A Phase 3, Single-Arm, Open-label Clinical Study to Evaluate the Safety and Immunogenicity of 4 Doses of V114 Administered to Healthy Infants in South Korea.
Phase: PHASE3
Conditions: Pneumococcal Disease
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04633226 
Document Date: 
23-Jun-2022
A Phase 3, Single-Arm, Open-label Clinical Study to Evaluate the 
Safety and Immunogenicity of 4 doses of V114 Administered to 
Healthy Infants in South Korea.

PRODUCT: V114  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Single-Arm, Open-label Clinical Study to Evaluate the Safety and 
Immunogenicity of 4 doses of V114 Administered to Healthy Infants in South Korea.
Protocol Number: 036-02
Compound Number: V114
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
EudraCT
2020-003181-39
IND
14115
Approval Date: 23 June 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 02
23-JUN-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change 
to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted 
only in an entity name change and update to the address.
Amendment 01
05-OCT-2021
The primary purpose of this amendment is to reduce the number of 
participants in the study from an enrollment target of approximately 100 to 
approximately 45 due to the enrollment challenges primarily related to the 
COVID-19 pandemic.
Original Protocol
24-SEP-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................19
2.1
Study Rationale....................................................................................................19
2.2
Background ..........................................................................................................19
2.2.1
V114 and Pneumococcal Disease................................................................19
2.2.2
Preclinical and Clinical Studies ...................................................................20
2.3
Benefit/Risk Assessment......................................................................................20
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................21
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................................................................................23
4.2.1.3
Future Biomedical Research..............................................................23
4.3
Justification for Dose...........................................................................................24
4.4
Beginning and End of Study Definition .............................................................24
4.4.1
Clinical Criteria for Early Study Termination .............................................24
5
STUDY POPULATION ................................................................................................24
5.1
Inclusion Criteria.................................................................................................25
5.2
Exclusion Criteria................................................................................................25
5.3
Lifestyle Considerations......................................................................................27
5.4
Screen Failures.....................................................................................................27
5.5
Participant Replacement Strategy......................................................................27
6
STUDY INTERVENTION............................................................................................27
6.1
Study Intervention(s) Administered...................................................................27
6.2
Preparation/Handling/Storage/Accountability .................................................29
6.2.1
Dose Preparation..........................................................................................29
6.2.2
Handling, Storage, and Accountability........................................................29
6.3
Measures to Minimize Bias: Randomization and Blinding..............................30
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6.3.1
Intervention Assignment..............................................................................30
6.3.2
Stratification.................................................................................................30
6.3.3
Blinding........................................................................................................30
6.4
Study Intervention Compliance..........................................................................30
6.5
Concomitant Therapy..........................................................................................30
6.5.1
Rescue Medications and Supportive Care ...................................................31
6.6
Dose Modification (Escalation/Titration/Other)...............................................31
6.7
Intervention After the End of the Study............................................................31
6.8
Clinical Supplies Disclosure................................................................................31
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................31
7.1
Discontinuation of Study Intervention...............................................................31
7.2
Participant Withdrawal From the Study...........................................................32
7.3
Lost to Follow-up .................................................................................................32
8
STUDY ASSESSMENTS AND PROCEDURES........................................................33
8.1
Administrative and General Procedures ...........................................................34
8.1.1
Informed Consent/Assent.............................................................................34
8.1.1.1
General Informed Consent/Assent.....................................................34
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................35
8.1.2
Inclusion/Exclusion Criteria ........................................................................35
8.1.3
Participant Identification Card.....................................................................35
8.1.4
Medical History ...........................................................................................35
8.1.5
Prior and Concomitant Medications Review...............................................35
8.1.5.1
Prior Medications...............................................................................35
8.1.5.2
Concomitant Medications..................................................................36
8.1.6
Assignment of Screening Number...............................................................36
8.1.7
Assignment of Treatment/Randomization Number.....................................36
8.1.8
Study Intervention Administration ..............................................................36
8.1.8.1
Timing of Dose Administration.........................................................37
8.1.9
Vaccination Report Card..............................................................................38
8.1.10
Discontinuation and Withdrawal .................................................................38
8.1.10.1
Withdrawal From Future Biomedical Research ................................38
8.1.11
Participant Blinding/Unblinding..................................................................39
8.1.12
Calibration of Equipment.............................................................................39
8.2
Immunogenicity Assessments .............................................................................39
8.2.1
Pneumococcal Electrochemiluminescence ..................................................39
8.3
Safety Assessments...............................................................................................40
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8.3.1
Physical Examinations.................................................................................40
8.3.2
Body Temperature Measurements ...............................................................40
8.3.3
Safety Assessment and Use of the Paper VRC............................................41
8.3.4
Clinical Safety Laboratory Assessments .....................................................42
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................42
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................42
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......44
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...44
8.4.4
Regulatory Reporting Requirements for SAE .............................................44
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................44
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................44
8.4.7
Events of Clinical Interest............................................................................44
8.5
Treatment of Overdose........................................................................................45
8.6
Pharmacokinetics.................................................................................................45
8.7
Pharmacodynamics..............................................................................................45
8.8
Biomarkers ...........................................................................................................45
8.8.1
Planned Genetic Analysis Sample Collection..............................................45
8.9
Future Biomedical Research Sample Collection...............................................45
8.10
Health Economics Medical Resource Utilization and Health Economics.......45
8.11
Visit Requirements...............................................................................................46
8.11.1
Screening......................................................................................................46
8.11.2
Treatment Period/Vaccination Visit ............................................................46
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........46
9
STATISTICAL ANALYSIS PLAN .............................................................................46
9.1
Statistical Analysis Plan Summary.....................................................................46
9.2
Responsibility for Analyses/In-house Blinding .................................................47
9.3
Hypotheses/Estimation ........................................................................................48
9.4
Analysis Endpoints...............................................................................................48
9.4.1
Safety Endpoints..........................................................................................48
9.4.2
Immunogenicity Endpoints..........................................................................48
9.5
Analysis Populations............................................................................................49
9.5.1
Immunogenicity Analysis Populations ........................................................49
9.5.2
Safety Analysis Populations ........................................................................49
9.6
Statistical Methods...............................................................................................50
9.6.1
Statistical Methods for Immunogenicity Analyses......................................50
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9.6.2
