A Phase 1, Randomized, Double-blind, Active-Comparator-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Polyvalent Pneumococcal Conjugate Vaccine in Healthy Japanese Adults.
Phase: PHASE1
Conditions: Pneumococcal Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04665050 
Document Date: 
20-Oct-2020
A Phase 1, Randomized, Double-blind, Active-Comparator-
controlled Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of a Polyvalent Pneumococcal Conjugate Vaccine 
in Healthy Japanese Adults.

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Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Phase 1, Randomized, Double-blind, Active-Comparator-controlled Study 
to Evaluate the Safety, Tolerability, and Immunogenicity of a Polyvalent Pneumococcal 
Conjugate Vaccine in Healthy Japanese Adults.
Protocol Number: 002-00
Compound Number: V116
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
Not Applicable
Approval Date:   20 October 2020
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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
Original Protocol
20-OCT-2020
Not applicable
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................18
2.1
Study Rationale....................................................................................................18
2.2
Background ..........................................................................................................18
2.2.1
Pharmaceutical and Therapeutic Background .............................................18
2.2.2
Preclinical and Clinical Studies ...................................................................20
2.2.3
Information on Other Study-related Therapy ..............................................20
2.2.3.1
PNEUMOVAX™23..........................................................................20
2.3
Benefit/Risk Assessment......................................................................................20
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................20
4
STUDY DESIGN............................................................................................................21
4.1
Overall Design......................................................................................................21
4.2
Scientific Rationale for Study Design.................................................................22
4.2.1
Rationale for Endpoints ...............................................................................22
4.2.1.1
Immunogenicity Endpoints................................................................22
4.2.1.2
Safety Endpoints................................................................................23
4.2.1.3
Future Biomedical Research..............................................................23
4.2.2
Rationale for the Use of Comparator...........................................................23
4.3
Justification for Dose...........................................................................................24
4.3.1
Starting Dose for This Study........................................................................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.................................................................................................24
5.2
Exclusion Criteria................................................................................................26
5.3
Lifestyle Considerations......................................................................................28
5.4
Screen Failures.....................................................................................................28
5.5
Participant Replacement Strategy......................................................................28
6
STUDY INTERVENTION............................................................................................28
6.1
Study Intervention(s) Administered...................................................................28
6.1.1
Medical Devices...........................................................................................30
6.2
Preparation/Handling/Storage/Accountability .................................................30
6.2.1
Dose Preparation..........................................................................................30
6.2.2
Handling, Storage, and Accountability........................................................30
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6.3
Measures to Minimize Bias: Randomization and Blinding..............................31
6.3.1
Intervention Assignment..............................................................................31
6.3.2
Stratification.................................................................................................31
6.3.3
Blinding........................................................................................................31
6.4
Study Intervention Compliance..........................................................................32
6.5
Concomitant Therapy..........................................................................................32
6.5.1
Rescue Medications and Supportive Care ...................................................33
6.6
Dose Modification ................................................................................................33
6.7
Intervention After the End of the Study............................................................33
6.8
Clinical Supplies Disclosure................................................................................33
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT WITHDRAWAL ...............................................................................33
7.1
Discontinuation of Study Intervention...............................................................33
7.2
Participant Withdrawal From the Study...........................................................33
7.3
Lost to Follow-up .................................................................................................34
8
STUDY ASSESSMENTS AND PROCEDURES........................................................34
8.1
Administrative and General Procedures ...........................................................35
8.1.1
Informed Consent.........................................................................................35
8.1.1.1
General Informed Consent.................................................................36
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................36
8.1.2
Inclusion/Exclusion Criteria ........................................................................36
8.1.3
Participant Identification Card.....................................................................36
8.1.4
Medical History ...........................................................................................37
8.1.5
Prior and Concomitant Medications Review...............................................37
8.1.5.1
Prior Medications...............................................................................37
8.1.5.2
Concomitant Medications..................................................................37
8.1.6
Assignment of Screening Number...............................................................37
8.1.7
Assignment of Treatment/Randomization Number.....................................37
8.1.8
Study Intervention Administration ..............................................................38
8.1.8.1
Timing of Dose Administration.........................................................38
8.1.9
Vaccination Report Card (VRC)..................................................................38
8.1.10
Telephone Contact on Day 15......................................................................39
8.1.11
Discontinuation and Withdrawal .................................................................39
8.1.11.1
Withdrawal From Future Biomedical Research ................................39
8.1.12
Participant Blinding/Unblinding..................................................................40
8.1.13
Calibration of Equipment.............................................................................40
8.2
Immunogenicity Assessments .............................................................................40
8.2.1
Multiplexed Opsonophagocytic Assay (MOPA).........................................41
8.2.2
Pneumococcal Electrochemiluminescence (PnECL)...................................41
8.3
Safety Assessments...............................................................................................41
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8.3.1
Physical Examinations.................................................................................42
8.3.2
Pregnancy Test.............................................................................................42
8.3.3
Body Temperature Measurement.................................................................42
8.3.4
Postvaccination Observation Period ............................................................42
8.3.5
Clinical Safety Laboratory Assessments .....................................................42
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................43
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................43
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety 
Events...........................................................................................................46
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event 
Information ..................................................................................................46
8.4.4
Regulatory Reporting Requirements for SAE .............................................46
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................46
8.4.6
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs..........................................................................47
8.4.7
Events of Clinical Interest............................................................................47
8.4.8
Adverse Events Reported on the VRC.........................................................47
8.4.8.1
Solicited Adverse Events...................................................................47
8.4.8.2
Unsolicited Adverse Events...............................................................47
8.5
Treatment of Overdose........................................................................................48
8.6
Pharmacokinetics.................................................................................................48
8.7
Pharmacodynamics..............................................................................................48
8.8
Biomarkers ...........................................................................................................48
8.9
Future Biomedical Research Sample Collection...............................................48
8.10
Medical Resource Utilization and Health Economics.......................................48
8.11
Visit Requirements...............................................................................................48
8.11.1
Screening......................................................................................................48
8.11.2
Treatment Period/Vaccination Visit ............................................................49
9
STATISTICAL ANALYSIS PLAN .............................................................................49
9.1
Statistical Analysis Plan Summary.....................................................................49
9.2
Responsibility for Analyses/In-house Blinding .................................................51
9.3
Hypotheses/Estimation ........................................................................................51
9.4
Analysis Endpoints...............................................................................................51
9.4.1
Immunogenicity Endpoints..........................................................................51
9.4.2
Safety Endpoints..........................................................................................51
9.5
Analysis Populations............................................................................................52
9.5.1
Immunogenicity Analysis Populations ........................................................52
9.5.2
Safety Analysis Population..........................................................................53
9.6
Statistical Methods...............................................................................................53
9.6.1
Statistical Methods for Immunogenicity Analyses......................................53
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9.6.2
Statistical Methods for Safety Analyses ......................................................54
9.6.3
Demographic and Baseline Characteristics .................................................57
9.7
Interim Analyses ..................................................................................................57
9.8
Multiplicity ...........................................................................................................57
9.9
Sample Size and Power Calculations .................................................................57
9.9.1
Immunogenicity Analyses ...........................................................................57
9.9.2
Safety Analyses............................................................................................57
9.10
Subgroup Analyses...............................................................................................57
9.11
Compliance (Medication Adherence).................................................................58
9.12
Extent of Exposure...............................................................................................58
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................59
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........59
10.1.1
Code of Conduct for Clinical Trials.............................................................59
10.1.2
Financial Disclosure.....................................................................................61
10.1.3
Data Protection.............................................................................................61
10.1.3.1
Confidentiality of Data ......................................................................62
10.1.3.2
Confidentiality of Participant Records...............................................62
10.1.3.3
Confidentiality of IRB/IEC Information............................................62
10.1.4
Publication Policy........................................................................................62
10.1.5
Compliance with Study Registration and Results Posting 
Requirements ...............................................................................................63
10.1.6
Compliance with Law, Audit, and Debarment ............................................63
10.1.7
Data Quality Assurance ...............................................................................64
10.1.8
Source Documents .......................................................................................65
10.1.9
Study and Site Closure.................................................................................65
10.2
Appendix 2: Clinical Laboratory Tests..............................................................66
10.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................67
10.3.1
Definition of AE ..........................................................................................67
10.3.2
Definition of SAE ........................................................................................68
10.3.3
Additional Events Reported.........................................................................69
10.3.4
Recording AE and SAE ...............................................................................69
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................73
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Qualtiy Complaints/Malfunctions: Definitions, Recording, 
and Follow-up.......................................................................................................74
10.4.1
Definitions....................................................................................................74
10.4.2
Medical Device/Combination Medicinal Products – Documenting 
and Reporting...............................................................................................74
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10.4.3
Recording, Assessing Causality, and Follow-up of Adverse Events 
due to Malfunctions (serious and nonserious) .............................................75
10.5
Appendix 5: Contraceptive Guidance................................................................76
10.5.1
Definitions....................................................................................................76
10.5.2
Contraception Requirements........................................................................77
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................79
10.7
Appendix 7: Country-specific Requirements....................................................84
10.8
Appendix 8: Abbreviations .................................................................................85
11
REFERENCES...............................................................................................................87
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LIST OF TABLES
Table 1
Study Interventions.........................................................................................29
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample 
Type................................................................................................................35
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events .....................................................................45
Table 4
