A Phase I, Double-Blind, Randomized, Multicenter Trial of the Safety,Tolerability, and Immunogenicity of V114 in Healthy Japanese Infants
Phase: PHASE1
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03848065  
Document Date: 
12-Dec-2018
A Phase I, Double-Blind, Randomized, Multicenter Trial of the 
Safety, Tolerability, and Immunogenicity of V114 in Healthy 
Japanese Infants

PRODUCT: V114
1
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Phase I, Double-Blind, Randomized, Multicenter Trial of the Safety, 
Tolerability, and Immunogenicity of V114 in Healthy Japanese Infants
Protocol Number: 028-00
Compound Number: V114
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
Not Applicable
Approval Date: 12-December-2018
 
 
053XZ2
082QBR

PRODUCT: V114
2
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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
 
 
053XZ2
082QBR

PRODUCT: V114
3
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Table of Contents
1
PROTOCOL SUMMARY ............................................................................................10
1.1
Synopsis.................................................................................................................10
1.2
Schema ..................................................................................................................13
1.3
Schedule of Activities (SoA) ................................................................................14
2
INTRODUCTION..........................................................................................................17
2.1
Study Rationale....................................................................................................17
2.2
Background ..........................................................................................................17
2.2.1
Pharmaceutical and Therapeutic Background .............................................19
2.2.1.1
V114...................................................................................................19
2.2.2
Preclinical and Clinical Studies ...................................................................19
2.2.3
Information on Other Study-related Therapy ..............................................19
2.2.3.1
PCV13 (Prevenar 13™/ Prevnar 13™) .............................................19
2.2.3.2
DTaP-IPV vaccine .............................................................................19
2.3
Benefit/Risk Assessment......................................................................................19
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS ................................................20
4
STUDY DESIGN............................................................................................................22
4.1
Overall Design ......................................................................................................22
4.2
Scientific Rationale for Study Design.................................................................22
4.2.1
Rationale for Endpoints ...............................................................................23
4.2.1.1
Immunogenicity Endpoints................................................................23
4.2.1.2
Safety Endpoints ................................................................................24
4.2.1.3
Future Biomedical Research..............................................................24
4.2.2
Rationale for the Use of Comparator/Placebo .............................................25
4.3
Justification for Dose ...........................................................................................25
4.4
Beginning and End of Study Definition .............................................................25
4.4.1
Clinical Criteria for Early Study Termination .............................................25
5
STUDY POPULATION ................................................................................................25
5.1
Inclusion Criteria.................................................................................................26
5.2
Exclusion Criteria ................................................................................................26
5.3
Lifestyle Considerations ......................................................................................28
5.4
Screen Failures.....................................................................................................28
5.5
Participant Replacement Strategy......................................................................28
6
STUDY INTERVENTION............................................................................................29
6.1
Study Intervention(s) Administered...................................................................29
6.2
Preparation/Handling/Storage/Accountability .................................................31
6.2.1
Dose Preparation..........................................................................................31
 
 
053XZ2
082QBR

PRODUCT: V114
4
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
6.2.2
Handling, Storage, and Accountability........................................................31
6.3
Measures to Minimize Bias: Randomization and Blinding..............................31
6.3.1
Intervention Assignment..............................................................................31
6.3.2
Stratification.................................................................................................32
6.3.3
Blinding........................................................................................................32
6.4
Study Intervention Compliance..........................................................................32
6.5
Concomitant Therapy..........................................................................................32
6.5.1
Rescue Medications and Supportive Care ...................................................33
6.6
Dose Modification (Escalation/Titration/Other)...............................................33
6.7
Intervention After the End of the Study............................................................33
6.8
Clinical Supplies Disclosure................................................................................34
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................34
7.1
Discontinuation of Study Intervention...............................................................34
7.2
Participant Withdrawal From the Study...........................................................35
7.3
Lost to Follow-up .................................................................................................35
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................36
8.1
Administrative and General Procedures ...........................................................37
8.1.1
Informed Consent.........................................................................................37
8.1.1.1
General Informed Consent.................................................................37
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................37
8.1.2
Inclusion/Exclusion Criteria ........................................................................38
8.1.3
Participant Identification Card.....................................................................38
8.1.4
Medical History ...........................................................................................38
8.1.5
Prior and Concomitant Medications Review ...............................................38
8.1.5.1
Prior Medications...............................................................................38
8.1.5.2
Concomitant Medications ..................................................................38
8.1.6
Assignment of Screening Number...............................................................39
8.1.7
Assignment of Treatment/Randomization Number .....................................39
8.1.8
Study Intervention Administration ..............................................................39
8.1.8.1
Timing of Dose Administration.........................................................40
8.1.9
Vaccination Report Card..............................................................................40
8.1.10
Discontinuation and Withdrawal .................................................................41
8.1.10.1
Withdrawal From Future Biomedical Research ................................41
8.1.11
Participant Blinding/Unblinding..................................................................41
8.1.12
Calibration of Equipment.............................................................................42
8.2
Immunogenicity Assessments .............................................................................42
 
 
053XZ2
082QBR

PRODUCT: V114
5
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
8.3
Safety Assessments...............................................................................................43
8.3.1
Physical Examinations.................................................................................44
8.3.2
Body Temperature Measurements ...............................................................44
8.3.3
Safety Assessment and Use of the VRC ......................................................44
8.3.4
Clinical Safety Laboratory Assessments .....................................................45
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................45
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................46
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......47
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...48
8.4.4
Regulatory Reporting Requirements for SAE .............................................48
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................48
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................48
8.4.7
Events of Clinical Interest (ECIs) ................................................................48
8.5
Treatment of Overdose........................................................................................48
8.6
Pharmacokinetics.................................................................................................49
8.7
Pharmacodynamics..............................................................................................49
8.8
Future Biomedical Research Sample Collection...............................................49
8.9
Planned Genetic Analysis Sample Collection ....................................................49
8.10
Biomarkers ...........................................................................................................49
8.11
Medical Resource Utilization and Health Economics.......................................49
8.12
Visit Requirements...............................................................................................49
8.12.1
Screening......................................................................................................50
8.12.2
Treatment Period/Vaccination Visit ............................................................50
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........50
9
STATISTICAL ANALYSIS PLAN .............................................................................50
9.1
Statistical Analysis Plan Summary.....................................................................50
9.2
Responsibility for Analyses/In-house Blinding .................................................52
9.3
Hypotheses/Estimation ........................................................................................52
9.4
Analysis Endpoints...............................................................................................52
9.4.1
Immunogenicity Endpoints..........................................................................52
9.4.2
Safety Endpoints ..........................................................................................53
9.5
Analysis Populations............................................................................................53
9.5.1
Immunogenicity Analysis Populations ........................................................53
9.5.2
Safety Analysis Population..........................................................................54
9.6
Statistical Methods...............................................................................................54
 
 
053XZ2
082QBR

PRODUCT: V114
6
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................54
9.6.2
Statistical Methods for Safety Analyses ......................................................55
9.6.3
Summaries of Demographics and Baseline Characteristics.........................57
9.7
Interim Analyses ..................................................................................................57
9.8
Multiplicity ...........................................................................................................58
9.9
Sample Size and Power Calculations .................................................................58
9.10
Subgroup Analyses...............................................................................................59
9.11
Compliance (Medication Adherence).................................................................59
9.12
Extent of Exposure...............................................................................................59
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .....................................................................................................60
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........60
10.1.1
Code of Conduct for Clinical Trials.............................................................60
10.1.2
Financial Disclosure.....................................................................................62
10.1.3
Data Protection.............................................................................................62
10.1.3.1
Confidentiality of Data ......................................................................63
10.1.3.2
Confidentiality of Participant Records...............................................63
10.1.3.3
Confidentiality of IRB/IEC Information............................................63
10.1.4
Committees Structure...................................................................................63
10.1.4.1
Internal Safety Data Assessment .......................................................63
10.1.5
Publication Policy........................................................................................64
10.1.6
Compliance with Study Registration and Results Posting Requirements ...64
10.1.7
Compliance with Law, Audit, and Debarment ............................................64
10.1.8
Data Quality Assurance ...............................................................................65
10.1.9
Source Documents .......................................................................................66
10.1.10
Study and Site Closure.................................................................................66
10.2
Appendix 2: Clinical Laboratory Tests..............................................................67
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................68
10.3.1
Definition of AE ..........................................................................................68
10.3.2
Definition of SAE ........................................................................................69
10.3.3
Additional Events Reported.........................................................................70
10.3.4
Recording AE and SAE ...............................................................................70
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................74
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................76
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................77
 
 
053XZ2
082QBR

PRODUCT: V114
7
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................78
10.7
Appendix 7: Country-specific Requirements ....................................................83
10.8
Appendix 8: Abbreviations .................................................................................84
11
REFERENCES...............................................................................................................85
 
 
053XZ2
082QBR

PRODUCT: V114
8
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
LIST OF TABLES
Table 1
Threshold levels of protective responses to DTaP-IPV...................................23
Table 2
Study Interventions ..........................................................................................30
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................47
Table 4
Analysis Strategy for Key Immunogenicity Variables ....................................55
Table 5
Analysis Strategy for Safety Parameters..........................................................57
Table 6
Detectable Difference in the Percent Incidence of a Safety Event   [N=40 / 
arm, =0.05 (two-sided)].................................................................................58
Table 7
Between-group Difference Estimates in the Proportion of Participants 
Achieving Threshold Value for Immunogenicity Measurements (N=36 / 
arm)..................................................................................................................59
 
 
053XZ2
082QBR

PRODUCT: V114
9
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
LIST OF FIGURES
Figure 1
V114-028 Study Design.............................................................................13
 
 
053XZ2
082QBR

PRODUCT: V114
10
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase I, Double-Blind, Randomized, Multicenter Trial of the Safety, 
Tolerability, and Immunogenicity of V114 in Healthy Japanese Infants
Short Title: Safety and Immunogenicity of V114 in Healthy Japanese Infants
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There is no formal hypothesis in this study.
The following objectives and endpoints will be assessed in healthy Japanese infants.
Primary Objectives
Primary Endpoints

Objective: To describe the safety and 
tolerability profiles of V114 given 
subcutaneously (V114-SC) and V114 
given intramuscularly (V114-IM) in 
healthy infants.

Solicited injection-site adverse 
events (AEs) during Day 1 to Day 
14 postvaccination

Solicited systemic AEs during Day 1 
to Day 14 postvaccination

Vaccine-related serious adverse 
events (SAEs) during Day 1 to 1 
month post-Dose 4 (PD4)
Secondary Objectives
Secondary Endpoints

Objective: To assess 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 1 month post-Dose 3 (PD3) for
each vaccination group.

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 1 month PD3

Objective: To assess the anti-PnPs 
serotype-specific IgG Geometric 
Mean Concentrations (GMCs) at 1 
month PD3 for each vaccination 
group. 

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 1 month PD3
 
 
053XZ2
082QBR

PRODUCT: V114
11
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018

Objective: To assess the proportion 
of participants meeting threshold 
values* for protective responses to 
DTaP-IPV (Diphtheria toxin, Tetanus 
toxin, Pertussis toxin, Pertussis 
filamentous hemagglutinin (FHA),
and Polio virus type 1/2/3) at 1 month 
PD3 for each vaccination group.
Threshold value*: Diphtheria toxin level ≥0.1 
IU/mL, Pertussis PT level ≥10 EU/mL 
Pertussis FHA level ≥10 EU/mL, Tetanus 
toxin level ≥0.01 IU/mL, Neutralizing 
antibody titers (NA) of Polio virus type 1/2/3 
≥1:8

The antibody responses for DTaP-
IPV at 1 month PD3
Overall Design:
Study Phase
Phase 1
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Healthy Japanese infants 
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control without placebo
Study Blinding
Double-blind
Masking
Participant or Subject
Care Provider
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 2 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last serology assay 
result or at the time of final contact with the last participant, 
whichever comes last.
 
 
053XZ2
082QBR

PRODUCT: V114
12
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Number of Participants:
Approximately 120 participants will be randomized (40 participants/group), estimating with 
36 evaluable participants complete the study in each group.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination Regimen
Use
V114-SC
V114
Refer to 
IB
4 doses
SC
Single dose at Visit 1, 
2, 3 and 5*
(Approximately 3, 4, 
5, and 12 to 15 months 
of age).
Experimental
V114-IM
V114
Refer to 
IB
4 doses
IM
Single dose at Visit 1, 
2, 3 and 5*
(Approximately 3, 4, 
5, and 12 to 15 months 
of age).
Experimental
PCV13-SC
PCV13
Refer to 
product 
labeling
4 doses
SC
Single dose at Visit 1, 
2, 3 and 5*
(Approximately 3, 4, 
5, and 12 to 15 months 
of age).
Experimental
Admin: Administration, PCV13: Pneumococcal 13-valent Conjugate Vaccine, IB: Investigator’s Brochure, 
IM: Intramuscular, SC: Subcutaneous
* DTaP-IPV (Diphtheria, tetanus, acellular pertussis, inactivated polio vaccine) is administrated with 
V114/PCV13 concomitantly at Visit 1, 2, 3 and 5.
Total 
Number
3 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 10-14 months, from 
the time the parent/legal guardian signs the Informed Consent Form (ICF) through 
the final contact.
 
