A Phase 1/Phase 2, Randomized, Double-blind Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Polyvalent Pneumococcal Conjugate Vaccine in Adults.
Phase: PHASE1
Conditions: Pneumonia, Pneumococcal
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04168190 
Document Date: 
11-May-2020
A Phase 1/Phase 2, Randomized, Double-blind Study to Evaluate 
the Safety, Tolerability, and Immunogenicity of a Polyvalent 
Pneumococcal Conjugate Vaccine in Adults.

PRODUCT: V116  
1
PROTOCOL/AMENDMENT NO.: 001-01 
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11-MAY-2020
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 1/Phase 2, Randomized, Double-blind Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of a Polyvalent Pneumococcal Conjugate Vaccine in 
Adults.
Protocol Number: 001-01
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
19316
Approval Date: 11 May 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
Amendment 1
11-MAY-2020
The primary purpose of this amendment is to include definitions for solicited 
and unsolicited adverse events.
Original Protocol
20-AUG-2019
Not applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
The primary purpose of this amendment is to include definitions for solicited and unsolicited adverse events.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
8.1.9 Vaccination Report 
Card (VRC)
8.3.4 Postvaccination 
Observation Period
8.4.8 Adverse Events 
Reported on the VRC
10.3.1 Definition of AE
Details related to AEs reported on the 
VRC were moved from Section 8.1.9 to 
Section 8.4.8.
The previous Section 8.3.4 (Safety 
Assessments and Use of the VRC/eVRC) 
was split into 2 sections: Section 8.3.4 
was renamed and retains details of the 
postvaccination observation period. Text 
related to AEs reported on the VRC was 
moved to Section 8.4.8.
Section 8.4.8 is a new section containing 
details of solicited and unsolicited AEs 
reported on the VRC.
The definitions of solicited and 
unsolicited AEs were added to 
Section 10.3.1.
The text was updated to include definitions for solicited 
and unsolicited AEs reported by the participant using 
the VRC.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria
10.5.2 Contraception 
Requirements
Updated inclusion criterion No. 4 to 
include different contraception 
requirements for Phase 1 and Phase 2.
Added subsections to Appendix 3 
(Section 10.5.2) to define different 
contraception requirements for Phase 1 
(Section 10.5.2.1) and Phase 2 
(Section 10.5.2.2).
Based on assessment of additional nonclinical data, 
contraception requirements for Phase 2 were made less 
restrictive compared with Phase 1.
1.2.2 Schema for Phase 2
1.3.2 Schedule of 
Activities for Phase 2
8 Study Assessments and 
Procedures (Table 4: 
Approximate Blood 
Volumes Drawn by Study 
Visit and Sample Type 
[Phase 2])
Added visit numbers for the telephone 
contacts in Phase 2:

Visit 2 (Day 15 telephone contact)

Visit 4 (Day 90 telephone contact)

Visit 5 (Day 180 telephone contact)
The Day 30 site visit in Phase 2 
(previously Visit 2) was renumbered to 
Visit 3
Visit numbers were added for telephone contacts.
1.3.1 Schedule of 
Activities for Phase 1
1.3.2 Schedule of 
Activities for Phase 2
Updated the Notes column for the 
provision and review of the VRC to refer 
to Section 8.1.9 for additional details.
Revision was made for clarity.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
4.2.1.3 Future Biomedical 
Research
8.1.1.2 Consent and 
Collection of Specimens 
for Future Biomedical 
Research
10.6 Appendix 6: 
Collection and 
Management of Specimens 
for Future Biomedical 
Research
Removed the word “substudy” from the 
description of future biomedical research.
Future biomedical research is not a separate substudy.
8.1.13 Participant 
Blinding/Unblinding
Added the following text to clarify 
emergency unblinding procedures:
Once an emergency unblinding has taken 
place, the investigator, site personnel, and 
Sponsor personnel may be unblinded so 
that the appropriate follow-up medical 
care can be provided to the participant.
Revisions were made for clarity.
Throughout
Editorial revisions.
Minor editorial changes to the text.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.2.1
Schema for Phase 1......................................................................................18
1.2.2
Schema for Phase 2......................................................................................19
1.3
Schedule of Activities...........................................................................................20
1.3.1
Schedule of Activities for Phase 1...............................................................20
1.3.2
Schedule of Activities for Phase 2...............................................................23
2
INTRODUCTION..........................................................................................................26
2.1
Study Rationale....................................................................................................26
2.2
Background ..........................................................................................................26
2.2.1
Pharmaceutical and Therapeutic Background .............................................26
2.2.2
Preclinical and Clinical Studies ...................................................................27
2.2.3
Information on Other Study-related Therapy ..............................................27
2.2.3.1
PNEUMOVAX™23..........................................................................27
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................28
4
STUDY DESIGN............................................................................................................31
4.1
Overall Design......................................................................................................31
4.2
Scientific Rationale for Study Design.................................................................32
4.2.1
Rationale for Endpoints ...............................................................................32
4.2.1.1
Immunogenicity Endpoints................................................................32
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator...........................................................34
4.3
Justification for Dose...........................................................................................34
4.3.1
Starting Dose for This Study........................................................................34
4.4
Beginning and End of Study Definition .............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................35
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
 
 
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5.4
Screen Failures.....................................................................................................39
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................43
6.2.1
Dose Preparation..........................................................................................43
6.2.2
Handling, Storage, and Accountability........................................................43
6.3
Measures to Minimize Bias: Randomization and Blinding..............................44
6.3.1
Intervention Assignment..............................................................................44
6.3.2
Stratification.................................................................................................44
6.3.3
Blinding........................................................................................................44
6.4
Study Intervention Compliance..........................................................................45
6.5
Concomitant Therapy..........................................................................................45
6.5.1
Rescue Medications and Supportive Care ...................................................46
6.6
Dose Modification ................................................................................................46
6.7
Intervention After the End of the Study............................................................46
6.8
Clinical Supplies Disclosure................................................................................46
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................46
7.1
Discontinuation of Study Intervention...............................................................46
7.2
Participant Withdrawal From the Study...........................................................46
7.3
Lost to Follow-up .................................................................................................47
8
STUDY ASSESSMENTS AND PROCEDURES........................................................47
8.1
Administrative and General Procedures ...........................................................49
8.1.1
Informed Consent.........................................................................................49
8.1.1.1
General Informed Consent.................................................................49
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................50
8.1.1.3
Consent and Collection of Blood Samples for Optional Assay 
Development......................................................................................50
8.1.2
Inclusion/Exclusion Criteria ........................................................................50
8.1.3
Participant Identification Card.....................................................................50
8.1.4
Medical History ...........................................................................................50
8.1.5
Prior and Concomitant Medications Review...............................................51
8.1.5.1
Prior Medications...............................................................................51
8.1.5.2
Concomitant Medications..................................................................51
8.1.6
Assignment of Screening Number...............................................................51
8.1.7
Assignment of Treatment/Randomization Number.....................................51
 
 
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8.1.8
Study Intervention Administration ..............................................................51
8.1.8.1
Timing of Dose Administration.........................................................52
8.1.9
Vaccination Report Card (VRC)..................................................................52
8.1.10
Telephone Contact on Day 15......................................................................53
8.1.11
Telephone Contact Questionnaire on Day 90 and Day 180.........................53
8.1.12
Discontinuation and Withdrawal .................................................................53
8.1.12.1
Withdrawal From Future Biomedical Research ................................53
8.1.13
Participant Blinding/Unblinding..................................................................54
8.1.14
Calibration of Equipment.............................................................................54
8.2
Immunogenicity Assessments .............................................................................55
8.2.1
Multiplex Opsonophagocytic Assay (MOPA).............................................55
8.2.2
Pneumococcal Electrochemiluminescence (PnECL)...................................55
8.3
Safety Assessments...............................................................................................56
8.3.1
Physical Examinations.................................................................................56
8.3.2
Pregnancy Test.............................................................................................56
8.3.3
Body Temperature Measurement.................................................................56
8.3.4
Postvaccination Observation Period ............................................................56
8.3.5
Clinical Safety Laboratory Assessments .....................................................57
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................57
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................58
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......60
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...60
8.4.4
Regulatory Reporting Requirements for SAE .............................................60
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................60
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................61
8.4.7
Events of Clinical Interest............................................................................61
8.4.8
Adverse Events Reported on the VRC.........................................................61
8.4.8.1
Solicited Adverse Events ...................................................................61
8.4.8.2
Unsolicited Adverse Events...............................................................62
8.5
Treatment of Overdose........................................................................................63
8.6
Pharmacokinetics.................................................................................................63
8.7
Pharmacodynamics..............................................................................................63
8.8
Biomarkers ...........................................................................................................63
8.9
Future Biomedical Research Sample Collection...............................................63
8.10
Optional Assay Development Blood Sample Collection...................................63
 
 
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8.11
Medical Resource Utilization and Health Economics.......................................63
8.12
Visit Requirements...............................................................................................64
8.12.1
Screening......................................................................................................64
8.12.2
Treatment Period/Vaccination Visit ............................................................64
9
STATISTICAL ANALYSIS PLAN .............................................................................64
9.1
Statistical Analysis Plan Summary.....................................................................64
9.2
Responsibility for Analyses/In-house Blinding .................................................67
9.3
Hypotheses/Estimation ........................................................................................68
9.4
Analysis Endpoints...............................................................................................68
9.4.1
Immunogenicity Endpoints in Phase 1 ........................................................68
9.4.2
Immunogenicity Endpoints in Phase 2 ........................................................68
9.4.3
Safety Endpoints in Phase 1 and Phase 2.....................................................69
9.5
Analysis Populations............................................................................................69
9.5.1
Immunogenicity Analysis Populations ........................................................69
9.5.2
Safety Analysis Populations ........................................................................70
9.6
Statistical Methods...............................................................................................70
9.6.1
Statistical Methods for Immunogenicity Analyses in Phase 1.....................70
9.6.2
Statistical Methods for Immunogenicity Analyses in Phase 2.....................71
9.6.3
Statistical Methods for Safety Analysis (Phase 1 and Phase 2)...................74
9.6.4
Summaries of Demographic and Baseline Characteristics ..........................76
9.7
Interim Analyses ..................................................................................................77
9.7.1
Phase 1 Interim Analysis .............................................................................77
9.7.2
Phase 2 Interim Analysis .............................................................................78
9.8
Multiplicity ...........................................................................................................78
9.9
Sample Size and Power Calculations .................................................................78
9.9.1
Immunogenicity Analyses ...........................................................................78
9.9.2
Safety Analyses............................................................................................79
9.10
Subgroup Analyses...............................................................................................80
9.11
Compliance (Medication Adherence).................................................................80
9.12
Extent of Exposure...............................................................................................80
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................81
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........81
10.1.1
Code of Conduct for Clinical Trials.............................................................81
10.1.2
Financial Disclosure.....................................................................................83
10.1.3
Data Protection.............................................................................................84
10.1.3.1
Confidentiality of Data ......................................................................84
10.1.3.2
Confidentiality of Participant Records...............................................84
 