Solicited Adverse Events for V116-002.........................................................47
Table 5
Analysis Strategy for Key Immunogenicity Variables...................................54
Table 6
Analysis Strategy for Safety Parameters........................................................56
Table 7
Protocol-required Safety Laboratory Assessments ........................................66
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LIST OF FIGURES
Figure 1
V116-002 Study Design .................................................................................15
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1, Randomized, Double-blind, Active-Comparator-controlled 
Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Polyvalent 
Pneumococcal Conjugate Vaccine in Healthy Japanese Adults.
Short Title: Phase 1 Study of a pPCV in Healthy Japanese Adults
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for the study.
The following objectives and endpoints will be evaluated in healthy Japanese 
pneumococcal vaccine naïve adults ≥20 years of age who are administered a single dose 
of Polyvalent Pneumococcal Conjugate Vaccine (pPCV) or PNEUMOVAX™23.
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability of pPCV with respect to the 
proportion of participants with AEs in the 
recipients of pPCV and PNEUMOVAX™23.
- Solicited injection-site AEs
- Solicited systemic AEs
- Vaccine-related SAEs
Secondary Objectives
Secondary Endpoints
- Objective: To describe the serotype-specific 
opsonophagocytic activity (OPA) Geometric 
Mean Titers (GMTs) and Immunoglobulin G 
(IgG) Geometric Mean Concentrations 
(GMCs) at 30 days postvaccination in the 
recipients of pPCV and PNEUMOVAX™23.
- Serotype-specific OPA and IgG
responses
- Objective: To describe the serotype-specific 
Geometric Mean Fold Rises (GMFR) from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for both OPA and
IgG responses in the recipients of pPCV and 
PNEUMOVAX™23.
- Serotype-specific OPA and IgG
responses
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Prevention
Indication
Pneumococcal infection
Population
Healthy Japanese adults 20 years of age and older
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control without placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 months from the time the first 
participant provides documented informed consent 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:
Total approximately 100 participants (approximately 34 participants in 20 to 64 years of 
age and approximately 66 participants in 65 years of age and older) will be randomized as 
described in Section 9.9.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Freq-
uency
Route 
of 
Admin
Vaccination 
Regimen
Use
pPCV
pPCV
Refer 
to IB
Single 
Dose
IM
Single Dose at 
Visit 1 
(Day 1)
Experi-
mental
PNEUMOVAX™23 PNEUMOVAX™23
Refer 
to 
product 
labeling
Single 
Dose
IM
Single Dose at 
Visit 1 
(Day 1)
Experi-
mental
Abbreviations: Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; 
pPCV = polyvalent pneumococcal conjugate vaccine.
Total 
Number of 
Intervention 
Groups/ 
Arms
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 30 days
from the time the participant provides documented informed consent form
through the final contact.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight 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
V116-002 Study Design
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1.3
Schedule of Activities
Study Period:
Screening/Intervention
Notes
Visit Number:
1
Telephone 
Contact
2
Scheduled Time:
Day 1
Day 15
Day 30
Visit Window:
-
Day 15 to
Day 19
Day 30 to 
Day 44
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study procedures.
Informed Consent for Future Biomedical Research
X
Participation in future biomedical research is optional and consent must be 
obtained before the blood sample (DNA sample) is collected.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Prior to randomization, review of prior medications/vaccinations, medical 
history, a complete physical examination, and temperature measurement 
are required at Visit 1 to determine eligibility. If Day 1 is rescheduled (see 
Section 5.2), these activities must be repeated prior to vaccination.
Medical History
X
The participant’s relevant medical history for the 5 years prior to study 
entry will be reviewed. History of tobacco use will also be collected for all 
participants.
Post-randomization Procedures
Assignment of Randomization Number
X
Participant Identification Card
X
Prior/Concomitant Medication and Nonstudy Vaccination 
Review
X
X
X
pPCV/PNEUMOVAX™23 Administration (blinded)
X
Participants will receive a single dose of either pPCV or 
PNEUMOVAX™23. Study vaccine will be administered by unblinded 
study site staff (see Section 6.3.3). The unblinded study site staff must not 
perform any other visit procedures.
Provide Vaccination Report Card (VRC)
X
See Section 8.1.9 for details.
Review VRC Data with Participant
X
X
See Section 8.1.9 for details.
Collect VRC From Participant
X
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Study Period:
Screening/Intervention
Notes
Visit Number:
1
Telephone 
Contact
2
Scheduled Time:
Day 1
Day 15
Day 30
Visit Window:
-
Day 15 to
Day 19
Day 30 to 
Day 44
Safety Procedures
Complete Physical Examination
X
To be performed by the investigator at screening and before vaccine is 
administered.
Pregnancy Test (if applicable)
X
X
A pregnancy test (sensitive to at least 25 IU β-human chorionic 
gonadotropin [β-hCG]) must be performed before administration of study 
vaccine in females who are of reproductive potential (see Section 8.3.2 and 
Appendix 5 for details).
Body Temperature Measurement
X
Each participant’s body temperature must be taken before vaccination (see 
Section 8.3.3 for details). Participants who have febrile illness occurring at 
or within 72 hours prior to vaccination may have their Day 1 Visit 
rescheduled (see Section 5.2 for details).
Postvaccination Observation Period
X
Participants will be observed for at least 30 minutes postvaccination (see 
Section 8.3.4 for details).
AE Monitoring
X
X
X
Nonserious AEs are to be reported from Day 1 through Day 30 following 
vaccination. SAEs, death and medical device incidents are to be reported 
from Day 1 through the duration of an individual’s study participation (see 
Section 8.4.1 for details).
Immunogenicity Procedures
Collect Blood (Serum) for Immunogenicity Assays 
(Including Retention Serum)
X
X
Day 1 blood samples must be collected before vaccination (see Section 4.1 
and Section 8.9 for details).
Future Biomedical Research
Collect Blood (DNA) for Future Biomedical Research
X
Sample will be collected from randomized participants who provide 
consent for future biomedical research (see Section 8.9). 
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2
INTRODUCTION
Merck Sharp & Dohme Corp. is developing an investigational polyvalent PCV (V116, 
hereafter referred to as pPCV) for the prevention of pneumococcal disease caused by the 
serotypes in the vaccine.
2.1
Study Rationale
Pneumococcal disease, in adults, specifically residual disease caused by serotypes not 
included in the licensed pneumococcal vaccines, remains an unmet medical need. To address 
the burden of residual pneumococcal disease in adults, pPCV is designed to target serotypes 
that account for the majority of invasive pneumococcal disease (IPD) in adults and includes 
serotypes not currently contained in any licensed pneumococcal vaccine.
Especially, the population of adults ≥65 years of age is at elevated risk for pneumococcal 
disease and associated morbidity and mortality due to aging related physiological changes in 
the respiratory system and high prevalence of other medical conditions associated with 
increased risk for pneumococcal disease [Drijkoningen, J. J 2014] [Janssens, J. P. 2004]
[Sunagawa, T.,et al 2018].
This study is designed to evaluate the safety, tolerability, and immunogenicity of pPCV 
compared with PNEUMOVAX™23 in healthy pneumococcal vaccine naïve Japanese adults.
The needs of pneumococcal vaccine for adults aged <65 years of age exist, especially for 
those at increased risk for pneumococcal disease (e.g., subjects with co-morbid condition 
such as chronic heart/lung/hepatic disease, diabetes, and/or acquired/congenital 
immunosuppression).
Study results will provide useful information about the safety, tolerability and 
immunogenicity profiles of pPCV in Japanese adults before evaluation in subsequent phases 
of pPCV clinical development in Japanese adults
2.2
Background
Refer to the IB for detailed background information on pPCV, including information on 
pneumococcal disease burden.
2.2.1
Pharmaceutical and Therapeutic Background
Streptococcus pneumoniae causes IPD that may be accompanied by meningitis or bacteremia 
pneumonia and non-IPD such as pneumonia, otitis media, and sinusitis in children and adults.
S. pneumoniae accounts for approximately 20% of the causative bacteria in community-onset 
pneumonia (community-acquired and hospital-acquired pneumonia) in adults.
Currently, many countries worldwide have incorporated licensed PCVs (e.g., Prevnar 13™) 
into their infant immunization programs. In Japan emergency promotion fund project with 
Prevnar™ was initiated in November 2010 and introduced into the National Immunization 
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2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical studies conducted with pPCV.
Phase 1/2 study involving healthy adults 18 years of age and older is still ongoing in US.
These participants have vaccine administered intramuscularly.
2.2.3
Information on Other Study-related Therapy
2.2.3.1
PNEUMOVAX™23
The label name of PNEUMOVAX™23 in Japan is PNEUMOVAX® NP.
Refer to the approved labeling for detailed background information on PNEUMOVAX™23.
PNEUMOVAX™23 is comprised of the polysaccharides from 23 of the most important 
serotypes causing disease in adults (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 
17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F). The formulation is not adjuvanted and no 
carrier protein is used. PNEUMOVAX™23 will be US commercial product in this study.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
vaccination with pPCV during participation, as clinical studies are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Approximately 50% of participants in this study will receive PNEUMOVAX™23, a 
pneumococcal vaccine for the prevention of pneumococcal disease that is licensed in Japan. 
pPCV is expected to provide comparable immune responses to PNEUMOVAX™23 for the 
serotypes in common while providing additional coverage for the serotypes unique to pPCV. 
It is unknown if the investigational pPCV will have the same clinical benefit as 
PNEUMOVAX™23. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for the study.
The following objectives and endpoints will be evaluated in healthy Japanese pneumococcal 
vaccine naïve adults ≥20 years of age who are administered a single dose of pPCV or 
PNEUMOVAX™23.
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Objectives
Endpoints
Primary
- Objective: To evaluate the safety and 
tolerability of pPCV with respect to the 
proportion of participants with AEs in the 
recipients of pPCV and PNEUMOVAX™23.
- Solicited injection-site AEs
- Solicited systemic AEs
- Vaccine-related SAEs
Secondary
- Objective: To describe the serotype-specific 
opsonophagocytic activity (OPA) Geometric 
Mean Titers (GMTs) and Immunoglobulin G 
(IgG) Geometric Mean Concentrations (GMCs)
at 30 days postvaccination in the recipients of 
pPCV and PNEUMOVAX™23.
- Serotype-specific OPA and IgG
responses
- Objective: To describe the serotype-specific 
Geometric Mean Fold Rises (GMFR) from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for both OPA and 
IgG responses in the recipients of pPCV and 
PNEUMOVAX™23.
- Serotype-specific OPA and IgG
responses
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, parallel-group, multi-site, double-blind (with in-
house blinding) study of pPCV in healthy Japanese adults ≥20 years of age who have not 
previously received any pneumococcal vaccine.
Approximately 100 participants (approximately 34 participants in 20 to 64 years of age and 
approximately 66 participants is 65 years of age and older) who have not previously received 
any pneumococcal vaccine (vaccine naïve) will be randomly assigned in a 1:1 ratio to receive 
a single dose of pPCV or PNEUMOVAX™23 at Visit 1 (Day 1). Randomization will be 
stratified by participant age at the time of randomization (20 to 64 years and ≥65 years) 
across the 2 vaccination groups. Safety and immunogenicity will be assessed at 30 days 
postvaccination.
Paper VRC will be used by all participants to record solicited injection site and solicited 
systemic AEs from Day 1 through Day 5 postvaccination, unsolicited injection site and 
systemic AEs from Day 1 through Day 30 postvaccination, and daily temperatures from Day 
1 through Day 5 postvaccination. Information for SAEs and deaths, regardless of whether the 
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events are considered to be vaccine related by the investigator, will be collected from the 
time consent is signed through completion of participation in the study.
Blood samples for immunogenicity assays will be drawn Visit 1(Day 1) and at Visit 2 (Day 
30). Blood samples must be drawn prior to study vaccine administration at Visit 1 (Day 1).
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 participants who provide optional 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
This study will assess the safety, tolerability and immunogenicity of pPCV in Japanese 
healthy adults ≥20 years of age. The healthy adults ≥ 20 years of age who are in general 
population in Phase 1 study and elderly ≥ 65 years of age who are at elevated risk for 
pneumococcal disease are included in this study. Participants will be stratified by age group 
(20 to 64 years of age and ≥ 65 years of age). 
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints are consistent with previous early phase studies evaluating 
PCVs.
Sera from participants will be used to measure vaccine induced, anti-pneumococcal 
polysaccharide (PnP) serotype-specific OPA and IgG responses for all serotypes included in 
pPCV using the Multiplexed Opsonophagocytic Assay (MOPA) and pneumococcal 
electrochemiluminescence (PnECL) assay, respectively.
Several studies have shown a positive correlation between serotype-specific IgG antibody 
concentrations and OPA titers in children and adults [Centers for Disease Control and 
Prevention 2010] [Anttila, M., et al 1999] [Romero-Steiner, S., et al 1997]. OPA assesses 
levels of functional antibodies capable of opsonizing pneumococcal capsular polysaccharides 
for presentation to phagocytic cells for engulfment and subsequent killing, and therefore is 
considered an important immunologic surrogate for protection against IPD in adults. It is 
noted that IgG antibody and OPA titer threshold values that correlate with protection in 
adults have not been defined; however, the OPA functional assay is considered a preferred 
endpoint in adults.
Details on the immunogenicity endpoints evaluated in this study can be found in Section 
9.4.1.
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4.2.1.2
Safety Endpoints
The safety endpoints (i.e., AEs and temperature) evaluated in this study were selected based 
on the anticipated product safety profile and published data from marketed PCVs.
The paper VRC will be used to collect participant-reported events during the postvaccination 
period, as detailed in Section 8.1.9.
Details on the safety endpoints evaluated in this study can be found in Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
PNEUMOVAX™23 was selected as the comparator for this study based on the following
rationale. Of the currently licensed pneumococcal vaccines, PNEUMOVAX™23 has the
most serotypes in common with pPCV, and antibody responses to PNEUMOVAX™23 are
generally comparable to Prevnar 13™ for the common serotypes. PNEUMOVAX™23 has 
been previously been evaluated in healthy Japanese adults 20 to 40 years of age. In Japan, 
PNEUMOVAX®NP (PNEUMOVAX™23) is approved for use in the population who are at 
least 2 years of age and at high risk of developing severe pneumococcal infections.
Additionally, PNEUMOVAX®NP (PNEUMOVAXTM23) is the only pneumococcal vaccine 
currently included in the NIP in Japan and is recommended for a) adults 65 years of age or 
older, and b) adults who are 60 to under 65 years old with heart, kidney and respiratory 
dysfunction, and with immunocompromised adults with HIV infection.
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4.3
Justification for Dose
4.3.1
Starting Dose for This Study
The dose of each serotype contained in pPCV was based on prior dose-ranging clinical trials 
(Phase1 part of V116-001 study).
The dose of PNEUMOVAX™23 selected for use in this trial is the approved dose in Japan. 
4.4
Beginning and End of Study Definition
The overall study begins when the first participant provides documented informed consent. 
The overall study ends when the last participant completes the last study-related contact, 
withdraws consent, 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 Japanese male and female participants ≥20 years of age will be enrolled in this 
study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. In the opinion of the investigator, is in good health. Any underlying chronic condition 
must be documented to be in stable condition according to the investigator’s judgment.
Demographics
2. Is male or female ≥20 years of age at the time of randomization.
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Male Participants
3. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 30 days after the last dose of study intervention:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
‒ Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
Female Participants
4.
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 