 
053XZ2
082QBR

PRODUCT: V114
13
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
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
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
V114-028 Study Design
 
 
053XZ2
082QBR

PRODUCT: V114
14
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
1.3
Schedule of Activities (SoA)
Study Period
Screening
Intervention
Notes
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Standard Age/ 
Scheduled Time
3 months
4 months
5 months
1 month
PD 3
12~15
months
1 month
PD 4
The age of the subject will fall
within the appropriate age range for 
each trial visit.
DOSE 1
DOSE 2
DOSE 3
POST
DOSE 3
DOSE 4
POST
DOSE 4
Visit Window
3 months of age
to 1 day
prior to 
4months of age
28 to 42
days after 
Visit 1
28 to 42
days after 
Visit 2
28 to 42
days after 
Visit 3
12 months of age 
to 1 day 
prior to
16 months of age  
28 to 42
days after 
Visit 5
Months of age is calculated 
according to the participant’s birth 
date.
Screening Procedures
Informed Consent
X
Consent must be obtained before 
any study procedures.
Informed Consent for Future 
Biomedical Research (FBR)
X
Consent for FBR samples is 
optional and must be obtained 
before the collection of the buccal 
swab DNA samples. 
Assignment of Screening 
Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Medical History
X
The participant’s medical history 
from the birth to first vaccination 
will be reviewed.
Post-enrollment procedures
Assignment of Randomization
Number
X
Prior/Concomitant Medication 
and Nonstudy Vaccination
Review
X
X
X
X
X
X
See Section 8.1.5 for details.
 
 
053XZ2
082QBR

PRODUCT: V114
15
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Study Period
Screening
Intervention
Notes
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Standard Age/ 
Scheduled Time
3 months
4 months
5 months
1 month
PD 3
12~15
months
1 month
PD 4
The age of the subject will fall
within the appropriate age range for 
each trial visit.
DOSE 1
DOSE 2
DOSE 3
POST
DOSE 3
DOSE 4
POST
DOSE 4
Visit Window
3 months of age
to 1 day
prior to 
4months of age
28 to 42
days after 
Visit 1
28 to 42
days after 
Visit 2
28 to 42
days after 
Visit 3
12 months of age 
to 1 day 
prior to
16 months of age  
28 to 42
days after 
Visit 5
Months of age is calculated 
according to the participant’s birth 
date.
V114 or PCV13 Administration
(Blinded)
X
X
X
X
Due to differences in appearance, 
vaccine administration will be 
performed by unblinded trial 
personnel who will have no contact 
with study participants other than 
for administration of study vaccine.
This includes all safety follow-up 
procedures (Section 6.3.3). 
Concomitant Vaccine (DTaP-
IPV) Administration
X
X
X
X
DTaP-IPV is administrated with 
V114/PCV13 concomitantly.
Nonstudy Pediatric Vaccines
(X)
(X)
(X)
(X)
(X)
(X)
Injectable vaccines should not be 
administrated in the same limb as
the study vaccine.
Provide Vaccination Report 
Card (VRC)
X
X
X
X
See Section 8.1.9 for details.
VRC Collection
X
X
X
X
Review VRC data
X
X
X
X
Immunogenicity Procedures
Collect Blood Samples for IgG 
Immunogenicity Assays 
X＊
X
X＊
X
＊Prior to vaccination
Collect Blood Samples for 
DTaP-IPV Immunogenicity 
Assays
X
X＊
X
＊Prior to vaccination
 
 
053XZ2
082QBR

PRODUCT: V114
16
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Study Period
Screening
Intervention
Notes
Visit Number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Standard Age/ 
Scheduled Time
3 months
4 months
5 months
1 month
PD 3
12~15
months
1 month
PD 4
The age of the subject will fall
within the appropriate age range for 
each trial visit.
DOSE 1
DOSE 2
DOSE 3
POST
DOSE 3
DOSE 4
POST
DOSE 4
Visit Window
3 months of age
to 1 day
prior to 
4months of age
28 to 42
days after 
Visit 1
28 to 42
days after 
Visit 2
28 to 42
days after 
Visit 3
12 months of age 
to 1 day 
prior to
16 months of age  
28 to 42
days after 
Visit 5
Months of age is calculated 
according to the participant’s birth 
date.
Safety Procedures
Full Physical Examination 
X
To be performed by the investigator 
before vaccination to check 
inclusion/exclusion
criteria/eligibility.
Targeted Physical Examination
X
X
X
To be performed by the investigator 
before vaccination.
Weight
X
Body Temperature 
Measurement
X
X
X
X
Pre-vaccination body temperatures 
measured by site staff. (See section 
8.3.2 for details)
30 Minutes Post Vaccination 
Observation Period
X
X
X
X
Subjects will be observed after 
study vaccination by blinded study  
personnel only.
AE Monitoring
=====================================================
Nonserious AEs are to be reported 
from Days 1 through 14 following 
each vaccination. SAEs and deaths
are to be reported throughout the 
duration of an individual’s study 
participation.
Future Biomedical Research
Collect Buccal Swabs for 
Future Biomedical Research
X
Collected from randomized
participants who provided consent 
for FBR (Section 8.8)
 
 
053XZ2
082QBR

PRODUCT: V114
17
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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 (PD) 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
PCV13 (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
Streptococcus pneumoniae is a major cause of morbidity and mortality in children (< 5 years 
of age) and older adults (≥ 65 years of age) worldwide [Cherian T 2007]. PD continues to be 
a leading cause of vaccine preventable disease worldwide and remains an unmet medical 
need despite the significant public health impact of currently available PCVs. Since the
introduction of multi-valent PCVs, the overall burden of PD has decreased significantly. 
However, the absolute and proportional burden of disease due to non-vaccine serotypes has
increased in regions where multi-valent PCVs have been introduced into infant immunization
schedules. Vaccinated and unvaccinated individuals remain susceptible to disease caused by
non-vaccine serotypes.
In 2016, data from United States (US) Centers for Disease Control and Prevention (CDC) 
showed that serotypes 22F and 33F accounted for ~16% of all Invasive Pneumococcal 
disease (IPD) cases in children <5 years of age. In Japan, the rate of serotypes 22F and 33F 
isolates from children <15 years with IPD in 2014 were 11.1% and 0.8% [Nakano S., et al 
2016]. Both 22F and 33F have been associated with serious clinical outcomes, including IPD, 
as demonstrated by their high degree of invasiveness compared with other serotypes not
currently covered by licensed PCVs. Furthermore, serotypes 22F and 33F have shown
relative resistance to certain antibiotics used in the treatment of community acquired
pneumonia [Golden AR.,et al 2016]. Thus, it is anticipated that vaccination with V114 will
contribute further to prevention of disease in both children and adults due to clinically 
important strains of S. pneumoniae compared to PCV13.
This clinical study is designed to describe the safety, tolerability, and immunogenicity of 
V114 administered subcutaneously or intramuscularly in healthy Japanese infants (3 months 
of age). 
2.2
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on V114.
 
 
053XZ2
082QBR

PRODUCT: V114
18
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Pneumococcal infection is a major cause of pneumonia, bacteremia, and meningitis. Data
from the Active Bacterial Core Surveillance (ABCS) network of the US CDC over the past 
12 years have clearly shown that IPD, including meningitis, bacteremia without focus, and 
pneumonia with bacteremia, is a major public health problem in children and adults 
[Pilishvili T., et al 2010] [Robinson KA., et al 2001] [Centers for Disease Control and 
Prevention 1997] [Centers for Disease Control and Prevention 2016]. Infection surveillance 
in Japan (2017) indicates that the total number of reports of IPD was 3,139, and prevalence 
was 9.37 per 100,000 population for children <5 years of age and 5.34 per 100,000 
population for adults 65 years of age and older. 
Although all age groups could be affected by IPD, the highest rates of disease occur in young 
children <5 years of age and adults ≥65 years of age [Chiba N., et al 2014]. The majority of 
disease has traditionally occurred in young children. However, with the universal adoption of 
PCV7 (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 Protein], Pfizer) the 
incidence of IPD in children <5 years of age in the U.S. declined significantly from 98.7 per 
100,000 population in 1998 to 20.2 per 100,000 population in 2008, and then 12.0 per 
100,000 population in 2011. (7-valent Conjugate Vaccine is also known as Prevenar™/ 
Prevnar™in many countries and will be referred to as PCV7 throughout this document.)
In Japan, PCV7 vaccination was introduced for children <5 years of age in November 2010 
by the Provisional Fund for the Urgent Promotion of Vaccination. PCV7 was incorporated 
into routine vaccination schedules in April 2013. PCV7 rapidly decreased IPD infections in 
children. However, pneumococcal infections caused by non-PCV7 serotypes (19A, 15A, 15B, 
15C, and 24F) increased in children during 2012 [Nakano S., et al 2016].
Subsequent to PCV7, new PCVs were developed to address the increase in IPD caused by 
these emergent serotypes. The 13-valent PCV was approved in the EU in 2009, the U.S. in 
2010, and Japan in 2013. (This vaccine is licensed globally as Prevenar 13™/Prevnar 13™, 
and will be referred to as PCV13 in this protocol.) Similar to PCV7, all 13 serotypes in 
PCV13 are conjugated with diphtheria CRM197 carrier protein. The widespread use of 
PCV13 in infants has further decreased the incidence of IPD caused by the original serotypes 
in PCV7 but also disease caused by the majority of the additional 6 serotypes included 
unique to PCV13.
Despite these significant advances, serotype replacement remains a concern as new serotypes 
begin to fill the niche created by the suppression of nasopharyngeal colonization of vaccine 
serotypes. In particular, serotypes 22F and 33F, the 2 additional serotypes contained in V114 
contributed in 1998 to approximately 1.3% of overall IPD in U.S. children under 5 years of 
age [Pilishvili T., et al 2010], but have now been estimated to represent ~16% of all IPD 
cases in this age group in 2016. 
In Japan, since April 2013, PCV7 has become a routine vaccine and was replaced by PCV13 
in November 2013. Recently, the vaccination rate has reached nearly 100% and serotypes 
22F and 33F contributed to approximately 12 % of overall IPD in children under 15 years of 
age in 2014.
 
 
053XZ2
082QBR

PRODUCT: V114
19
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
V114
The investigational Merck Sharp & Dohme Corp. (MSD), PCV15 (V114) is a 15-valent 
vaccine, containing pneumococcal polysaccharide conjugates of the 13 serotypes in PCV13
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, and 23F) plus 2 additional serotypes (22F and 
33F). V114 contains 32 μg of polysaccharides (2 μg for each serotype except serotype 6B 
which is present at 4 μg), 32 μg of CRM197 carrier protein, and 125 μg of aluminum 
phosphate adjuvant (APA). In clinical studies conducted outside Japan, V114 has been 
administered intramuscularly to healthy adults 18 to 49 years of age, healthy adults 50 years 
of age and older and infants 6 to 12 weeks of age. In a clinical study conducted in Japan, 
V114 has been administered intramuscularly to healthy adults 50 years of age and older. 
There are no significant safety findings or issues related to V114 in clinical studies to date. 
Please refer to the IB on V114.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on the preclinical and clinical studies conducted with V114.
2.2.3
Information on Other Study-related Therapy
2.2.3.1
PCV13 (Prevenar 13™/ Prevnar 13™)
Refer to approved labeling for detailed background information on PCV13.
PCV13 contains the 7 pneumococcal serotypes included in PCV7 (4, 6B, 9V, 14, 18C, 19F, 
23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A). PCV7 and PCV13 are also 
known as Prevenar™/ Prevnar™ and Prevenar 13™ /Prevnar 13™in many countries; these 
vaccines will be referred to as PCV7 and PCV13 throughout this document.
2.2.3.2
DTaP-IPV vaccine
Refer to approved labeling for detailed background information on DTaP-IPV vaccine
administered concomitantly. Licensed DTaP-IPV vaccines will be provided and administered 
concomitantly according to the recommended schedule.
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.
A subset of subjects will receive 4 dose of PCV13 which is the standard of care and is 
serving as the active comparator in this trial. V114 is expected to provide comparable 
immune responses and safety profile to PCV13 for the shared pneumococcal serotypes while 
 
 
053XZ2
082QBR

PRODUCT: V114
20
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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 as PCV13.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no formal hypothesis testing in this study.
The following objectives and endpoints will be assessed in healthy Japanese infants 3 months 
of age.
Primary Objectives
Primary Endpoints

Objective: To describe the safety and 
tolerability profiles of V114 given 
subcutaneously (V114-SC) and V114 
given intramuscularly (V114-IM) in 
healthy infants.

Solicited injection-site adverse events
(AEs) during Day 1 to Day 14 
postvaccination

Solicited systemic AEs during Day 1 
to Day 14 postvaccination

Vaccine-related serious adverse events
(SAEs) during Day 1 to 1 month post-
Dose 4 (PD4)
Secondary Objectives
Secondary Endpoints

Objective: To assess 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 1 month post-Dose 3 (PD3) for
each vaccination group.

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 1 month PD3

Objective: To assess the anti-PnPs 
serotype-specific IgG Geometric 
Mean Concentrations (GMCs) at 1 
month PD3 for each vaccination 
group. 

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 1 month PD3
 
 
053XZ2
082QBR

PRODUCT: V114
21
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018

Objective: To assess the proportion 
of participants meeting threshold 
values* for protective responses to 
DTaP-IPV (Diphtheria toxin, Tetanus 
toxin, Pertussis toxin, Pertussis
filamentous hemagglutinin (FHA) and 
Polio virus type 1/2/3) at 1 month 
PD3 for each vaccination group.
Threshold value*: Diphtheria toxin level ≥0.1 
IU/mL, Pertussis PT level ≥10 EU/mL, 
Pertussis FHA level ≥10 EU/mL, Tetanus 
toxin level ≥0.01 IU/mL, Neutralizing 
antibody titers (NA) of Polio virus type 1/2/3 
≥1:8

The antibody responses for DTaP-IPV 
at 1 month PD3
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints

Objective: To assess the anti-PnPs
serotype-specific IgG response rates 
(proportion of participants meeting 
serotype-specific IgG threshold value 
of ≥0.35 μg/mL) at pre-Dose 4 and 1 
month PD4 for each vaccination 
group. 