 
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10.1.3.3
Confidentiality of IRB/IEC Information............................................84
10.1.4
Committees Structure...................................................................................85
10.1.4.1
Internal Data Monitoring Committee.................................................85
10.1.5
Publication Policy........................................................................................85
10.1.6
Compliance with Study Registration and Results Posting Requirements ...85
10.1.7
Compliance with Law, Audit, and Debarment ............................................86
10.1.8
Data Quality Assurance ...............................................................................86
10.1.9
Source Documents .......................................................................................87
10.1.10
Study and Site Closure.................................................................................87
10.2
Appendix 2: Clinical Laboratory Tests..............................................................89
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................91
10.3.1
Definition of AE ..........................................................................................91
10.3.2
Definition of SAE ........................................................................................92
10.3.3
Additional Events Reported.........................................................................93
10.3.4
Recording AE and SAE ...............................................................................94
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................99
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................100
10.5
Appendix 5: Contraceptive Guidance..............................................................101
10.5.1
Definitions..................................................................................................101
10.5.2
Contraception Requirements......................................................................102
10.5.2.1
Contraception Requirements in Phase 1 ..........................................102
10.5.2.2
Contraception Requirements in Phase 2 ..........................................103
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................105
10.7
Appendix 7: Country-specific Requirements..................................................110
10.8
Appendix 8: Abbreviations ...............................................................................111
11
REFERENCES.............................................................................................................113
 
 
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LIST OF TABLES
Table 1
Study Interventions for Phase 1 .................................................................41
Table 2
Study Interventions for Phase 2 .................................................................42
Table 3
Approximate Blood Volumes Drawn by Study Visit and by Sample 
Type (Phase 1) ...........................................................................................48
Table 4
Approximate Blood Volumes Drawn by Study Visit and by Sample 
Type (Phase 2) ...........................................................................................49
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................59
Table 6
Solicited Adverse Events for V116-001 ....................................................62
Table 7
Analysis Strategy for Key Immunogenicity Variables in Phase 1.............71
Table 8
Analysis Strategy for Key Immunogenicity Variables in Phase 2.............74
Table 9
Analysis Strategy for Safety Parameters....................................................76
Table 10
Differences in the Incidence of Adverse Event Rates Between the 
2 Vaccination Groups in Phase 2 That Can be Detected With 
Approximately 80% Probability ................................................................80
Table 11
Protocol-required Safety Laboratory Assessments....................................90
 
 
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LIST OF FIGURES
Figure 1
V116-001 Study Design: Phase 1 ..............................................................18
Figure 2
V116-001 Study Design: Phase 2 ..............................................................19
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1/Phase 2, Randomized, Double-blind Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of a Polyvalent Pneumococcal Conjugate Vaccine in 
Adults.
Short Title: Phase 1/Phase 2 Study of a pPCV in Adults
Acronym:
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for Phase 1 of this study. For Phase 2, hypotheses are aligned with 
objectives in the Objectives and Endpoints table.
In Phase 1, objectives and endpoints will be evaluated in pneumococcal vaccine-naïve adults 
18 to 49 years of age who are administered a single dose of pPCV-1, pPCV-2, or 
PNEUMOVAX™23.
In Phase 2, objectives and endpoints will be evaluated in pneumococcal vaccine-naïve adults 
≥50 years of age who are administered a single dose of pPCV or PNEUMOVAX™23.
Primary Objectives
Primary Endpoints
Phase 1
- Objective: To evaluate the safety and 
tolerability of pPCV-1 and pPCV-2 with 
respect to the proportion of participants with 
AEs.
- Solicited injection-site AEs
- Solicited systemic AEs
- Vaccine-related SAEs
Phase 2
- Objective: To evaluate the safety and 
tolerability of pPCV with respect to the 
proportion of participants with AEs.
- Solicited injection-site AEs
- Solicited systemic AEs
- Vaccine-related SAEs
 
 
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Phase 2
- Objective: To evaluate the serotype-specific 
OPA GMTs at 30 days postvaccination.
Hypothesis (H1): pPCV is noninferior to 
PNEUMOVAX™23 as measured by the 
serotype-specific OPA GMTs for the 
common serotypes at 30 days 
postvaccination. 
Hypothesis (H2): The serotype-specific OPA 
GMTs for the unique serotypes in pPCV at 
30 days postvaccination are statistically 
significantly greater following vaccination 
with pPCV than those following vaccination 
with PNEUMOVAX™23.
- Serotype-specific OPA responses
Secondary Objectives
Secondary Endpoints
Phase 1
- Objective: To describe the serotype-specific 
OPA GMTs and IgG GMCs as measured at 
30 days postvaccination.
- Serotype-specific OPA and IgG responses
Phase 1
- Objective: To describe the serotype-specific 
GMFR from prevaccination (Day 1) to 
30 days postvaccination (Day 30) for both 
OPA and IgG responses 
- Serotype-specific OPA and IgG responses
Phase 2
- Objective: To evaluate serotype-specific 
IgG GMCs at 30 days postvaccination.
Hypothesis (H3): pPCV is noninferior to 
PNEUMOVAX™23 as measured by the 
serotype-specific IgG GMCs for the common 
serotypes at 30 days postvaccination. 
Hypothesis (H4): The serotype-specific IgG 
GMCs for the unique serotypes in pPCV at 
30 days postvaccination are statistically 
significantly greater following vaccination 
with pPCV than those following vaccination 
with PNEUMOVAX™23.
- Serotype-specific IgG responses
Phase 2
- Objective: To evaluate serotype-specific 
GMFR from prevaccination (Day 1) to 
30 days postvaccination (Day 30) for both 
OPA and IgG responses 
- Serotype-specific OPA and IgG responses.
 
 
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Phase 2
- Objective: To evaluate the proportion of 
participants who achieve a ≥4-fold increase 
in serotype-specific OPA responses from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30)
- Serotype-specific OPA responses
Overall Design:
Study Phase
Phase 1/Phase 2
Primary Purpose
Prevention
Indication
Pneumococcal infection
Population
Phase 1: Adults 18 to 49 years of age
Phase 2: Adults 50 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 18 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result or 
at the time of final contact with the last participant, 
whichever comes last.
 
 
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Number of Participants:
Approximately 590 total participants (90 participants in Phase 1 and 500 participants in 
Phase 2) will be enrolled as detailed in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Study Interventions for Phase 1:
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin
Vaccination 
Regimen
Use
pPCV-1
pPCV
Refer to 
IB
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
pPCV-2
pPCV
Refer to 
IB
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
PNEUMOVAX™23 PNEUMOVAX™23
Refer to 
product 
labeling
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
Abbreviations: Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; pPCV = polyvalent 
pneumococcal conjugate vaccine.
Study Interventions for Phase 2:
Intervention Group 
Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin
Vaccination 
Regimen
Use
pPCV
pPCV
Refer to 
IB
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
PNEUMOVAX™23
PNEUMOVAX™23
Refer to 
product 
labeling
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
Abbreviations: Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; pPCV = polyvalent 
pneumococcal conjugate vaccine.
Total 
Number
5 total intervention groups (3 groups in Phase 1 and 2 groups in Phase 2)
Duration of 
Participation
Each participant will participate in the study for approximately 6 months from 
the time the participant signs the Informed Consent Form through the final 
contact.
 
 
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PROTOCOL/AMENDMENT NO.: 001-01 
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11-MAY-2020
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
1.2
Schema
1.2.1
Schema for Phase 1
The Phase 1 study design is depicted in Figure 1.
Figure 1
V116-001 Study Design: Phase 1
 
 
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PRODUCT: V116  
19
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
1.2.2
Schema for Phase 2
The Phase 2 study design is depicted in Figure 2.
Figure 2
V116-001 Study Design: Phase 2
 
 
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PRODUCT: V116  
20
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
1.3
Schedule of Activities
1.3.1
Schedule of Activities for Phase 1
Study Period:
Intervention
Notes
Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 15
Day 30
Day 90
Day 180
Visit Window:
-
Day 15 to 
Day 19
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study 
procedures.
Informed Consent for Optional Assay Development 
Blood Samples
X
Consent for optional assay development blood 
samples must be obtained before any of these 
samples are collected from the participant.
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.
Postrandomization Procedures
Assignment of Randomization Number
X
Participant Identification Card
X
Prior/Concomitant Medication and Nonstudy 
Vaccination Review
X
X
X
 
 
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PRODUCT: V116  
21
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
Study Period:
Intervention
Notes
Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 15
Day 30
Day 90
Day 180
Visit Window:
-
Day 15 to 
Day 19
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
pPCV-1/pPCV-2/PNEUMOVAX™23 
Administration (blinded)
X
Participants will receive a single dose of either 
pPCV-1, pPCV-2, 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 Paper Vaccination Report Card (VRC)
X
See Section 8.1.9 for details.
Review Paper VRC Data With Participant
X
X
See Section 8.1.9 for details.
Collect Paper VRC From Participant
X
Complete Telephone Contact Questionnaire
X
X
See Section 8.1.11 for details.
Safety Procedures
Complete Physical Examination
X
To be performed by the investigator or medically 
qualified designee to determine study eligibility at 
screening and before vaccine is administered.
Pregnancy Test (if applicable)
X
X
A pregnancy test consistent with local 
requirements (sensitive to at least 25 IU beta 
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).
Hematology
X
X
Day 1 blood samples should be collected before 
vaccination.
 
 
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PRODUCT: V116  
22
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
Study Period:
Intervention
Notes
Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 15
Day 30
Day 90
Day 180
Visit Window:
-
Day 15 to 
Day 19
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
Chemistry
X
X
Day 1 blood samples should be collected before 
vaccination.
AE Monitoring
X
X
X
X
X
Nonserious AEs are to be reported from Day 1 
through Day 30 following vaccination. Serious 
adverse events (SAEs) and deaths 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
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
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). The sample 
should be obtained at Day 1 before vaccine is 
administered, or at a later date as soon as the 
informed consent is obtained.
Assay Development Samples
Serum for Optional Assay Development
X
X
Samples will be collected from randomized 
participants who provide consent for assay 
development sample collection (see Section 8.10).
Day 1 blood samples must be collected before 
vaccination.
 