Is not a WOCBP
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), or be abstinent from heterosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 5 
during the intervention period and for at least 30 days after the last dose of study 
intervention. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention.

A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 
24 hours before the first dose of study intervention.

If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
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
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
5. The participant has provided documented informed consent for the study. The participant 
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 
positive culture at another sterile site) or known history of other culture-positive 
pneumococcal disease within 3 years of Visit 1 (Day 1).
2. Has a known hypersensitivity to any component of the pneumococcal polysaccharide 
vaccine, PCV, or any diphtheria toxoid-containing vaccine.
3. Has a known or suspected impairment of immunological function including, but not 
limited to, a history of congenital or acquired immunodeficiency, documented HIV 
infection, functional or anatomic asplenia, or history of autoimmune disease.
4. Has a coagulation disorder contraindicating intramuscular vaccination.
5. *Had a recent febrile illness (defined as axillary temperature ≥37.5°C or equivalent) or 
received antibiotic therapy for any acute illness occurring within 72 hours before receipt 
of study vaccine.
6. Has a known malignancy that is progressing or has required active treatment within the
3 years prior to signing the informed consent. (Note: participants with basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ 
[e.g., breast carcinoma, cervical cancer in situ] that have undergone potentially curative 
therapy are not excluded).
7. A WOCBP who has a positive urine or serum pregnancy test before vaccination at Visit 1 
(Day 1).
Prior/Concomitant Therapy
8. Has received any pneumococcal vaccine or is expected to receive any pneumococcal 
vaccine during the study, outside of the protocol.
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9. *Has received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for 
≥14 consecutive days and has not completed intervention at least 30 days prior to study 
vaccination.
10. *Has received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) starting from 14 days prior to study 
vaccination. (Note: Topical, ophthalmic, intra-articular or soft-tissue [e.g., bursa, tendon 
steroid injections], and inhaled/nebulized steroids are permitted).
11. Is receiving immunosuppressive therapy, including chemotherapeutic agents used to treat 
cancer or other conditions, and interventions associated with organ or bone marrow 
transplantation, or autoimmune disease.
12. *Has received any non-live vaccine starting from 14 days prior to study vaccination or is 
scheduled to receive any non-live vaccine through 30 days following study vaccination. 
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.
13. *Has received any live vaccine starting from 30 days before study vaccination or is 
scheduled to receive any live vaccine through 30 days following study vaccination.
14. Has received a blood transfusion or blood products, including immunoglobulin, starting 
from 6 months before study vaccination or is scheduled to receive a blood transfusion or 
blood product until the Visit 2 postvaccination blood draw is complete. Autologous blood 
transfusions are not considered an exclusion criterion.
Prior/Concurrent Clinical Study Experience
15. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
Diagnostic Assessments
Not applicable
Other Exclusions
16. In the opinion of the investigator, has a history of clinically relevant drug or alcohol use 
that would interfere with participation in protocol-specified activities.
17. Has history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study.
18. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
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For items with an asterisk (*), if the participant meets these exclusion criteria, the 
Day 1 Visit may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 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 (pPCV and PNEUMOVAX™23) will be packaged to support enrollment.
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm Name
Arm Type
Intervention Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route 
of 
Admin
Vaccination
Regimen
Use
IMP/
NIMP
Sourcing
pPCV
Experimental
pPCV
Biological/
Vaccine
Sterile 
Solution
Refer to IB
1.0 mL
IM
Single dose
at Visit 1
(Day 1)
Experimental
IMP
Central
PNEUMOVAX™23
Active 
Comparator
PNEUMOVAX™23* Biological/
Vaccine
Sterile 
Solution
Refer to 
product 
labeling
0.5 mL
IM
Single dose
at Visit 1
(Day 1)
Experimental
IMP
Central
Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; IMP = investigational medicinal product; NIMP = non-investigational medicinal product; 
pPCV = polyvalent pneumococcal conjugate vaccine.
Definition of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
*: Pneumococcal vaccine polyvalent, US commercial product
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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.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Combination Medicinal Product(s) (MSD marketed/MSD investigation medicinal product 
and medical device or nonMSD marketed/nonMSD investigational product and medical 
device) provided for use in this study are pPCV and PNEUMOVAX™23, a single-dose pre-
filled syringe. Refer to Appendix 4 for instruction on reporting events associated with these 
combination medicinal products.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
As detailed in Section 6.3.3, study vaccine will be prepared by an unblinded member of the 
study site staff.
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.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an IRT system. There are 2 
study intervention arms. Participants will be assigned randomly in a 1:1 ratio to receive either 
pPCV or PNEUMOVAX™23.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
Age at time of randomization
-
Participants 20 to 64 years of age
-
Participants ≥65 years of age.
-
Enrollment into the age groups will be restricted to approximately 34 participants in 
the 20 to 64 years of age, and approximately 66 participants in the ≥65 years of age.
6.3.3
Blinding
A double-blinding technique will be used. pPCV and PNEUMOVAX™23 will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified study site 
personnel. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the clinical evaluation of the participants are unaware of the intervention 
assignments.
Because pPCV and PNEUMOVAX™23 have a different appearance, a member of the study 
site staff will be unblinded for the purposes of receiving, maintaining, preparing and/or 
dispensing, and administering these study vaccines. Procedures for handling, preparing, and 
administering the unblinded vaccines are located in the Investigator Study File Binder.
To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel will not be present in the examination room when study vaccines are administered. 
Contact between participants and unblinded study personnel after vaccination administration 
is strictly prohibited. Blinded site personnel will be responsible for all safety and 
immunogenicity follow-up procedures after vaccine administration.
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An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) directly involved with the conduct of this 
study will remain blinded to the participant-level intervention assignment.
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Given that a single dose of pPCV or PNEUMOVAX™23 will be administered in this study, 
intervention compliance will not be assessed.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study (see Section 5.2). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
If the participant is scheduled to receive any nonstudy vaccine, the investigator should 
discuss this with the Sponsor Clinical Director as soon as possible. All nonstudy vaccinations 
should be recorded on the appropriate eCRF.
Listed below are specific restrictions for concomitant therapy or vaccination:
•
Any administration of a nonstudy pneumococcal vaccine is prohibited during the study.
•
Live and non-live vaccines may only be administered prior to or following the receipt of 
study vaccine according to the time frames specified in Exclusion Criteria (Section 5.2). 
Exception: Inactivated influenza vaccine may be administered but must be given at least 
7 days before receipt of any study vaccine or at least 15 days after receipt of any study 
vaccine.
•
Participants should not receive systemic corticosteroids (prednisone equivalent of 
≥20 mg/day for ≥14 consecutive days) starting from 30 days prior to vaccination through 
30 days following vaccination.
•
Participants should not receive systemic corticosteroids exceeding physiologic 
replacement doses (prednisone equivalent dose >5 mg/day) starting from 14 days prior to 
vaccination.
Note: Topical, ophthalmic, intra-articular or soft-tissue (e.g., bursa, tendon steroid 
injections), and inhaled/nebulized steroids are permitted.
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Any deviation from the above requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded, but supplies are provided open label; therefore, an unblinded 
pharmacist or unblinded qualified study site personnel will be used to maintain the blinding 
of study staff who are directly involved in the clinical evaluation of participants in the study. 
Study intervention identity (name, strength, or potency) is included in the label text.
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity. The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.12). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
See Section 8.1.12 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
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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 8.1.11. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
The investigator or designee must make every effort to regain contact with the participant at 
each missed visit (eg, telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (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.
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Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may 
require that additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant at each study visit will not 
exceed 40 mL, and the total amount of blood collected over the duration of the study will not 
exceed 70 mL (Table 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Type
Visit 1
Day 1
Visit 2
Day 30
Total
Parameter
Approximate Blood Volume (mL)
Blood (serum) for Immunogenicity assessment (including 
retention samples)
30 mL
30 mL
60 mL
Blood (DNA) for Future Biomedical Researcha
8.5 mL
N/A
8.5 mL
Expected total (mL)
38.5 mL
30 mL
68.5 mL
DNA = deoxyribonucleic acid.
a Blood for future biomedical research will only be obtained from participants who provide separate consent for collection 
of the optional sample.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant 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.
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8.1.1.1
General Informed Consent
Informed consent given by the participant 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 and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant 
before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant should be informed in a timely manner if new information becomes available that 
may be relevant to the participant’s willingness to continue participation in the study. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain documented informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent 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.
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. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
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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. The participant’s 
relevant medical history for the 5 years prior to Visit 1 (Day 1) will be obtained to ensure that 
the participant satisfies the inclusion and exclusion criteria of the study. History of tobacco 
use will be collected for all participants.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 30 days before the study vaccination at Visit 1 
(Day 1).
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
The participant will use their paper VRC (Section 8.1.9) to record new and/or concomitant 
medications taken after Visit 1 (Day 1) and nonstudy vaccines received since Visit 1 through 
Day 30 postvaccination.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer pPCV or PNEUMOVAX™23. Study vaccines should be administered by 
appropriately qualified members of the study personnel (physician or nurse). Procedures for 
handling, preparing, and administering the unblinded vaccines are provided in the 
Investigator Study File Binder. Unblinded study personnel should follow the preparation and 
administration instructions for PNEUMOVAX™23 as specified in the product label.