Serotype-specific IgG responses for 
the 15 serotypes contained in V114 at
pre-Dose 4 and 1 month PD4 

Objective:To assess the anti-PnPs 
serotype-specific IgG GMCs at pre-
Dose 4 and 1 month PD4 for each 
vaccination group.

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at pre-Dose 4 and 1 
month PD4

Objective:To assess the proportion of 
participants meeting threshold values
for protective responses to DTaP-IPV  
at pre-Dose 4 and 1 month PD4 for
each vaccination group.

The antibody responses for DTaP-IPV 
at pre-Dose 4 and 1month PD4

Objective:To assess the geometric 
mean titers (GMTs) for DTaP-IPV at 
1 month PD3, pre-Dose 4 and 1month 
PD4 for each vaccination group.

The antibody responses for DTaP-IPV 
at 1 month PD3, pre-Dose4 and 
1month PD4
 
 
053XZ2
082QBR

PRODUCT: V114
22
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, randomized, double-blind trial of the safety, tolerability, and 
immunogenicity of 2 different administration routes of V114 (subcutaneous [SC] or 
intramuscular [IM]) in healthy Japanese infants to be conducted in conformance with Good 
Clinical Practices (GCPs). PCV13 will be given with SC as the active control. 
This trial will enroll approximately 120 healthy Japanese infants 3 months of age. Subjects 
will be randomly assigned to receive V114-SC (n=40), V114-IM (n=40) or PCV13-SC
(n=40). A 0.5 mL subcutaneous or intramuscular  dose of the study vaccine will be 
administered to healthy infants at approximately 3, 4, 5, and 12 to 15 months of age. National 
Immunization Program (NIP) vaccine of DTaP-IPV (vaccine that protects against diphtheria, 
tetanus, pertussis and polio) will be administered at the same time as the study vaccine.
Although PCV13 is indicated for healthy infants from 2 months of age in Japan and V114 is 
able to be administered at 2 months of age, study drug (V114 or PCV13) will be 
administered from 3 months of age in this trial to align with the schedule of DTaP(-IPV), 
which is indicated for healthy infants from 3 months of age in Japan.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This is a Phase I study to assess the safety, tolerability and immunogenicity of V114 in 
healthy Japanese infant. PCV13 is indicated for healthy infants from 2 months to 5 years of 
age in Japan with official funding (NIP) since 2013.
Although SC route is typically selected for most pediatric vaccines in Japan, IM route is 
needed especially for infants in which the injection sites are limited based on the statement 
from Japan pediatric society which suggested that IM route was desirable in terms of lower 
frequency of injection-site AEs and generally better immunogenicity compared with SC
[Japan Pediatric Society 2014], and hence the safety and immunogenicity in both routes of 
V114 will be assessed in this study. In addition, the potential impact of V114 administration 
on the immune response to concomitant DTaP-IPV will be assessed secondary and 
exploratory in this study per Japanese regulation to assess the effects of V114 on the 
immunologenicity and safety for simultaneous vaccinations.
Study results will provide necessary information about the safety and immunogenicity 
profiles of V114 in Japanese infants before evaluation in subsequent phases of V114 clinical 
development in Japanese pediatric.
 
 
053XZ2
082QBR

PRODUCT: V114
23
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Serotype-specific IgG
Sera from participants will be used to measure vaccine-induced serotype-specific IgG for all 
15 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23, and 33F) included in 
V114 using the pneumococcal electrochemiluminescence (PnECL) assay. Anti-PnPs 
serotype-specific IgG responses will be measured at baseline, 1 month PD3 for infant series
(primary series), pre-Dose 4 for toddler (booster) to evaluate the anamnestic antibody
responses and the persistence of protective immunity and 1 month PD4 for booster to 
measure the responses after Dose 4.
Immunogenicity endpoints for the comparison of PCVs in children are based on IgG
antibodies responses. Such responses are consistent with the recommendations from the 
World Health Organization (WHO) and many regulatory agencies worldwide and include 
serotype-specific measurements of the following endpoints: a) the proportion of subjects 
achieving IgG antibody concentrations ≥0.35 μg/mL 4 weeks after third dose; and b) the IgG 
GMCs measured 4 weeks after the third and fourth doses. 
Immunogenicity of DTaP-IPV
For the objectives, the immunogenicity endpoint is the proportion of subjects meeting 
threshold values for protective responses to diphtheria toxin, pertussis toxin, pertussis FHA,
tetanus toxin, and polio virus type 1/2/3 at 1 month PD3, pre-Dose 4 and 1month PD4. The 
infection control threshold levels of responses to DTaP-IPV are defined as shown in Table 1
based on the WHO [World Health Organization 2017-1] [World Health Organization 2017-
2], Japanese infection survey [Ministry of Health, Labor and Welfare., et al 2013] and 
clinical findings [Plotkin SA. 2010][Kato T.1990].
Table 1
Threshold levels of protective responses to DTaP-IPV
DTaP-IPV
Diphtheria
Toxin  
Tetanus
Toxin
Pertussis 
Toxin
Pertussis 
FHA
Polio 
Type 1
Polio 
Type 2
Polio 
Type 3
Infection 
control 
threshold 
level
≥0.1 IU/mL
≥0.01 IU/mL
≥10 EU/mL
≥10 EU/mL
NA≥1:8
NA≥1:8
NA≥1:8
FHA: filamentous hemagglutinin, NA: Neutralizing antibody titers (dilution)
In addition, the endpoints also include evaluation of the GMTs for components of DTaP-IPV
measured at 1 month PD3, pre-Dose 4 and 1 month PD4.
 
 
053XZ2
082QBR

PRODUCT: V114
24
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
4.2.1.2
Safety Endpoints
The safety endpoints described in this study were selected based on the product’s safety 
profile demonstrated in previous studies and published data from marketed PCVs and 
feedback received from regulatory agencies during product development.
The participant’s parent/guardian will utilize a paper Vaccination Report Card (VRC) to 
document the following: 

Axillary body temperatures that will be measured on Day 1 (day of vaccination) through 
Day 7 following each vaccination.

Solicited injection-site AEs (redness, swelling, hard lump and pain/tenderness) from Day 
1 through Day 14 following each postvaccination.

Solicited systemic AEs (irritability, drowsiness, hives/welts, appetite loss) from Day 1 
through Day 14 following each postvaccination.

Any other injection-site or systemic AEs from Day 1 through Day 14 following each 
postvaccination.

Serious AEs will be collected from the time the consent form is signed through 
completion of the subject’s participation in the study (until 1 month PD4)
All participants will be observed for 30 minutes after receipt of the study vaccine for any 
immediate reactions. The investigator (or medically-qualified designee) will assess the 
vaccine relatedness of all serious and non-serious AEs, the intensity of all serious and non-
serious AEs. During the VRC-specified safety follow-up period (Day 1 through Day 14 of 
each study vaccination), clinical adverse events will be recorded on the VRC by the 
participant’s parent/guardian on the day of occurrence. The investigator will use the 
information provided by the participant’s parent/guardian both on the VRC, and verbally at 
the time of VRC review.
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 
 
 
053XZ2
082QBR

PRODUCT: V114
25
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
PCV13 is currently the only recommended vaccine for the prevention of pneumococcal
disease in Japanese infants and is also used in many other countries worldwide. It will be
used as the active comparator in this study.
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 
PCV13. Refer to the V114 IB for details on dosing schedule.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory assay 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, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or an unacceptably 
high number of discontinuations or withdrawals due to administrative reasons.
5
STUDY POPULATION
Healthy male and female participants of 3 months of age 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.
 
 
053XZ2
082QBR

PRODUCT: V114
26
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Be healthy (based on a review of medical history and physical examination) based on the 
clinical judgment of the investigator.
Demographics
2.
Be male or female 3 months of age inclusive (3 months of age to1 day prior to 4 months 
of age), at the time of obtaininig the informed consent.
Informed Consent
3.
Have a legally acceptable representative who understands the study procedures, alternate 
treatments available, and risks involved with the study and voluntarily agrees to 
participate by giving written informed consent. The legally acceptable representative may 
also provide consent for future biomedical research. However, the participant may 
participate in the main study without participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of invasive pneumococcal disease (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 vaccines, any component of the pneumococcal conjugate 
vaccine or any diphtheria toxoid-containing vaccine
3. Has any contraindication to the PCV13 and/or DTaP-IPV vaccine being administered in 
the study (Refer to approved labeling for contraindication details on PCV13 and DTaP-
IPV vaccine).
4. *Has a recent febrile illness (axillary temperature ≥37.5°C) 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 hepatitis B surface antigen – positive test.
8. Has a known functional or anatomic asplenia.
 
 
053XZ2
082QBR

PRODUCT: V114
27
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
9. Has failure to thrive based on the clinical judgement of the investigator.
10. Has thrombocytopenia or a known coagulation disorder contraindicating intramuscular
vaccination.
11. Has a history of autoimmune disease (including but not limited to systemic lupus 
erythematosus, antiphospholipid syndrome, Bechet’s disease, autoimmune thyroid 
disease, polymyositis and dermatomyositis, scleroderma, type 1 diabetes mellitus, or 
other autoimmune disorders).
12. Has a known neurologic or cognitive behavioral disorder, including encephalitis/myelitis, 
acute disseminating encephalomyelitis, pervasive development disorder, and related 
disorders.
Prior/Concomitant Therapy
13. Has received a dose of any pneumococcal and/or DTaP-IPV vaccine (or vaccine 
containing any DTaP-IPV component) prior to study entry.
14. *Meets one or more of the following systemic corticosteroid exclusion criteria:

Has received systemic corticosteroids (equivalent of ≥ 2 mg/kg total daily dose of
prednisone or ≥ 20 mg/d for persons weighing > 10 kg) for ≥ 14 consecutive days and 
has not completed this course of treatment at least 30 days prior to trial
randomization.

Has received systemic corticosteroids within 14 days prior to the first dose of study 
vaccine at randomization.

Is expected to require systemic corticosteroids (equivalent of ≥ 2 mg/kg total daily 
dose of prednisone or ≥ 20 mg/d for persons weighing > 10 kg) for ≥ 14 consecutive 
days within 14 days prior to or 30 days after each vaccination during conduct of the 
study.
Note: Topical, ophthalmic and inhaled steroids are permitted.
15. *Has received other licensed non-live vaccines within the 14 days before receipt of first 
dose of study vaccine.
16. *Has received a licensed live virus vaccine within the 28 days before receipt of first dose 
of study vaccine.
17. Has received a blood transfusion or blood products, including immunoglobulins before
receipt of first dose of study vaccine.
 
 
053XZ2
082QBR

PRODUCT: V114
28
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Prior/Concurrent Clinical Study Experience
18. 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
19. Has any other reason that, in the opinion of the investigator, may interfere with the
evaluation required by the study. (Refer to the Vaccination Guideline in Japan). Reasons 
may include, but are not limited to, being unable to keep appointments or planning to 
relocate during the study.
20. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For item with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study vaccination OR withdraws from the study will not 
be replaced.
 
 
053XZ2
082QBR

PRODUCT: V114
29
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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, PCV13 and DTaP-IPV) will be packaged to support enrollment .
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
 
 
053XZ2
082QBR

PRODUCT: V114
30
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Table 2
Study Interventions
Arm Name
Arm Type
Interve
ntion 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
V114-SC
Experimental
V114
Biological
/Vaccine
Sterile 
Suspension
Refer to IB
0.5 mL
SC
Single Dose at 
Visit 1, 2, 3 and 
5
Experimental
IMP
Cenral
V114- IM
Experimental
V114
Biological
/Vaccine
Sterile 
Suspension
Refer to IB
0.5 mL
IM
Single Dose at 
Visit 1, 2, 3 and 
5
Experimental
IMP
Cenral
PCV13-SC
Active
Comparator
PCV13*
Biological
/Vaccine
Sterile 
Suspension
Refer to product 
labeling
0.5 mL
SC
Single Dose at 
Visit 1, 2, 3 and 
5
Experimental
IMP
Cenral
Concomitant 
Vaccine
(Not 
Applicable)
DTaP-
IPV**
Biological
/Vaccine
Sterile 
Suspension
Refer to product 
labeling
0.5 mL
SC
Single Dose at 
Visit 1, 2, 3 and 
5
Concomitant
IMP
Central
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) are 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
PCV13 *: Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)  DTaP-IPV **: Adsorbed Diphtheria-purified Pertussis-tetanus-inactivated 
polio (Sabin strain) Combined Vaccine
All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon local country operational requirements. 
If local sourcing, every attempt should be made to source these supplies from a single lot/batch number where possible (eg, not 
applicable in the case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
 
 
053XZ2
082QBR

PRODUCT: V114
31
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to
administer the proper dose to each participant. The rationale for selection of doses to be used
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule. There are 3 study intervention groups. Participants will be assigned randomly in a 
1:1:1 ratio to V114-SC study vaccination group, V114-IM study vaccination group or active 
control group (PCV13-SC), respectively.
 