 
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PRODUCT: V116  
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PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
1.3.2
Schedule of Activities for Phase 2
Study Period:
Intervention
Notes
Visit Number:
1
2
3
4
5
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 15
Day 30
Day 90
Day 180
Visit Window:
-
Day 15 to 
Day 19
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study 
procedures.
Informed Consent for Optional Assay Development 
Blood Samples
X
Consent for optional assay development blood 
samples must be obtained before any of these 
samples are collected from the participant.
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.
Postrandomization Procedures
Assignment of Randomization Number
X
Participant Identification Card
X
 
 
05H6VD
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PRODUCT: V116  
24
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
Study Period:
Intervention
Notes
Visit Number:
1
2
3
4
5
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 15
Day 30
Day 90
Day 180
Visit Window:
-
Day 15 to 
Day 19
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
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 electronic Vaccination Report Card (eVRC)
X
See Section 8.1.9 for details.
Review eVRC Data With Participant
X
X
See Section 8.1.9 for details.
Collect eVRC From Participant
X
Complete Telephone Contact Questionnaire
X
X
See Section 8.1.11 for details.
Safety Procedures
Complete Physical Examination
X
To be performed by the investigator or medically 
qualified designee at screening and before vaccine 
is administered.
Pregnancy Test (if applicable)
X
X
A pregnancy test consistent with local 
requirements (sensitive to at least 25 IU beta 
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).
 
 
05H6VD
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PRODUCT: V116  
25
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
Study Period:
Intervention
Notes
Visit Number:
1
2
3
4
5
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 15
Day 30
Day 90
Day 180
Visit Window:
-
Day 15 to 
Day 19
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
AE Monitoring
X
X
X
X
X
Nonserious AEs are to be reported from Day 1 
through Day 30 following vaccination. Serious 
adverse events (SAEs) and deaths 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
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
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). The sample 
should be obtained at Day 1 before vaccine is 
administered, or at a later date as soon as the 
informed consent is obtained.
Assay Development Samples
Serum for Optional Assay Development
X
X
Samples will be collected from randomized 
participants who provide consent for assay 
development sample collection (see Section 8.10).
Day 1 blood samples must be collected before 
vaccination.
 
 
05H6VD
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PRODUCT: V116  
26
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
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, specifically residual disease in adults, 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 IPD in adults and includes serotypes not 
currently contained in any licensed pneumococcal vaccine.
This Phase 1/Phase 2 clinical study is designed to evaluate the safety, tolerability, and 
immunogenicity of pPCV compared with PNEUMOVAX™23 in adults.
The Phase 1 portion of this study will be conducted in a population of adults 18 to 49 years 
of age. This population is in general good health and, based on age, is not at increased risk 
for pneumococcal disease.
The Phase 2 portion of this study will be conducted in a population of adults ≥50 years of 
age. This population 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].
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
Pneumococcal disease (ie, disease caused by Streptococcus pneumoniae) is the single largest 
vaccine-preventable cause of death in children and older adults (≥65 years of age) 
worldwide. Direct vaccination of children with PCVs has decreased the incidence of disease 
caused by vaccine serotypes and has led to herd protection in unvaccinated individuals from 
other age groups, referred to as an indirect effect. This indirect effect of childhood 
vaccination with PCVs has resulted in a decrease in hospital admissions for pneumococcal 
disease in adults ≥65 years of age, with an estimated 29% and 34% reduction in IPD and 
non-invasive pneumococcal pneumonia admissions, respectively [Simonsen, L., et al 2014]. 
Additionally, in some countries, including the US, this indirect effect led to the 
recommendation to vaccinate adults with PCVs. However, current surveillance does not 
definitively support that a reduction of disease has been observed due to direct vaccination of 
adults with currently licensed PCVs. A significant burden of pneumococcal disease remains 
with an estimated 24 cases of IPD per 100,000 in adults >65 years of age in the US, and 
surveillance data estimates serotypes included in currently licensed PCVs account for only 
 
 
05H6VD
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PRODUCT: V116  
28
PROTOCOL/AMENDMENT NO.: 001-01 
V116-001-01 FINAL PROTOCOL
11-MAY-2020
17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F). The formulation is not adjuvanted and no 
carrier protein is used.
In the US, PNEUMOVAX™23 is recommended by the ACIP for routine use in 
immunocompetent adults ≥65 years of age [Kobayashi, M., et al 2015]. PNEUMOVAX™23
is also recommended in the US for use in adults aged 19 to 64 years of age with underlying 
medical conditions that increase the risk for serious pneumococcal infection [Centers for 
Disease Control and Prevention 2010] and in immunocompromised adults ≥19 years of age
as part of a sequential regimen with Prevnar 13™[Kobayashi, M., et al 2015]. Children 2 to 
18 years of age with underlying medical conditions are recommended to receive 
PNEUMOVAX™23 after completing all recommended Prevnar 13™doses [Centers for 
Disease Control and Prevention (CDC) 2013].
Many countries follow similar age-based and/or risk-based recommendations for the use of 
PNEUMOVAX™23 [Castiglia P. 2014].
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 33% of participants in Phase 1 and 50% of participants in Phase 2 will 
receive PNEUMOVAX™23, a pneumococcal vaccine for the prevention of pneumococcal 
disease that is licensed in the US, EU, and other regions. 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 Phase 1 of this study. For Phase 2, hypotheses are aligned with 
objectives in the Objectives and Endpoints table.
In Phase 1, objectives and endpoints will be evaluated in pneumococcal vaccine-naïve adults 
18 to 49 years of age who are administered a single dose of pPCV-1, pPCV-2, or 
PNEUMOVAX™23.
In Phase 2, objectives and endpoints will be evaluated in pneumococcal vaccine-naïve adults 
≥50 years of age who are administered a single dose of pPCV or PNEUMOVAX™23.
 
 
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PRODUCT: V116  
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PROTOCOL/AMENDMENT NO.: 001-01 
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11-MAY-2020
Objectives
Endpoints
Primary
Phase 1
•
Objective: To evaluate the safety and 
tolerability of pPCV-1 and pPCV-2 with 
respect to the proportion of participants 
with AEs.
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
Vaccine-related SAEs
Phase 2
•
Objective: To evaluate the safety and 
tolerability of pPCV with respect to the 
proportion of participants with AEs.
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
Vaccine-related SAEs
Phase 2
•
Objective: To evaluate the 
serotype-specific OPA GMTs at 30 days
postvaccination.
Hypothesis (H1): pPCV is noninferior to 
PNEUMOVAX™23 as measured by the 
serotype-specific OPA GMTs for the 
common serotypes at 30 days 
postvaccination.
Hypothesis (H2): The serotype-specific 
OPA GMTs for the unique serotypes in 
pPCV at 30 days postvaccination are 
statistically significantly greater 
following vaccination with pPCV than
those following vaccination with 
PNEUMOVAX™23.
•
Serotype-specific OPA responses
Secondary
Phase 1
•
Objective: To describe the
serotype-specific OPA GMTs and IgG 
GMCs as measured at 30 days
postvaccination.
•
Serotype-specific OPA and IgG
responses
 
 
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PRODUCT: V116  
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PROTOCOL/AMENDMENT NO.: 001-01 
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11-MAY-2020
Objectives
Endpoints
Phase 1
•
Objective: To describe the
serotype-specific GMFR from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for both OPA 
and IgG responses 
•
Serotype-specific OPA and IgG
responses
Phase 2
•
Objective: To evaluate serotype-specific 
IgG GMCs at 30 days postvaccination.
Hypothesis (H3): pPCV is noninferior to 
PNEUMOVAX™23 as measured by the
serotype-specific IgG GMCs for the 
common serotypes at 30 days 
postvaccination.
Hypothesis (H4): The serotype-specific 
IgG GMCs for the unique serotypes in 
pPCV at 30 days postvaccination are 
statistically significantly greater 
following vaccination with pPCV than 
those following vaccination with 
PNEUMOVAX™23.
•
Serotype-specific IgG responses
Phase 2
•
Objective: To evaluate serotype-specific 
GMFR from prevaccination (Day 1) to 
30 days postvaccination (Day 30) for both 
OPA and IgG responses 
•
Serotype-specific OPA and IgG
responses.
Phase 2
•
Objective: To evaluate the proportion of 
participants who achieve a ≥4-fold 
increase in serotype-specific OPA 
responses from prevaccination (Day 1) to 
30 days postvaccination (Day 30)
•
Serotype-specific OPA responses
 
 
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PRODUCT: V116  
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PROTOCOL/AMENDMENT NO.: 001-01 
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11-MAY-2020
4
STUDY DESIGN
4.1
Overall Design
This is a 2-part, randomized, active-controlled, parallel-group, multi-site, double-blind (with 
in-house blinding) study of pPCV in adults who have not previously received any 
pneumococcal vaccine.
In the Phase 1 portion of the study, approximately 90 participants 18 to 49 years of age 
(inclusive) who have not previously received any pneumococcal vaccine (vaccine naïve) will 
be randomly assigned in a 1:1:1 ratio to receive a single dose of either pPCV-1 
(30 participants), pPCV-2 (30 participants), or PNEUMOVAX™23 (30 participants) at 
Visit 1 (Day 1). pPCV-1 and pPCV-2 are the 2 different dosage levels of pPCV that will be 
evaluated. Safety will be assessed via telephone contact 15 days postvaccination, and safety
and immunogenicity will be assessed at 30 days postvaccination. Additional safety 
assessments via telephone contact will occur at 90 and 180 days postvaccination. An siDMC 
will review the safety and tolerability data throughout Phase 1 and Phase 2. The siDMC is a 
standing, internal Sponsor committee established to monitor early phase clinical studies. 
Additional details are provided in Appendix 1 and in the siDMC charter.
An interim analysis will be performed once the primary 30-day postvaccination safety and 
immunogenicity data are available for all Phase 1 participants. At this point, the database will 
be locked and an analysis will be performed to summarize the safety and immunogenicity 
data. The siDMC will review all safety and immunogenicity data to evaluate the benefit risk 
profile and to make a recommendation regarding proceeding to Phase 2. The Sponsor study 
team will also review the unblinded aggregate data and, in conjunction with the 
recommendation of the siDMC, a decision will be made whether to proceed to Phase 2, and 
which dose should be selected for further evaluation. If the decision is made to proceed to 
Phase 2, enrollment will commence immediately.
In the Phase 2 portion of the study, approximately 500 participants ≥50 years of age 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 either pPCV (250 participants) or 
PNEUMOVAX™23 (250 participants) on Day 1. Randomization will be stratified by 
participant age at enrollment (50 to 64 years, 65 to 74 years, and ≥75 years) across the 
2 vaccination groups. Safety will be assessed via telephone contact 15 days postvaccination,
and safety and immunogenicity will be assessed at 30 days postvaccination. Additional safety 
assessments via telephone contact will occur at 90 and 180 days postvaccination.
An interim analysis will be performed prior to the completion of Phase 2 once the primary 
30-day postvaccination safety and immunogenicity data are available for all Phase 2 
participants and the 6-month safety data are available for at least 50% of Phase 2 participants.
This interim analysis will be performed to support clinical development decisions.
In both phases, a 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 
 
