs will be 
provided.
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., race, 
and gender, gestational age), baseline characteristics, prior and concomitant vaccinations and therapies 
will be summarized by vaccination group either by descriptive statistics or categorical tables.
Calculated age based on the difference in months between the birthdate and randomization date will be 
used for summaries of age.
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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 of the protocol. 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 of the protocol 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
The study will be considered to have met its primary immunogenicity objective if non-inferiority is 
demonstrated with respect to IgG GMCs and response rates for the 13 shared serotypes and superiority 
is demonstrated respect to IgG GMCs and response rates for the 2 unique serotypes at 30 days PTD. All 
hypotheses will be tested individually for each serotype at a 1-sided 0.025 alpha level. This approach 
controls the 1-sided type-I error rate at 0.025; thus, no multiplicity adjustment is required. The study will 
be considered to have met its secondary objective for a specific concomitant vaccine if non-inferiority is 
demonstrated for all the antigens included in that concomitant vaccine.
No multiplicity adjustments will be made for the safety comparisons.
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3.9
SAMPLE SIZE AND POWER CALCULATIONS
3.9.1
Sample Size and Power for Immunogenicity Analyses
The study will randomize participants in a 1:1 ratio to the 2 vaccination groups. The overall sample size 
will be approximately 1180, with 590 participants in each vaccination group. The sample size was 
chosen to ensure sufficient power for the multiple endpoints across both primary and secondary 
hypotheses. It is assumed that approximately 472 participants per vaccination group will be evaluable 
for PP immunogenicity analyses at 30 days PPS (based on an 80% evaluability rate), and approximately 
443 participants per vaccination group will be evaluable for PP immunogenicity analyses at 30 days 
PTD (based on a 75% evaluability rate).
With this study sample size and the assumptions listed below, the overall power for the primary 
hypotheses is >95% for demonstrating non-inferiority of V114 to Prevenar 13™ for the 13 shared 
serotypes and superiority for the 2 unique serotypes for V114 formulations. The overall power for the 
secondary hypotheses for concomitant antigens evaluation is approximately 90%. Details of individual 
hypothesis component are provided below.
For the primary immunogenicity endpoint/hypothesis (H1), the study has >95% power at a 1-sided 
2.5% alpha level to demonstrate V114 is non-inferior to Prevenar 13™at 30 days PTD for anti-PnP 
serotype-specific IgG responses at or above the threshold value of ≥0.35 μg/mL for the 13 shared 
serotypes between V114 and Prevenar 13™ based on the following assumptions: (1) an approximately 
75% evaluability rate at PTD as observed in previous Phase 2 V114 pediatric studies; (2) a 
non-inferiority margins of -0.1 for the difference (V114-Prevenar 13™); and (3) underlying 
serotype-specific IgG response rates (proportion of participants meeting serotype-specific IgG threshold 
value of ≥0.35 μg/mL at 30 days PTD of V114 or Prevenar 13™) are 95% at 30 days PTD.
For the primary immunogenicity endpoint/hypothesis (H2), the study has >95% power at a 1-sided 
2.5% alpha level to demonstrate V114 is superior to Prevenar 13™at 30 days PTD for anti-PnP 
serotype-specific IgG responses at or above the threshold value of ≥0.35 μg/mL for the 2 unique
serotypes contained in V114 based on the following assumptions: (1) an approximately 75% evaluability 
rate at 30 days PTD as observed in previous V114 pediatric Phase 2 studies; (2) a superiority margin of 
0.1 for the difference (V114-Prevenar 13™); and (3) underlying serotype-specific IgG response rates 
(proportion of participants meeting serotype-specific IgG threshold value of ≥0.35 μg/mL at 30 days 
PTD of V114 or Prevenar 13™) are 95% in V114 group and 2% in Prevenar 13™ group at 30 days 
PTD.
For the primary immunogenicity endpoint/hypothesis (H3), the study has >95% power at a 1-sided 
2.5% alpha level to demonstrate V114 is non-inferior to Prevenar 13™at 30 days PTD for anti-PnP 
serotype-specific IgG GMCs at 30 days PTD based on the following assumptions: (1) an approximately 
75% evaluability rate at 30 days PTD as observed in previous V114 pediatric Phase 2 studies; (2) a 
non-inferiority margin of 0.5 (V114/Prevenar 13™); (3) Standard Deviation (SD) of anti-PnP
serotype-specific IgG GMCs in log scale is 1.1 as those observed in previous MSD studies; and (4) the 
true GMT ratio (V114/Prevenar 13™) for anti-PnP serotype-specific IgG GMCs is 1.0.