Statistical Methods for Safety Analyses ......................................................51
9.6.3
Demographic and Baseline Characteristics .................................................52
9.7
Interim Analyses ..................................................................................................52
9.8
Multiplicity ...........................................................................................................52
9.9
Sample Size and Power Calculations .................................................................53
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................53
9.9.2
Sample Size and Power for Safety Analyses ...............................................53
9.10
Subgroup Analyses...............................................................................................54
9.11
Compliance (Medication Adherence).................................................................54
9.12
Extent of Exposure...............................................................................................54
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................55
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........55
10.1.1
Code of Conduct for Clinical Trials.............................................................55
10.1.2
Financial Disclosure.....................................................................................57
10.1.3
Data Protection.............................................................................................57
10.1.3.1
Confidentiality of Data ......................................................................58
10.1.3.2
Confidentiality of Participant Records...............................................58
10.1.3.3
Confidentiality of IRB/IEC Information............................................58
10.1.4
Publication Policy........................................................................................58
10.1.5
Compliance with Study Registration and Results Posting Requirements ...59
10.1.6
Compliance with Law, Audit, and Debarment ............................................59
10.1.7
Data Quality Assurance ...............................................................................60
10.1.8
Source Documents .......................................................................................61
10.1.9
Study and Site Closure.................................................................................61
10.2
Appendix 2: Clinical Laboratory Tests..............................................................62
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................63
10.3.1
Definition of AE ..........................................................................................63
10.3.2
Definition of SAE ........................................................................................64
10.3.3
Additional Events Reported.........................................................................65
10.3.4
Recording AE and SAE ...............................................................................65
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................69
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................70
10.5
Appendix 5: Contraceptive Guidance................................................................71
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10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................72
10.7
Appendix 7: Country-specific Requirements....................................................77
10.8
Appendix 8: Abbreviations .................................................................................78
11
REFERENCES...............................................................................................................82
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LIST OF TABLES
Table 1
Study Interventions....................................................................................28
Table 2
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................43
Table 3
Analysis Strategy for Key Immunogenicity Variables..............................51
Table 4
Analysis Strategy for Safety Parameters....................................................52
Table 5
95% CIs for Varying Hypothetical IgG GMCs and Varying Standard 
Deviations ..................................................................................................53
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LIST OF FIGURES
Figure 1
V114-036 Study Design.............................................................................15
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Single-Arm, Open-label Clinical Study to Evaluate the Safety and 
Immunogenicity of 4 doses of V114 Administered to Healthy Infants in South Korea.
Short Title: Safety and immunogenicity of V114 in healthy infants in South Korea
Acronym: PNEU-PED KOR
Hypotheses, Objectives, and Endpoints:
The following objectives and endpoints will be evaluated in healthy infants enrolled at 
approximately 2 months of age (from 42 to 90 days [inclusive]) administered V114.
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
- Solicited injection-site AEs from Day 1 
through Day 7 postvaccination.
- Solicited systemic AEs from Day 1 through 
Day 7 postvaccination.
- Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation.
- Objective: To evaluate the 
anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
response rates (proportion of participants 
meeting serotype-specific IgG threshold value 
of ≥0.35 μg/mL) at 30 days after Dose 3.
- Objective: To evaluate the anti-
pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
Geometric Mean Concentrations (GMCs) at 
30 days after Dose 3.
- Anti-PnPs serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 30 
days Postdose 3 (PD3).
Secondary Objectives
- Objective: To evaluate the anti-
pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
Geometric Mean Concentrations (GMCs) at 
30 days after Dose 4.
- Anti-PnP serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 30 
days Postdose 4 (PD4).
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Healthy infants
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 25 months from the time the first participant 
(or their legally acceptable representative) provides 
documented  informed consent/assent until the last 
participant’s last study-related contact.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result or 
at the time of final contact with the last participant, 
whichever comes last.
Number of Participants:
Approximately 45 participants will be randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Vaccination 
Regimen
Use
V114
V114
Refer to 
IB
4 dose
IM
Single dose at 
Visits 1,2, 3, 
and 5 (~2, 4, 
6, and 12-15 
months of 
age)
Experi-
mental
Abbreviations: IB = Investigator’s Brochure; IM= intramuscular
Total 
Number of 
Intervention 
Groups/ 
Arms
1 intervention group
Duration of 
Participation
Each participant will participate in the study for approximately 11 to 15
months from the time the participant’s parent or legally acceptable 
representative provides documented informed consent.
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.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
V114-036 Study Design
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1.3
Schedule of Activities
Study Period:
Intervention
Comments
Visit Number
1
2
3
4
5
6
Scheduled Time:
Age: ~2 
months
(Dose 1)
Age: ~4 
months
(Dose 2)
Age: ~6 
months
(Dose 3)
~1 month 
after Dose 3
Age: ~12 to 
15 months
(Dose 4)
~1 month after 
Dose 4
Months of age is calculated according to the participant’s
birth date
Visit Windowa
≥42 days of 
age to ≤90 
days of age
4 months 
of age to 1 
day before
5 months 
of age
6 months of 
age to 1 day 
before 7 
months of 
age
Day 28 to 
Day 42 
Postdose 3
12 months 
of age to 1 
day before
16 months 
of age
Day 28 to Day 
42 Postdose 4
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study procedures.
Informed Consent 
for FBR
X
Participation in FBR is optional and consent must be obtained 
before collection of buccal swab DNA samples.
Assignment of 
Screening Number
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Review of prior medications/vaccinations, a complete 
physical examination, and temperature measurement are 
required at Visit 1 to determine eligibility.
Medical History 
X
Postrandomization Procedures
Assignment of 
Treatment/
Randomization
Number
X
Prior/Concomitant 
Medication and 
Nonstudy
Vaccination Review
X
X
X
X
X
X
V114
Administration
X
X
X
X
Before V114 administration, ensure the participant has no 
new contraindication to V114.
Participants must be afebrile for at least 72 hours before V114 
administration.
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Study Period:
Intervention
Comments
Visit Number
1
2
3
4
5
6
Scheduled Time:
Age: ~2 
months
(Dose 1)
Age: ~4 
months
(Dose 2)
Age: ~6 
months
(Dose 3)
~1 month 
after Dose 3
Age: ~12 to 
15 months
(Dose 4)
~1 month after 
Dose 4
Months of age is calculated according to the participant’s
birth date
Visit Windowa
≥42 days of 
age to ≤90 
days of age
4 months 
of age to 1 
day before
5 months 
of age
6 months of 
age to 1 day 
before 7 
months of 
age
Day 28 to 
Day 42 
Postdose 3
12 months 
of age to 1 
day before
16 months 
of age
Day 28 to Day 
42 Postdose 4
Nonstudy Pediatric 
Vaccines
(X)
(X)
(X)
(X)
Sponsor will not provide nonstudy pediatric vaccines, but
they are permitted to be given during the study. If given at the 
same time, oral vaccines are recommended to be given before
the study vaccine and other injectable vaccines. Other 
injectable vaccines are administered after the study vaccine 
and in a separate limb.
See Section 6.5 for details on concomitant vaccines.
Provide Paper VRC
X
X
X
X
A paper VRC will be provided to record AEs, body 
temperature, concomitant medications, and nonstudy
vaccinations. Instructions for using the paper VRC will be 
reviewed with the participant’s parent or legally acceptable 
representative.
See Section 8.1.9 and 8.3.3 for details regarding the 
completion of the paper VRC.
Collect Paper VRC 
and Review VRC 
data with 
Participant’s Parent 
or Legally 
Acceptable 
Representative
X
X
X
X
See Section 8.1.9 for details.
Safety Procedures
Complete Physical 
Examination
X
To be performed by the investigator or medically qualified 
designee before vaccine is administered (see Section 8.3.1).
Targeted Physical 
Examination
X
X
X
To be performed by the investigator or medically qualified 
designee before vaccine is administered (see Section 8.3.1).
Body Temperature 
Measurement
X
X
X
X
Each participant’s body temperature must be taken before 
vaccination (see Section 8.3.2 for method). Participants who 
have febrile illness at or within 72 hours of vaccination must 
be rescheduled. 
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Study Period:
Intervention
Comments
Visit Number
1
2
3
4
5
6
Scheduled Time:
Age: ~2 
months
(Dose 1)
Age: ~4 
months
(Dose 2)
Age: ~6 
months
(Dose 3)
~1 month 
after Dose 3
Age: ~12 to 
15 months
(Dose 4)
~1 month after 
Dose 4
Months of age is calculated according to the participant’s
birth date
Visit Windowa
≥42 days of 
age to ≤90 
days of age
4 months 
of age to 1 
day before
5 months 
of age
6 months of 
age to 1 day 
before 7 