 
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Day 1 through Day 5 postvaccination. Information for SAEs and deaths, regardless of 
whether the events are considered to be vaccine related by the investigator, will be collected 
from the time consent is signed through completion of participation in the study.
Blood samples for immunogenicity assays will be drawn immediately before vaccine 
administration (Day 1) and at 30 days postvaccination (Day 30). After completion of 
immunogenicity testing to evaluate the study objectives and hypotheses, serum samples will 
be stored to conduct any additional study-related testing as required by regulatory agencies or 
the Sponsor. For 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 be conducted in 2 parts.
The first-in-human Phase 1 portion of the study will assess the safety and tolerability of 
2 different dosage levels of pPCV (pPCV-1 and pPCV-2) in adults 18 to 49 years of age.
Two different doses are being evaluated to assess antibody concentrations related to 
polysaccharide antigen dose in a polyvalent pneumococcal vaccine and to ensure confidence 
in the dose selected for further evaluation in Phase 2. The population in Phase 1 includes 
adults who are in general good health and, based on age, are not at increased risk for 
pneumococcal disease.
The dose selection for Phase 2 will be based on Phase 1 safety and immunogenicity data.
The Phase 2 portion of the study will assess safety, tolerability, and immunogenicity of 
pPCV in adults ≥50 years of age. As the incidence of IPD is directly related to age, with over 
half of all cases occurring in adults 50 years of age or older [Drijkoningen, J. J 2014], this 
population is at increased risk for pneumococcal disease and its associated morbidity and 
mortality.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints and associated comparative statistical criteria are consistent 
with previous early phase studies evaluating PCVs.
Sera from participants will be used to measure vaccine-induced, anti-PnP serotype-specific 
OPA GMTs and IgG GMCs for all serotypes included in pPCV using the MOPA and PnECL 
assay, respectively.
 
 
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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.
In the Phase 1 portion of this study, anti-PnP serotype-specific OPA GMTs and IgG GMCs 
will be evaluated as secondary endpoints.
In the Phase 2 portion of this study, anti-PnP serotype-specific OPA GMTs will be evaluated 
as a primary endpoint and serotype-specific IgG GMCs will be evaluated as a secondary 
endpoint.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1 and Section 9.4.2.
4.2.1.2
Safety Endpoints
The safety endpoints (ie, AEs and temperature) evaluated in this study were selected based 
on the anticipated product safety profile and published data from marketed PCVs.
Vaccination report cards will be used to collect participant-reported events during the 
postvaccination period, as detailed in Section 8.1.9. Participants in Phase 1 will use paper 
VRCs and participants in Phase 2 will use eVRCs. The VRCs were structured as 
recommended in the final US Food and Drug Administration Patient-reported Outcome 
Guidance [U.S. Food and Drug Administration 2009].
Details on the safety endpoints evaluated in this study can be found in Section 9.4.3.
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 
 
 
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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
Placebo-controlled clinical studies for new PCVs are no longer practical given the proven 
clinical efficacy and widespread use of licensed pneumococcal vaccines worldwide.
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. Globally, 
PNEUMOVAX™23 is the primary pneumococcal vaccine recommended for adults 65 years 
of age and older, and thus its use as a comparator in this study will provide useful 
information for many key regions. In the US, PNEUMOVAX™23 is indicated for use in 
persons 50 years of age or older, which is consistent with the population to be enrolled in 
Phase 2. Additionally, as of June 2019, ACIP changed their guideline to recommend that all 
adults 65 years of age and older should receive PNEUMOVAX™23, and that vaccination 
with Prevnar 13™ as part of a sequential regimen with PNEUMOVAX™23 is not routinely 
recommended for adults who do not have an immunocompromising condition, but rather 
should be based on shared clinical decision between the health care provider and the patient.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
A dose of 2 µg/each PnP is proposed for clinical development of pPCV, which is consistent 
with the dose used in other PCVs. The proposed human dose of pPCV is based on 
dose-ranging evaluation of pPCV in animal studies, as well as evaluation of other 
pneumococcal vaccines in humans. To gain confidence in the safety and immunogenicity of 
pPCV and to confirm the proposed human dose for pPCV clinical development, 2 different 
doses will be evaluated in Phase 1: a 1.0x dose with 2 µg/each PnP, and a 2.0x dose with 
4 µg/each PnP. For additional information related to dose, refer to the IB.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
 
 
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Healthy male and female participants between the ages of 18 and 49 years (inclusive) will be 
enrolled in Phase 1 of this study.
Healthy male and female participants ≥50 years of age will be enrolled in Phase 2 of 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. For Phase 1:
•
Is male or female, from 18 years to 49 years of age inclusive, at the time of signing 
the informed consent.
For Phase 2:
•
Is male or female ≥50 years of age at the time of signing the informed consent.
 
 
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Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
3. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 3 months (90 days [a spermatogenesis cycle]) after the 
last dose of study intervention:
•
Refrain from donating sperm
PLUS either:
•
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
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
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
-
For Phase 1:

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, 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 6 months after the last dose of study intervention and 
agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use 
for the purpose of reproduction during this period. The investigator should 
 
 
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evaluate the potential for contraceptive method failure (ie, noncompliance, 
recently initiated) in relationship to the first dose of study intervention.
For Phase 2:

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 
6 months 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 as 
required by local regulations) within 24 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, 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.
•
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 provides written informed consent for the study. The participant may also 
provide consent for future biomedical research and/or assay development sample 
collection. However, the participant may participate in the main study without 
participating in future biomedical research or assay development sample collection.
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.
 
 
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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 (including 
but not limited to the autoimmune conditions outlined in the Investigator Trial File 
Binder for this study).
4. Has a coagulation disorder contraindicating intramuscular vaccination.
5. *Had a recent febrile illness (defined as oral or tympanic temperature ≥100.4°F 
[≥38.0°C] or axillary or temporal temperature ≥99.4°F [≥37.4°C]) 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 
[eg, 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.
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 [eg, 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.
 
 
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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 Day 30 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.
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.
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.
 
 
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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 interventions to be used in this study are outlined in Table 1 (Phase 1) and Table 2
(Phase 2).
 
 
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Table 1
Study Interventions for Phase 1
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-1
Experimental
pPCV
Biological
/Vaccine
Sterile 
Solution
Refer to IB
0.5 mL
IM
Single dose 
at Visit 1 
(Day 1)
Experimental
IMP
Central
pPCV-2
Experimental
pPCV
Biological
/Vaccine
Sterile 
Solution
Refer to IB
1.0 mL
IM
Single dose 
at Visit 1 
(Day 1)
Experimental
IMP
Central
PNUEMOVAX™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.
 
 
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Table 2
Study Interventions for Phase 2
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
Based on 
Phase 1 
Results
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.
 
 
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All supplies indicated in Table 1 and Table 2 will be provided per the "Sourcing" column
depending upon local country operational requirements. If local sourcing, every attempt 
should be made to source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
The rationale for selection of doses to be used in this study is provided in Section 4.3.
Specific procedures that are required for dose preparation are outlined in the Investigator 
Trial File Binder.
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.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
In Phase 1, intervention allocation/randomization will occur centrally using an IRT system. 
There are 3 study intervention arms. Participants will be assigned randomly in a 1:1:1 ratio to 
receive either pPCV-1, pPCV-2, or PNEUMOVAX™23.
In Phase 2, 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 in Phase 1 will not be stratified.
Intervention allocation/randomization in Phase 2 will be stratified according to the following 
factors:
•
Participant age at time of randomization (50 to 64, 65 to 74, and ≥75 years of age).
6.3.3
Blinding
In both Phase 1 and Phase 2, 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 study intervention administration or 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 Trial File Binder.
To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel will not be present in the examination room when study vaccines are administered. 
Contact between participants and unblinded study personnel after vaccination administration 
is strictly prohibited. Blinded site personnel will be responsible for all safety and 
immunogenicity follow-up procedures after vaccine administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) and Merck Research Laboratories employees 
directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
 
 
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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 (eg, bursa, tendon steroid 
injections), and inhaled/nebulized steroids are permitted.
Any deviation from the above requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
 
 
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6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
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/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.13). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
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.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
 
 
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.12. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant 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.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
 
 
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•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
In Phase 1, the maximum amount of blood collected from each participant at each study visit 
will not exceed 105 mL, and the total amount of blood collected over the duration of the 
study will not exceed 195 mL (Table 3).
In Phase 2, the maximum amount of blood collected from each participant at each study visit 
will not exceed 80 mL, and the total amount of blood collected over the duration of the study 
will not exceed 150 mL (Table 4).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Table 3
Approximate Blood Volumes Drawn by Study Visit and by Sample Type 
(Phase 1)
Visit 1
Day 1
Visit 2
Day 30
Total
Parameter
Approximate Blood Volume (mL)
Immunogenicity assessment (including retention 
samples)
30 mL
30 mL
60 mL
Blood chemistry and hematology
13 mL
13 mL
26 mL
DNA for future biomedical researcha
8.5 mL
N/A
8.5 mL
Assay developmenta
50 mL
50 mL
100 mL
Expected total (mL)
101.5 mL
93 mL
194.5 mL
DNA = deoxyribonucleic acid.
a Samples for future biomedical research and assay development will only be obtained from participants who provide 
separate consent for collection of these optional samples.
 
 
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Table 4
Approximate Blood Volumes Drawn by Study Visit and by Sample Type 
(Phase 2)
Visit 1
Day 1
Visit 3
Day 30
Total
Parameter
Approximate Blood Volume (mL)
Immunogenicity assessment (including retention 
samples)
30 mL
30 mL
60 mL
DNA for Future Biomedical Researcha
8.5 mL
N/A
8.5 mL
Assay developmenta
40 mL
40 mL
80 mL
Expected total (mL)
78.5 mL
70 mL
148.5 mL
DNA = deoxyribonucleic acid.
a Samples for future biomedical research and assay development will only be obtained from participants who provide 
separate consent for collection of these optional samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant prior to participating in a clinical 
study or future biomedical research. If there are changes to the participant’s status during the 
study (eg, health or age of majority requirements), the investigator or medically qualified 
designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the 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 a study and the study population will be added to the consent form template 
at the protocol level.
 