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For the primary immunogenicity endpoint/hypothesis (H4), the study has >95% power at a 1-sided 
2.5% alpha level to demonstrate V114 is superior to Prevenar 13™at 30 days PTD for anti-PnP 
serotype-specific IgG GMCs for the 2 unique serotypes contained in V114 based on the following 
assumptions: (1) an approximately 75% evaluability rate at PTD as observed in previous Phase 2 V114 
pediatric studies; (2) a superiority margins of 2.0 (V114/Prevenar 13™); and (3) SD of anti-PnP
serotype-specific IgG GMCs in log scale is 1.1 as those observed in previous MSD studies; and (4) the 
true GMT ratio (V114/Prevenar 13™) for anti-PnP serotype-specific IgG GMCs is 10.0.
The study is considered to have met its primary objective if V114 is non-inferior to Prevenar 13™for 
the 13 shared serotypes and superior to Prevenar 13™for the 2 unique serotypes contained in V114.
For the hypotheses driven secondary endpoints, the power is 90.9% and >95% for each of the 
2 non-inferiority hypotheses when INFANRIX™ hexa and Rotarix™ administered concomitantly with 
V114 or Prevenar 13™, respectively. This is based on the assumptions of approximately 80% 
evaluability rate at PPS for Rotarix™ and 75% evaluability rate at PTD for INFANRIX™ hexa. The 
assumed response rates, GMT, and non-inferiority margins are listed in Table 6.
Table 6
Summary of Endpoints and Power for Concomitant Vaccine Antigens
Antigen
Endpoint
Time Point
Assumed 
Response 
Rate 
or 
Standard 
Deviation
NI Margin
Power
INFANRIX™ hexa
Diphtheria toxoid
% ≥0.1 IU/mL
PTD
95%
-10%
90.9%
Tetanus toxoid
% ≥0.1 IU/mL
PTD
97%
-5%
Pertussis – PT 
% ≥5 EU/mL 
PTD
90%
-10%
Pertussis – FHA 
% ≥5 EU/mL 
PTD
90%
-10%
Pertussis – PRN 
% ≥5 EU/mL 
PTD
90%
-10%
Hib-PRP
% ≥0.15 µg/mL
PTD
90%
-10%
HBsAg
% ≥10 mIU/mL
PTD
95%
-10%
Poliovirus 1
% with Nab ≥1:8 dilution
PTD
97%
-5%
Poliovirus 2
% with Nab ≥1:8 dilution
PTD
97%
-5%
Poliovirus 3
% with Nab ≥1:8 dilution
PTD
97%
-5%
Rotarix™
Rotavirus
GMT Ratio
PPS
SD = 1.7
2-Fold
>95%
EU = endotoxin unit; FHA = filamentous hemagglutinin; GMT = geometric mean titer; HBsAg = hepatitis B surface antigen; 
Hib = Haemophilus influenzae type b; IU = international unit; Nab = neutralizing antibodies; NI = non-inferiority; PPS = post primary 
series; PRN = pertactin; PRP = polyribosylribitol phosphate; PT = pertussis toxin; PTD = post-toddler dose; SD = standard deviation (in 
log scale).
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3.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of participants 
vaccinated and the underlying incidence of participants with an SAE in the study population. 
Calculations below assume that 100% of the randomized participants will be evaluable for safety 
analyses. There is an 80% chance of observing at least 1 SAE among 590 participants in each of the 
V114 group and Prevenar 13™group if the underlying incidence of an SAE is 0.27% (1 of every 
368 participants receiving the vaccine). There is a 50% chance of observing at least 1 SAE among 
590 participants in each of the V114 group and Prevenar 13™group if the underlying incidence of an
SAE is 0.12% (1 of every 861 participants receiving the vaccine). If no SAEs are observed among 
590 participants in each of the V114 group and Prevenar 13™group, this study will provide 97.5% 
confidence that the underlying percentage of participants with an SAE is <0.62% (1 in every 
160 participants).
Table 7 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 590 participants in each group and are based on a 2-sided 5% alpha level. The 
calculations are based on an asymptotic method proposed by Farrington and Manning (1990) 
[Ref. 5.4: 04FS6L]; no multiplicity adjustments were made.
Table 7
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 590 Participants 
in Each Group)
Incidence of Adverse Event
Risk Difference
V114 (%)
N=590
Prevenar 13™ (%)
N=590
Percentage Points
1.6
0.1
1.5
5.0
2
3.0
9.2
5
4.2
15.4
10
5.4
21.3
15
6.3
26.9
20
6.9
37.7
30
7.7
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].
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3.10
SUBGROUP ANALYSES
To determine whether the intervention effect is consistent across various subgroups, the estimate of the 
between-group intervention effect (with a nominal 95% CI) will be summarized for the primary 
immunogenicity endpoints (the proportion of participants with anti-PnPs serotype-specific IgG 
≥0.35 µg/mL and anti-PnPs IgG GMC at 30 Days PTD) for each subgroup with ≥5% of the total number 
of randomized participants in each vaccination group.
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. 
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 Prevenar 13™ at each vaccination schedule.
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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