 
053XZ2
082QBR

PRODUCT: V114
32
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique will be used. V114 and PCV13 will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study personnel. The 
participant and the investigator who are involved in the clinical evaluation of the participants 
will remain blinded to the group assignments until end of the study.
Because the V114 and PCV13 have a different appearance, a member of the study site 
personnel will be unblinded for the purposes of receiving, maintaining, preparing and/or 
dispensing, and administering the study vaccine. Procedures for handling, preparing, and
administering the unblinded vaccines are located in the Investigator Trial File Binder.
Due to differences in appearance, vaccine administration will be performed by unblinded 
study personnel who will have no contact with study participants other than administration of 
study vaccine, which includes all safety follow up procedures at each vaccination visit. 
Additionally, blinded site personnel and participant’s parent/guardian will remain blinded
such as not to be present in the same room or to be separated with a curtain when V114 and 
PCV13 are administered. Contact between participants and unblinded study personnel after 
each vaccination administration is strictly prohibited. Blinded study personnel will be 
responsible for all safety and immunogenicity follow-up procedures after study vaccine 
administration.
An unblinded Clinical Research Associate will monitor study vaccine accountability at the 
study site. All other Sponsor personnel or delegate(s) directly involved with the conduct of 
this study will remain blinded to the participant-level intervention assignment until the end of
the study. See Section 8.1.11 for a description of the method of unblinding a participant 
during the study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified plan for V114 or PCV13 vaccination indicated in 
Section 1.3 require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study (See section 5.2 for details). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
 
 
053XZ2
082QBR

PRODUCT: V114
33
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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 trial, one of the individuals 
listed on the Sponsor Contact Information page must be notified as soon as possible. Any 
concurrent medication or medical treatment must be recorded on the appropriate electronic 
case report form (eCRF). It is important to record the use of any analgesic or antipyretic use 
on the VRC and appropriate eCRF.
The V114/PCV13 and concomitant vaccine (DTaP-IPV) will be administered at Visit 1, 2, 3
and 5 (approximately 3, 4, 5 and 12 to 15 months of age). Subjects should not receive 
systemic corticosteroids (equivalent of 2 mg/kg total daily dose of prednisone or 20 mg/d 
for persons weighing >10 kg for 14 consecutive days) starting from 14 days prior to each 
vaccination through 30 days after each vaccination. Topical, ophthalmic and inhaled steroids 
are permitted.
Other nonstudy pediatric vaccines (oral or injectable) including NIP vaccine can be 
administered concomitantly according to the recommended schedule. If given at a study visit,
nonstudy pediatric vaccines should be administrated with the study vaccine. These 
vaccinations should be recorded on the appropriate eCRF. To avoid any confounding results,
nonstudy injectable vaccines should not be administered in the same limb as study vaccine.
During the influenza season, it is anticipated that participants 6 months of age and older may 
be given an influenza vaccine. Influenza vaccine should be administered either 7 days before
or 15 days after the administration of the study vaccine.
Documentation of which limb was used for the administration of study vaccines and 
nonstudy vaccines should be recorded on the appropriate eCRF. As the trial is reporting 
injection-site AEs from the study vaccine, including DTaP-IPV vaccine (and not from the 
nonstudy pediatric vaccines), this information should also be recorded on the VRC to inform 
the parent/guardian of the appropriate limb to monitor for AEs related to the study vaccine.
No other investigational compound or device may be administered at any time during this
study without prior approval by the Sponsor.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
 
 
053XZ2
082QBR

PRODUCT: V114
34
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to open supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity. The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.11). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
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 vaccinations
will still continue to participate in the study as specified in Section 1.3 and Section 8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10 and Section 
8.12.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
-
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
-
The participant’s treatment assignment is unblinded by the investigator or through the 
emergency unblinding call center.
 
 
053XZ2
082QBR

PRODUCT: V114
35
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
-
The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, see Section 1.3 and Section 8.12.3 for those procedures to be completed at each 
specified visit.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued,
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
-
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
-
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
-
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
 
 
053XZ2
082QBR

PRODUCT: V114
36
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
8
STUDY ASSESSMENTS AND PROCEDURES
-
Study procedures and their timing are summarized in the SoA.
-
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
-
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
-
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
-
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
-
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
-
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
For all the participants in the Immunogenicity, approximately 3 mL of blood will be drawn at
Visit 1 and approximately 5 mL of blood will be drawn at the Visit 4, 5 and 6. The maximum
amount of blood collected from each participant over the duration of the study during
planned study visits will not exceed 18 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
053XZ2
082QBR

PRODUCT: V114
37
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research.If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
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.
 
 
053XZ2
082QBR

PRODUCT: V114
38
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study. The investigator should 
consult with the Sponsor’s Clinical Director for any questions about participant eligibility.
If the participant meets any of the exclusion criteria with an asterisk (*), Visit 1 may be
rescheduled for a time when these criteria are not met.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee before 
vaccination at Visit 1. Weight at baseline, birth weight and gestational age will be recorded
on the appropriate eCRF.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations from birth
and medications taken by the participant within 30 days before the first dose of study vaccine
at Visit 1.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record 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.
 
 
053XZ2
082QBR

PRODUCT: V114
39
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
It is important to record any analgesic or antipyretic use that occurs on the day of vaccination 
on the VRC and appropriate eCRF. Concomitant medications taken after Visit 1 and 
nonstudy pediatric vaccines received since Visit 1 will be recorded with the VRC as specified 
in Section 8.3.3.
Nonstudy pediatric vaccines administered during the study should be recorded on the 
appropriate eCRF. Injectable vaccines should not be administered in the same limb as study 
vaccine. Documentation of which limb was used for the administration of study vaccine must 
be recorded on the VRC (Section 8.3.3) and appropriate eCRF. 
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit
requirements are provided in Section 8.12.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The treatment/randomization number identifies the participant for all procedures occurring 
after allocation/randomization. Once a 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 randomization number.
8.1.8
Study Intervention Administration
Unblinded study personnel not otherwise involved in the conduct of the study will prepare
and administer the study vaccine. Study vaccines should be administered by appropriately
qualified members of the study personnel (physician or nurse). Procedures for handling,
preparing, and administering the unblinded vaccines are provided in the Investigator Trial
File Binder. Unblinded study personnel should follow the preparation and administration
instructions for PCV13 as specified in the product label.
V114 and PCV13 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.
V114 is provided as a vial. Prior to administration of study vaccine, the unblinded study 
personnel 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 
 
 
053XZ2
082QBR

PRODUCT: V114
40
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
action should be repeated, as necessary. If appearance is otherwise, the vaccine should not be
administered. The vaccine should not be used if the vaccine cannot be resuspended.
A 0.5-mL vaccination dose of V114/PCV13 will be administered to healthy infants at Visit 1,
2, 3 and 5 (approximately 3, 4, 5, and 12 to 15 months of age). PCV13 will be supplied as a
pre-filled syringe. V114/PCV13 is recommended to be administered in the right thigh. If an 
abnormality (i.e., rash) is observed at the site where the previous dose of the vaccine was 
administered, it is permissible to use another 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 [Simons FE., et al 2011].
Concomitant study vaccine (DTaP-IPV) should be administered subcutaneously on the same 
time as V114/PCV13. DTaP-IPV is recommended to be administered in the left thigh, and 
nonstudy pediatric vaccines (oral and injectable) administrated concomitantly should be 
given with study vaccines. To avoid any confounding results, nonstudy injectable vaccines 
should not be administered in the same limb as study vaccine. 
Unblinded study personnel should not have contact with participants for any study-related 
procedures/assessments other than administration of vaccines, which includes all safety 
follow-up procedures at vaccination visit. All clinical assessments will be conducted by 
blinded personnel, and the participant or participant’s parent/guardian will remain blinded to 
the group assignments until the end of study. Vaccination information, such as Component 
Identification Number and date of vaccination, location of administration must be recorded 
on the appropriate eCRF as per the Data Entry Guidelines.
8.1.8.1
Timing of Dose Administration
The study vaccine will be administered as indicated in Section 1.3. All participants will be 
observed for 30 minutes following each vaccination for any immediate reactions. This 
observation must be performed by blinded site personnel for V114 or PCV13 (Section 1.3 
and Section 6.3.3).
Participants must be afebrile (axillary temperature <37.5°C) for at least 72 hours prior to 
vaccination. 
Blood samples for participants in the study must be collected before study vaccination.
8.1.9
Vaccination Report Card
The investigator or delegate will train the participant’s parent/guardian in the use of the VRC 
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 
VRC as described in Section 1.3 and Section 8.3.3. The investigator or delegate will review 
 
 
053XZ2
082QBR

PRODUCT: V114
41
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
the data captured on the VRC with the participant’s parent/guardian as indicated in 
Section 1.3.
For the AEs outlined above, the investigator will use the information provided by the 
participant’s parent/guardian both on the VRC, and verbally at the time of VRC review, to 
apply the appropriate assessment of intensity as described in Appendix 3.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the protocol-specified 
vaccinations should be encouraged to continue to be followed for all remaining study visits
as outlined in the 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.
8.1.10.1
Withdrawal From Future Biomedical Research
Consent for future biomedical research may be withdrawn by the participant’s legally 
acceptable representative. Consent may be withdrawn by the legally acceptable 
representative at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant’s legally acceptable representative 
of completion of withdrawal. Any analyses in progress at the time of request for withdrawal 
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 (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main study records)
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.11
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND
 
 
053XZ2
082QBR

PRODUCT: V114
42
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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 (e.g., 
date, reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding that is part of the study design has taken place, the
investigator, site personnel, and Sponsor personnel may be unblinded so that the appropriate 
follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced anti-PnPs serotype-specific
IgG for all the 15 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and
33F) contained in V114 using the PnECL v2.0 assay. DTaP-IPV antibody titers will be 
measured by neutralization assay (diphtheria toxin and poliovirus 1/2/3), particle 
agglutination assay (tetanus toxin) and enzyme-linked immunosorbent assay (ELISA) 
methodology (pertussis PT and pertussis FHA).
Blood collection, storage and shipment instructions for serum samples will be provided in the
operations/laboratory manual.
 
 
053XZ2
082QBR

PRODUCT: V114
43
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
The Sponsor has developed and optimized a multiplex, electrochemiluminescence 
(ECL)-based detection method for the quantitation of IgG serotype-specific antibodies to the
15 PnPs serotypes contained in V114. The PnECL v2.0 assay is based on the Meso-Scale
Discovery technology, which employs disposable multi-spot microtiter plates. The benefits
of the ECL multiplex technology over the prior ELISA methodology include speed,
equivalent or better sensitivity, increased dynamic range, the ability to multiplex, and
reduction in required serum sample and reagent volumes. The measurement of immune
responses to the 15 serotypes included in V114 is performed using an assay format consisting
of 2 groups of 7 and 8 serotypes each. The PnECL v2.0 assay for all 15 serotypes has
undergone validation. The validation study evaluated various performance parameters of the
assay including precision, ruggedness, relative accuracy, dilutional linearity, selectivity, and
specificity. The validation results were evaluated against pre-specified acceptance criteria for
each of the parameters.
The WHO Expert Committee on Biological Standardization has recommended that in-house 
assays used in immunogenicity studies designed to evaluate protection against IPD be 
bridged to the WHO reference assay in order to maintain the link between immune responses 
to vaccination and the clinical demonstration of protective efficacy against IPD conferred by 
the 7 conjugated polysaccharides in Prevnar™. In 2012 and 2014, the Sponsor formally 
bridged the original PnECL assay to the WHO IgG ELISA in order to determine the PnECL 
threshold values that correspond to 0.35 µg/mL in the WHO ELISA for each of the 7 
Prevnar™ serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and for each of the additional 6 
serotypes (1, 3, 5, 6A, 7F, and 19A) in Prevnar 13™.
A confirmatory study was performed to formally bridge the optimized PnECL assay (v2.0) to 
the WHO reference ELISA, and to assess the PnECL threshold values that correspond to 
0.35 µg/mL measured using the WHO ELISA for each of the serotypes in V114, including 
the PCV13 serotypes and serotypes 22F and 33F, which were not previously assessed. The 
bridging of the optimized PnECL to the WHO ELISA is complete, and the data showed good 
concordance between the PnECL and WHO ELISA around the 0.35 μg/mL threshold value 
for all 15 serotypes. It is recommended that a single PnECL threshold value of 0.35 µg/mL 
be applied to each of the 15 serotypes.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are
provided below. The total amount of blood/tissue to be drawn/collected over the course of
the study (from prevaccination to postvaccination 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.
 
 
053XZ2
082QBR

PRODUCT: V114
44
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
8.3.1
Physical Examinations
A full physical examination will be performed at Visit 1. A targeted physical examination 
will be performed at subsequent vaccination visits (Visit 2, 3, and 5). Any clinically 
significant abnormality will be recorded on the appropriate eCRF.
The full and targeted physical examination procedures both include obtaining vital signs 
(heart rate, respiratory rate, and axillary temperature), auscultation of the heart and lung, and 
examination of the abdomen. In addition, a full physical examination will include an 
assessment of the head, eyes, ears, nose and throat, skin, lymph nodes, neurological system, 
and musculoskeletal system. 
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Body Temperature Measurements
Pre-vaccination axillary temperatures will be taken by study personel as indicated in 
Section 1.3. Participants who have febrile illness (axillary temperature ≥37.5°C) occurring at 
or within 72 hours of Visits 1, 2, 3, and 5 must be rescheduled.  Post-vaccination axillary 
temperatures must be recorded on the VRC. Temperature readings should be taken at 
approximately the same time each day. Use of temporal or tympanic thermometers to collect 
temperature for this study is prohibited.
The participant’s parent/guardian will be asked to record the participant’s temperature 
reading on the VRC from Day 1 through Day 7 following each vaccination. Temperature 
measurement must be recorded in the VRC if fever is suspected during Day 8 through 
Day 14.
8.3.3
Safety Assessment and Use of the VRC
All participants will be observed for 30 minutes after each vaccination for any immediate 
reactions. If any immediate AEs are observed during this period, the time at which the event 
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event, must be recorded on the appropriate eCRF.
Participant’s parent/guardian will use the VRC (Section 8.1.9) to document the following 
information:
-
Axillary temperatures measured Day 1 (day of vaccination) through Day 7 following 
each vaccination; Day 8 through Day 14 following each vaccination if fever is suspected
-
Solicited injection-site AEs (swelling, redness, pain or tenderness, and hard lump) Day 1 
through Day 14 postvaccination
 
 
053XZ2
082QBR

PRODUCT: V114
45
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
-
Solicited systemic AEs (irritability, drowsiness, appetite lost, and hives or welts) Day 1 
through Day 14 postvaccination
-
Any other unsolicited injection-site or systemic AEs Day 1 through Day 14 
postvaccination
-
The limb that was used for the administration of study vaccine
(Note: The study will report injection-site AEs from V114/PCV13 and DTaP-IPV [and 
not from nonstudy concomitant injectable vaccines]; the locations of study vaccines 
administration can be used by the participant’s parent/guardian to monitor the appropriate 
limb for injection-site AEs related to V114/PCV13 and DTaP-IPV)
-
Concomitant medications and nonstudy vaccinations Day 1 through 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.
 