 
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant.
8.1.1.3
Consent and Collection of Blood Samples for Optional Assay Development
The investigator or medically qualified designee will explain the consent for the optional 
assay development blood samples to the participant, answer all of his/her questions, and 
obtain written informed consent before performing any procedure related to the optional 
assay development blood samples collection. A copy of the informed consent will be given to 
the participant.
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 written informed consent. At the time of intervention randomization,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. 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.
 
 
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review 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 (Phase 1) or eVRC (Phase 2) (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 randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer pPCV or PNEUMOVAX™23. Study vaccines should be prepared and 
administered by appropriately qualified members of the study personnel (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed 
by local/state, country, and institutional guidance. Procedures for handling, preparing, and 
administering the unblinded vaccines are provided in the Investigator Trial File Binder. 
Unblinded study personnel should follow the preparation and administration instructions for 
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.
 
 
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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 (oral or tympanic temperature ≥100.4°F [≥38.0°C] or axillary or 
temporal temperature ≥99.4°F [≥37.4°C]) 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 Phase 1 will use a paper VRC and participants in Phase 2 will use an eVRC.
The information collected on the paper VRC will be consistent with the information collected 
on the eVRC.
The paper VRCs/eVRCs are structured as recommended in the final Food and Drug 
Administration Patient-Reported Outcome Guidance [U.S. Food and Drug Administration 
2009]. The investigator or delegate will train the participant in the use of the paper VRC 
(Phase 1) or eVRC (Phase 2) at Visit 1 (Day 1).
The participant will use the paper VRC/eVRC 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/eVRC with 
the participant at the telephone contact on Day 15 (Section 8.1.10). A full review of the 
completed paper VRC/eVRC will occur at the Day 30 postvaccination visit.
 
 
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Any differences between paper VRC/eVRC 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
(Phase 1) or eVRC (Phase 2) with the participant at the telephone contact on Day 15. Any 
differences between the paper VRC/eVRC data and the clinical database must be 
documented in the participant’s source record. A full review of the completed paper 
VRC/eVRC will occur at the Day 30 postvaccination visit.
8.1.11
Telephone Contact Questionnaire on Day 90 and Day 180
Site personnel will contact the participant approximately 3 months and 6 months after the last 
dose of study vaccine to collect additional information based on a Telephone Contact 
Questionnaire provided by the Sponsor. Data to be reported from this discussion will include 
SAEs and/or any updates to previously reported safety information.
8.1.12
Discontinuation and Withdrawal
Participants who receive a single-dose intervention cannot discontinue study intervention 
(see Section 7.1).
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.12.1
Withdrawal From Future Biomedical Research
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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8.1.13
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity and toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
 
 
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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 
of serotype-specific antibodies and, therefore, the immunogenicity of pneumococcal vaccine 
formulations.
Serotype-specific IgG will be measured using the PnECL v2.0 assay to assess the 
concentration of binding antibodies to capsular polysaccharide of S. pneumoniae.
8.2.1
Multiplex 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. MSD has developed and optimized 
the MOPA in a high throughput microcolony platform. The MOPA assay for pPCV will be 
qualified. The qualification studies will evaluate various performance parameters of the assay 
including precision, ruggedness, relative accuracy/dilutional linearity, and the limit of 
detection of the assay.
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 
PnECL v2.0 assay is based on the Meso-Scale Discovery technology, which employs 
disposable multi-spot microtiter plates. The benefits of the ECL multiplex technology over 
the prior enzyme-linked immunosorbent assay methodology include speed, equivalent or 
better sensitivity, increased dynamic range, the ability to multiplex, and reduction in required 
serum sample and reagent volumes. The measurement of immune responses to the serotypes 
contained in pPCV is performed using an assay format consisting of 3 groups of 8, 9, and 
7 serotypes each. The PnECL v2.0 assay for pPCV will be qualified. The qualification
studies will evaluate various performance parameters of the assay including precision, 
ruggedness, relative accuracy/dilutional linearity, and the limit of detection of the assay.
 
 
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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.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 1 (Day 1).
A complete physical examination includes, but is not limited to, the assessment of general 
appearance, vital signs (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 consistent with local requirements (sensitive to at least 25 IU β-hCG) must 
be performed before vaccination at Visit 1 (Day 1) 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 oral body temperatures using their paper VRC (Phase 1) or
eVRC (Phase 2) (Section 8.1.9) from Day 1 to Day 5 postvaccination.
For this study, any oral or tympanic temperature ≥100.4°F (≥38.0°C) or axillary or temporal 
temperature ≥99.4°F (≥37.4°C) 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 
 
 
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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.
•
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.
 
 
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before randomization must be reported by the investigator if they cause the participant to 
be excluded from the study, or are the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo treatment, or a 
procedure.

All nonserious AEs and other reportable safety events (excluding pregnancy and 
lactation exposure) must be reported by the investigator from the day of 
randomization through 30 days postvaccination.

All SAEs must be reported by the investigator throughout the duration of the 
individuals participation in the study, regardless of whether or not related to the 
Sponsor’s product.

All pregnancies and exposure during breastfeeding must be reported by the 
investigator from the day of randomization through 6 months postvaccination.
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.
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 5.
 
 
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time Period:
After the Protocol-specified 
Follow-up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
- any death until participant 
completion of study
(Follow ongoing to outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported – Follow 
to completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest in Phase 1
(require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest in Phase 2 (do 
not require regulatory 
reporting)
There are no ECIs in Phase 2 of this study.
Not applicable
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
 
 
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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, any 
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
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for Phase 1 of this study include:
a.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
There are no ECIs for Phase 2 of this study.
8.4.8
Adverse Events Reported on the VRC
Participants will use a paper VRC (Phase 1) or eVRC (Phase 2) (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 6.
 
 
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Table 6
Solicited Adverse Events for V116-001
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 injection-site AEs for toxicity, and all solicited systemic 
AEs for both toxicity and causality (Appendix 3).
In addition, the investigator will review all solicited AEs for the following:
•
Is the event a symptom of another diagnosis?
•
Is the event ongoing at the end of the solicited period?
•
Does the event meet serious criteria?
A solicited AE that meets any of the above criteria must also be reported on the appropriate 
eCRF as specified in the data entry guidelines.
Phase 1:
Solicited injection-site AEs and solicited systemic AEs reported by the participant using the 
paper VRC will be entered by study site personnel on the appropriate eCRF.
Phase 2:
Solicited injection-site AEs and solicited systemic AEs reported by the participant using the 
eVRC will be transferred directly to the Sponsor database.
8.4.8.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 6, or 
2) predefined in Table 6 but reported at any time outside of the solicited time period. In 
Phase 1 and Phase 2, unsolicited AEs reported by the participant will be entered by study site 
personnel on the appropriate eCRF.
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/toxicity, 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 
Trial File Binder (or equivalent).
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
DNA for future research
•
Leftover study serum after completion of immunogenicity testing stored for future 
research
8.10
Optional Assay Development Blood Sample Collection
If the participant signs the consent for the optional assay development blood samples, these 
additional blood samples will be obtained at Day 1 and Day 30. These blood samples will be 
used to support future development work on improving bioanalytical measurements, which 
requires high-volume single-donor samples to monitor performance of the assay over time.
Sample collection, storage, and shipment instructions for the optional assay development 
blood samples will be provided in the operations/laboratory manual.
8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
 
 
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8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Screening procedures will be conducted at Visit 1 (Day 1) as outlined in Section 1.3.
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.
8.12.2
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. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in an sSAP and referenced in the CSR for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
Study Design Overview
A Phase 1/Phase 2, Randomized, Double-blind Study to Evaluate the 
Safety, Tolerability, and Immunogenicity of a Polyvalent Pneumococcal 
Conjugate Vaccine in Adults.
Treatment Assignment
In Phase 1, participants will be randomly assigned in a 1:1:1 ratio to 
receive either pPCV-1, pPCV-2, or PNEUMOVAX™23.
In Phase 2, participants will be randomly assigned in a 1:1 ratio to receive 
either pPCV or PNEUMOVAX™23. Randomization in Phase 2 will be 
stratified by age at study entry (50 to 64 years, 65 to 74 years, and 
≥75 years).
Analysis Populations
Safety: APaT population
Primary Immunogenicity: PP population
Supportive Immunogenicity: FAS population
 
 
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Primary Endpoints in 
Phase 1
The primary safety endpoints in Phase 1 include:

Proportion of participants with solicited injection-site AEs

Proportion of participants with solicited systemic AEs

Proportion of participants with vaccine-related SAEs
Key Secondary Endpoints 
in Phase 1
The key secondary immunogenicity endpoints in Phase 1 include:

Ratio of serotype-specific OPA GMTs for the common serotypes in 
pPCV and PNEUMOVAX™23

Ratio of serotype-specific OPA GMTs of pPCV and 
PNEUMOVAX™23 for the serotypes unique to pPCV

Ratio of serotype-specific IgG GMCs for the common serotypes in 
pPCV and PNEUMOVAX™23
Primary Endpoints in 
Phase 2
The primary safety endpoints in Phase 2 include:

Proportion of participants with solicited injection-site AEs

Proportion of participants with solicited systemic AEs

Proportion of participants with vaccine-related SAEs.
The primary immunogenicity endpoints in Phase 2 include:

Ratio of serotype-specific OPA GMTs for the common serotypes in 
pPCV and PNEUMOVAX™23

Ratio of serotype-specific OPA GMTs of pPCV and 
PNEUMOVAX™23 for the serotypes unique to pPCV
Key Secondary Endpoints 
in Phase 2
The key secondary immunogenicity endpoints in Phase 2 include:

Ratio of serotype-specific IgG GMCs for the common serotypes in 
pPCV and PNEUMOVAX™23

Ratio of serotype-specific IgG GMCs of pPCV and 
PNEUMOVAX™23 for the serotypes unique to pPCV
Statistical Methods for Key 
Immunogenicity Analyses 
in Phase 1
Immunogenicity analyses will be conducted separately for each serotype.
Immunogenicity endpoints will be analyzed at 30 days postvaccination 
compared with prevaccination (Day 1) to describe the IgG antibody 
concentrations in response to the vaccination. The ratio of OPA GMTs
and IgG GMCs (pPCV-1/PNEUMOVAX™23 and 
pPCV-2/PNEUMOVAX™23) will be presented along with 95% CIs by 
vaccination group.
The OPA GMT ratio estimation and 95% CI will be calculated using a 
cLDA method.
Statistical Methods for Key 
Immunogenicity Analyses 
in Phase 2
Immunogenicity analyses will be conducted separately for each serotype.
To address the primary noninferiority hypothesis (H1), a noninferiority 
test comparing OPA GMTs for the common serotypes in pPCV and 
PNEUMOVAX™23 (control group) will be conducted. A noninferiority 
margin of 0.33 corresponding to a 3.0-fold lower OPA GMT in the pPCV
group compared with the control group will be used. Rejecting the null 
hypothesis at the 1-sided α=0.025 level corresponds to the lower bound of 
 