Study vaccines should be removed from the refrigerator no more than 1 hour before 
vaccination. The time of removal and time of vaccination should be documented in the 
participant’s chart.
Study vaccine will be administered as a single IM injection, preferably in the deltoid region 
of the participant’s arm. Adequate treatment provision, including epinephrine and equipment 
for maintaining an airway, should be available for immediate use should an anaphylactic or 
anaphylactoid reaction occur [Centers for Disease Control and Prevention 2015].
Unblinded study personnel should not have contact with participants for any study related 
procedures/assessments after administration of study vaccine, which includes all safety 
follow up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant will be blinded to the study vaccine received. 
Vaccination information, such as time of vaccination, must be recorded on the appropriate 
eCRF as per the data entry guidelines.
8.1.8.1
Timing of Dose Administration
Vaccinations may be administered at any time of day and without regard to timing of meals.
Each participant's body temperature must be taken before vaccine administration. Individuals 
who present with fever (axillary temperature ≥99.5°F [≥37.5°C]) or equivalent) will have the 
vaccination delayed until fever is resolved for at least 72 hours.
The collection of blood samples and administration of pregnancy tests (if applicable) must be 
done before vaccine administration.
All participants will be observed for at least 30 minutes after vaccination for any immediate 
reactions. This observation must be performed by blinded site personnel for all study 
vaccines (Section 1.3 and Section 6.3.3).
8.1.9
Vaccination Report Card (VRC)
Participants in this study will use a paper VRC as indicated in Section 1.3. The investigator 
or delegate will train the participant in the use of the paper VRC at Visit 1 (Day 1).
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The participant will use the paper VRC to record body temperature (Section 8.3.3); 
concomitant medications and nonstudy vaccinations (Section 8.1.5.2); and injection-site 
reactions, vaccine-specific complaints, and other complaints or illnesses (Section 8.4.8).
The investigator or delegate will discuss information entered into the paper VRC with the 
participant at the telephone Contact on Day 15 (Section 8.1.10). A full review of the 
completed paper VRC will occur at Visit 2 (Day 30).
Any differences between paper VRC data and the clinical database must be documented in 
the participant’s source record.
8.1.10
Telephone Contact on Day 15
The investigator or delegate will discuss any information entered into the paper VRC with 
the participant at the telephone contact on Day 15. A full review of the completed paper will 
occur at Visit 2 (Day 30).
8.1.11
Discontinuation and Withdrawal
Participants who receive a single-dose intervention cannot discontinue study intervention see 
Section 7.1.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit (Visit 2) 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.
8.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent 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@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
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8.1.12
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced OPA and IgG responses. 
These endpoints will be tested for all immunogenicity blood draws specified in Section 1.3. 
Blood collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
The MOPA will be used for measuring OPA responses. Opsonization of pneumococci for 
phagocytosis is an important mechanism by which antibodies to polysaccharides protect 
against disease in vivo. The OPA assay is a useful tool for assessing the protective function 
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of serotype-specific antibodies and, therefore, the immunogenicity of pneumococcal vaccine 
formulations.
Serotype-specific IgG will be measured using the V116 PnECL assay to assess the 
concentration of binding antibodies to capsular polysaccharide of S. pneumoniae.
8.2.1
Multiplexed Opsonophagocytic Assay (MOPA)
The MOPA, developed and published by Professor Moon Nahm (Director of the US World 
Health Organization pneumococcal serology reference laboratory and National Institutes of 
Health pneumococcal reference laboratories) [Burton, Robert L. and Nahm, Moon H. 2006], 
is a multiplexed OPA assay capable of measuring 4 serotypes at a time, against a total of 24 
serotypes of pneumococci. The MOPA is an antibody-mediated killing assay that measures 
the ability of human serum to kill S. pneumoniae serotypes with the help of complement and 
phagocytic effector cells. The ability of the assay to simultaneously test 4 serotypes/run 
reduces the amount of serum needed for testing. The assay readout is the opsonization index, 
which is the reciprocal of the highest dilution that gives ≥50% bacterial killing, as 
determined by comparison to assay background controls. The MOPA assay for pPCV will be 
qualified. The qualification studies will evaluate various performance parameters of the assay 
including precision, ruggedness, specificity, and relative accuracy/dilutional linearity.
8.2.2
Pneumococcal Electrochemiluminescence (PnECL)
The Sponsor has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to PnP serotypes contained in pPCV. The 
V116 PnECL assay is based on the Meso-Scale Discovery technology, which employs 
disposable multi-spot microtiter plates. Pneumococcal polysaccharide (PnP) are bound to the 
surface of 96 well 10-plex carbon microplates, and serum containing purported anti-PnPs 
antibodies is added. The anti-PnPs antibodies bind to the coated plates and form an antibody-
antigen complex.  The bound antibody-antigen complex is detected using a ruthenium 
labeled anti-human IgG. Chemiluminescent signal emitted from the ruthenium tag upon 
electrochemical stimulation initiated at the electrode surfaces of the microplates is measured. 
Antibodies to the PnP serotypes can be measured in mass units (µg/mL) read from a standard 
curve generated from a reference standard. The V116 PnECL assay for pPCV will be 
qualified. The qualification studies will evaluate various performance parameters of the assay 
including precision, ruggedness, specificity, relative accuracy/dilutional linearity, and the
limit of detection of the assay.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator before vaccination at 
Visit 1 (Day 1).
A complete physical examination includes, but is not limited to, the assessment of general 
appearance, vital signs (e.g., heart rate, respiratory rate, blood pressure, and body 
temperature), eyes, throat, mouth, cardiovascular, respiratory, gastrointestinal, skin, 
neurologic, and psychiatric systems, and other organ systems as indicated.
In the source documents, investigators should document physical examination data and the 
status of all active medical conditions.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Pregnancy Test
A pregnancy test (sensitive to at least 25 IU β-hCG) must be performed before vaccination at 
Visit 1 (Day 1) and Visit 2 (Day 30) in WOCBP as described in Section 1.3. Urine or serum 
tests can be used, and results must be negative before vaccination can occur. A detailed 
definition of WOCBP is provided in Appendix 5.
8.3.3
Body Temperature Measurement
Each participant’s body temperature must be taken before vaccination as described in Section 
1.3.
Participants will also record axillary body temperatures using their paper VRC 
(Section 8.1.9) from Day 1 to Day 5 postvaccination.
For this study, any axillary temperature ≥99.5°F [≥37.5°C] or equivalent will be considered 
an AE of fever. All fevers must be reported Day 1 through Day 30, unless the fever is a 
symptom of another reported AE.
8.3.4
Postvaccination Observation Period
All participants will be observed for at least 30 minutes following vaccination for any 
immediate reactions. If any immediate AEs are observed during this period, the time at which 
the event occurred within this timeframe, as well as the event itself, any concomitant 
medications that were administered, and resolution of the event must be recorded on the 
appropriate eCRF.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
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The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the CRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the results must be recorded in the appropriate CRF (eg, SLAB).
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study, every attempt should be made to perform repeat assessments until 
the values return to normal or baseline or if a new baseline is established as determined by 
the investigator.
8.4
Adverse Events, 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 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-
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specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo, or a procedure.
From the time of randomization through 30 days following the study vaccination, all AEs, 
SAEs, and other reportable safety events must be reported by the investigator.
All SAEs must be reported by the investigator 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
An SAE that is considered by an investigator, who is a qualified physician, to be vaccine 
related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
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
Pregnancy/Lactation 
Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
ECI (require regulatory 
reporting)
There are no ECIs in this study.
ECI (do not require 
regulatory reporting)
There are no ECIs in this study.
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
ECI=event of clinical interest; 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
Although pregnancy and infant exposure during breastfeeding are not considered AEs, a 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole,
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as
serious events (Important Medical Events). If the pregnancy continues to term, the outcome
(health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest
There are no events of clinical interest in this study
8.4.8
Adverse Events Reported on the VRC
Participants will use a paper VRC (Section 8.1.9) to report solicited and unsolicited AEs.
The definitions of solicited and unsolicited AEs can be found in Appendix 3.
8.4.8.1
Solicited Adverse Events
Solicited AEs for this study are summarized in Table 4.
Table 4
Solicited Adverse Events for V116-002
Type of Solicited 
Adverse Event
Predefined Solicited
Adverse Events
Solicited Time 
Period
Injection site
Injection-site tenderness/pain
Injection-site redness/erythema
Injection-site swelling
Day 1 to Day 5 
postvaccination
Systemic
Headache
Muscle pain/myalgia
Joint pain/arthralgia
Tiredness/fatigue
Day 1 to Day 5 
postvaccination
All solicited injection-site AEs will be considered related to study intervention. The 
investigator will assess all solicited systemic AEs for causality (Appendix 3).
8.4.8.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 4, or 
2) predefined in Table 4 but reported at any time outside of the solicited time period.
As detailed in Section 8.4, the investigator will assess unsolicited AEs that meet the 
definition of an AE or SAE with respect to seriousness, intensity and causality.
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8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of study vaccine in any 
24-hour period.
The Sponsor does not recommend specific treatment for an 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 
Study File Binder (or equivalent).
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
If the participant 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 testing stored for future research
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
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 (Day 1) as outlined in Section 1.3.
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In the event that Day 1 is rescheduled (see Section 5.2), a review of prior medications/
vaccinations and medical history, a complete physical examination, and a body temperature 
measurement must be repeated prior to vaccination.
8.11.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study. Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12. This is an estimation/exploratory study, no hypothesis 
testing will be performed (and therefore no multiplicity adjustments will be made).
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Study Design Overview
A Phase 1, Randomized, Double-blind Active-Comparator-controlled Study to 
Evaluate the Safety, Tolerability, and Immunogenicity of a Polyvalent 
Pneumococcal Conjugate Vaccine in Healthy Japanese Adults.
Treatment Assignment
Approximately 100 participants will be randomly assigned in a 1:1 ratio to 
receive either Polyvalent Pneumococcal Conjugate Vaccine (pPCV) or 
PNEUMOVAX™23 (PPSV23). Randomization will be stratified by age at 
study entry (20 to 64 years and ≥65 years).
Analysis Populations
Safety: All Participants as Treated (APaT)
Primary Immunogenicity: Per Protocol (PP)
Supportive Immunogenicity: Full Analysis Set (FAS)
Primary Endpoint(s)
The primary safety endpoints include:

Proportion of participants with solicited injection-site AEs

Proportion of participants with solicited systemic AEs

Proportion of participants with vaccine-related SAEs
Secondary Endpoints
The key secondary immunogenicity endpoints include:

Ratio of serotype-specific OPA GMTs at 30 days postvaccination for the 
common serotypes in pPCV and PPSV23

Ratio of serotype-specific OPA GMTs at 30 days postvaccination for the 
serotypes unique to pPCV

Ratio of serotype specific IgG GMCs at 30 days postvaccination for the 
common serotypes in pPCV and PPSV23

Ratio of serotype specific IgG GMCs at 30 days postvaccination for the 
serotypes unique to pPCV

Serotype-specific GMFRs from prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for OPA responses

Serotype-specific GMFRs from prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for IgG responses
Statistical Methods for 
Key Safety Analyses
The analysis of safety will follow a tiered approach. The tiers differ with respect 
to the analyses that will be performed. No Tier 1 events are defined in this 
study. For Tier 2 events, 95% CIs will be provided for between-group 
differences in the proportion of participants with events; these analyses will be 
performed using the Miettinen and Nurminen（M&N）method [Miettinen, O. 
and Nurminen, M. 1985].
Statistical Methods for 
Key 
Immunogenicity
Analyses
Immunogenicity analyses will be conducted separately for each serotype.
Immunogenicity endpoints will be analyzed at 30 days postvaccination to 
describe the antibody concentrations in response to the vaccination. The ratio of 
OPA GMTs and IgG GMCs (pPCV/PPSV23) will be presented along with 95% 
CIs.
The OPA GMT ratio estimation and 95% CI will be calculated using a cLDA 
method. IgG GMCs will be analyzed in the same way.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
No multiplicity adjustment is planned in this study.
Sample Size and Power 
A total of 100 participants will be enrolled. Assuming a 90% evaluability rate, 
90 participants are expected to be included the immunogenicity analysis.
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9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. This study will be conducted as a double-
blind study under in-house blinding procedures. The official, final database will not be 
unblinded until medical/scientific review has been performed, protocol deviations have been 
identified, and data have been declared final and complete.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Immunogenicity Endpoints
There are no primary immunogenicity analysis endpoints.
Secondary immunogenicity analysis endpoints include:
•
Ratio (pPCV/PPSV23) of serotype-specific OPA GMTs for the common serotypes 
in pPCV and PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio (pPCV/PPSV23)
of serotype-specific OPA GMTs of pPCV and 
PNEUMOVAX™23 for the serotypes unique to pPCV at 30 days postvaccination.
•
Ratio (pPCV/PPSV23) of serotype-specific IgG GMCs for the common serotypes in 
pPCV and PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio 
(pPCV/PPSV23)
of 
serotype-specific 
IgG 
GMCs 
of 
pPCV 
and 
PNEUMOVAX™23 for the serotypes unique to pPCV at 30 days postvaccination.
•
Serotype-specific GMFRs from prevaccination (Day 1) to 30 days postvaccination 
(Day 30) for both OPA and IgG responses.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and postvaccination body temperature measurements.
The safety analysis endpoints include:
•
Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, and tenderness/pain) from Day 1 through Day 5 postvaccination
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•
Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue) from Day 1 through Day 5 
postvaccination
•
Proportion of participants with vaccine-related SAEs from Day 1 through the 
duration of participation in the study.
•
Proportions of participants with the broad AE categories consisting of any AE and 
any vaccine-related AE from Day 1 through Day 30 postvaccination
•
Proportions of participants with the broad AE categories consisting of any SAE and 
death from Day 1 through the duration of participation in the study.
•
Proportion of participants with maximum axillary temperature measurements which 
is less than 37.5°C, more than or equal 37.5°C by 0.5°C intervals from Day 1 
through Day 5 postvaccination.
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 those participants without deviations from 
the protocol that may substantially affect the results of the immunogenicity endpoint(s).
Potential deviations include but are not limited to:
•
Failure to receive correct clinical material as per the randomization schedule at Visit 
1 (Day 1) (i.e., participants who were cross-treated)
•
Having no valid serology results (i.e., participants who are missing serology results 
for both Day 1 and Day 30 [30 to 44 days following vaccination]).
The final determination on major protocol deviations, and thereby the composition of the PP 
population, will be made prior to the final unblinding of the database and will be documented 
in a separate memo. Participants will be included in the vaccination group to which they are 
randomized for the analysis of immunogenicity data using the PP population.
The FAS population will be used for supplementary analysis of the immunogenicity data.
The FAS population consists of all randomized participants who received at least 1 
vaccination and have at least 1 serology result. Participants will be included in the 
vaccination group to which they are randomized for the analysis of immunogenicity data 
using the FAS population.
Details on the approach to handling missing data are provided in Section 9.6
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9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who receive study vaccine. Participants 
will be included in the group corresponding to the clinical material they actually received for 
the analysis of safety data using the APaT population. For most participants, this will be the 
group to which they are randomized. Participants who receive incorrect clinical material will 
be included in the group corresponding to the clinical material actually received.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
The immunogenicity analyses will be conducted for each serotype separately.
The geometric mean ratios and 95% CIs of IgG GMCs and OPA GMTs will be calculated 
using a cLDA method proposed by Liang and Zeger [Liang, K-Y and Zeger, S. L. 2000] 
utilizing data from all vaccination groups. In this model, the response vector consists of the 
log-transformed prevaccination (Day 1) and postvaccination (Day 30) antibody titers. The 
repeated measures model will include terms for time, age stratification, the interaction of 
time-by-vaccination group and age stratification-by-time. The treatment difference in terms 
of a geometric mean ratio at a given postvaccination time point will be estimated from this 
model. The term for time will be treated as a categorical variable. An unstructured covariance 
matrix will be used to model the correlation among repeated measurements. This model 
allows the inclusion of participants who are missing either the baseline or postbaseline 
measurements, thereby increasing efficiency. IgG GMCs will be analyzed in the same way. 
The GMFRs from prevaccination to 30 days postvaccination for both OPA and IgG response 
will be estimated by vaccination group, and the corresponding 95% CIs will be based on the 
sample t-distribution. For titers and concentrations that are smaller than the lower bound of 
the assay’s detectable range, half of the lower bound will be used as the value of them.
The analysis strategy for key immunogenicity variables is listed in Table 5.
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Table 5
Analysis Strategy for Key Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Secondary Endpoints
Ratio of the serotype-specific OPA GMTs at 
30 days postvaccination.
cLDA†
(point estimate, 95% 
CI)
PP/FAS
Model-based
Ratio of the serotype-specific IgG GMCs at 
30 days postvaccination.
cLDA†
(point estimate, 95% 
CI)
PP/FAS
Model-based
The serotype specific GMFR from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for OPA responses
Descriptive Statistics
(point estimate, 95% 
CI)
PP/FAS
Observed data
The serotype specific GMFR from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for IgG responses
Descriptive Statistics
(point estimate, 95% 
CI)
PP/FAS
Observed data
cLDA = constrained longitudinal data analysis; FAS = Full Analysis Set; GMC = geometric mean concentration; 
GMFR = geometric mean fold rise; GMT = geometric mean titer; IgG = immunoglobulin G; OPA = 
opsonophagocytic activity; PP = Per-protocol. 
†: cLDA model with terms for time, age stratification, the interaction of time-by-vaccination group and age 
stratification-by-time.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, postvaccination temperature measurements.
The analysis of AEs and temperature measurements will follow a tiered approach (Table 6). 
The tiers differ with respect to the analyses that will be performed. Events are either 
prespecified as Tier 1 events or will be classified as belonging to Tier 2 or Tier 3 based on 
the number of events observed. 
Tier 1 Events
Safety events or AEs of special interest that are identified a priori constitute Tier 1 events 
that will be subject to inferential testing for statistical significance with p-values and 95% CIs 
provided for between-treatment differences in the proportion of participants with events.
No Tier 1 events are defined for this study.
Tier 2 Events
Tier 2 events will be assessed via point estimates and risk differences with 95% CIs provided 
for differences in the proportion of participants with events; these analyses will be performed 
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using the M&N method [Miettinen, O. and Nurminen, M. 1985], an unconditional, 
asymptotic method.
For this study, solicited injection-site AEs from Day 1 through Day 5 postvaccination, 
solicited systemic AEs from Day 1 through Day 5 postvaccination, and axillary temperature
measurements collected from Day 1 through Day 5 postvaccination are considered Tier 2 
events. In addition, the broad AE categories consisting of the percentage of participants with 
any AE, any vaccine-related AE, any solicited injection-site AE, any solicited systemic AE, 
any SAE, any vaccine-related SAE, and death will be considered Tier 2 events. Nonserious 
AEs will be followed for 30 days postvaccination, while SAEs will be followed through the 
duration of participation in the study.
AEs (specific terms as well as SOC terms) will be classified as belonging to Tier 2 if at least 
4 participants in any vaccination group exhibit the event. The threshold of at least 4 events 
was chosen because the 95% CI for the between-group difference in percent incidence will 
always include zero when vaccination groups of equal size each have less than 4 events and 
thus would add little to the interpretation of potentially meaningful differences.