months of 
age
Day 28 to 
Day 42 
Postdose 3
12 months 
of age to 1 
day before
16 months 
of age
Day 28 to Day 
42 Postdose 4
15-Minute 
Postvaccination 
Observation Period
X
X
X
X
The observation period can be extended if clinically 
indicated.
AE Monitoring
X
X
X
X
X
X
Nonserious AEs are to be reported from Days 1 through 14
after each vaccination. SAEs and deaths are to be reported 
throughout the duration of an individual’s study participation.
Serum for 
Immunogenicity 
Assays (Including 
Retention Serum)
X
X
Blood samples must be collected before vaccination where 
applicable.
Collect Buccal 
Swabs (DNA) for 
FBR
X
Buccal swab DNA samples for analysis should be obtained 
before vaccination at Visit 1, on randomized and FBR 
consented participants only, or at a later date as soon as the 
informed consent is obtained.
AE = adverse event; DNA = deoxyribonucleic acid; paper; FBR = future biomedical research; SAE = serious adverse event; VRC = paper Vaccination Report Card; (X) = Not 
provided by Sponsor, but permitted in the study
a
For calculating the visit windows, the day of vaccination is considered Day 1. To calculate visit windows for subsequent vaccinations, confirm participant date of birth and 
ensure the age of the participant will fall within the appropriate age range for each study visit.
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2
INTRODUCTION
MSD is developing an investigational 15-valent PCV (called V114) for the prevention of 
pneumococcal disease caused by the serotypes in the vaccine. V114 contains the 13 serotypes 
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) present in the licensed vaccine Prevenar
13™(pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein], Wyeth 
Pharmaceuticals, a subsidiary of Pfizer, Inc., Philadelphia, PA), plus 2 additional serotypes 
(22F, 33F).
2.1
Study Rationale
Pneumococcal disease remains an important worldwide concern despite the availability of 
PCVs. This is due to the emergence of nonvaccine serotypes that are being increasingly 
isolated in cases of IPD. Given the worldwide distribution, the increased proportion of 
nonvaccine serotypes and the value of multiple suppliers to strengthen global supply, there is 
a continued need to develop new PCVs with expanded serotype coverage. V114 contains all 
the pneumococcal serotypes contained in Prevenar 13™plus 2 additional serotypes (22F, 
33F), which have emerged as important causes of IPD and will address an unmet medical and 
public health need for a PCV with expanded coverage.
The purpose of this study is to show the safety and immunogenicity of a 4-dose schedule (3 
doses in the infant primary series followed by 1 toddler dose) of V114 in healthy South 
Korean infants approximately 2 months of age (42 to 90 days of age). 
The 3 + 1 PCV immunization schedule in this study is the same as that currently 
recommended by the South Korean NIP. It is generally recommended that Prevenar 13™is
to be given at the same time as other NIP pediatric vaccines. The concomitant administration 
of V114 with NIP pediatric vaccines (with the exception of influenza vaccine and LJEV 
vaccine as detailed in Section 6.5) will be allowed in this Phase 3 clinical study at the 
discretion of investigators.
2.2
Background
2.2.1
V114 and Pneumococcal Disease
Refer to the IB for V114 for detailed background information including information on 
pneumococcal disease burden.
Streptococcus pneumoniae remains a significant cause of disease worldwide, with clinical 
manifestations including meningitis, sepsis, pneumonia, sinusitis, and otitis media. 
Currently, many countries worldwide have incorporated licensed PCVs (eg, Prevenar 13™
and/or Synflorix™ (pneumococcal polysaccharide conjugate vaccine [adsorbed], 
GlaxoSmithKline Biologicals S.A, Rixensart, Belgium) into their infant immunization 
programs. In South Korea, Prevenar™was introduced as an optional vaccine in 2003 
followed by Prevenar 13™and Synflorix™in 2010. Prevenar 13™and Synflorix™were 
then included in the South Korean NIP in 2014 [Lee, J. K., et al 2017]. Since PCVs have 
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been introduced into the NIP, the overall burden of IPD in children caused by vaccine 
serotypes has decreased [Kim, S. H., et al 2016]. Widespread use of PCVs have reduced the 
burden of pneumococcal disease caused by the serotypes contained in the vaccines in 
children who received the vaccines, as well as unvaccinated individuals through herd 
protection [Centers for Disease Control and Prevention 2008] [Ruckinger, S., et al 2009] 
[Farrell, D. J, et al 2007] [Pilishvili, Tamara, et al 2010] [Lexau, C. A., et al 2005] [Metlay, J. 
P., et al 2006] [Whitney, Cynthia G., et al 2003] [Moore, M. R., et al 2015] [Lepoutre, A., et 
al 2015] [Weiss, S., et al 2015] [Martinelli, D., et al 2014] [Guevara, M., et al 2016] [Waight, 
P. A., et al 2015] [Jokinen, J., et al 2015] [Palmu, A. A., et al 2015] [Wagenvoort, G. H., et al 
2016]. Despite this, an increase in the burden of IPD caused by serotypes not contained in 
currently available vaccines has been observed.
V114 contains all the pneumococcal serotypes contained in Prevenar 13™plus 2 additional 
serotypes (22F, 33F). The selection of 22F and 33F was primarily based on the emergence of 
these 2 serotypes as important causes of IPD in the era of Prevenar 13™.
In South Korea, the prevalence of serotype 22F isolates from children ≤5 years with invasive 
or noninvasive pneumococcal disease during the period of 2014 to 2016 was 2.4% [Park, D. 
C., et al 2019]. In 2013 the prevalence of IPD caused by serotype 33F in children under 18 
years of age was 5.6%. [Cho, E. Y., et al 2016]. Of particular concern is the high degree of 
invasiveness of serotype 22F and 33F compared with other serotypes not currently covered 
by licensed PCVs, resulting in both being associated with serious clinical outcomes.
Furthermore, serotypes 22F and 33F have shown relative resistance to certain antibiotics 
used in the treatment of community acquired pneumonia [Golden, A. R., 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 with
Prevenar 13™.
The additional serotypes contained in V114 will provide broader coverage against the leading 
serotypes associated with pneumococcal disease worldwide. V114 is designed to meet 
continuing medical and public health needs for PCVs globally, as well as address the 
emergence of pneumococcal disease caused by serotypes not contained in currently licensed 
PCVs.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
V114.
2.3
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. All participants will receive study 
vaccine.
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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
The following objectives and endpoints will be evaluated in healthy infants enrolled at 
approximately 2 months of age (from 42 to 90 days [inclusive]) administered V114.
Objectives
Endpoints
Primary
•
Objective 1: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
•
Solicited injection-site AEs from Day 1 
through Day 7 postvaccination.
•
Solicited systemic AEs from Day 1 
through Day 7 postvaccination.
•
Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation.
•
Objective: To evaluate the anti-
pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G 
(IgG) response rates (proportion of 
participants meeting serotype-specific IgG 
threshold value of ≥0.35 μg/mL) at 30 
days after Dose 3.
•
Objective: To evaluate the anti-PnPs 
serotype-specific IgG Geometric Mean 
Concentrations (GMCs) at 30 days after
Dose 3.
•
Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 30 days Postdose 
3 (PD3).
Secondary
•
Objective: To evaluate the anti-PnPs 
serotype-specific IgG GMCs at 30 days 
after Dose 4.
•
Anti-PnP serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 30 days Postdose 
4 (PD4).
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4
STUDY DESIGN
4.1
Overall Design
This is a single-arm, multisite, open-label study of V114 in healthy infants in South Korea.
Approximately 45 infants will be enrolled to receive V114.
A 0.5 mL intramuscular dose of V114 will be administered to healthy infants at 
approximately 2, 4, 6, and 12 to 15 months of age.
Participants will be followed for injection-site and systemic AEs through Day 7 after each 
vaccination with V114. Information for SAEs and deaths, regardless of whether the events 
are considered vaccine related by the investigator, will be collected from the time consent is 
signed through completion of participation in the study.
Blood samples for immunogenicity assays will be collected at 2 time points: (1) 30 days after 
the completion of the 3-dose primary series (PD3), and (2) 30 days after Dose 4 (PD4).
After completion of immunogenicity testing to evaluate the study objectives, serum samples 
will be stored to conduct any additional study-related testing as required by regulatory 
agencies or the Sponsor. For study participants whose parent or legally acceptable 
representative provided consent for future biomedical research leftover sera from the study 
may be used for other purposes such as the development and/or validation of pneumococcal 
assays after completion of all study-related immunogenicity testing.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The global pediatric V114 Phase 3 program, with over 9 studies, and including 
approximately 5228 individuals has accumulated comprehensive safety and immunogenicity 
data, comparing V114 to Prevenar 13™PCV13. These data are sufficient for filing and 
licensure in South Korea; further comparator data are not needed. However, no South Korean 
infants or children participated in the global V114 pediatric program.
The purpose of this study is to show the safety and immunogenicity of a 4-dose schedule (3 
doses in the infant primary series followed by 1 toddler dose) of V114 in healthy South 
Korean infants approximately 2 months of age (42 to 90 days of age).
The safety and immunogenicity endpoints, including the duration of the safety follow-up
period, are consistent with previous studies evaluating PCVs evaluating safety and 
immunogenicity in an infant population. These infants are at increased risk for pneumococcal 
disease and its associated morbidity and mortality [Drijkoningen, J. J 2014]. The enrollment 
of infants in this study is intended to assess safety and immunogenicity in a population that is 
representative of children receiving commercially available PCVs.
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4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Sera from participants will be used to measure vaccine-induced, serotype-specific IgG 
responses for all 15 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 
33F) included in V114 using the PnECL assay.
The use of the serotype-specific IgG antibody level of ≥0.35 µg/mL has been recommended 
by a WHO expert panel as an acceptable threshold value for evaluating the clinical 
performance of PCVs after a routine childhood vaccination regimen [World Health 
Organization 2008] [World Health Organization 2005]. The response rate (ie, the proportion 
of participants meeting the serotype-specific IgG threshold value of ≥0.35 μg/mL) is a 
primary endpoint in this study.
Anti-PnPs serotype-specific IgG responses will be measured at 2 time points:

Approximately 30 days after Dose 3 to evaluate the immune response to the primary 
vaccination series (IgG GMCs and IgG response rates) 

Approximately 30 days after Dose 4 to evaluate anamnestic antibody responses (IgG 
GMCs)
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile shown in previous studies, published data from marketed PCVs, and guidance from 
regulatory agencies during product development. The VRC used to record AEs during the 
postvaccination periods, as defined in Section 8.1.9, was structured as recommended in the 
final Food and Drug Administration Guidance for Industry: Patient-Reported Outcome 
Measures [U.S. Food and Drug Administration 2009].
Details on the safety endpoints evaluated in this study can be found in Section 8.3.3 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in Appendix 
3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
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 
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FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information 
to develop safer, more effective drugs/vaccines, and/or to ensure that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of FBR research are 
presented in Appendix 6.
4.3
Justification for Dose
The dose and dosing schedule of V114 is similar to that used in previous pediatric V114 
clinical studies, which showed safety and comparable immune responses to those of Prevenar
13™. Refer to V114 IB for details on dosing schedule.
The 3 + 1 PCV immunization schedule in this study is the same as that currently used by the 
South Korean NIP.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative 
provides documented consent. The overall study ends when the last participant completes the 
last study-related  contact, withdraws from the study, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Healthy male and female infants approximately 2 months of age, from 42 to 90 days
(inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Is healthy (based on a review of medical history and physical examination) based on the 
clinical judgment of the investigator.
Demographics
2. Is a South Korean male or female, approximately 2 months of age, from 42 days to 90 
days inclusive, at the time of signing the informed consent.
Informed Consent/Assent
3. Has a parent or legally acceptable representative who understands the study procedures, 
alternate treatments available, and risks involved with the study and voluntarily agrees to 
participate by providing documented informed consent. The parent or legally acceptable 
representative may also provide consent for future biomedical research. However, the 
participant may participate in the main study without participating in future biomedical 
research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or other 
sterile site) or known history of other culture positive pneumococcal disease.
2. Has a known hypersensitivity to any component of the PCV, any component of the 
licensed pediatric vaccines to be administered concomitantly in the study, or any 
diphtheria toxoid-containing vaccine.
3. *Had a recent febrile illness (rectal temperature ≥38.1°C [≥100.5°F] or axillary 
temperature ≥37.8°C [≥100.0°F]) occurring within 72 hours before receipt of study 
vaccine.
4. Has a known or suspected impairment of immunological function, including congenital 
or acquired immunodeficiency.
5. Has or his/her mother has a documented HIV infection.
6. Has or his/her mother has a documented hepatitis B surface antigen – positive test.
7. Has known or history of functional or anatomic asplenia.
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8. Has a health or developmental disorder that, based on the clinical judgment of the 
investigator, could affect evaluation of the vaccine.
9. Has a bleeding disorder contraindicating intramuscular vaccination.
10. Has a history of autoimmune disease.
11. Has a known or suspected history of neurologic disorder, including encephalitis/myelitis, 
acute disseminating encephalomyelitis and related disorders.
Prior/Concomitant Therapy
12. Has received a dose of any pneumococcal vaccine before study entry.
13. *Meets 1 or more of the following systemic corticosteroid exclusion criteria:
a. Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/d for persons weighing >10 kg) for ≥14 consecutive days and 
has not completed this course of treatment at least 30 days before the first dose of 
study vaccine at treatment/randomization.
b. Has received or is expected to receive systemic corticosteroids within 14 days before
any dose of study vaccine.
c. Is expected to require systemic corticosteroids within 30 days after any study 
vaccination during conduct of the study.
Note: Topical, ophthalmic, and inhaled steroids are permitted.
14. *Has received a licensed nonlive vaccine within 14 days before receipt of study vaccine 
or is scheduled to receive any licensed nonlive vaccine within 14 days after receipt of 
study vaccine. 
Exception: Inactivated influenza vaccine may be administered, but must be given at least 
7 days before receipt of study vaccine or at least 15 days after receipt of study vaccine.
Participant may receive nonstudy pediatric licensed nonlive vaccines on the same day as 
study vaccine is given (Day 1).
15. *Has received a licensed live vaccine within 28 days before receipt of study vaccine or is 
scheduled to receive any live vaccine within 14 days after receipt of study vaccine.
Exception: Participant may receive nonstudy pediatric licensed live vaccines on same day 
as study vaccine is given (Day 1).
16. Has received a blood transfusion or blood products, including immunoglobulins.
Prior/Concurrent Clinical Study Experience
17. Has participated in another clinical study of an investigational product before the 
beginning or anytime during the duration of the current clinical study. Participants 
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enrolled in observational studies may be included; these will be reviewed on a case by 
case basis for approval by the Sponsor.
Other Exclusions
18. Has any other reason that, in the opinion of the investigator, may interfere with the 
evaluation required by the study. Reasons may include, but are not limited to, being 
unable to keep appointments or planning to relocate during the study.
19. Is or has an immediate family member (eg, parent/legal guardian, sibling) who is 
investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as whose legally acceptable representative provides consent to 
participate in the clinical study, but are not subsequently randomized in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the CONSORT publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any AEs or SAEs meeting reporting requirements as outlined in the 
data entry guidelines.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (V114) will be packaged to support enrollment. Clinical supplies will be 
affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
V114
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension
Refer to IB
0.5 mL
IM
Single dose 
at Visits 1, 2, 
3, and 5 (~2, 
4, 6, and 12 
to 15 months 
of age, 
respectively)
Experimental
IMP
Central
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of dose to be used in this study is 
provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment and will receive a 
treatment/randomization number.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the vaccine administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan for V114 indicated in Section 1.3
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (see Section 5.2 for details). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant's parent or legally acceptable representative.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin, 
blood, or blood products during a participant’s participation in this study, 1 of the individuals 
listed on the Sponsor Contact Information page must be notified as soon as possible. Any 
concurrent medication or medical treatment must be recorded on the appropriate eCRF. It is 
important to record the use of any analgesic or antipyretic use that occurs on the day of 
vaccination on the paper VRC and appropriate eCRF.
Nonstudy pediatric vaccines are permitted to be administered according to local
recommended schedule, regional, and/or country guidelines, and according to the restrictions 
outlined in Section 5.2.
During influenza season, it is anticipated that participants 6 months of age and older may be 
given an influenza vaccine. Influenza vaccine should be administered either 7 days before or 
15 days after the administration of the study vaccine. 
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It is anticipated that participants 12 months of age and older may be given LJEV, which 
should be administered either more than 28 days before or more than 14 days after the 
administration of the study vaccination dose 4. If LJEV is to be given at Visit 6, it should be 
administered after the blood collection.
Other nonstudy concomitant vaccines (oral or injectable) can be administered on the same 
day as V114. Nonstudy oral concomitant vaccines should be given before V114 and other 
injectable concomitant vaccines. Precautions must be taken to prevent choking during the 
administration of oral vaccines. Other pediatric injectable vaccines administered 
concomitantly should be given after V114, and in a separate limb.
It is recommended that V114 be administered in the right thigh. To avoid any confounding 
results, nonstudy injectable vaccines should not be administered in the same limb as V114. 
Documentation of which limb was used for the administration of V114 should be recorded on 
the appropriate eCRF. As the study is reporting injection-site AEs for V114 (and not from 