 
053XZ2
082QBR

PRODUCT: V114
46
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the day of allocation/randomization to the first vaccination and from the day of each 
vaccination through 14 days postvaccination. SAEs must also be reported throughout the 
duration of the individual’s participation in the study, regardless of whether or not related to 
the Sponsor’s product.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
1.
A death that occurs prior to the participant completing the study.
OR
2.
An SAE that is considered by an investigator who is a qualified physician to be 
vaccine-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
 
 
053XZ2
082QBR

PRODUCT: V114
47
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion 
of study
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Not applicable since participants are infants.
Not applicable
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.
 
 
053XZ2
082QBR

PRODUCT: V114
48
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are infants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest (ECIs)
There are no events of clinical interest in this study.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study 
vaccine in any 24-hour period.
 
 
053XZ2
082QBR

PRODUCT: V114
49
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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 eCRF data entry guidelines. Paper reporting procedures can be found in the Investigator
Trial File Binder (or equivalent).
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
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 for IgG at the central laboratory stored for future research after
aliquoting samples for completion of immunogenicity
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
 
 
053XZ2
082QBR

PRODUCT: V114
50
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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/vaccination visit 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 or PCV13)
but continue to participate in protocol-specified, AE-monitoring activities as outlined in
Section 1.3, as long as the participant’s legally acceptable representative does not withdraw
consent. Blood draws for immunogenicity testing in the study could occur if agreed to by the
participant’s legally acceptable representative at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to
analyses made after the protocol has been finalized, but prior to unblinding, will be
documented in a supplemental Statistical Analysis Plan (sSAP) and referenced in the Clinical
Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in
the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan
is provided in Sections 9.2 - 9.12.
Trial Design Overview
A Phase I, Double-Blind, Randomized, Multicenter Trial of the Safety, Tolerability, 
and Immunogenicity of V114 in Healthy Japanese Infants
Treatment Assignment
This is a double-blind trial with three vaccination groups. Participants will be 
randomized to V114-SC, V114-IM, and PCV13-SC in a 1:1:1 ratio.
Analysis Populations
Safety
All Participants as Treated (APaT)
Immunogenicity
Primary: Per-protocol (PP)
Primary Endpoints
1.
Solicited injection-site AEs (redness, swelling, hard lump, pain/tenderness) 
from Day 1 through Day 14 postvaccination
2.
Solicited systemic AEs (irritability, drowsiness, hives/welts, appetite loss) from 
Day 1 through Day 14 postvaccination
3.
Vaccine-related SAEs from Day 1 through 1 month PD4
 
 
053XZ2
082QBR

PRODUCT: V114
51
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Secondary Endpoints
The following endpoints at 1 month PD3:
1.
Anti-PnPs serotype-specific IgG response rates (proportion of participants 
meeting serotype-specific IgG threshold value of ≥0.35 μg/mL) for the 15 
serotypes contained in V114
2.
IgG GMCs for the 15 serotypes contained in V114
3.
Proportion of participants meeting threshold values for diphtheria toxin, tetanus 
toxin, pertussis toxin, pertussis FHA as well as polio virus types 1, 2 and 3.
Statistical Methods for 
Key Immunogenicity 
Analyses
The proportion of participants with IgG concentrations ≥0.35 μg/mL at 1 month PD3 
for the 15 serotypes contained in V114 will be summarized by vaccination group. 
Within-group 95% CIs will be calculated based on the method of Clopper and 
Pearson. The between-group differences, along with the corresponding 95% CIs 
based on the method of Miettinen and Nurminen [Miettinen O., et al 1985], will be 
calculated. The proportion of participants meeting threshold values at 1 month PD3 
for diphtheria toxin, tetanus toxin, pertussis toxin, pertussis FHA as well as polio 
virus types 1, 2 and 3 will be analyzed in the same fashion.
The IgG concentrations at 1 month PD3 will be natural log transformed and 
analyzed using an analysis of variance (ANOVA) model with a single factor for 
vaccination group. The within-group means and the between-group mean 
differences, along with the corresponding 95% CIs, will be estimated using this 
model. The point estimates as well as the lower and upper limits of the 95% CIs will 
be exponentiated to obtain the estimates on the original scale for IgG GMCs by 
vaccination group and IgG GMC ratios.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with 
respect to the analyses that will be performed.
Tier 1 safety endpoints include solicited injection-site AEs and solicited systemic 
AEs during Day 1 to Day 14 postvaccination that are specifically prompted for on 
the VRC. Endpoints not defined as Tier 1 will be classified as belonging to "Tier 2" 
or "Tier 3". Tier 2 endpoints include AE summary measures (any AE, any vaccine-
related AE, any SAE, any vaccine-related SAE, discontinuation of study vaccine due 
to an AE), AEs [specific terms as well as system organ classes (SOCs)] that occur in 
at least 4 subjects in any vaccination group, and axillary temperatures (≥37.5 °C, 
≥38.0 °C, ≥39.0 °C, ≥40.0 °C) collected from Day 1 through Day 7.
p-Values (for Tier 1 endpoints) and 95% CIs (for Tier 1 and Tier 2 endpoints) will be 
provided for between-group differences in the percentage of participants with events. 
These analyses will be performed using the Miettinen and Nurminen method.
Interim Analysis
An interim analysis will be performed after all participants continuing on the trial 
have completed the study visit at 1 month PD3 and the data (safety and 
immunogenicity) up to that point have become available. Group summaries of the 
results will be reviewed; however, the study team will remain blinded at the subject 
level. Only designated unblinded Sponsor personnel will review the safety data at 
the subject level, and will be responsible for communicating in a blinded manner to 
the blinded study team. The information noted above will be used to make scientific 
decisions regarding future studies. The conduct of this trial will not be altered by the 
interim analysis.
Multiplicity
Multiplicity adjustment is not planned.
Sample Size and Power
A total of 120 participants will be equally randomized, with 40 participants in each 
of the three vaccination groups. If the true incidence of a particular safety event is 
4%, then there is 80% probability that the event is observed in at least one in 40 
participants.
 
 
053XZ2
082QBR

PRODUCT: V114
52
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this trial will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
This trial will be conducted as a double-blind trial under in-house blinding procedures. The 
Sponsor personnel, except those who are specifically designated to serve as unblinded roles
(see Sections 6.3.3 and 9.7), will remain blinded to the treatment assignment of individual 
participants until the end of the trial. Site personnel, except those who are specifically 
designated to serve as unblinded roles (see Section 6.3.3), as well as participants and their 
parents/legal guardians, will also remain blinded until the end of the trial.
The Clinical Biostatistics department will generate the randomized allocation schedule for
trial treatment assignment. Randomization will be implemented using interactive response
technology (IRT) or its equivalent.
The planned interim analysis is described in Section 9.7. The results of the interim analysis 
will not be shared with the investigators prior to the completion of the trial. Subject-level
unblinding will be restricted to the unblinded statistician and unblinded statistical
programmer performing the interim analysis, as well as designated unblinded Sponsor 
personnel who will review safety data at the subject level. Group summaries will be reviewed 
by the Sponsor’s trial team in order to make scientific decisions for future studies.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety endpoints are listed below.
9.4.1
Immunogenicity Endpoints
The key immunogenicity endpoints include the following, in recipients of V114-SC, V114-
IM and PCV13-SC:
(1) Anti-PnPs serotype-specific IgG response rates (proportion of participants meeting 
serotype-specific IgG threshold value of ≥0.35 μg/mL measured by the PnECL assay) at 
1 month PD3 for the 15 serotypes contained in V114.
(2) Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes contained in V114, based on 
the serotype-specific IgG responses as measured by the PnECL assay at 1 month PD3.
(3) The proportion of participants meeting threshold values at 1 month PD3 for diphtheria
toxin (≥0.1 IU/mL), tetanus toxin (≥0.01 IU/mL), pertussis toxin (≥10 EU/mL), pertussis
FHA (≥10 EU/mL) as well as polio virus types 1 [neutralizing antibody titers (NA) ≥1:8],
2 (NA ≥1:8) and 3 (NA ≥1:8).
 
 
053XZ2
082QBR

PRODUCT: V114
53
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
The same measures at pre Dose 4 and 1 month PD4, as well as GMTs of DTaP-IPV at 1 
month PD3, pre Dose 4 and 1 month PD4 will also be analyzed.
9.4.2
Safety Endpoints
Refer to Section 4.2.1.2 for the description of the safety measurements in this trial.
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this trial. The PP population consists of those participants who are not considered 
protocol violators.
Potential deviations that may result in the exclusion of a participant from the PP population 
for all immunogenicity analyses (serotype-specific IgG and DTaP-IPV at 1 month PD3, pre-
dose 4 and 1 month PD4) include:

Failure to complete vaccination of V114 or PCV13 at Doses 1 through 3 with correct
clinical material and route of administration as per the randomization schedule and
according to the protocol-specified visit window (refer to Section 1.3).

Receipt of prohibited medication or prohibited vaccine prior to study vaccination at Dose 
1, 2 or 3
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 or endpoint 
for analysis) include:

Failure to receive V114 or PCV13 at Dose 4 with correct clinical material and route of 
administration as per the randomization schedule and according to the protocol-specified 
visit window: this will result in the exclusion from all PP analyses (serotype-specific IgG 
and DTaP-IPV) at 1 month PD4.

Failure to complete vaccination of DTaP-IPV at Doses 1 through 3 according to the 
protocol-specified visit window: this will result in the exclusion from the PP analysis of 
DTaP-IPV at all timepoints.

Failure to receive DTaP-IPV at Dose 4 according to the protocol-specified visit window: 
this will result in the exclusion from PP analysis of DTaP-IPV at 1 month PD4.

Receipt of prohibited medication or prohibited vaccine prior to a blood sample 
collection: the impact on the analysis of immunogenicity data will be assessed on a case-
by-case basis.
 
 
053XZ2
082QBR

PRODUCT: V114
54
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018

Collection of blood sample at the time point for the analysis outside of the pre-specified 
window, or lack of valid serology results: this will result in the exclusion from the PP 
analysis for particular timepoint(s) and/or endpoint(s) whose valid results are not 
available.
The final determination on protocol violations for 1 month PD3 analysis will be made prior 
to the database lock at 1 month PD3 for the interim analysis and will be documented in a 
separate memo. Protocol violators at Pre-dose 4 and 1 month PD4 will be identified prior to 
the final database lock at 1 month PD4.
The FAS population will also be used for supplementary analysis of the key immunogenicity 
endpoints. The FAS population consists of all randomized participants who received at least 
one vaccination and have at least one serology result. Participants will be included in the 
vaccination group to which they are randomized for the analysis of immunogenicity data.
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this trial. The APaT 
population consists of all randomized participants who received at least one dose of trial 
vaccine. Participants will be included in the group corresponding to the clinical material and 
route of administration they actually received for the analysis of safety data using the APaT 
population. For most participants this will be the group to which they are randomized. 
Participants who receive incorrect clinical material or whose route of administration is 
incorrect will be included in the group as outlined below:

Participants who receive the same clinical material (V114 or PCV13) with the same 
route of administration throughout the trial will be considered belonging to the group 
corresponding to the clinical material and route of administration.

Participants whose clinical materials (V114 and PCV13) and/or route of administration 
are partially different among the vaccinations will be summarized separately from any of 
the 3 vaccination groups.

Incorrect route of administration for DTaP-IPV will not alter the vaccination group for 
safety analysis; the group will be determined based on the clinical material and route of 
administration for V114 or PCV13 only.
9.6
Statistical Methods
The results from all possible pairwise comparisons (V114-SC vs. PCV13-SC, V114-IM vs. 
PCV13-SC, V114-SC vs. V114-IM) will be presented for those analyses which involve 
calculations of between-group differences.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the secondary objectives. Methods
related to the exploratory objectives will be described in the sSAP.
 
 
053XZ2
082QBR

PRODUCT: V114
55
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
The immunogenicity analyses will be conducted for each serotype separately.
The proportion of participants with IgG concentrations ≥0.35 μg/mL at 1 month PD3 will be 
summarized by vaccination group. Within-group 95% CIs will be calculated based on the 
method of Clopper and Pearson. The between-group differences, along with the 
corresponding 95% CIs based on the method of Miettinen and Nurminen, will be calculated.
The proportion of participants meeting threshold values at 1 month PD3 for diphtheria toxin,
tetanus toxin, pertussis toxin, pertussis FHA as well as polio virus types 1, 2 and 3 will be 
analyzed in the same fashion.
The IgG concentrations at 1 month PD3 will be natural log transformed and analyzed using 
an ANOVA model with a factor for vaccination group. The within-group means and the 
between-group mean differences, along with the corresponding 95% CIs, will be estimated 
using this model. The point estimates as well as the lower and upper limits of the 95% CIs 
will be exponentiated to obtain the estimates on the original scale for IgG GMCs by 
vaccination group and IgG GMC ratios.
Table 4 summarizes key immunogenicity analyses.
Table 4
Analysis Strategy for Key Immunogenicity Variables
Endpoint / Variable
(Description, Time Point)
Statistical 
Method†
Analysis 
Population
Missing Data 
Approach
Secondary objective #1
Proportion of participants with serotype-
specific IgG ≥0.35 μg/mL at 1 month PD 3
Miettinen and 
Nurminen
PP (Primary)
FAS 
(Supportive)
Missing data 
will not be 
imputed
Secondary objective #2
Serotype-specific IgG GMCs at 1 month 
PD3
ANOVA‡
PP (Primary)
FAS 
(Supportive)
Missing data 
will not be 
imputed
Secondary objective #3
Proportion of participants meeting threshold 
values for diphtheria toxin, tetanus toxin,
pertussis toxin, pertussis FHA as well as 
polio virus types 1, 2 and 3 at 1 month PD3
Miettinen and 
Nurminen
PP (Primary)
FAS 
(Supportive)
Missing data 
will not be 
imputed
† Statistical models are described in further detail below:
‡ ANOVA model with natural log-transformed antibody responses as response variable and vaccination group as a 
single factor
IgG = immunoglobulin G, PD = post-dose, GMC = geometric mean concentration, PP = per-protocol, FAS = full 
analysis set, ANOVA = analysis of variance, FHA = filamentous hemagglutinin
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs and body temperature. Analysis will be performed at each dose and across all doses, as 
outlined below.
 