Because many 95% CIs for Tier 2 events may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in 
review, not a formal method for assessing the statistical significance of the between-group 
differences in AEs.
Tier 3 Events
Events not defined above are considered Tier 3 events. Only point estimates by vaccination 
group will be provided for Tier 3 events.
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Table 6
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoints
95% CI for Between 
group Comparison a
Descriptive 
Statistics
Tier 2
Injection-site redness/erythema (Days 1 to 5)
X
X
Injection-site swelling (Days 1 to 5)
X
X
Injection-site tenderness/pain (Days 1 to 5)
X
X
Muscle pain/myalgia (Days 1 to 5)
X
X
Joint Pain/arthralgia (Days 1 to 5)
X
X
Headache (Days 1 to 5)
X
X
Tiredness/fatigue (Days 1 to 5)
X
X
Any AEb
X
X
Any vaccine-related AEb
X
X
Any solicited injection-site AE (Days 1 to 5)b
X
X
Any solicited systemic AE (Days 1 to 5)b
X
X
Any serious AEb
X
X
Any vaccine-related SAEb
X
X
Deathb
X
X
Maximum axillary temperature measurements 
which is less than 37.5°C, more than or equal 
37.5°C by 0.5°C intervals (Days 1 to 5)
X
X
Specific AEs by SOC and PTc 
(incidence ≥4 participants in at least 1 of the 
vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PTc 
(incidence <4 participants in all of the 
vaccination groups)
X
AE = adverse event; CI = confidence interval; M&N = Miettinen and Nurminen; PT = preferred term; SAE = serious 
adverse event; SOC = system organ class; X = results will be provided.
a These analyses will be performed using the M&N method [Miettinen, O. and Nurminen, M. 1985].
b These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of “Any AE” will 
provide the number and percentage of participants with at least 1 AE.
 c Includes only those endpoints not prespecified as Tier 2 endpoints.
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9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants randomized 
and vaccinated, and the reasons for discontinuation, will be displayed by group.
Demographic variables (e.g., age) and prior and concomitant therapies and vaccines will be 
summarized by group.
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
No multiplicity adjustment is planned in this study.
9.9
Sample Size and Power Calculations
9.9.1
Immunogenicity Analyses
Approximately 100 participants (approximately 34 participants in the 20 to 64 years of age, 
and approximately 66 participants in the ≥65 years of age) will be enrolled, with 
approximately 50 participants in each of the 2 vaccination groups. Assuming 90% 
evaluability (approximately 45 participants per group), the half width of 95%CI for the ratios 
between vaccination groups with respect to IgG and OPA is 0.524, 0.842, respectively, in 
natural log scale based on the following assumptions:
•
The overall standard deviation of natural log-transformed IgG results is 1.25, OPA 
results is 2.01. This assumption is based on observations from V114 PN015 study.
•
90% evaluability rate (approximately 45 participants per group).
9.9.2
Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants enrolled and the incidence rate of SAEs in the general population. If the 
incidence rate of an SAE is 1 of every 50 recipients of the vaccine (2%), then there is a 
63.6% chance of observing at least 1 such SAE among 50 participants in the pPCV group.
9.10
Subgroup Analyses
Serotype-specific OPA and IgG responses will be summarized by vaccination group in each 
age subgroup (i.e., 20-64 years and ≥ 65 years).
Following safety endpoints will be summarized by vaccination group in each age subgroup 
(i.e., 20-64 years and ≥ 65 years).
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•
Solicited injection-site AEs (redness/erythema, swelling, tenderness/pain)
(Days 1 to 5)
•
Solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, 
tiredness/fatigue) (Days 1 to 5)
•
Any AE, Any vaccine-related AE, Any serious AE, Any vaccine-related SAE, Death
•
Maximum axillary temperature measurements which is less than 37.5°C, more than 
or equal 37.5°C by 0.5°C intervals (Days 1 to 5)
9.11
Compliance (Medication Adherence)
Given that participants will receive a single dose of pPCV or PNEUMOVAX™23, 
compliance will not be calculated. However, the number and proportion of randomized 
participants receiving pPCV or PNEUMOVAX™23 will be summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered pPCV or PNEUMOVAX™23.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design 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 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. 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 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish 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. 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.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
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.
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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 
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

The tests detailed in Table 7 will be performed by the local laboratory.

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum) should be conducted at Visit 1 (Day 1) and Visit 
2 (Day 30).
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
Table 7
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Other Screening 
Tests

Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)

Serum or urine β-human chorionic gonadotropin (β-hCG) pregnancy test (for 
WOCBP)

All study-required laboratory assessments will be performed by a central laboratory, 
with the exception of pregnancy tests.
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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.
Definition of Unsolicited and Solicited AE

An unsolicited AE is an AE that was not solicited using a VRC and that is communicated 
by a participant who has signed the informed consent. Unsolicited AEs include serious 
and nonserious AEs.

Solicited AEs are predefined local (at the injection site) and systemic events for which 
the participant is specifically questioned, and which are noted by the participant in their 
VRC.
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.
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d. Results in persistent or significant disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
In offspring of participant taking the product regardless of time to diagnosis.
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.
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
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
·
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).

Injection site erythema/redness or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
Assessment of causality

Did the Sponsor’s product cause the AE?
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
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge.
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study; or (3) 
Sponsor’s product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

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?
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
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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.
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
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the 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 
Qualtiy Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to all medical 
devices/combination medicinal products as described below. For purposes of this section, 
medical devices/combination medicinal products in scope for device information collection 
include medical devices/combination medicinal products intended to be used by a study 
participant according to the study protocol, that are manufactured by the Sponsor or for the 
Sponsor by a third party, licensed by the Sponsor for human use and/or drug-device 
combination products as listed in Section 6.1.1. Product Quality Complaints/Malfunctions 
must be reported to the Sponsor.
10.4.1
Definitions
Medical Device - Devices, etc. (other than regenerative medicine products) intended for use 
in the diagnosis, treatment or prevention of disease in humans or animals, or intended to 
affect the structure or functions of the body of humans or animals.
Combination Medicinal Product - A product comprised of two or more regulated 
components, i.e., a drug and a device; a device and a cellular and tissue-based product; a 
cellular and tissue-based product and a drug; or a drug, a device, and a cellular and tissue-
based product according to regulations.
Malfunction - Failure of quality, safety and performance, etc. of investigational device in a 
broad sense such as damage or operational failure.
Serious Adverse Event due to Malfunction - Any serious adverse event due to malfunction 
in the characteristics and/or performance of a device (this study is a pre-filled syringe) as 
well as any inadequacy in the labeling or the instructions for use which has led to the death of 
a participant and/or the associated person or to a serious deterioration in his/her state of 
health. 
Malfunction which may lead to Serious Adverse Events - Any malfunction of a medical 
device which might have led to the death of a participant and/or the associated person or to a 
serious deterioration in his/her state of health. “Which might have led to” means that there is 
the possibility that death or a serious deterioration might have occurred in a participant 
and/or the associated person, although these cases have not actually occurred.
10.4.2
Medical Device/Combination Medicinal Products – Documenting and 
Reporting
In order to fulfill regulatory reporting obligations, medical device/combination medicinal 
product information will be collected. Serious adverse event due to malfunction will be 
reported to the Sponsor in the same time frame as SAEs as per Section 8.4.1 via CRF (paper 
or electronic) and as per data entry guidelines. All serious adverse events due to malfunctions
will be followed until resolution, stabilization, until the event is otherwise explained, or the 
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participant or associated person is lost to follow-up. Malfunction which may lead to serious 
adverse events will be reported to the Sponsor within 5 calendar days of learning of the 
information via a paper reporting form.
Sponsor shall review reported events by the investigator to fulfill the legal responsibility of 
notifying appropriate regulatory authorities and other entities as needed about certain safety 
information relating to medical devices/combination medicinal products being used in 
clinical studies.
10.4.3
Recording, Assessing Causality, and Follow-up of Adverse Events due to 
Malfunctions (serious and nonserious)
Recording

When adverse event due to malfunction (serious or nonserious) occurs, it is the 
responsibility of the investigator to review all documentation (e.g., hospital progress 
notes, laboratory reports, and diagnostic reports) related to the event.