 
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the 2-sided 95% CI on the GMT ratio (pPCV/control) being >0.33 and 
would lead to the conclusion that the OPA GMT for pPCV is noninferior 
to that of the control vaccine, for the given common serotype.
To address the second primary hypothesis (H2), a test comparing OPA 
GMTs for the serotypes unique to pPCV will be conducted. Rejecting the 
null hypothesis at the 1-sided α=0.025 level corresponds to the lower 
bound of the 2-sided 95% CI on the GMT ratio (pPCV/control) being 
>1.0 and would lead to the conclusion that the OPA GMT for pPCV is 
statistically significantly greater than that of the control vaccine, for the 
given unique serotype.
The statistical margins specified for H1 and H2 are consistent with
previous early phase comparative studies [Jackson, L. A., et al 2013].
The OPA GMT ratio estimation, 95% CI, and the hypothesis test 
(ie, 1-sided p-value) will be calculated using a cLDA method.
Statistical Methods for Key 
Safety Analyses in Phase 1 
and Phase 2
The analysis of safety will follow a tiered approach. 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 M&N method [Miettinen, O. 
and Nurminen, M. 1985].
Interim Analyses (IA)
There are 2 interim analyses planned for this study:
Phase 1 Interim Analysis:
An interim analysis will be performed once the primary 30-day 
postvaccination safety and immunogenicity data are available for all 
Phase 1 participants. At this point, the database will be locked and an 
analysis will be performed to summarize the safety and immunogenicity 
data. The siDMC will review unblinded Phase 1 safety and 
immunogenicity data reports and evaluate the benefit and risk profile to 
make a recommendation regarding proceeding to Phase 2. The Sponsor 
study team will review the Phase 1 safety and immunogenicity aggregate 
data reports to inform the clinical development decision to proceed to 
Phase 2. The study team will not be unblinded to participant-level data. 
The unblinded Phase 1 data will be provided by an unblinded statistician 
who is not part of the blinded study team, and the clinical database will 
remain blinded to both the Sponsor study team and participating sites 
throughout the duration of the Phase 1/Phase 2 study.
Phase 2 Interim Analysis:
An interim analysis is planned to support clinical development decisions 
prior to the completion of the Phase 2 portion of this study. This analysis 
will be conducted once the primary 30-day postvaccination safety and 
immunogenicity data are available for all Phase 2 participants and the 
6-month safety data are available for at least 50% of Phase 2 participants. 
This analysis will represent the final analysis of the primary 
immunogenicity endpoints and will be considered a preliminary analysis of 
the safety data. These analyses will be conducted by an unblinded 
statistician who is not part of the blinded study team. The siDMC will 
review unblinded Phase 2 safety and immunogenicity data reports and 
evaluate the benefit and risk profile. The Sponsor study team will review 
the Phase 2 safety and immunogenicity aggregate data reports to inform 
further clinical development. The Sponsor study team will not be 
 
 
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unblinded to participant-level data, and the clinical database will remain 
blinded to both the Sponsor study team and participating sites throughout 
the duration of the Phase 1/Phase 2 study.
Multiplicity
This study will be considered to have met its primary immunogenicity 
objectives if success is demonstrated for all common and unique serotypes 
included in each primary immunogenicity hypothesis. The 
intersection-union test controls the overall type I error at the 1-sided 
0.025 level within each group; therefore, no multiplicity adjustment will be 
required.
The overall alpha level for the secondary immunogenicity objectives, 
relating to both the set of common and unique serotypes, as measured by
IgG, is also controlled at the 1-sided 0.025 level.
No multiplicity adjustments will be made for the safety comparisons.
Sample Size and Power
In Phase 1, approximately 90 participants will be enrolled, with 
approximately 30 participants in each of the 3 vaccination groups.
In Phase 2, Approximately 500 participants will be enrolled, with 
approximately 250 participants in each of the 2 vaccination groups. 
Assuming 90% evaluability (approximately 225 participants per group), 
there is 98.7% power to declare primary noninferiority to 
PNEUMOVAX™23 for the common serotypes and 99.2% power to 
declare pPCV is statistically significantly greater than 
PNEUMOVAX™23 for the unique serotypes based on OPA GMT ratios. 
The overall estimate of power for the primary hypothesis, as the product of 
the powers for the set of noninferiority hypotheses and the set of 
superiority (ie, statistically significantly greater) hypotheses, is 98%. This 
sample size also provides adequate power for the secondary hypotheses. 
Specifically, there is 87% power for the secondary noninferiority 
hypothesis and 92% power for the secondary superiority (ie, statistically 
significantly greater) hypothesis. The overall power for the secondary 
hypotheses is 80%.
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. At the time of the interim analyses, 
the unblinded Phase 1 and Phase 2 data will be provided by an unblinded statistician who is 
not part of the blinded study team, and the clinical database will remain blinded to both the 
Sponsor study team and participating sites throughout the duration of the Phase 1/Phase 2 
study.
Section 6.3.3 specifies the roles and responsibilities of the site and Sponsor personnel who 
will be unblinded during the study. 
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for
study treatment assignment. Randomization will be implemented in an IRT.
Blinding details related to the planned interim analyses are described in Section 9.7.
 
 
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9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints are listed below.
9.4.1
Immunogenicity Endpoints in Phase 1 
There are no primary immunogenicity analysis endpoints in Phase 1.
Secondary immunogenicity analysis endpoints in Phase 1 include:
•
Ratio of serotype-specific IgG GMCs for the common serotypes in pPCV and 
PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio of serotype-specific OPA GMTs for the common serotypes in pPCV and 
PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio of serotype-specific OPA GMTs 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.
The specific sets of serotypes described as common or unique will be clearly defined in the 
sSAP to be written prior to database lock.
9.4.2
Immunogenicity Endpoints in Phase 2
Primary immunogenicity analysis endpoints in Phase 2 include:
•
Ratio of serotype-specific OPA GMTs for the common serotypes in pPCV and 
PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio of serotype-specific OPA GMTs of pPCV and PNEUMOVAX™23 for the 
serotypes unique to pPCV at 30 days postvaccination.
Secondary immunogenicity analysis endpoints in Phase 2 include:
•
Ratio of serotype-specific IgG GMCs for the common serotypes in pPCV and 
PNEUMOVAX™23 at 30 days postvaccination.
•
Ratio of serotype-specific IgG GMCs of pPCV and PNEUMOVAX™23 for the 
serotypes unique to pPCV at 30 days postvaccination.
 
 
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•
Serotype-specific GMFRs from prevaccination (Day 1) to 30 days postvaccination 
(Day 30) for both OPA and IgG responses.
•
Difference in the proportion of participants who achieve a ≥4-fold increase in 
serotype-specific OPA responses from prevaccination (Day 1) to 30 days
postvaccination.
The specific sets of serotypes described as common or unique will be clearly defined in the 
sSAP to be written prior to database lock.
9.4.3
Safety Endpoints in Phase 1 and Phase 2
Safety analyses will be conducted separately for Phase 1 and Phase 2. Safety and tolerability 
will be assessed by clinical review of all relevant parameters, including AEs and 
postvaccination body temperature measurements.
The safety analysis endpoints that address the primary objective 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.
Additional Safety analysis endpoints include:
•
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 temperature measurements meeting the 
Brighton Collaboration cut points 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:
 
 
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•
Failure to receive correct clinical material as per the randomization schedule at Visit 1 
(Day 1) (ie, participants who were cross-treated)
•
Having no valid serology results (ie, participants who are missing serology results for 
both Day 1 and Day 30 [30 to 44 days following vaccination]).
Determinations on protocol deviations will be made by blinded study team members prior to 
the planned Phase 1 interim analysis (Section 9.7.1), prior to the planned Phase 2 interim 
analysis (Section 9.7.2), and prior to the final unblinding of the database. Participants will be 
included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the PP population.
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.
9.5.2
Safety Analysis Populations
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.
Details on the approach to handling missing data are provided in Section 9.6.
9.6
Statistical Methods
No statistical hypothesis testing is planned for Phase 1, but rather estimation will be
performed for both the safety and immunogenicity data.
For immunogenicity analyses in Phase 2, unless otherwise specified, all statistical tests will 
be conducted at the α=0.05 level (2-sided). Results that will be considered statistically
significant (versus nominally significant) after consideration of the strategy for controlling
type-I errors are described in Section 9.8.
9.6.1
Statistical Methods for Immunogenicity Analyses in Phase 1
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 3 vaccination groups. In this model, the response vector consists of the 
 
 
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log-transformed prevaccination (Day 1) and postvaccination (Day 30) antibody titers. The 
repeated measures model will include terms for time, the interaction of time-by-vaccination 
group (with a restriction of the same baseline mean across groups). The treatment difference 
in terms of a geometric mean ratio at a given postvaccination time point will be estimated 
and tested 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. 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. 
The analysis strategy for key immunogenicity variables in Phase 1 is listed in Table 7.
Table 7
Analysis Strategy for Key Immunogenicity Variables in Phase 1
Endpoint/Variable
(Description, Time point)
Statistical
Method
Analysis
Population
Missing Data 
Approach
Secondary Endpoints
Ratio of IgG GMCs at 30 days postvaccination for 
common serotypes
cLDAa
(point estimate, 
95% CI)
PP/FAS
Model-based
Ratio of OPA GMTs at 30 days postvaccination for 
common serotypes
cLDAa
(point estimate, 
95% CI)
PP/FAS
Model-based
Ratio of OPA GMTs at 30 days postvaccination for 
unique serotypes in pPCV
cLDAa
(point estimate, 
95% CI)
PP/FAS
Model-based
GMFRs from prevaccination to 30 days 
postvaccination for both OPA and IgG responses
Descriptive Statistics 
(point estimate, 
95% CI)
PP/FAS
Missing data will 
not be imputed
CI = confidence interval; 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.
a cLDA model with terms for time and the interaction of time-by-vaccination group.
9.6.2
Statistical Methods for Immunogenicity Analyses in Phase 2
This section describes the statistical methods that address the primary and secondary Phase 2 
immunogenicity objectives. The margins of noninferiority and superiority (ie, statistically 
significantly greater) presented below are consistent with previous early phase comparative 
studies [Jackson, L. A., et al 2013].
 