 
053XZ2
082QBR

PRODUCT: V114
56
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
The analysis of safety results will follow a tiered approach (Table 5). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as SOCs) are
either pre-specified as “Tier 1” endpoints, or will be classified as belonging to "Tier 2" or
"Tier 3" based on the number of participants with events.
Tier 1 events
AEs of special interest that are identified a priori constitute “Tier 1” safety endpoints that
will be subject to inferential testing for statistical significance (at =0.05, two-sided) with p-
values and 95% CIs to be provided for between-group differences in the proportion of
participants with events. These analyses will be performed using the Miettinen and Nurminen 
method, an unconditional, asymptotic method. For this protocol, Tier 1 safety endpoints
include solicited injection-site AEs (redness, swelling, hard lump, pain/tenderness) and
solicited systemic AEs (irritability, drowsiness, hives/welts, appetite loss) during Day 1 to
Day 14 postvaccination that are specifically prompted for on the VRC.
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 Miettinen and Nurminen method.
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 percent 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 vaccination group, 
AE summary measures (any AE, any vaccine-related AE, any SAE, any vaccine-related SAE,
discontinuation of study vaccine due to an AE), and axillary temperatures (≥37.5 °C, 
≥38.0 °C, ≥39.0 °C, ≥40.0 °C) collected from Day 1 through Day 7, will also be treated as 
Tier 2 events. For the purpose of the analysis of safety data in this study, an AE will be 
considered related to study vaccine if it is considered related to V114/PCV13 or DTaP-IPV.
Tier 3 events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point
estimates by treatment group will be provided for Tier 3 safety parameters.
 
 
053XZ2
082QBR

PRODUCT: V114
57
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Table 5
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoints
p-Value
95% CI
Descriptive 
statistics
Tier 1
Injection-site redness (Days 1 to 14)
X
X
X
Injection-site swelling (Days 1 to 14)
Injection-site hard lump (Days 1 to 14)
Injection-site pain/tenderness (Days 1 to 14)
Irritability (Days 1 to 14)
Drowsiness (Days 1 to 14)
Hives/welts (Days 1 to 14)
Appetite loss (Days 1 to 14)
Tier 2
Any AE
X
X
Any vaccine-related AE
Any SAE
Any vaccine-related SAE
Discontinuation of study vaccine due to an 
AE
Specific AEs or SOCs† (incidence ≥4 
participants in any vaccination group)
Axillary temperature (Days 1 to 7)
Tier 3
Specific AEs or SOCs† (incidence <4 
participants in all vaccination groups)
X
† Includes only those endpoints not pre-specified as Tier 1 or Tier 2.
X = Results will be provided.
9.6.3
Summaries of Demographics 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 subjects 
randomized and vaccinated, and the reasons for discontinuation, will be displayed by group. 
Demographic variables, prior and concomitant therapies and vaccines will be summarized by 
group.
9.7
Interim Analyses
An interim analysis will be performed after all participants continuing on the trial have
completed the study visit at 1 month PD3 and the data (safety and immunogenicity) up to that
point have become available. An unblinded statistician and a statistical programmer who are
otherwise not involved in the trial or the project will have access to the treatment assignment
of individual participants to analyze the data. The project team will review group level
summary results but will not be unblinded at the subject level. Designated unblinded Sponsor
personnel will review subject level safety data and communicate their recommendation 
regarding the future study to the project team in a manner that maintains subject level 
blinding for blinded Sponsor personnel. The information noted above will be used to make
scientific decisions regarding the future study. The results of the interim analysis will not be
 
 
053XZ2
082QBR

PRODUCT: V114
58
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
shared with the investigators until the end of the trial. The conduct of this trial will not be
altered by the interim analysis.
9.8
Multiplicity
Multiplicity adjustment is not planned.
9.9
Sample Size and Power Calculations
This is an estimation study. A total of 120 participants will be equally randomized, with 40 
participants in each of the three vaccination groups (V114-SC, V114-IM and PCV13-SC).
Safety
If the true incidence of a particular safety event is 4%, then there is 80% probability that the
event is observed in at least one in 40 participants. Detectable differences with 80% power 
with respect to the percent incidence of a particular safety event are summarized in Table 6
[N=40 / arm, =0.05 (two-sided)].
Table 6
Detectable Difference in the Percent Incidence of a Safety Event 
[N=40 / arm, =0.05 (two-sided)]
True % incidence
Detectable 
difference
with 80% power
Group 1
Group 2†
2.5%
5.0%
10.0%
20.0%
40.0%
20.3%
26.2%
35.2%
49.3%
70.1%
17.8%
21.2%
25.2%
29.3%
30.1%
† Corresponding to the detectable difference with 80% power. 
Immunogenicity at 1 month PD3 (proportion of participants achieving threshold)
It is expected that 36 participants per arm will be included in the PP population at 1 month 
PD3.
The between-group differences and corresponding 95% CIs for the proportion of participants 
achieving the threshold value for the IgG of a particular pneumococcal serotype or a 
component of DTaP-IPV (diphtheria toxin, tetanus toxin, pertussis toxin, pertussis FHA, or
polio virus types 1, 2 or 3) will be as follows, depending on the numbers of participants 
achieving the threshold value in the two groups.
 
 
053XZ2
082QBR

PRODUCT: V114
59
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Table 7
Between-group Difference Estimates in the Proportion of Participants Achieving 
Threshold Value for Immunogenicity Measurements (N=36 / arm)
Number of participants 
achieving threshold value
Proportion of participants 
achieving threshold value
Difference in 
proportion
Group 1 – Group 2
Estimate (95% CI)
Group 1
Group 2
Group 1
Group 2
31
31
86.1%
86.1%
0.0% (-17.2%, 17.2%)
33
91.7%
5.6% (-10.2%, 21.9%)
35
97.2%
11.1% (-2.2%, 26.5%)
31
33
86.1%
91.7%
-5.6% (-21.9%, 
10.2%)
33
91.7%
0.0% (-14.9%, 14.9%)
35
97.2%
5.6% (-7.0%, 19.6%)
31
35
86.1%
97.2%
-11.1% (-26.5%, 
2.2%)
33
91.7%
-5.6% (-19.6%, 7.0%)
35
97.2%
0.0% (-11.9%, 11.9%)
9.10
Subgroup Analyses
No subgroup analysis is planned.
9.11
Compliance (Medication Adherence)
The number and proportion of randomized participants receiving each vaccination will be
summarized
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized
participants administered V114 or PCV13 and the number and proportion of randomized
participants administered DTaP-IPV at each schedule.
 
 
053XZ2
082QBR

PRODUCT: V114
60
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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 
 
 
053XZ2
082QBR

PRODUCT: V114
61
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
 
 
053XZ2
082QBR

PRODUCT: V114
62
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
053XZ2
082QBR

PRODUCT: V114
63
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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
Internal Safety Data Assessment
Internal safety data assessment will be conducted at the interim analysis in this study. The 
assessment will be conducted by the members of Sponsor senior management, none of whom 
are directly associated with the conduct of the study.  The member of internal safety data 
assessment will review the interim safety data that are unblinded at the subject level (Section 
9.7).  The information noted above will be used to make scientific decisions regarding the 
subsequent phases of V114 clinical development in Japanese pediatric. The results of the 
interim analysis will not be shared with the investigators and the project team until the end of 
the trial.
Specific details regarding responsibilities for internal safety data assessment will be 
described in separate internal procedures manual.
 
 
053XZ2
082QBR

PRODUCT: V114
64
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
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.
 
 
053XZ2
082QBR

PRODUCT: V114
65
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
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 
 
 
053XZ2
082QBR

PRODUCT: V114
66
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
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.
 
 
053XZ2
082QBR

PRODUCT: V114
67
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
10.2
Appendix 2: Clinical Laboratory Tests
Not applicable.
 
 
053XZ2
082QBR

PRODUCT: V114
68
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.”
 
 
053XZ2
082QBR

PRODUCT: V114
69
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
 
 
053XZ2
082QBR

PRODUCT: V114
70
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
-
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.
 
 
053XZ2
082QBR

PRODUCT: V114
71
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
-
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
-
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
-
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).

Injection site redness or swelling 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?
 
 
053XZ2
082QBR

PRODUCT: V114
72
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance 
assessment (diary, etc.), seroconversion or identification of vaccine virus in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE 
compatible with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such 
as underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the 
study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s product(s) is/are 
used only 1 time.)
 
 
053XZ2
082QBR

PRODUCT: V114
73
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor’s product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to 
be indicative of a Sponsor’s product relationship).
- Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal 
sequence of the AE onset relative to the administration of the Sponsor’s 
product is reasonable. The AE is more likely explained by the 
Sponsor’s product than by another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal 
sequence of the AE onset relative to administration of the Sponsor’s 
product is not reasonable OR the AE is more likely explained by 
another cause than the Sponsor’s product. (Also entered for a 
participant with overdose without an associated AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
 
 
053XZ2
082QBR

PRODUCT: V114
74
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Follow-up of AE and SAE
-
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
-
New or updated information will be recorded in the CRF.
-
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
-
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
-
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
-
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
-
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
-
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
 
 
053XZ2
082QBR

PRODUCT: V114
75
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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).
 
 
053XZ2
082QBR

PRODUCT: V114
76
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
053XZ2
082QBR

PRODUCT: V114
77
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Not applicable.
 
 
053XZ2
082QBR

PRODUCT: V114
78
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b.
Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.
DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.
Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment 
in the future biomedical research substudy
 
 
053XZ2
082QBR

PRODUCT: V114
79
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
 
 
053XZ2
082QBR

PRODUCT: V114
80
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
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.
 
 
053XZ2
082QBR

PRODUCT: V114
81
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.
Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.
Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10.
Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.
Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
 
 
053XZ2
082QBR

PRODUCT: V114
82
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
13.
References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-
pharmacogenetics-genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide 
for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
053XZ2
082QBR

PRODUCT: V114
83
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
053XZ2
082QBR

PRODUCT: V114
84
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event
APaT
all participants as treated
ANOVA
analysis of variance
CSR
Clinical Study Report
CDC
Centers for Disease Control and Prevention
ECG
electrocardiogram
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
FAS
full analysis set
FDAAA
Food and Drug Administration Amendments Act
FBR
Future Biomedical Research
GCP
Good Clinical Practice
GMC
geometric mean concentration 
GMT
geometric mean titer
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IPD
invasive pneumococcal disease
IRB
Institutional Review Board
MSD
Merck Sharp & Dohme Corp. 
NIP
National Immunization Program
PCV
pneumococcal conjugate vaccine
PD
pneumococcal disease
PD3
post-Dose 3 
PD4
post-Dose 4
PnECL
pneumococcal electrochemiluminescence
PnPs
pneumococcal polysaccharide 
PP
Per-protocol
RNA
ribonucleic acid
SAE
serious adverse event
SoA
schedule of activities
SOC
system organ classes
sSAP
supplemental statistical analysis plan
VRC
Vaccination Report Card
WHO
World Health Organization
 
 
053XZ2
082QBR

PRODUCT: V114
85
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
11
REFERENCES
[Cherian T. 2007]
Cherian T. WHO expert consultation on serotype
composition of pneumococcal conjugate vaccines for use in
resource-poor developing countries, 26-27 October 2006,
Geneva. Vaccine. 2007;25:6557-64.
[Nakano S., et al 2016]
Nakano S, Fujisawa T, Ito Y, et al. Serotypes, antimicrobial
susceptibility, and molecular epidemiology of invasive and
non-invasive Streptococcus pneumoniae isolates in pediatric
patients after the introduction of 13-valent conjugate vaccine
in a nationwide surveillance study conducted in Japan in
2012-2014. Vaccine. 2016; 34:67-76.
[Golden AR., et al 2016]
Golden AR, Adam HJ, Zhanel GG, et al. Invasive 
Streptococcus pneumoniae in Canada, 2011–2014: 
Characterization of new candidate 15-valent pneumococcal 
conjugate vaccine serotypes 22F and 33F. Vaccine. 2016; 
34:2527-30.
[Pilishvili T., et al 2010]
Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions
in invasive pneumococcal disease in the era of conjugate
vaccine. J Infect Dis. 2010; 201:32-41.
[Robinson KA., et al, 2001]
Robinson KA, Baughman W, Rothrock G, et al.
Epidemiology of invasive Streptococcus pneumoniae
infections in the United States, 1995-1998: Opportunities for
prevention in the conjugate vaccine era. JAMA. 2001; 
285:1729-35.
[Centers for Disease Control
and Prevention 1997]
Centers for Disease Control and Prevention. Active Bacterial 
Core Surveillance (ABCS) Report Emerging Infections 
Program Network Streptococcus pneumoniae, 1997
[Centers for Disease Control
and Prevention 2016]
Centers for Disease Control and Prevention. Active Bacterial 
Core Surveillance (ABCS) Report Emerging Infections 
Program Network Streptococcus pneumoniae, 2016
[Chiba N., et al 2014]
Chiba N, Morozumi M, Shouji M, et al. Changes in Capsule 
and Drug Resistance of Pneumococci after Introduction of 
PCV7, Japan, 2010–2013. Emerg Infect Dis. 2014; 20:1132-
9. 
[Japan Pediatric Society 2014]
Japan Pediatric Society. Request for guideline of
administration method of vaccination. 2014Jun14 [in 
Japanese]
 
 
053XZ2
082QBR

PRODUCT: V114
86
PROTOCOL/AMENDMENT NO.: 028-00
V114-028-00 FINAL PROTOCOL
12-DEC-2018
[World Health Organization 
2017-1]
World Health Organization. Weekly epidemiological record
(Diphtheria vaccine: WHO position paper – August 2017).
2017, 92, 417-36.
[World Health Organization 
2017-2]
World Health Organization. Weekly epidemiological record
(Tetanus vaccines: WHO position paper – February 2017).
2017, 92, 53-76.
[Ministry of Health, Labor and 
Welfare., et al 2013]
Ministry of Health, Labor and Welfare, Infectious disease 
Surveillance Center.  Infectious disease epidemic prediction 
research report. 2013.
https://www.niid.go.jp/niid/images/epi/yosoku/AnnReport/20
13-all.pdf
[Plotkin PA. 2010]
Plotkin PA. Correlates of Protection Induced by Vaccination.
Clin Vaccine Immunol. 2010; 17:1055-65.
[Kato T. 1990]
Kato T. DTaP. J Pediatric Practice 1990; 53:2275-81 [in 
Japanese]
[Simons FE., et al 2011]
Simons FE, Ardusso LR, Bilò MB, et al. World Allergy 
Organization Guidelines for the Assessment and Management 
of Anaphlaxis. 2011; 2:13-37.
[Miettinen, O., et al 1985].
Miettinen O, Nurminen M. Comparative analysis of two 
rates. Stat Med 1985; 4:213-26.
 