Any serious adverse event due to malfunction occurring during the study will be recorded 
in the participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate CRF (paper or electronic) as per instructions provided in 
the EDC data entry guidelines (or equivalent). 

It is important that the investigator provides his/her assessment of causality (relationship
to the medical device) at the time of the initial report.
Assessing Causality

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.

The investigator will use clinical judgment to determine the relationship.

Alternative causes should also be considered and investigated, such as underlying 
disease(s), concomitant therapy, and other risk factors as well as the temporal relationship 
of the event to study intervention administration.
Follow-up

The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantc,d
IUSc.e
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b Typical use failure rates are higher than perfect-use failure rates (i.e., when used consistently and 
correctly).
c Male condoms must be used in addition to female participant hormonal contraception. 
d If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited 
to those which inhibit ovulation.
e IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol-defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:

Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and LAM.

Male condom with cap, diaphragm, or sponge with spermicide.

Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
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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 8.9 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@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
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specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International 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
AE
adverse event 
APaT
All Participants as Treated
β-hCG
β-human chorionic gonadotropin
CFR
Code of Federal Regulations
CI
confidence interval
cLDA
constrained longitudinal data analysis
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CSR
Clinical Study Report
CTFG
Clinical Trials Facilitation Group
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
events of clinical interest
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection
EMA
European Medicines Agency
EU
European Union
FAS
Full Analysis Set
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMT
geometric mean titer
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IM
intramuscular
IPD
invasive pneumococcal disease
IRB
Institutional Review Board
IRT
interactive response technology
IU
intersection-union
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
lactational amenorrhea method
M&N
Miettinen and Nurminen
MOPA
multiplexed opsonophagocytic assay
MSD
Merck Sharp & Dohme Corp.
OPA 
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PK
pharmacokinetic
PnECL
pneumococcal electrochemiluminescence
PnP
pneumococcal polysaccharide
PP
Per protocol
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Abbreviation
Expanded Term
pPCV
polyvalent pneumococcal conjugate vaccine
RNA
ribonucleic acid
SAE
serious adverse event
SLAB
supplemental laboratory test
SoA
Schedule of Activities
SOC
system organ class
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
US
United States
VRC
vaccination report card
WOCBP
woman (or women) of childbearing potential
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11
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03NWQ5
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PRODUCT: V116  
89
PROTOCOL/AMENDMENT NO.: 002-00 
V116-002-00 FINAL PROTOCOL
20-OCT-2020
[Sando, E., et al 2019]
Sando E, Suzuki M, Furumoto A, et al. 
Impact of the pediatric 13-valent 
pneumococcal conjugate vaccine on 
serotype distribution and clinical 
characteristics of pneumococcal pneumonia 
in adults: The Japan Pneumococcal Vaccine 
Effectiveness Study (J-PAVE). Vaccine. 
2019 Apr;37(20):2687-93.
05JDDF
[Sunagawa, T., et al 2018]
Sunagawa T, Kozuki A, Fukuzumi M, et al. 
Epidemiological surveillance of invasive 
pneumococcal disease in Japan, 2013 to 
2017: research for adult IPD surveillance: 
MHLW science research grants: summary 
report. 2018. 4 p. Japanese.
05348N
[Ubukata, K., et al 2018]
Ubukata K, Takata M, Morozumi M, et al. 
Effects of Pneumococcal Conjugate Vaccine 
on Genotypic Penicillin Resistance and 
Serotype Changes, Japan, 2010–2017.
Emerg Infect Dis. 2018 Nov;24(11):2010-
20.
05JDDG
[Waight, P. A., et al 2015]
Waight PA, Andrews NJ, Ladhani SN, 
Sheppard CL, Slack MP, Miller E. Effect of 
the 13-valent pneumococcal conjugate 
vaccine on invasive pneumococcal disease 
in England and Wales 4 years after its 
introduction: an observational cohort study. 
Lancet Infect Dis. 2015 May;15(5):535-43.
04KTF2
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A Phase 1, Randomized, Double-blind, Active-Comparator-controlled Study to 
Evaluate the Safety, Tolerability, and Immunogenicity of a Polyvalent Pneumococcal 
Conjugate Vaccine in Healthy Japanese Adults.
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TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................................2
LIST OF TABLES...................................................................................................................3
1
INTRODUCTION...........................................................................................................4
2
SUMMARY OF CHANGES..........................................................................................4
3
ANALYTICAL AND METHODOLOGICAL DETAILS ..........................................4
Statistical Analysis Plan Summary.........................................................................4
Responsibility for Analyses / In-house Blinding ...................................................5
Hypotheses/Estimation...........................................................................................5
Analysis Endpoints.................................................................................................5
Immunogenicity Endpoints.......................................................................5
Safety Endpoints.......................................................................................6
Analysis Populations..............................................................................................7
Immunogenicity Analysis Populations .....................................................7
Safety Analysis Population.......................................................................7
Statistical Methods .................................................................................................7
Statistical Methods for Immunogenicity Analyses...................................7
Statistical Methods for Safety Analyses .................................................10
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................12
Interim Analyses...................................................................................................12
Multiplicity...........................................................................................................12
Sample Size and Power Calculations ...................................................................12
Immunogenicity Analyses ......................................................................12
Safety Analyses.......................................................................................12
Subgroup Analyses...............................................................................................12
Compliance (Medication Adherence) ..................................................................13
Extent of Exposure ...............................................................................................13
4
LIST OF REFERENCES.............................................................................................13
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LIST OF TABLES
Table 1  Analysis Strategy for Key Immunogenicity Variables............................................... 8
Table 2  Limits of Quantitation for OPA and IgG Serotype-specific Responses ..................... 9
Table 3  Analysis Strategy for Safety Parameters .................................................................. 11
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Supplemental Statistical Analysis Plan (sSAP)
1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP will provide additional sensitivity 
statistical analysis details, data derivations and documents modifications or additions to the 
analysis plan that are not “principal” in nature and result from information that was not 
available at the time of protocol finalization.
2
SUMMARY OF CHANGES
A summary of changes is provided in the table below.
Section
Description of change
Rationale
3.6.1
Add text around analysis of cross-
reactive serotypes and RCDC
Addition for clarity
3.6.1
Added [Table 2] that lists serotype-
specific limits of quantitation for OPA 
and IgG responses and text around 
them
Addition for clarity
3
ANALYTICAL AND METHODOLOGICAL DETAILS
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in [Sec. 3.2] to [Sec. 3.12].
Study Design Overview
A Phase 1, Randomized, Double-blind Active-Comparator-controlled Study to 
Evaluate the Safety, Tolerability, and Immunogenicity of a Polyvalent 
Pneumococcal Conjugate Vaccine in Healthy Japanese Adults.
Treatment Assignment
Approximately 100 participants will be randomly assigned in a 1:1 ratio to receive 
either Polyvalent Pneumococcal Conjugate Vaccine (pPCV) or 
PNEUMOVAX™23 (PPSV23). Randomization will be stratified by age at study 
entry (20 to 64 years and ≥65 years).
Analysis Populations
Safety: All Participants as Treated (APaT)
Primary Immunogenicity: Per Protocol (PP)
Supportive Immunogenicity: Full Analysis Set (FAS)
Primary Endpoint(s)
The primary safety endpoints include:

Proportion of participants with solicited injection-site AEs

Proportion of participants with solicited systemic AEs

Proportion of participants with vaccine-related SAEs
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Secondary Endpoints
The key secondary immunogenicity endpoints include:

Ratio of serotype-specific OPA GMTs at 30 days postvaccination for the 
common serotypes in pPCV and PPSV23

Ratio of serotype-specific OPA GMTs at 30 days postvaccination for the 
serotypes unique to pPCV

Ratio of serotype specific IgG GMCs at 30 days postvaccination for the 
common serotypes in pPCV and PPSV23

Ratio of serotype specific IgG GMCs at 30 days postvaccination for the 
serotypes unique to pPCV

Serotype-specific GMFRs from prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for OPA responses