nonstudy pediatric vaccines), this information should also be recorded on the paper VRC to 
inform the parent or legally acceptable representative of the appropriate limb to monitor for 
AEs related to the V114.
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 after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
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As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccination 
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10 and Section 
8.11.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant 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.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant’s legally acceptable 
representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant’s legally acceptable representative and 
reschedule the missed visit. If the participant’s legally acceptable representative is 
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contacted, the participant’s legally acceptable representative should be counseled on the 
importance of maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the 
participant’s legally acceptable representative at each missed visit (eg, telephone calls 
and/or a certified letter to the participant’s legally acceptable representative last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used 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, and assent if applicable, be obtained from 
the participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
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Approximately 5 mL of blood will be drawn at each of Visits 4, and 6 for immunogenicity 
assays. The maximum amount of blood collected from each participant over the duration of 
the study will not exceed 10 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each potential 
participant or their legally acceptable representative prior to participating in this 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 documented informed consent is in place.
8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent form. The form must include the trial protocol number, 
trial protocol title, dated signature, and /agreement of the participant (or his/her legally 
acceptable representative) and of the person conducting the consent discussion. 
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
The initial informed consent/assent form, any subsequent revised informed consent/assent 
form, and any written information provided to the participant must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study. 
The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
participant’s or the participant’s legally acceptable representative’s dated signature.
Specifics about the study and the study population are to be included in the study informed 
consent/assent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
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8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant, or the participant’s legally acceptable representative, answer 
all of his/her questions, and obtain documented informed consent/assent before performing 
any procedure related to future biomedical research. A copy of the informed consent/assent 
will be given to the participant before performing any procedure related to future biomedical 
research.
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 documented informed consent/assent. At the time of intervention
treatment/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee before 
vaccination at Visit 1. Note: Birth weight and gestational age will be documented in the 
participant’s medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record any prior vaccinations and 
medications taken by the participant within 30 days before the first dose of study vaccine at 
Visit 1.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin, 
blood, or blood products during a participant’s participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate eCRF.
It is important to record any analgesic or antipyretic use that occurs on the day of vaccination 
on the paper VRC and appropriate eCRF. Concomitant medications taken after Visit 1 and
nonstudy vaccines received since Visit 1 will be recorded in the paper VRC as specified in 
Section 8.3.3.
The administration of nonstudy pediatric vaccines during the study should be recorded on the 
appropriate eCRF. To avoid any confounding results, concomitant injectable vaccines should 
not be administered in the same limb as V114. Documentation of which limb was used for 
the administration of V114 must be recorded on the paper VRC (Section 8.1.9 and 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 treatment/randomization. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Before each vaccine administration, the investigator (or designee) must review medical 
history to ensure that the participant has no new contraindication to the vaccine(s) scheduled 
to be given. This information should be documented in the participant’s medical record.
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Study vaccine will be administered by the investigator and/or study staff according to the 
specifications within the pharmacy manual.
Study vaccines should be prepared and administered by appropriately qualified members of 
the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local/state, country, and institutional 
guidance.
Study vaccines should be removed from the refrigerator no more than 1 hour before 
vaccination. The time of removal and time of vaccination should be documented in the 
participant’s medical record.
If the V114 is provided as a syringe: Before administration of study vaccine, the investigator 
(or designee) should shake vigorously to obtain a homogenous white suspension. If white-
colored insoluble particle appears, the investigator (or designee) should use rapid, horizontal 
hand shaking for 5 to 10 seconds while holding the syringe in between the thumb and index 
finger until complete resuspension. This action should be repeated, as necessary. If the 
appearance is otherwise, the vaccine should not be administered. 
If V114 is provided as a vial: Before administration of study vaccine, the investigator (or 
designee) should use rapid, horizontal hand -shaking for up to 5 seconds while holding the 
vial in between the thumb and index finger to obtain a homogenous white suspension. This 
action should be repeated, as necessary. If the appearance is otherwise, the vaccine should 
not be administered.
The vaccine should not be used if the vaccine cannot be resuspended.
A 0.5-mL intramuscular dose of study vaccine will be administered to healthy South Korean
infants at approximately 2, 4, 6, and 12 to 15 months of age. It is recommended that the study 
vaccines are administered in the right thigh. Documentation of which limb was used for the 
administration of V114 should be recorded on the appropriate eCRF. This information should 
also be recorded on the paper VRC to inform the participant’s parent or legally acceptable 
representative of the appropriate limb to monitor for AEs related to V114.
If an abnormality (ie, rash) is observed at the site where the previous dose of the study 
vaccine was administered, it is permissible to use the anterolateral muscle of the other limb to 
administer the following dose of the study vaccine. Adequate treatment provision, including 
epinephrine and equipment for maintaining an airway, should be available for immediate use 
should an anaphylactic or anaphylactoid reaction occur [Centers for Disease Control and 
Prevention 2015].
8.1.8.1
Timing of Dose Administration
V114 will be administered as indicated in Section 1.3. All participants will be observed for at 
least 15 minutes after each vaccination for any immediate reactions. This observation must 
be performed by site personnel for V114 (Section 1.3).
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Participants must be afebrile for at least 72 hours before each V114 administration (Section 
1.3 and Section 8.3.2). 
8.1.9
Vaccination Report Card
The investigator or delegate will train the participant’s parent or legally acceptable 
representative in the use of the paper VRC as indicated in Section 1.3.
After providing paper VRC, contact the participant’s parent or legally acceptable 
representative at least once at approximately Day 3 poststudy vaccination, to ensure timely 
completion of paper VRC during Day 1 to Day 7 for solicited injection-site AEs, solicited 
systemic AEs and temperature. The main purpose of the contact is to ensure the participant’s 
legally acceptable representative records on the paper VRC and to answer any questions 
related to VRC. While these contacts are not for collection of AEs, if any potential SAE 
information is reported it should be reviewed during the contact.
The investigator or delegate will review the data captured on the paper VRC with the 
participant’s parent or legally acceptable representative as indicated in Section 1.3. For the 
AEs outlined above, the investigator will use the information provided by the participant’s 
parent or legally acceptable representative on the paper 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 Section 1.3 and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit 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 parent or 
legally acceptable representative. Consent may be withdrawn by the parent or legally 
acceptable representative at any time by contacting the principal investigator for the main 
study. If medical records for the study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant’s consent for FBR 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 parent or legally acceptable representative of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before 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.