 
053XZ2
082QBR

V114
PAGE 1
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
Supplemental Statistical Analysis Plan (sSAP)
1
INTROCUCTION
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 analyses 
for this trial, this supplemental SAP 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
[15-Nov-2019]
Section 3.6.1 Statistical Methods for Immunogenicity Analyses
The following analyses have been added:

Analyses of IgG (proportion of participants ≥0.35 µg/mL and GMC) in subjects with 
baseline IgG <0.35 µg/mL.

Reverse cumulative distribution curves
Appendix
Reference to the patient registration center has been removed, and the reference to the 
unblinded clinical scientist has been added.
05CNPJ
082QBW

V114
PAGE 2
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
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 – 3.12.
Trial Design Overview
A Phase I, Double-Blind, Randomized, Multicenter Trial of the Safety, Tolerability, and 
Immunogenicity of V114 in Healthy Japanese Infants
Treatment Assignment
This is a double-blind trial with three vaccination groups. Participants will be randomized to 
V114-subcutaneous (SC), V114-intramuscular (IM), and PCV13-SC in a 1:1:1 ratio.
Analysis Populations
Safety
All Participants as Treated (APaT)
Immunogenicity
Primary: Per-protocol (PP)
Primary Endpoints
Solicited injection-site adverse events (AEs) (redness, swelling, hard lump, pain/tenderness)
from Day 1 through Day 14 postvaccination
Solicited systemic AEs (irritability, drowsiness, hives/welts, appetite loss) from Day 1 
through Day 14 postvaccination
Vaccine-related serious AEs (SAEs) from Day 1 through 1 month post-Dose 4 (PD4)
Secondary Endpoints
The following endpoints at 1 month post-Dose 3 (PD3):
Anti-pneumococcal polysaccharide (PnPs) serotype-specific immunogloburin G (IgG)
response rates (proportion of participants meeting serotype-specific IgG threshold value of 
≥0.35 μg/mL) for the 15 serotypes contained in V114
IgG geometric mean concentrations (GMCs) for the 15 serotypes contained in V114
Proportion of participants meeting threshold values for diphtheria toxin, tetanus toxin, 
pertussis toxin, pertussis filamentous hemagglutinin (FHA) as well as polio virus types 1, 2
and 3.
05CNPJ
082QBW

V114
PAGE 3
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
Statistical Methods for Key 
Immunogenicity Analyses
The proportion of participants with IgG concentrations ≥0.35 μg/mL at 1 month PD3 for the 
15 serotypes contained in V114 will be summarized by vaccination group. Within-group 95% 
confidence intervals (CIs) will be calculated based on the method of Clopper and Pearson.
The between-group differences, along with the corresponding 95% CIs based on the method 
of Miettinen and Nurminen [Miettinen O., et al 1985], will be calculated. The proportion of 
participants meeting threshold values at 1 month PD3 for diphtheria toxin, tetanus toxin,
pertussis toxin, pertussis FHA as well as polio virus types 1, 2 and 3 will be analyzed in the 
same fashion.
The IgG concentrations at 1 month PD3 will be natural log transformed and analyzed using an 
analysis of variance (ANOVA) model with a single factor for vaccination group. The within-
group means and the between-group mean differences, along with the corresponding 95% CIs, 
will be estimated using this model. The point estimates as well as the lower and upper limits 
of the 95% CIs will be exponentiated to obtain the estimates on the original scale for IgG 
GMCs by vaccination group and IgG GMC ratios.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with respect to the 
analyses that will be performed.
Tier 1 safety endpoints include solicited injection-site AEs and solicited systemic AEs during 
Day 1 to Day 14 postvaccination that are specifically prompted for on the vaccination report 
card (VRC). Endpoints not defined as Tier 1 will be classified as belonging to "Tier 2" or 
"Tier 3". Tier 2 endpoints include AE summary measures (any AE, any vaccine-related AE, 
any SAE, any vaccine-related SAE, discontinuation of study vaccine due to an AE), AEs 
[specific terms as well as system organ classes (SOCs)] that occur in at least 4 subjects in any 
vaccination group, and axillary temperatures (≥37.5 °C, ≥38.0 °C, ≥39.0 °C, ≥40.0 °C) 
collected from Day 1 through Day 7.
p-Values (for Tier 1 endpoints) and 95% CIs (for Tier 1 and Tier 2 endpoints) will be 
provided for between-group differences in the percentage of participants with events. These 
analyses will be performed using the Miettinen and Nurminen method.
Interim Analysis
An interim analysis will be performed after all participants continuing on the trial 
have completed the study visit at 1 month PD3 and the data (safety and 
immunogenicity) up to that point have become available. Group summaries of the 
results will be reviewed; however, the study team will remain blinded at the subject 
level. Only designated unblinded Sponsor personnel will review the safety data at 
the subject level, and will be responsible for communicating in a blinded manner to 
the blinded study team. The information noted above will be used to make scientific 
decisions regarding future studies. The conduct of this trial will not be altered by the 
interim analysis.
Multiplicity
Multiplicity adjustment is not planned.
Sample Size and Power
A total of 120 participants will be equally randomized, with 40 participants in each of the 
three vaccination groups. If the true incidence of a particular safety event is 4%, then there is 
80% probability that the event is observed in at least one in 40 participants.
05CNPJ
082QBW

V114
PAGE 4
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
3.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this trial will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
This trial will be conducted as a double-blind trial under in-house blinding procedures. The 
Sponsor personnel, except those who are specifically designated to serve as unblinded roles
(see Section 6.3.3 of the protocol, and Section 3.7), will remain blinded to the treatment 
assignment of individual participants until the end of the trial. Site personnel, except those 
who are specifically designated to serve as unblinded roles (see Section 6.3.3 of the 
protocol), as well as participants and their parents/legal guardians, will also remain blinded 
until the end of the trial.
The Clinical Biostatistics department will generate the randomized allocation schedule for
trial treatment assignment. Randomization will be implemented using interactive response
technology (IRT) or its equivalent.
The planned interim analysis is described in Section 3.7. The results of the interim analysis 
will not be shared with the investigators prior to the completion of the trial. Subject-level
unblinding will be restricted to the unblinded statistician and unblinded statistical 
programmer performing the interim analysis, as well as designated unblinded Sponsor 
personnel who will review safety data at the subject level. Group summaries will be reviewed 
by the Sponsor’s trial team in order to make scientific decisions for future studies.
3.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3 of the protocol.
3.4
Analysis Endpoints
Immunogenicity and safety endpoints are listed below.
3.4.1
Immunogenicity Endpoints
The key immunogenicity endpoints include the following, in recipients of V114-SC, V114-
IM and PCV13-SC:
(1) Anti-PnPs serotype-specific IgG response rates [proportion of participants meeting 
serotype-specific IgG threshold value of ≥0.35 μg/mL measured by the pneumococcal 
electrochemiluminescence (PnECL) assay] at 1 month PD3 for the 15 serotypes 
contained in V114.
(2) Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes contained in V114, based on 
the serotype-specific IgG responses as measured by the PnECL assay at 1 month PD3.
(3) The proportion of participants meeting threshold values at 1 month PD3 for diphtheria 
toxin (≥0.1 IU/mL), tetanus toxin (≥0.01 IU/mL), pertussis toxin (≥10 EU/mL), pertussis 
FHA (≥10 EU/mL) as well as polio virus types 1 [neutralizing antibody titers (NA) 
≥1:8], 2 (NA ≥1:8) and 3 (NA ≥1:8).
05CNPJ
082QBW

V114
PAGE 5
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
The same measures at pre Dose 4 and 1 month PD4, as well as geometric mean titers (GMTs)
of diphtheria, tetanus, acellular pertussis, inactivated polio vaccine (DTaP-IPV) at 1 month 
PD3, pre Dose 4 and 1 month PD4 will also be analyzed.
3.4.2
Safety Endpoints
Refer to Section 4.2.1.2 of the protocol for the description of the safety measurements in this 
trial.
3.5
Analysis Populations
3.5.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this trial. The PP population consists of those participants who are not considered 
protocol violators.
Potential deviations that may result in the exclusion of a participant from the PP population 
for all immunogenicity analyses (serotype-specific IgG and DTaP-IPV at 1 month PD3, pre-
dose 4 and 1 month PD4) include:

Failure to complete vaccination of V114 or PCV13 at Doses 1 through 3 with correct 
clinical material and route of administration as per the randomization schedule and 
according to the protocol-specified visit window (refer to Section 1.3 of the protocol).

Receipt of prohibited medication or prohibited vaccine prior to study vaccination at Dose 
1, 2 or 3
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 or endpoint 
for analysis) include:

Failure to receive V114 or PCV13 at Dose 4 with correct clinical material and route of 
administration as per the randomization schedule and according to the protocol-specified 
visit window: this will result in the exclusion from all PP analyses (serotype-specific IgG 
and DTaP-IPV) at 1 month PD4.

Failure to complete vaccination of DTaP-IPV at Doses 1 through 3 according to the 
protocol-specified visit window: this will result in the exclusion from the PP analysis of 
DTaP-IPV at all timepoints.

Failure to receive DTaP-IPV at Dose 4 according to the protocol-specified visit window: 
this will result in the exclusion from PP analysis of DTaP-IPV at 1 month PD4.

Receipt of prohibited medication or prohibited vaccine prior to a blood sample 
collection: the impact on the analysis of immunogenicity data will be assessed on a case-
by-case basis.

Collection of blood sample at the time point for the analysis outside of the pre-specified 
window, or lack of valid serology results: this will result in the exclusion from the PP 
analysis for particular timepoint(s) and/or endpoint(s) whose valid results are not 
available.
05CNPJ
082QBW

V114
PAGE 6
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
The final determination on protocol violations for 1 month PD3 analysis will be made prior 
to the database lock at 1 month PD3 for the interim analysis and will be documented in a 
separate memo. Protocol violators at Pre-dose 4 and 1 month PD4 will be identified prior to 
the final database lock at 1 month PD4.
The full analysis set (FAS) population will also be used for supplementary analysis of the 
key immunogenicity endpoints. The FAS population consists of all randomized participants 
who received at least one vaccination and have at least one serology result. Participants will 
be included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data.
3.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this trial. The APaT 
population consists of all randomized participants who received at least one dose of trial 
vaccine. Participants will be included in the group corresponding to the clinical material and 
route of administration they actually received for the analysis of safety data using the APaT 
population. For most participants this will be the group to which they are randomized. 
Participants who receive incorrect clinical material or whose route of administration is 
incorrect will be included in the group as outlined below:

Participants who receive the same clinical material (V114 or PCV13) with the same 
route of administration throughout the trial will be considered belonging to the group 
corresponding to the clinical material and route of administration.

Participants whose clinical materials (V114 and PCV13) and/or route of administration 
are partially different among the vaccinations will be summarized separately from any of 
the 3 vaccination groups.