 
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The immunogenicity analyses will be conducted for each serotype separately.
Primary Endpoints/Hypotheses
For the common serotypes, the primary noninferiority hypotheses (H1) regarding OPA GMT 
levels between recipients of pPCV and PNEUMOVAX™23 is:
H0: GMT1/GMT2 ≤0.33 versus
H1: GMT1/GMT2 >0.33
where GMT1 is the serotype-specific OPA GMT for the pPCV group and GMT2 is the 
serotype-specific OPA GMT for the PNEUMOVAX™23 group. A ratio of 0.33 corresponds 
to a 3.0-fold lower OPA GMT in the pPCV group compared with the PNEUMOVAX™23
group. Rejecting the null hypothesis (H0) at the 1-sided α=0.025 level corresponds to the
lower bound of the 2-sided 95% CI on the GMT ratio (pPCV/PNEUMOVAX™23) being 
>0.33 and would lead to the conclusion that the OPA response to pPCV for the common 
serotype is noninferior to that of PNEUMOVAX™23.
For the serotypes that are unique to pPCV, the primary superiority (ie, statistically 
significantly greater) hypotheses (H2) regarding OPA levels between recipients of pPCV
group and PNEUMOVAX™23 group is:
H0: GMT1/GMT2 ≤1.0 versus
H1: GMT1/GMT2 >1.0
where GMT1 is the OPA GMT for the pPCV group and GMT2 is the OPA GMT for the 
PNEUMOVAX™23 group. Rejecting the null hypothesis (H0) at the 1-sided α=0.025 level 
corresponds to the lower bound of the 2-sided 95% CI on the GMT ratio 
(pPCV/PNEUMOVAX™23) being >1.0 and would lead to the conclusion that the OPA 
response to pPCV for the unique serotype is statistically significantly greater than that of 
PNEUMOVAX™23.
The GMT ratio estimation, 95% CI, and the hypothesis test (ie, 1-sided p-value) will be 
calculated using a cLDA method proposed by Liang and Zeger [Liang, K-Y and Zeger, S. L. 
2000] utilizing data from both 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, the interaction of 
time-by-vaccination group (with a restriction of the same baseline mean across groups), age 
stratum (ie, 50 to 64 years, 65 to 74 years, and ≥75 years) at vaccination, and age
stratum-by-time interaction. This model will allow for different baseline means for each age
stratum, but restrict the baseline mean within each age stratum to be the same for all
vaccination groups. The treatment difference in terms of a geometric mean ratio at a given 
postvaccination time point will be estimated and tested 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. The Kenward-Roger adjustment will 
be used with REML to make proper statistical inference. This model allows the inclusion of 
 
 
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participants who are missing either the baseline or postbaseline measurements, thereby 
increasing efficiency.
For titer measurements 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 the titer.
Secondary Endpoints/Hypotheses
The same statistical approach as used for the primary endpoints will be used to address the 
secondary immunogenicity hypotheses (H3 and H4) that compare the IgG GMC responses of 
pPCV with PNEUMOVAX™23, except that a noninferiority margin of 0.5 will be used to 
evaluate noninferiority of the common serotypes, which corresponds to a 2.0-fold lower
IgG GMC in the pPCV group compared with the PNEUMOVAX™23 group. 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 sample 
t-distribution. The difference between the pPCV group and the PNEUMOVAX™23 group in 
the proportion of participants with ≥4-fold increase in serotype-specific OPA responses from 
prevaccination (Day 1) to 30 days postvaccination will be estimated. The corresponding 95% 
CIs about these differences will be calculated using the M&N method, stratifying by age at 
enrollment (50 to 64 years, 65 to 74 years, and ≥75 years) [Miettinen, O. and Nurminen, M. 
1985].
The analysis strategy for key immunogenicity variables in Phase 2 is listed in Table 8.
 
 
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Table 8
Analysis Strategy for Key Immunogenicity Variables in Phase 2
Endpoint/Variable
(Description, Time point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
Ratio of OPA GMTs at 30 days 
postvaccination for common 
serotypes
cLDAa
(point estimate, 95% CI, p-valueb)
PP/FAS
Model-based
Ratio of OPA GMTs at 30 days 
postvaccination for unique serotypes
cLDAa
(point estimate, 95% CI, p-valueb)
PP/FAS
Model-based
Secondary Endpoints
Ratio of IgG GMCs at 30 days 
postvaccination for common 
serotypes
cLDAa
(point estimate, 95% CI, p-valueb)
PP/FAS
Model-based
Ratio of IgG GMCs at 30 days 
postvaccination for unique serotypes
cLDAa
(point estimate, 95% CI, p-valueb)
PP/FAS
Model-based
GMFRs from prevaccination to 
30 days postvaccination for both 
OPA and IgG responses
Descriptive Statistics
(point estimate, 95% CI)
PP/FAS
Missing data 
will not be 
imputed
Difference in proportion of 
participants with a ≥4-fold increase 
in serotype-specific OPA responses
from prevaccination to 30 days 
postvaccination
Descriptive Statistics
(point estimate, 95% CI)
PP/FAS
Missing data 
will not be 
imputed
CI = confidence interval; 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.
a cLDA model with terms for time, the interaction of time-by-vaccination group, age stratum, and the interaction of age 
stratum-by-time.
b p-values for noninferiority or superiority (ie, statistically significantly greater) hypothesis.
9.6.3
Statistical Methods for Safety Analysis (Phase 1 and Phase 2)
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs, postvaccination temperature measurements, and laboratory measurements 
(Phase 1 only). Safety analyses will be conducted separately for Phase 1 and Phase 2.
 
 
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The analysis of AEs and temperature measurements will follow a tiered approach (Table 9).
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.
Laboratory measurements collected during Phase 1 (see Appendix 2) will be summarized 
separately. Details regarding the analysis of laboratory measurements will be provided in the 
sSAP.
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.
This study will solicit for predefined injection-site and systemic AEs. However, as this is the 
first clinical study of pPCV, no data exists around which a comparative, data-driven safety 
hypothesis can be formulated and tested. As a result, the solicited injection-site and systemic 
AEs reported in this study will be analyzed as Tier 2 events.
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 [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 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.
Adverse events (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.
 
 
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Tier 3 Events
Events not defined above are considered Tier 3 events. Only point estimates by treatment 
group will be provided for Tier 3 events.
Table 9
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 temperature measurements meeting the 
Brighton Collaboration cut points (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.
Note: AEs includes both clinical and laboratory AEs (laboratory AEs will be collected in Phase 1 only).
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.
9.6.4
Summaries of 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 
 
 
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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 (eg, age) and prior and concomitant therapies and vaccines will be
summarized by group. Separate summaries will be provided for Phase 1 and Phase 2.
No other analyses are planned for this study.
9.7
Interim Analyses
A review of Phase 1 and Phase 2 safety and tolerability data will be conducted by an 
unblinded siDMC. Immunogenicity data will also be provided to the siDMC to enable a 
benefit-risk assessment. A description of the structure and function of the siDMC, along with 
the timing and content of the safety review, will be outlined in the siDMC charter. 
Information regarding the composition of the siDMC is provided in Appendix 1.
Blinding to intervention assignment will be maintained at all investigational sites. 
Participant-level unblinding will be restricted to an internal unblinded statistician and 
statistical programmer performing any planned or requested safety reviews by the siDMC.
Any safety reviews conducted while the study is ongoing will be provided by the internal
unblinded statistician to the siDMC. Prior to final study unblinding, the internal unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
safety reviews.
Two prespecified analyses are planned prior to the completion of this study, as described 
below.
9.7.1
Phase 1 Interim Analysis
An interim analysis will be performed once the primary 30-day postvaccination safety and 
immunogenicity data are available for all Phase 1 participants. At this point, the database will 
be locked and an analysis will be performed to summarize the safety and immunogenicity 
data. This analysis will not occur until medical/scientific review of the data has been 
performed and protocol deviations have been identified. The siDMC will review unblinded 
Phase 1 safety and immunogenicity data reports and evaluate the benefit and risk profile to 
make a recommendation regarding proceeding to Phase 2. The Sponsor study team will 
review the Phase 1 safety and immunogenicity aggregate data reports to inform the clinical 
development decision to proceed to Phase 2. The Sponsor study team will not be unblinded 
to participant-level data. The unblinded Phase 1 data will be provided by an unblinded 
statistician who is not part of the blinded study team, and the clinical database will remain 
blinded to both the Sponsor study team and participating sites throughout the duration of the 
Phase 1/Phase 2 study. Additionally, based on the analysis of this Phase 1 data, power and 
sample size assumptions for Phase 2 will be examined and the sample size may be adjusted.
 
 
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9.7.2
Phase 2 Interim Analysis
An interim analysis is planned to support clinical development decisions prior to the 
completion of the Phase 2 portion of this study. This analysis will be conducted once the
primary 30-day postvaccination safety and immunogenicity data are available for all Phase 2 
participants and the 6-month safety data are available for at least 50% of Phase 2 participants.
This analysis will represent the final analysis of the primary immunogenicity endpoints and 
will be considered a preliminary analysis of the safety data. These analyses will be conducted 
by an unblinded statistician who is not part of the blinded study team. The siDMC will 
review unblinded Phase 2 safety and immunogenicity data reports and evaluate the benefit 
and risk profile. The Sponsor study team will review the Phase 2 safety and immunogenicity 
aggregate data reports to inform further clinical development. The Sponsor study team will 
not be unblinded to participant-level data.
9.8
Multiplicity
As described in Section 9.6.2, there are 2 types of hypothesis tests for the Phase 2 
immunogenicity analysis: (1) a separate noninferiority test for each of the common serotypes 
between pPCV and PNEUMOVAX™23, and (2) a separate superiority (ie, statistically 
significantly greater) test for each of the serotypes that are unique to pPCV. This study will 
be considered to have met its primary immunogenicity objective if success is demonstrated 
for all common serotypes and all unique serotypes included in the primary immunogenicity 
hypotheses. The intersection-union test controls the overall type I error at the 1-sided 
0.025 level within each group; therefore, no multiplicity adjustment will be required within 
each group [Berger, R. L. 1982]. The intersection-union test refers to the fact that the set of 
statistical null hypotheses to be tested can be expressed as a union, and the set of statistical 
alternative hypotheses as an intersection. Thus, the overall statistical null hypothesis can only 
be rejected if each of the set of statistical null hypotheses are rejected.
The same multiplicity strategy will be applied to the 2 secondary study hypotheses for which 
there is also a noninferiority hypothesis for the common serotypes between pPCV and 
PNEUMOVAX™23, and a superiority (ie, statistically significantly greater) hypothesis for 
the serotypes unique to pPCV, as measured by IgG. In this way, for the secondary hypotheses 
to be supported by the data, all statistical tests will have to be statistically significant. This 
approach controls the type I error at 0.025 (1-sided) for the set of primary hypothesis tests 
and separately at 0.025 (1-sided) for the set of secondary hypothesis tests.
No multiplicity adjustments will be made for the safety comparisons.
9.9
Sample Size and Power Calculations
9.9.1
Immunogenicity Analyses
In Phase 1, approximately 90 participants will be enrolled, with approximately 
30 participants in each of the 3 vaccination groups.
 