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If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the 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
This is an open-label study; there is no blinding for this study.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Pneumococcal Electrochemiluminescence assay will be used to measure vaccine-induced, 
anti-PnPs serotype-specific immune responses for all 15 serotypes included in V114.
Blood collection, storage and shipment instructions for serum samples will be provided in the 
operations/laboratory manual.
8.2.1
Pneumococcal Electrochemiluminescence
The Sponsor has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 PnPs serotypes contained in V114. 
The PnECL v2.0 assay is based on the Meso Scale Discovery technology, which employs 
disposable multispot 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 
prespecified acceptance criteria for each of the parameters.
The WHO Expert Committee on Biological Standardization has recommended that in-house 
assays used in immunogenicity studies designed to evaluate protection against IPD be 
bridged to the WHO reference assay to maintain the link between immune responses to 
vaccination and the clinical demonstration of protective efficacy against IPD conferred by the 
7 conjugated polysaccharides in Prevenar™. In 2012 and 2014, the Sponsor formally bridged 
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the original PnECL assay to the WHO IgG ELISA to determine the PnECL threshold values 
that correspond to 0.35 µg/mL in the WHO ELISA for each of the 7 Prevenar™serotypes (4, 
6B, 9V, 14, 18C, 19F, and 23F) and for each of the additional 6 serotypes (1, 3, 5, 6A, 7F, 
and 19A) in Prevenar 13™.
A confirmatory study was performed to formally bridge the optimized PnECL assay (v2.0) to 
the WHO reference ELISA, and to assess the PnECL threshold values that correspond to 
0.35 µg/mL measured using the WHO ELISA for each of the serotypes in V114, including 
the Prevnar 13™ serotypes and serotypes 22F and 33F, which were not previously assessed. 
The bridging of the optimized PnECL to the WHO ELISA is complete, and the data showed 
good concordance between the PnECL and WHO ELISA around the 0.35 μg/mL threshold 
value for all 15 serotypes. It is recommended that a single PnECL threshold value of 
0.35 µg/mL be applied to each of the 15 serotypes.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) at Visit 1 for all participants. A targeted 
physical examination will be performed at subsequent vaccination visits as indicated in 
Section 1.3. Any clinically significant abnormality will be recorded on appropriate eCRF.
The complete and targeted physical examination procedures both include obtaining vital 
signs (heart rate, respiratory rate, and 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 
medical record/source documentation.
8.3.2
Body Temperature Measurements
Prevaccination temperatures will be taken by study personnel as indicated in Section 1.3. 
Participants who have febrile illness (rectal temperature ≥38.1°C [≥100.5°F] or axillary 
temperature ≥37.8°C [≥100.0°F]) at or within 72 hours of study vaccination must be 
rescheduled.
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The participant’s parent or legally acceptable representative will be asked to record the 
participant’s temperature reading on the paper VRC from Day 1 through Day 7 after each 
vaccination. 
Rectal is the preferred method of obtaining participant’s temperature at prevaccination and 
on the paper VRC. Axillary (underarm) is an acceptable method, but temperature needs to be 
confirmed by rectal measurement if fever is detected. If an axillary temperature is reported to 
be ≥37.8°C (≥100.0°F), a rectal temperature must be taken. In this case, both axillary and 
rectal temperatures must be recorded on the paper VRC. Temperature readings should be 
taken at approximately the same time each day if possible. Use of temporal or tympanic 
thermometers to collect temperature for this study is prohibited.
8.3.3
Safety Assessment and Use of the Paper VRC
All participants will be observed for at least 15 minutes after each vaccination for any 
immediate reactions. The observation period can be extended if clinically indicated. If any 
immediate AEs are observed during this period, the time at which the event occurred within 
this timeframe, as well as the event itself, any concomitant medications that were 
administered, and resolution of the event, must be recorded on the appropriate eCRF.
The limb that was used for the administration of V114 will be recorded in the paper VRC 
(Note: the study will report injection-site AEs from V114 only, not from concomitant 
injectable vaccines; the location of V114 administration can be used by the participant’s 
parent or legally acceptable representative to monitor the appropriate limb for injection-site 
AEs related to V114).
Participant’s parent or legally acceptable representative will use the paper VRC (Section 
8.1.9) to document the following information:
•
Rectal/axial temperatures measured Day 1 (day of vaccination) through Day 7 after each 
vaccination
•
Solicited injection-site AEs (swelling, redness, pain or tenderness, and hard lump) Day 1 
through Day 7 postvaccination
•
Solicited systemic AEs (irritability, drowsiness, appetite lost, and hives or welts) Day 1 
through Day 7 postvaccination
•
Any other unsolicited injection-site or systemic AEs Day 1 through Day 14
postvaccination
•
Use of any analgesic or antipyretic on the day of vaccination
•
Concomitant medications and nonstudy vaccinations Day 1 to Day 14 postvaccination
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8.3.4
Clinical Safety Laboratory Assessments
There are no laboratory safety evaluations required by the protocol.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before treatment/randomization must be reported by the 
investigator if they cause the participant to be excluded from the study, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the day of allocation/randomization to the first vaccination and from the day of each 
vaccination through 14 days postvaccination. SAEs must also be reported throughout the 
duration of the individual's participation in the study, regardless of whether or not related to 
the Sponsor's product.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
•
A death that occurs prior to the participant completing the study, but outside the time 
period specified in the previous paragraph.
OR
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•
An SAE that is considered by an investigator, who is a qualified physician, to be vaccine 
related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 2.
Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
- any death until 
participant 
completion of study
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days of 
learning of event
(unless serious)
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days of 
learning of event
NSAE=nonserious adverse event; SAE=serious adverse event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, 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 with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are infants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest
There are no events of clinical interest in this study.
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8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study 
vaccine in any 24-hour period.
No specific information is available on the treatment of overdose. 
All reports of overdose must be reported by the investigator within 5 calendar days to the
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in
the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
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.
8.6
Pharmacokinetics
Pharmacokinetics parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.8.1
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.9
Future Biomedical Research Sample Collection
If the participant’s parent or legally acceptable representative provides documented informed 
consent for future biomedical research, the following specimens will be obtained as part of 
future biomedical research:
•
DNA for future research
•
Leftover main study serum from immunogenicity assay stored for future research
8.10
Health Economics Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not evaluated in this study.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Screening procedures will be conducted at Visit 1 as outlined in Section 1.3. Potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Section 5. Screening procedures may be repeated after consultation with the Sponsor.
8.11.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
A participant may discontinue from study intervention (including receipt of V114), but
continue to participate in protocol-specified, AE-monitoring activities as outlined in 
Section 1.3, as long as the participant’s parent or legally acceptable representative does not 
withdraw consent. Blood draws for immunogenicity testing could occur if agreed to by the 
participant’s parent or 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 before final database lock, will be 
documented in an sSAP and referenced in the 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 through 9.12.
Study Design Overview
A Phase 3, Single-Arm, Open-label Clinical Study to Evaluate the Safety 
and Immunogenicity of 4 doses of V114 Administered to Healthy Infants 
in South Korea
Treatment Assignment
Participants will be allocated to V114.
Analysis Populations
Immunogenicity: Per-Protocol
Safety: All Participants as Treated
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Primary Endpoint(s)
Immunogenicity:

Anti-PnPs serotype-specific IgG response rates (proportion of 
participants with anti-PnPs serotype-specific IgG ≥0.35 μg/mL) at 
30 days PD3

Anti-PnPs serotype-specific IgG GMCs at 30 days PD3
Safety:

Proportion of participants with solicited injection-site AEs 
(swelling, redness/erythema, tenderness/pain, and hard 
lump/induration) from Day 1 through Day 7 after vaccination with 
V114

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, appetite lost/decreased appetite, and hives 
or welts/urticaria) from Day 1 through Day 7 after vaccination with 
V114

Proportion of participants with vaccine-related SAEs from Day 1 
through completion of study participation
Key Secondary Endpoints
Anti-PnPs serotype-specific IgG GMCs at 30 days PD4
Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes in V114 separately. To address the primary 
immunogenicity objectives, estimation of the IgG response rates and 
GMCs will include descriptive summaries and 95% CIs at 30 days PD3.
A similar statistical approach will be used to evaluate the IgG GMCs at 
30 days PD4.
Statistical Methods for Key 
Safety Analyses
The analysis strategy for safety parameters after each vaccination is 
described in Section 9.6.2. Safety parameters will be summarized via 
descriptive statistics. In addition, for select safety parameters, 95% CIs 
will be provided.
Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
Immunogenicity:
This study will allocate approximately 45 participants to V114. It is 
assumed that approximately 38 participants will be evaluable for 
immunogenicity analyses at 30 days PD3 (85% evaluability rate), and 
approximately 36 participants will be evaluable for immunogenicity 
analyses at 30 days PD4 (80% evaluability rate). There are no 
hypotheses to be evaluated, but Section 9.9.1 provides information about 
the expected variability of the IgG GMCs given the sample size.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as a nonrandomized, open-label study; ie, subjects, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
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The Clinical Biostatistics department will generate the treatment/randomization schedule(s) 
for study treatment assignment. Treatment/randomization will be implemented using an IRT
system.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study and no formal 
hypothesis testing will be performed.
9.4
Analysis Endpoints
Immunogenicity and safety endpoints that will be summarized are listed below.
9.4.1
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements after any vaccination with V114.
The safety endpoints include:

Proportion of participants with solicited injection-site AEs (swelling, 
redness/erythema, tenderness/pain, and hard lump/induration) from Day 1 through 
Day 7 after any vaccination with V114

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, hives or welts/urticaria, and appetite loss/decreased appetite) 
from Day 1 through Day 7 after any vaccination with V114

Proportions of participants with the broad AE categories consisting of any AE and a 
vaccine-related AE from Day 1 through Day 7 after any vaccination with V114

Proportions of participants with an SAE, a vaccine-related SAE, and discontinuation 
due to an AE, and death from Day 1 through completion of study participation

Participants body temperature measured from Day 1 through Day 7 after any 
vaccination with V114
9.4.2
Immunogenicity Endpoints
A description of immunogenicity assessments is contained in Section 8.2.
The immune responses will be measured for each of the following serotypes contained in 
V114: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F. The primary 
immunogenicity endpoints include:

Proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 μg/mL at 30 
days PD3.
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
Anti-PnPs serotype-specific IgG GMCs at 30 days PD3.
The secondary immunogenicity analysis endpoints include:

Anti-PnPs serotype-specific IgG GMCs at 30 days PD4.
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 study. The PP population consists of all randomized participants without 
deviations from the protocol that may substantially affect the results of the immunogenicity 
endpoint(s). Potential deviations that may result in the exclusion of a participant from the PP 
population for all immunogenicity analyses include:

Failure to receive primary infant series vaccination (V114 Doses 1, 2, and 3) as per 
vaccination schedule

Receipt of prohibited medication or prohibited vaccine before study vaccination
Additional potential deviations that may result in the exclusion from the PP immunogenicity 
analyses at a particular time point include:

Failure to receive Dose 4 of V114 according to vaccination schedule required at the 
time point for the analysis

Failure to receive the scheduled doses of V114 with the specified intervals/time 
window (at least 28 days between Doses 1 and 2 and between Doses 2 and 3 [for PD3 
analysis], 12 months to 1 day before 16 months of age for Dose 4 [for PD4 analyses])

Receipt of prohibited medication or prohibited vaccine before a blood sample 
collection