Serotype-specific GMFRs from prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for IgG responses
Statistical Methods for 
Key Safety Analyses
The analysis of safety will follow a tiered approach. The tiers differ with respect 
to the analyses that will be performed. No Tier 1 events are defined in this study. 
For Tier 2 events, 95% CIs will be provided for between-group differences in the 
proportion of participants with events; these analyses will be performed using the 
Miettinen and Nurminen (M&N) method [Ref. 5.4: 04J96G].
Statistical Methods for 
Key Immunogenicity
Analyses
Immunogenicity analyses will be conducted separately for each serotype.
Immunogenicity endpoints will be analyzed at 30 days postvaccination to describe 
the antibody concentrations in response to the vaccination. The ratio of OPA 
GMTs and IgG GMCs (pPCV/PPSV23) will be presented along with 95% CIs.
The OPA GMT ratio estimation and 95% CI will be calculated using a cLDA 
method. IgG GMCs will be analyzed in the same way.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
No multiplicity adjustment is planned in this study.
Sample Size and Power 
A total of 100 participants will be enrolled. Assuming a 90% evaluability rate, 90 
participants are expected to be included the immunogenicity analysis.
Responsibility for Analyses / In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. This study will be conducted as a double-
blind study under in-house blinding procedures. The official, final database will not be 
unblinded until medical/scientific review has been performed, protocol deviations have been 
identified, and data have been declared final and complete.
Hypotheses/Estimation
Objectives and hypotheses are stated in Section 3 in protocol.
Analysis Endpoints
Immunogenicity Endpoints 
There are no primary immunogenicity analysis endpoints.
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Secondary immunogenicity analysis endpoints include:
•
Ratio (pPCV/PPSV23) of serotype-specific OPA GMTs for the common serotypes in 
pPCV and PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio (pPCV/PPSV23) of serotype-specific OPA GMTs of pPCV and 
PNEUMOVAX™23 for the serotypes unique to pPCV at 30 days postvaccination.
•
Ratio (pPCV/PPSV23) of serotype-specific IgG GMCs for the common serotypes in 
pPCV and PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio (pPCV/PPSV23) of serotype-specific IgG GMCs of pPCV and 
PNEUMOVAX™23 for the serotypes unique to pPCV at 30 days postvaccination.
•
Serotype-specific GMFRs from prevaccination (Day 1) to 30 days postvaccination 
(Day 30) for both OPA and IgG responses.
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and postvaccination body temperature measurements.
The safety analysis endpoints include:
•
Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, and tenderness/pain) from Day 1 through Day 5 postvaccination
•
Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue) from Day 1 through Day 5 
postvaccination
•
Proportion of participants with vaccine-related SAEs from Day 1 through the duration 
of participation in the study.
•
Proportions of participants with the broad AE categories consisting of any AE and 
any vaccine-related AE from Day 1 through Day 30 postvaccination.
•
Proportions of participants with the broad AE categories consisting of any SAE and 
death from Day 1 through the duration of participation in the study.
•
Proportion of participants with maximum axillary temperature measurements which 
is less than 37.5°C, more than or equal 37.5°C by 0.5°C intervals from Day 1 through 
Day 5 postvaccination.
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Analysis Populations
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 those participants without deviations from 
the protocol that may substantially affect the results of the immunogenicity endpoint(s).
Potential deviations include but are not limited to:
•
Failure to receive correct clinical material as per the randomization schedule at 
Visit 1 (Day 1) (i.e., participants who were cross-treated)
•
Having no valid serology results (i.e., participants who are missing serology results 
for both Day 1 and Day 30 [30 to 44 days following vaccination]).
The final determination on major protocol deviations, and thereby the composition of the PP 
population, will be made prior to the final unblinding of the database and will be documented 
in a separate memo. Participants will be included in the vaccination group to which they are 
randomized for the analysis of immunogenicity data using the PP population.
The FAS population will be used for supplementary analysis of the immunogenicity data.
The FAS population consists of all randomized participants who received at least 1 
vaccination and have at least 1 serology result. Participants will be included in the 
vaccination group to which they are randomized for the analysis of immunogenicity data 
using the FAS population.
Details on the approach to handling missing data are provided in [Sec. 3.6].
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who receive study vaccine. Participants 
will be included in the group corresponding to the clinical material they actually received for 
the analysis of safety data using the APaT population. For most participants, this will be the 
group to which they are randomized. Participants who receive incorrect clinical material will 
be included in the group corresponding to the clinical material actually received.
Statistical Methods
Statistical Methods for Immunogenicity Analyses
The immunogenicity analyses will be conducted for each serotype separately.
The geometric mean ratios and 95% CIs of IgG GMCs and OPA GMTs will be calculated 
using a cLDA method proposed by Liang and Zeger [Ref. 5.4: 03RS5G] utilizing data from 
all vaccination groups. In this model, the response vector consists of the log-transformed 
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prevaccination (Day 1) and postvaccination (Day 30) antibody titers. The repeated measures 
model will include terms for time, age stratification, the interaction of time-by-vaccination 
group and age stratification-by-time. The treatment difference in terms of a geometric mean 
ratio at a given postvaccination time point will be estimated from this model. The term for 
time will be treated as a categorical variable. An unstructured covariance matrix will be used
to model the correlation among repeated measurements. This model allows the inclusion of 
participants who are missing either the baseline or postbaseline measurements, thereby 
increasing efficiency. IgG GMCs will be analyzed in the same way. The GMFRs from 
prevaccination to 30 days postvaccination for both OPA and IgG response will be estimated 
by vaccination group, and the corresponding 95% CIs will be based on the sample t-
distribution. For titers and concentrations that are smaller than the lower bound of the assay’s 
detectable range, half of the lower bound will be used as the value of them.
A similar statistical approach will be used to estimate the treatment effect for each cross-
reactive serotype in an exploratory manner. 
Reverse Cumulative Distribution Curves (RCDC) for both OPA titers and IgG concentrations 
at Day 1 (Baseline) and Day 30 (30 days postvaccination) will be graphically displayed by 
serotype.The analysis strategy for key immunogenicity variables is listed in [Table 1].
Table 1  Analysis Strategy for Key Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Secondary Endpoints
Ratio of the serotype-specific OPA GMTs at 
30 days postvaccination.
cLDA†
(point estimate, 95% CI)
PP/FAS
Model-based
Ratio of the serotype-specific IgG GMCs at 
30 days postvaccination.
cLDA†
(point estimate, 95% CI)
PP/FAS
Model-based
The serotype specific GMFR from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for OPA responses
Descriptive Statistics
(point estimate, 95% CI)
PP/FAS
Observed data
The serotype specific GMFR from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for IgG responses
Descriptive Statistics
(point estimate, 95% CI)
PP/FAS
Observed data
cLDA = constrained longitudinal data analysis; FAS = Full Analysis Set; GMC = geometric mean 
concentration; GMFR = geometric mean fold rise; GMT = geometric mean titer; IgG = immunoglobulin 
G; OPA = opsonophagocytic activity; PP = Per-protocol. 
†: cLDA model with terms for time, age stratification, the interaction of time-by-vaccination group and 
age stratification-by-time.
The detectable ranges for OPA and IgG response differ for each serotype. The limits of 
quantitation define the range of responses over which the assay provides precise and accurate 
measurements. For all serotypes measured using the multiplex opsonophagocytic assay 
(MOPA), the laboratory reports OPA titers down to the limits of detection (LOD) of 8, and 
titers below 8 will be reported as <8. The MOPA lab does not apply the lower limit of 
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Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, postvaccination temperature measurements.
The analysis of AEs and temperature measurements will follow a tiered approach [Table 3]. 
The tiers differ with respect to the analyses that will be performed. Events are either 
prespecified as Tier 1 events or will be classified as belonging to Tier 2 or Tier 3 based on 
the number of events observed. 
Tier 1 Events
Safety events or AEs of special interest that are identified a priori constitute Tier 1 events 
that will be subject to inferential testing for statistical significance with p-values and 95% CIs 
provided for between-treatment differences in the proportion of participants with events.
No Tier 1 events are defined for this study.
Tier 2 Events
Tier 2 events will be assessed via point estimates and risk differences with 95% CIs provided 
for differences in the proportion of participants with events; these analyses will be performed 
using the M&N method [Ref. 5.4: 04J96G], an unconditional, asymptotic method.
For this study, solicited injection-site AEs from Day 1 through Day 5 postvaccination, 
solicited systemic AEs from Day 1 through Day 5 postvaccination, and axillary temperature 
measurements collected from Day 1 through Day 5 postvaccination are considered Tier 2 
events. In addition, the broad AE categories consisting of the percentage of participants with 
any AE, any vaccine-related AE, any solicited injection-site AE, any solicited systemic AE, 
any SAE, any vaccine-related SAE, and death will be considered Tier 2 events. Nonserious 
AEs will be followed for 30 days postvaccination, while SAEs will be followed through the 
duration of participation in the study.
AEs (specific terms as well as SOC terms) will be classified as belonging to Tier 2 if at least 
4 participants in any vaccination group exhibit the event. The threshold of at least 4 events 
was chosen because the 95% CI for the between-group difference in percent incidence will 
always include zero when vaccination groups of equal size each have less than 4 events and 
thus would add little to the interpretation of potentially meaningful differences.
Because many 95% CIs for Tier 2 events may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in 
review, not a formal method for assessing the statistical significance of the between-group 
differences in AEs.
Tier 3 Events
Events not defined above are considered Tier 3 events. Only point estimates by vaccination 
group will be provided for Tier 3 events.
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Serious Adverse Event due to Malfunction ,and malfunction which may lead to Serious 
Adverse Events, if any, will be listed.
Table 3  Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoints
95% CI for Between
group Comparison a
Descriptive 
Statistics
Tier 2
Injection-site redness/erythema (Days 1 to 5)
X
X
Injection-site swelling (Days 1 to 5)
X
X
Injection-site tenderness/pain (Days 1 to 5)
X
X
Muscle pain/myalgia (Days 1 to 5)
X
X
Joint Pain/arthralgia (Days 1 to 5)
X
X
Headache (Days 1 to 5)
X
X
Tiredness/fatigue (Days 1 to 5)
X
X
Any AEb
X
X
Any vaccine-related AEb
X
X
Any solicited injection-site AE (Days 1 to 5)b
X
X
Any solicited systemic AE (Days 1 to 5)b
X
X
Any serious AEb
X
X
Any vaccine-related SAEb
X
X
Deathb
X
X
Maximum axillary temperature measurements 
which is less than 37.5°C, more than or equal 
37.5°C by 0.5°C intervals (Days 1 to 5)
X
X
Specific AEs by SOC and PTc 
(incidence ≥4 participants in at least 1 of the 
vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PTc 
(incidence <4 participants in all of the 
vaccination groups)
X
AE = adverse event; CI = confidence interval; M&N = Miettinen and Nurminen; PT = preferred term; SAE = serious 
adverse event; SOC = system organ class; X = results will be provided.
a These analyses will be performed using the M&N method [Ref. 5.4: 04J96G].
b These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of “Any AE” will 
provide the number and percentage of participants with at least 1 AE.
c Includes only those endpoints not prespecified as Tier 2 endpoints.
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V116
PAGE 13
PROTOCOL NO. 002-00
Supplemental SAP
19-Aug-2021 Amendment 01
Following safety endpoints will be summarized by vaccination group in each age subgroup 
(i.e., 20-64 years and ≥ 65 years). The counts and risk difference with 95%CI will be 
provided.
•
Solicited injection-site AEs (redness/erythema, swelling, tenderness/pain) (Days 1 to 
5)
•
Solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, 
tiredness/fatigue) (Days 1 to 5)
•
Any AE, Any vaccine-related AE, Any serious AE, Any vaccine-related SAE, Death
•
Maximum axillary temperature measurements which is less than 37.5°C, more than or 
equal 37.5°C by 0.5°C intervals (Days 1 to 5)
Compliance (Medication Adherence)
Given that participants will receive a single dose of pPCV or PNEUMOVAX™23, 
compliance will not be calculated. However, the number and proportion of randomized 
participants receiving pPCV or PNEUMOVAX™23 will be summarized [Sec. 3.12].
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered pPCV or PNEUMOVAX™23.
4
LIST OF REFERENCES
[Ref. 5.4: 03RS5G]
Liang K-Y, Zeger SL. Longitudinal data analysis of continuous and 
discrete responses for pre-post designs. Sankhya: The Indian Journal 
of Statistics 2000;62(Series B, Pt 1):134-48.
[Ref. 5.4: 04J96G]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat 
Med. 1985 Apr-Jun;4(2):213-26.
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