 
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In Phase 2, Approximately 500 participants will be enrolled, with approximately 
250 participants in each of the 2 vaccination groups. Assuming 90% evaluability 
(approximately 225 participants per group), there is 98.7% power to declare primary
noninferiority to PNEUMOVAX™23 for the common serotypes and 99.2% power for
superiority (ie, statistically significantly greater) for the unique serotypes based on OPA
GMT ratios. The overall estimate of power for the primary hypothesis, as the product of the 
powers for the set of noninferiority hypotheses and the set of superiority (ie, statistically 
significantly greater) hypotheses, is 98%. This sample size also provides adequate power for 
the secondary hypotheses. Specifically, there is 87% power for the secondary noninferiority 
hypothesis and 92% power for the secondary superiority (ie, statistically significantly 
greater) hypothesis. The overall power for the secondary hypotheses is 80%. The sample size 
and power calculations are based on the following assumptions:
•
The standard deviation of natural log-transformed OPA assay and IgG results are 2.2 and 
1.73, respectively. These assumptions are based on observations from previous studies 
with PNEUMOVAX™23.
•
For the common serotypes, the assumed true geometric mean ratios of OPA GMTs and 
IgG GMCs are 1.
•
For the unique serotypes, the assumed true geometric mean ratios of OPA GMTs and IgG 
GMCs are 3 and 2, respectively.
•
90% evaluability rate (approximately 225 participants per group).
9.9.2
Safety Analyses
For safety comparisons, all participants are expected to be evaluable.
In Phase 1, if no SAEs are observed among the 30 participants in each vaccination group, this 
study provides 68.7% confidence that the true SAE rate is <1.2% (1 out of every 
83 participants). In Phase 2, if no SAEs are observed among the 250 participants in each 
vaccination group, this study provides 97.9% confidence that the true SAE rate is <1.5% 
(1 out of every 67 participants).
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. In Phase 2, if 
the incidence rate of an SAE is 1 of every 143 recipients of the vaccine (0.7%), then there is 
an 80% chance of observing at least 1 such SAE among 250 participants in the pPCV group. 
If the incidence rate is 1 of every 332 recipients of the vaccine (0.3%), then there is a 50% 
chance of observing at least 1 SAE among 250 participants in the pPCV group.
For the Phase 2 safety comparisons, risk differences between the 2 vaccination groups that 
could be detected with an 80% probability are summarized in Table 10 for a variety of 
hypothetical true incidence rates. These calculations assume that there are 250 evaluable 
participants in both groups and are based on a 2-sided significance level of α=0.05. No 
multiplicity adjustments were made in these calculations.
 
 
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Table 10
Differences in the Incidence of Adverse Event Rates Between the 2 Vaccination 
Groups in Phase 2 That Can be Detected With Approximately 80% Probability
Incidence of Adverse Event
Risk Difference
pPCV (%)
PNEUMOVAX™23 (%)
Percentage Points
3.6
0.1
3.5
7.6
2.0
5.6
12.3
5.0
7.3
19.2
10.0
9.2
25.5
15.0
10.5
31.4
20.0
11.4
42.5
30.0
12.5
The incidence rates for each vaccination group are hypothetical and do not represent actual adverse events in either 
group.
The incidences assume a 2-sided 5% alpha level with 250 participants in each group. No multiplicity adjustments 
were made.
The calculations are based on an asymptotic method proposed by Farrington and Manning [Farrington, C. P. 1990].
9.10
Subgroup Analyses
Subgroup analyses will be provided for Phase 2, where the geometric mean ratio between 
pPCV and PNEUMOVAX™23 as assessed by OPA GMTs and IgG GMCs will be 
summarized by age subgroup (ie, 50 to 64 years, 65 to 74 years, and ≥75 years).
Further details of subgroup analyses will be documented in the sSAP.
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
In Phase 1, the extent of exposure will be summarized by the number and proportion of 
randomized participants administered pPCV-1, pPCV-2, or PNEUMOVAX™23.
In Phase 2, 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.
 
 
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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.
 
 
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10.1.4
Committees Structure
10.1.4.1
Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate siDMC will 
monitor the interim data from this study. The siDMC is comprised of members of Sponsor 
Senior Management, none of whom are directly associated with the conduct of this study. 
The siDMC will monitor the study at an appropriate frequency (Section 9.7[Interim 
Analyses] ) for evidence of adverse effects of study intervention and immunogenicity data, as 
described in the detailed monitoring guidelines. The siDMC will determine whether the study 
should continue (or other modifications, prespecified or otherwise, should be made) 
according to the protocol, considering the overall risk and benefit to study participants. The 
siDMC will also make recommendations to the Sponsor protocol team regarding steps to 
ensure both participant safety and the continued ethical integrity of the study.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the 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 
 
 
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Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
 
 
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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
 
 
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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 11 will be performed by the central laboratory.
•
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be 
entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing:
- Pregnancy testing requirements for study inclusion are described in Section 5.1.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted 30 days after the last dose of study intervention.
- Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.
 
 
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Table 11
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
(Phase 1 only)
Platelet Count 
RBC Indices:
MCV
MCH
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
(Phase 1 only)
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Creatinine
Alkaline 
phosphatase
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose 
(nonfasting)
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 (as needed for 
WOCBP)
•
All study-required laboratory assessments will be performed by a central laboratory, 
with the exception of pregnancy tests.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
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
 
 
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10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
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/toxicity
•
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.
 
 
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•
The investigator will make an assessment of toxicity for each AE and SAE (and other 
reportable event) reported during the study. A toxicity grade will be assigned to 
injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in the following tables. The toxicity grading scales used in 
this study are adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007.”
Injection-Site AE Toxicity Grading Scale
Injection Site 
Reaction to Study 
Vaccine/Placeboa
Grade 1
Grade 2
Grade 3
Grade 4
Injection-site AEs occurring Days 1 through 5 following receipt of study vaccine/placebo
Pain/Tenderness
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Erythema/Redness
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or 
exfoliative 
dermatitis or 
results in ER 
visit or 
hospitalization
Induration/Swelling
Size measured as 
B
Size measured as
C or D
Size measured as
E→
Necrosis or ER 
visit or 
hospitalization
Other 
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Any injection-site reaction that begins ≥6 days after receipt of study vaccine/placebo
Pain/tenderness
Erythema/Redness
Induration/Swelling
Other
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
AE = adverse event; ER = emergency room; eVRC = electronic Vaccine Report Card; SAE = serious adverse event; 
VRC = vaccination report card.
a Based upon information provided by the participant on the paper VRC/eVRC and verbally during VRC review. 
Erythema/Redness and Induration/Swelling are specific injection-site AEs with size designations of letters A through E→, 
based upon a graphic in the paper VRC/eVRC. Size A is not assigned a toxicity grade; however, injection-site AEs that 
measure size A should be reported as adverse experiences. If the participant has an ER visit or is hospitalized for any 
injection-site AE, that AE is to be assigned a toxicity grade of 4, regardless of the size measured.
 
 
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Specific Systemic AE Toxicity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Headache
No interference 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or some 
interference with 
activity
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity
ER visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
ER = emergency room
Other Systemic AE Toxicity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)b
Illness or clinical AE 
(as defined 
according to 
applicable 
regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
required medical 
intervention
ER visit or 
hospitalization
ER = emergency room; eVRC = electronic Vaccine Report Card; SAE = serious adverse event; VRC = vaccination report 
card.
a Based upon information provided by the patient on the paper VRC/eVRC and verbally during the eVRC review during the 
primary safety follow-up period. For SAEs reported beyond the primary safety follow-up period, grading will be based upon 
the initial report and/or follow-up of the event.
b AEs resulting in death will be assessed as Grade 4.
Vital Sign (Temperature) Toxicity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever 
(°C)b
(°F)b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
a Participant should be at rest for all vital sign requirements.
b Oral temperature; no recent hot or cold beverages or smoking.
 
 
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
 
 
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-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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.
 
 
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•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the 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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance
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
10.5.2.1
Contraception Requirements in Phase 1
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
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.
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
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
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).
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.
 
 
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•
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.
1.
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.
10.5.2.2
Contraception Requirements in Phase 2
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
•
IUSd
•
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
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc
- Oral
- Injectable
 
 
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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 (ie, when used consistently and 
correctly).
c   If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
d   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).
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.
2.
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 participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in 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 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.  Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.  Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13. References
1.  National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.  International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3.  Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4.  Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACIP
Advisory Committee on Immunization Practices
AE
adverse event 
ALT
Alanine Aminotransferase
APaT
All-Participants-as-Treated
AST
Aspartate Aminotransferase
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
eVRC
electronic Vaccination Report Card
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
 
 
05H6VD
07XD6Y

PRODUCT:  V116  
112
PROTOCOL/AMENDMENT NO.:  001-01  
V116-001-01 FINAL PROTOCOL
11-MAY-2020
Abbreviation
Expanded Term
PnECL
pneumococcal electrochemiluminescence
PnP
pneumococcal polysaccharide
PP
Per-protocol
pPCV
polyvalent pneumococcal conjugate vaccine
REML
restricted or residual maximum likelihood
RNA
ribonucleic acid
SAE
serious adverse event
SLAB
supplemental laboratory test
SoA
Schedule of Activities
siDMC
standing internal Data Monitoring Committee
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
 
 
05H6VD
07XD6Y

PRODUCT:  V116  
113
PROTOCOL/AMENDMENT NO.:  001-01  
V116-001-01 FINAL PROTOCOL
11-MAY-2020
11
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PRODUCT:  V116  
114
PROTOCOL/AMENDMENT NO.:  001-01  
V116-001-01 FINAL PROTOCOL
11-MAY-2020
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05H6VD
07XD6Y

PRODUCT:  V116  
115
PROTOCOL/AMENDMENT NO.:  001-01  
V116-001-01 FINAL PROTOCOL
11-MAY-2020
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05H6VD
07XD6Y

PRODUCT:  V116  
116
PROTOCOL/AMENDMENT NO.:  001-01  
V116-001-01 FINAL PROTOCOL
11-MAY-2020
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05H6VD
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PRODUCT:  V116  
117
PROTOCOL/AMENDMENT NO.:  001-01  
V116-001-01 FINAL PROTOCOL
11-MAY-2020
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