Collection of blood sample at the time point for the analysis outside the prespecified
window (as described in Section 1.3)
The final determination on protocol deviations, and thereby the composition of the PP 
population, will be made before the final database lock.
A supportive analysis using the FAS population may also be performed for the primary 
immunogenicity endpoints. The FAS population consists of all randomized participants who 
received at least 1 study vaccination and have at least 1 serology result.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized
participants who received at least one dose of study vaccination.
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At least 1 temperature measurement obtained after study intervention is required for 
inclusion in the analysis of temperature.
9.6
Statistical Methods
Statistical testing and inference for immunogenicity and safety analyses are described in 
Section 9.6.1 and Section 9.6.2, respectively. Section 9.6.3 describes how demographic and 
baseline characteristics will be summarized.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives. 
Immunogenicity analyses will be conducted for each of the 15 pneumococcal serotypes in 
V114 separately. To address the primary immunogenicity objectives, evaluation of the IgG
response rates and GMCs at 30 days after the third dose of V114 will include descriptive 
summaries and 95% CIs. For IgG response rates, the CIs will be calculated based on the 
exact binomial method proposed by Clopper and Pearson [CLOPPER, C. J. and PEARSON, 
E. S. 1934]. For IgG GMCs, point estimates will be calculated by exponentiating the 
estimates of the mean of the natural log values. The CIs will be derived by exponentiating the 
CIs of the mean of the natural log values based on the t-distribution.
To address the secondary immunogenicity objective, evaluation of the IgG GMCs at 30 days 
after the fourth dose of V114 will include descriptive summaries and 95% CIs.
The primary and secondary endpoints may be summarized separately as soon as complete 
data for the specified time points become available.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 3.
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Table 3
Analysis Strategy for Key Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
IgG response rates at 30 days PD3
P
Descriptive Statistics 
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
IgG GMCs at 30 days PD3
P
Descriptive Statistics 
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoint
IgG GMCs at 30 days PD4
P
Descriptive Statistics 
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
† P=Primary approach; S=Supportive approach.
CI = confidence interval; FAS = Full Analysis Set; GMC = geometric mean concentration;
IgG = immunoglobulin G; PP = Per-Protocol.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements.
The analysis strategy of safety parameters is summarized in Table 4. The proportion of 
participants with solicited injection-site AEs (swelling, redness/erythema, tenderness/pain, 
and hard lump/induration from Day 1 to Day 7 postvaccination) and solicited systemic AEs 
(irritability, drowsiness/somnolence, hives or welts/urticaria, and appetite loss/decreased 
appetite from Day 1 to Day 7 postvaccination) will be provided along with the corresponding 
CIs (based on the exact binomial method proposed by Clopper and Pearson [CLOPPER, C. J. 
and PEARSON, E. S. 1934]). In addition, the broad AE categories consisting of the 
proportion of participants with any AE, a vaccine-related AE, an SAE, a vaccine-related 
SAE, discontinuation due to an AE, and the proportion of participants who died will be 
summarized in the same manner. The proportion of participants with maximum temperature 
measurements meeting the Brighton Collaboration cut points (from Day 1 through Day 7)
[Marcy, S. M., et al 2004] will also be provided along with the corresponding 95% CIs. Point 
estimates will be provided for all other safety parameters (specific AE terms and system 
organ class terms).
Medical device incidents due to syringe, if any, will be listed.
The safety parameters may be summarized separately as soon as complete data become 
available at 30 days after the third dose of V114 and 30 days after the fourth dose of V114.
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Table 4
Analysis Strategy for Safety Parameters
Safety Endpoint
95% CI
Descriptive Statistics
Injection-site redness/erythema (Day 1 to Day 7) †
X
X
Injection-site swelling (Days 1 to 7) †
X
X
Injection-site tenderness/pain (Days 1 to 7) †
X
X
Injection-site hard lump/induration (Days 1 to 7) †
X
X
Irritability (Days 1 to 7) †
X
X
Drowsiness/somnolence (Days 1 to 7) †
X
X
Hives or welts/urticaria (Days 1 to 7) †
X
X
Appetite loss/decreased appetite (Days 1 to 7) †
X
X
Any AE‡
X
X
Any Vaccine-related AE‡
X
X
Any SAE‡
X
X
Any Vaccine-related SAE‡
X
X
Discontinuation due to AE‡
X
X
Death‡
X
X
Maximum temperature measurements meeting the 
Brighton Collaboration cut points (Days 1 to 7)
X
X
Specific AEs by SOC and PT
X
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = 
system organ class; X = results will be provided.
† Includes solicited events only.
‡ These endpoints are broad adverse event categories. For example, descriptive statistics for the safety endpoint 
of “Any AE” will provide the number and percentage of participants with at least 1 AE.
9.6.3
Demographic and Baseline Characteristics
The relevant demographic and baseline characteristics will be assessed using summary 
tables. No statistical hypothesis tests will be performed on these characteristics. The number 
and percentage of participants screened and randomized and the primary reasons for 
screening failure and discontinuation will be displayed. Demographic variables, baseline 
characteristics, prior and concomitant vaccinations and therapies will be summarized either 
by descriptive statistics or categorical tables.
9.7
Interim Analyses
There are no planned interim analyses for this study.
9.8
Multiplicity
No adjustment will be made for multiplicity.
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9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. This study will randomize approximately 45 participants to 
receive V114. It is assumed that approximately 38 participants will be evaluable for PP 
immunogenicity analyses at 30 days PD3 (based on an 85% evaluability rate), and 36
participants will be evaluable for PP immunogenicity analyses at 30 days PD4 (based on an
80% evaluability rate).
The width of the 95% CIs for the serotype-specific IgG GMCs depends on the sample size, 
variability of the natural log concentrations, and the magnitude of the IgG GMC. In Table 5, 
the 95% CIs for various hypothetical IgG GMCs at 30 days PD3 and various hypothetical 
standard deviation estimates for the natural log titers are displayed.
Table 5
95% CIs for Varying Hypothetical IgG GMCs and Varying Standard Deviations
Standard Deviation of
Natural Log Titers†
Serotype-specific IgG GMC†
1
5
10
1.0
(0.73, 1.37)
(3.64, 6.87)
(7.28, 13.74)
1.5
(0.62, 1.61)
(3.10, 8.06)
(6.21, 16.11)
2.0
(0.53, 1.89)
(2.65, 9.44)
(5.29, 18.89)
Based on 38 evaluable participants.
† The estimates of the standard deviation and IgG GMCs are representative of those observed in a previous 
MSD study.
CI = confidence interval; GMC = geometric mean concentration; IgG = immunoglobulin G.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE among 45
participants if the underlying incidence of an SAE is 3.5% (1 of every 28 participants 
receiving the vaccine). There is a 50% chance of observing at least 1 SAE among 45
participants if the underlying incidence of an SAE is 1.5% (1 of every 65 participants 
receiving the vaccine). If no SAEs are observed among 45 participants, this study will 
provide 97.5% confidence that the underlying percentage of participants with an SAE is 
<7.9% (1 in every 13 participants).
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9.10
Subgroup Analyses
Subgroup analyses (eg, sex = female vs male) will be performed for the primary
immunogenicity endpoints and selected safety endpoints (summary of AEs). Details of
subgroup analyses will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
The number and proportion of randomized participants receiving V114 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.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants documented informed consent, 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 
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Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
Not applicable
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
    An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
    NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
    NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
    Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
    Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
    New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
    Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
    Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
    For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
    Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
    Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
    Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
    Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
    Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
b.   Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.   Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.   Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.   Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.   Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
    When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
    The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
    It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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    There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
    The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
    An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used 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 erythema/redness, or swelling or hard lump/induration from the day of 
vaccination through Day 7 postvaccination will be evaluated by maximum size.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:

Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?

Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?

Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?

Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study; or (3) 
Sponsor’s product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
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
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.

No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
    The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
    New or updated information will be recorded in the CRF.
    The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
    The primary mechanism for reporting to the Sponsor will be the EDC tool.

Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).

If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
    The site will enter the SAE data into the electronic system as soon as it becomes 
available.
    After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
    If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
    Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
    If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
    In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
    Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
    Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
Not applicable. 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 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 with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' 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 sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6.  Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.  Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.  Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1.  National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4.  Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not Applicable
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACCP
American College of Chest Physicians
ADA
antidrug antibodies
ADL
activities of daily living  
AE
adverse event 
APaT
All Participants as Treated
AR
adverse reaction
ART
antiretroviral therapy
ATD
accelerated titration design
ATP
adenosine triphosphate
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
BICR
blinded independent central review
BID
twice daily
BMI
body mass index
BP
blood pressure
CAC
Clinical Adjudication Committee
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CF
compact flash
CG
Cockcroft-Gault
CHS
cough hypersensitivity syndrome
CI
confidence interval
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSD
Cough Severity Diary
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DAIDS
Division of AIDS
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
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Abbreviation
Expanded Term
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
ePROs
electronic patient-reported outcomes
EQ-5D
EuroQoL-5D
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FAS
Full Analysis Set
FFPE
formalin-fixed, paraffin embedded
FSH
follicle stimulating hormone 
FVC
forced vital capacity
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
GMC
geometric mean concentration
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
iCRO
imaging CRO
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug 
IO
immuno-oncology
IPD
Invasive pneumococcal disease
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
interactive response technology
ITP
idiopathic thrombocytopenic purpura
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
IWRS
integrated web response system
KPS
Karnofsky performance status
LAM
lactational amenorrhoea method
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Abbreviation
Expanded Term
LCQ
Leicester Cough Questionnaire
LJEV
Live Japanese encephalitis vaccine
mAb
monoclonal antibody
MAD
maximum administered dose
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified Toxicity Probability Interval
NCI
National Cancer Institute
NCS
not clinically significant
NEAB
noneosinophilic bronchitis
NIP
National Immunization Program
NSCLC
non-small cell lung cancer
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
OR
objective response
ORR
objective response rate
OS
overall survival
OSF
on-site formulation
OTC
over-the-counter
PBPK
physiologically-based PK
PCV
pneumococcal conjugate vaccine
PD3
postdose 3
PD4
postdose 4
PD-1
programmed cell-death 1
PD-L1
programmed cell-death ligand 1
PD-L2
programmed cell-death ligand 2
PET
positron emission tomography 
PFS
progression free survival
PGIC
Patient Global Impression Change
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PnECL
pneumococcal electrochemiluminescence
PO
orally
PnP
pneumococcal polysaccharide
PP
per-protocol
PQC
product quality complaint
PR
partial response
PRO
patient-reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks
QOL
quality of life
QP2
Department of Quantitative Pharmacology and Pharmacometrics
RCC
refractory chronic cough
RNA
ribonucleic acid
rP2D
recommended Phase 2 dose
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
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Abbreviation
Expanded Term
siDMC
Standing Internal Data Monitoring Committee
SIM
Site Imaging Manual
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TMDD
target-mediated drug disposition
UACS
upper airway cough syndrome
UCC
unexplained chronic cough
UDS
urine drug screen
URTI
upper respiratory tract infection
V 
volume of distribution
VAS
Visual Analog Scale
VRC
paper Vaccination Report Card
VS
vital sign
WBC
white blood cell
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
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11
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