Incorrect route of administration for DTaP-IPV will not alter the vaccination group for 
safety analysis; the group will be determined based on the clinical material and route of 
administration for V114 or PCV13 only.
05CNPJ
082QBW

V114
PAGE 7
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
3.6
Statistical Methods
The results from all possible pairwise comparisons (V114-SC vs. PCV13-SC, V114-IM vs. 
PCV13-SC, V114-SC vs. V114-IM) will be presented for those analyses which involve 
calculations of between-group differences.
3.6.1
Statistical Methods for Immunogenicity Analyses
The immunogenicity analyses will be conducted for each serotype separately.
The proportion of participants with IgG concentrations ≥0.35 μg/mL at 1 month PD3 will be 
summarized by vaccination group. Within-group 95% CIs will be calculated based on the 
method of Clopper and Pearson. The between-group differences, along with the 
corresponding 95% CIs based on the method of Miettinen and Nurminen, will be calculated.
The proportion of participants meeting threshold values at 1 month PD3 for diphtheria toxin, 
tetanus toxin, pertussis toxin, pertussis FHA as well as polio virus types 1, 2 and 3 will be 
analyzed in the same fashion. The data (serotype-specific IgGs as well as diphtheria toxin, 
tetanus toxin, pertussis toxin, pertussis FHA as well as polio virus types 1, 2 and 3) obtained 
at pre Dose 4 and 1 month PD4 will also be analysed in the same fashion.
The IgG concentrations at 1 month PD3 will be natural log transformed and analyzed using 
an ANOVA model with a factor for vaccination group. The within-group means and the 
between-group mean differences, along with the corresponding 95% CIs, will be estimated 
using this model. The point estimates as well as the lower and upper limits of the 95% CIs 
will be exponentiated to obtain the estimates on the original scale for IgG GMCs by 
vaccination group and IgG GMC ratios. The serotype-specific IgG concentrations obtained at 
pre Dose 4 and 1 month PD4, as well as the antibody titers for diphtheria toxin, tetanus toxin, 
pertussis toxin, pertussis FHA and polio virus types 1, 2 and 3 obtained at 1 month PD3, pre 
Dose 4 and 1 month PD4 will be analyzed in the same fashion.
The same analysis will also be peformed for IgG (proportion of participants concentrations 
≥0.35 µg/mL and GMC) in subjects whose baseline IgG were <0.35 µg/mL.
For concentration or titer measurements that are smaller than the lower bound of the assay 
detectable range, half of the lower bound will be used for analyses.
Reverse cumulative distribution curves will be drawn by serotype and timepoint.
Table 1 summarizes immunogenicity analyses.
05CNPJ
082QBW

V114
PAGE 8
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
Table 1
Analysis Strategy for Immunogenicity Variables
Endpoint / Variable
(Description, Time Point)
Statistical 
Method†
Analysis 
Population
Missing Data 
Approach
Secondary objective #1
Proportion of participants with serotype-
specific IgG ≥0.35 μg/mL at 1 month PD 3
Miettinen and 
Nurminen
PP (Primary)
FAS (Supportive)
Missing data will 
not be imputed
Secondary objective #2
Serotype-specific IgG GMCs at 1 month 
PD3
ANOVA‡
PP (Primary)
FAS (Supportive)
Missing data will 
not be imputed
Secondary objective #3
Proportion of participants meeting threshold 
values for diphtheria toxin, tetanus toxin,
pertussis toxin, pertussis FHA as well as 
polio virus types 1, 2 and 3 at 1 month PD3
Miettinen and 
Nurminen
PP (Primary)
FAS (Supportive)
Missing data will 
not be imputed
Tertiary/Exploratory Objective #1
Proportion of participants with serotype-
specific IgG ≥0.35 μg/mL at:

Pre Dose 4

1 month PD4
Miettinen and 
Nurminen
PP
Missing data will 
not be imputed
Tertiary/Exploratory Objective #2
Serotype-specific IgG GMCs at:

Pre Dose 4

1 month PD4
ANOVA‡
PP
Missing data will 
not be imputed
Tertiary/Exploratory Objective #3
Proportion of participants meeting threshold 
values for diphtheria toxin, tetanus toxin,
pertussis toxin, pertussis FHA as well as 
polio virus types 1, 2 and 3 at:

Pre Dose 4

1 month PD4
Miettinen and 
Nurminen
PP
Missing data will 
not be imputed
Tertiary/Exploratory Objective #4
GMTs for diphtheria toxin, tetanus toxin,
pertussis toxin, pertussis FHA as well as 
polio virus types 1, 2 and 3 at:

1 month PD3

Pre Dose 4

1 month PD4
ANOVA‡
PP
Missing data will 
not be imputed
† Statistical models are described in further detail below:
‡ ANOVA model with natural log-transformed antibody responses as response variable and vaccination group as a 
single factor
IgG = immunoglobulin G, PD = post-dose, GMC = geometric mean concentration, PP = per-protocol, FAS = full 
analysis set, ANOVA = analysis of variance, FHA = filamentous hemagglutinin
05CNPJ
082QBW

V114
PAGE 9
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and body temperature. Analysis will be performed at each dose and across all doses, as 
outlined below.
The analysis of safety results will follow a tiered approach (Table 2). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as SOCs) are 
either pre-specified as “Tier 1” endpoints, or will be classified as belonging to "Tier 2" or 
"Tier 3" based on the number of participants with events.
Tier 1 events
AEs of special interest that are identified a priori constitute “Tier 1” safety endpoints that 
will be subject to inferential testing for statistical significance (at =0.05, two-sided) with p-
values and 95% CIs to be provided for between-group differences in the proportion of 
participants with events. These analyses will be performed using the Miettinen and Nurminen 
method, an unconditional, asymptotic method. For this protocol, Tier 1 safety endpoints 
include solicited injection-site AEs (redness, swelling, hard lump, pain/tenderness) and 
solicited systemic AEs (irritability, drowsiness, hives/welts, appetite loss) during Day 1 to 
Day 14 postvaccination that are specifically prompted for on the VRC.
In addition, solicited injection-site AEs listed above will be summarized separately by study 
vaccine [V114/PCV13 (V114-SC, V114-IM, PCV13-SC), DTaP-IPV].
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 Miettinen and Nurminen method.
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 percent 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 vaccination group, 
AE summary measures (any AE, any vaccine-related AE, any SAE, any vaccine-related 
SAE, discontinuation of study vaccine due to an AE), and axillary temperatures (≥37.5 °C, 
≥38.0 °C, ≥39.0 °C, ≥40.0 °C) collected from Day 1 through Day 7, will also be treated as 
Tier 2 events. For the purpose of the analysis of safety data in this study, an AE will be 
considered related to study vaccine if it is considered related to V114/PCV13 or DTaP-IPV.
05CNPJ
082QBW

V114
PAGE 10
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
Tier 3 events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group will be provided for Tier 3 safety parameters.
Table 2
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoints
p-Value
95% CI
Descriptive 
statistics
Tier 1
Injection-site redness (Days 1 to 14)
X
X
X
Injection-site swelling (Days 1 to 14)
Injection-site hard lump (Days 1 to 14)
Injection-site pain/tenderness (Days 1 to 14)
Irritability (Days 1 to 14)
Drowsiness (Days 1 to 14)
Hives/welts (Days 1 to 14)
Appetite loss (Days 1 to 14)
Tier 2
Any AE
X
X
Any vaccine-related AE
Any SAE
Any vaccine-related SAE
Discontinuation of study vaccine due to an 
AE
Specific AEs or SOCs† (incidence ≥4 
participants in any vaccination group)
Axillary temperature (Days 1 to 7)
Tier 3
Specific AEs or SOCs† (incidence <4 
participants in all vaccination groups)
X
† Includes only those endpoints not pre-specified as Tier 1 or Tier 2.
X = Results will be provided.
3.6.3
Summaries of Demographics 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 subjects 
randomized and vaccinated, and the reasons for discontinuation, will be displayed by group. 
Demographic variables, prior and concomitant therapies and vaccines will be summarized by 
group.
The proportion of participants with serotype-specific IgG concentrations at baseline above 
the lower bound of the assay detectable range will be summarized by vaccination group.
05CNPJ
082QBW

V114
PAGE 11
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
3.7
Interim Analyses
An interim analysis will be performed after all participants continuing on the trial have 
completed the study visit at 1 month PD3 and the data (safety and immunogenicity) up to that 
point have become available. An unblinded statistician and a statistical programmer who are 
otherwise not involved in the trial or the project will have access to the treatment assignment 
of individual participants to analyze the data. The project team will review group level 
summary results but will not be unblinded at the subject level. (See Appendix for details.) 
Designated unblinded Sponsor personnel will review subject level safety data and 
communicate their recommendation regarding the future study to the project team in a 
manner that maintains subject level blinding for blinded Sponsor personnel. The information
noted above will be used to make scientific decisions regarding the future study. The results 
of the interim analysis will not be shared with the investigators until the end of the trial. The 
conduct of this trial will not be altered by the interim analysis.
3.8
Multiplicity
Multiplicity adjustment is not planned.
3.9
Sample Size and Power Calculations
This is an estimation study. A total of 120 participants will be equally randomized, with 40 
participants in each of the three vaccination groups (V114-SC, V114-IM and PCV13-SC).
Safety
If the true incidence of a particular safety event is 4%, then there is 80% probability that the 
event is observed in at least one in 40 participants. Detectable differences with 80% power 
with respect to the percent incidence of a particular safety event are summarized in Table 3
[N=40 / arm, =0.05 (two-sided)].
Table 3
Detectable Difference in the Percent Incidence of a Safety Event 
[N=40 / arm, =0.05 (two-sided)]
True % incidence
Detectable difference
with 80% power
Group 1
Group 2†
2.5%
5.0%
10.0%
20.0%
40.0%
20.3%
26.2%
35.2%
49.3%
70.1%
17.8%
21.2%
25.2%
29.3%
30.1%
† Corresponding to the detectable difference with 80% power. 
Immunogenicity at 1 month PD3 (proportion of participants achieving threshold)
It is expected that 36 participants per arm will be included in the PP population at 1 month 
PD3.
05CNPJ
082QBW

V114
PAGE 12
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
The between-group differences and corresponding 95% CIs for the proportion of participants 
achieving the threshold value for the IgG of a particular pneumococcal serotype or a 
component of DTaP-IPV (diphtheria toxin, tetanus toxin, pertussis toxin, pertussis FHA, or
polio virus types 1, 2 or 3) will be as follows, depending on the numbers of participants 
achieving the threshold value in the two groups.
Table 4
Between-group Difference Estimates in the Proportion of Participants Achieving 
Threshold Value for Immunogenicity Measurements (N=36 / arm)
Number of participants 
achieving threshold 
value
Proportion of participants 
achieving threshold value
Difference in 
proportion
Group 1 – Group 2
Estimate (95% CI)
Group 1
Group 2
Group 1
Group 2
31
31
86.1%
86.1%
0.0% (-17.2%, 17.2%)
33
91.7%
5.6% (-10.2%, 21.9%)
35
97.2%
11.1% (-2.2%, 26.5%)
31
33
86.1%
91.7%
-5.6% (-21.9%, 10.2%)
33
91.7%
0.0% (-14.9%, 14.9%)
35
97.2%
5.6% (-7.0%, 19.6%)
31
35
86.1%
97.2%
-11.1% (-26.5%, 2.2%)
33
91.7%
-5.6% (-19.6%, 7.0%)
35
97.2%
0.0% (-11.9%, 11.9%)
3.10
Subgroup Analyses
No subgroup analysis is planned.
3.11
Compliance (Medication Adherence)
The number and proportion of randomized participants receiving each vaccination will be 
summarized
3.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V114 or PCV13 and the number and proportion of randomized 
participants administered DTaP-IPV at each schedule.
05CNPJ
082QBW

V114
PAGE 13
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
APPENDIX
Access control of study data and results at interim analysis
Access to the data and results of the interim analysis will be restricted (See Section 3.7). For 
this purpose, access to the study folders within the computing platform for analysis and 
reporting will be controlled as follows.
Table 5
Access granted by folder and membership
CPI region
TEST
PROD
PROD
Folder name (under “v114-pcv”)
prot028-ia
prot028-ia
prot028-ia-summary
Folder use
Develop analysis 
programs under 
blinded 
environment
Perform interim 
analysis under 
unblinded 
environment
Group summary 
results of interim 
analysis results 
posted
Project team
Y
N
Y
Unblinded statistician / unblinded 
statistical programmer / unblinded 
clinical scientist
Y
Y
Y
Designated unblinded Sponsor personnel 
for reviewing safety data
N/A
Y
N/A
Y = access granted, N = access not granted, N/A = not applicable
CPI = computing platform integration (computing platform for analysis and reporting)
“prot028-ia” folder in the TEST region
This folder will be used by the protocol statistical programmer and the protocol statistician to 
develop analysis programs. This will not require any information of the actual treatment 
allocation of individual participants (only dummy treatment codes will be used). Prior to the 
database lock for the interim analysis, the study team will review the “dry run” output that 
are generated using the available study data up to that point in combination with the dummy 
treatment codes. Review of the dry run output will be conducted using the associated “-
clinical” folder.
05CNPJ
082QBW

V114
PAGE 14
PROTOCOL NO. 028-00
Supplemental SAP
  
    
15 NOV 2019
“prot028-ia” folder in the PROD region
This folder will be used by the unblinded statistician and the unblinded statistical 
programmer to perform interim analysis. An unblinded clinical scientist will inform the 
unblinded statistician and the unblinded statistical programmer of any vaccination with 
incorrect product and/or route of administration. Based on this information, in combination 
with the exclusion from analysis memo created by the blinded study team members before 
the database lock for the interim analysis, the unblinded statistician or the unblinded 
statistical programmer will flag subjects and/or datapoints within the datasets for exclusion 
from analysis.
All tables, listings and figures for the interim analysis will be generated in this folder by the 
unblinded statistician and the unblinded statistical programmer and will be provided with the 
designated Sponsor personnel who will review the safety data unblinded at the subject level.
This will be performed using the associated “-clinical” folder.
“prot028-ia-sumamry” folder in the PROD region
After the database lock for the interim analysis is achieved, the unblinded statistician and the 
unblinded statistical programmer will post group level summary results to this folder for 
review by the project team. The protocol statistician will prepare the Early Results Memo
based on the group level summary results using the tables posted in this folder.
It is the responsibility of the unblinded statistician to mask or remove part of the output 
before providing the output with the project team in order to avoid potential subject level 
unblinding. Examples include:

AEs, disposition events, medical history, prior / concomitant medications observed in 
only one participant or in only one vaccination group

minimum and maximum (e.g., baseline body weight).
05CNPJ
082QBW