A Phase 3 Randomized, Double-blind, Placebo-Controlled Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 When Administered Concomitantly With Influenza Vaccine in Adults 50 Years of Age or Older
Phase: PHASE3
Conditions: Pneumonia, Pneumococcal
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05526716 
Document Date: 
09-Jun-2023
A Phase 3 Randomized, Double-blind, Placebo-Controlled Clinical 
Study to Evaluate the Safety, Tolerability, and Immunogenicity of 
V116 When Administered Concomitantly with Influenza Vaccine 
in Adults 50 Years of Age or Older

PRODUCT: V116
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Double-blind, Placebo-Controlled Clinical Study to 
Evaluate the Safety, Tolerability, and Immunogenicity of V116 When Administered 
Concomitantly with Influenza Vaccine in Adults 50 Years of Age or Older
Protocol Number: 005-01
Compound Number: V116
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT05526716
EU CT
Not Applicable
EudraCT
Not Applicable
JRCT
Not Applicable
WHO
Not Applicable
UTN
Not Applicable
IND
19316
Not Applicable
Not Applicable
Approval Date: 09 June 2023
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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
09-JUN-2023
The primary reason for this amendment is to 
update the noninferiority margin for HAI 
analysis.
Original Protocol
18-MAY-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendment:
The primary reason for this amendment is to update the noninferiority margin for HAI 
analysis.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 9.6.1,
Statistical 
Methods for 
Immunogenicity 
Analyses
For hypothesis 2 (H2), the statistical 
noninferiority criterion for HAI was revised 
from 0.50 to 0.67. The power calculations were 
updated accordingly.
This change was made to address an agency 
request. The statistical criteria for noninferiority 
of HAI immune responses was updated for 
consistency with the current standard of 
evaluation for influenza vaccines.
Section Number 
and Name
Description of Change
Brief Rationale
Other Changes in Amendment
Throughout 
document
The structure of the protocol has been updated.
To comply with current industry regulations
and guidelines. This restructuring does not 
affect the clinical or regulatory integrity of the 
protocol. All other relevant changes and their 
primary reasons are included for completeness.
Section 1.1, 
Synopsis
For hypothesis 2 (H2), the statistical 
noninferiority criterion for HAI was revised 
from 0.50 to 0.67.
This change was made to address an agency 
request. The statistical criteria for noninferiority 
of HAI immune responses was updated for 
consistency with the current standard of 
evaluation for influenza vaccines.
Section 2.2.1,
Pharmaceutical and 
Therapeutic 
Background
Clarified that serotype 20A is called serotype 
20 throughout the protocol.
To clarify serotype identity.
Section 3, 
Hypotheses, 
Objectives, and 
Endpoints
For hypothesis 2 (H2), the statistical 
noninferiority criterion for HAI was revised 
from 0.50 to 0.67.
Refer to Section 1.1 rationale.
Section 6.1, Study 
Intervention(s) 
Administration 
Terminology in the Dose Formulation column 
of Table 1 (Study Interventions) was revised. 
“Sterile Solution (Prefilled Syringe)” was 
revised to “Injection, Solution” and “Sterile 
Suspension (Prefilled Syringe)” was revised to 
“Injection, Suspension”.
To align with ISO standards.
Section 9.1, 
Statistical Analysis 
Plan Summary
For hypothesis 2 (H2), the statistical 
noninferiority criterion for HAI was revised 
from 0.50 to 0.67.
Refer to Section 1.1 rationale.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 9.9.1, 
Sample Size and 
Power for 
Immunogenicity 
Analyses
Updated the power calculations.
Refer to Section 1.1 rationale.
Section 10.1.6,
Compliance with 
Study Registration 
and Results Posting 
Requirements
Updated references to EU regulations.
To comply with EU CTR requirements.
Section 10.6, 
Appendix 6: 
Collection and 
Management of 
Specimens for 
Future Biomedical 
Research
Updated reference from Section 8.8 to Section 
8.9 under scope of future biomedical research.
To correct section reference.
Throughout 
document
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the protocol.
To ensure clarity and accurate interpretation of 
the intent of the protocol, including alignment 
of terms with MedDRA preferred terminology.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................20
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................23
2.2
Background ..........................................................................................................24
2.2.1
Pharmaceutical and Therapeutic Background .............................................24
2.2.2
Information on Other Study-related Therapy ..............................................25
2.2.2.1
Quadrivalent Influenza Vaccine ........................................................25
2.2.2.2
Pneumococcal Vaccination Guidelines..............................................25
2.3
Benefit/Risk Assessment......................................................................................26
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................28
4
STUDY DESIGN............................................................................................................31
4.1
Overall Design......................................................................................................31
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................32
4.2.1.1
Immunogenicity Endpoints................................................................32
4.2.1.1.1
Pneumococcal Immunogenicity Endpoints..............................32
4.2.1.1.2
Influenza Immunogenicity Endpoints......................................33
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator/Placebo .............................................34
4.3
Justification for Dose...........................................................................................34
4.4
Beginning and End-of-Study Definition ............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................34
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................36
5.3
Lifestyle Considerations......................................................................................38
5.4
Screen Failures.....................................................................................................38
5.5
Participant Replacement Strategy......................................................................38
6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................39
6.1.1
Medical Devices...........................................................................................42
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6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Rescue Medications and Supportive Care ...................................................45
6.6
Dose Modification ................................................................................................45
6.7
Intervention After the End of the Study............................................................45
6.8
Clinical Supplies Disclosure................................................................................45
6.9
Standard Policies..................................................................................................45
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........................................................48
8.1
Administrative and General Procedures ...........................................................49
8.1.1
Informed Consent.........................................................................................49
8.1.1.1
General Informed Consent.................................................................49
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................50
8.1.1.3
Consent and Collection of Specimens 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
8.1.8
Study Intervention Administration ..............................................................52
8.1.8.1
Timing of Dose Administration.........................................................52
8.1.9
Electronic Vaccination Report Card ............................................................52
8.1.10
Telephone Contact Questionnaire................................................................53
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8.1.11
Discontinuation and Withdrawal .................................................................53
8.1.11.1
Withdrawal From Future Biomedical Research ................................53
8.1.12
Participant Blinding/Unblinding..................................................................54
8.1.13
Calibration of Equipment.............................................................................54
8.2
Immunogenicity Assessments .............................................................................54
8.2.1
Multiplex Opsonophagocytic Assay (MOPA).............................................55
8.2.2
Pneumococcal Electrochemiluminescence (Pn ECL)..................................55
8.2.3
Hemagglutination Inhibition (HAI) Assay ..................................................56
8.3
Safety Assessments...............................................................................................56
8.3.1
Physical Examinations.................................................................................56
8.3.2
Pregnancy Testing........................................................................................56
8.3.3
Body Temperature Measurements ...............................................................57
8.3.4
Postvaccination Observation Period ............................................................57
8.3.5
Clinical Safety Laboratory Assessments .....................................................57
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................58
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 ..........................................61
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 on the VRC ........................................................................61
8.4.8.1
Solicited Adverse Event.....................................................................62
8.4.8.2
Unsolicited Adverse Events...............................................................62
8.5
Treatment of Overdose........................................................................................62
8.6
Pharmacokinetics.................................................................................................62
8.7
Pharmacodynamics..............................................................................................62
8.8
Biomarkers ...........................................................................................................62
8.9
Future Biomedical Research Sample Collection...............................................62
8.10
Optional Assay Development Blood Sample Collection...................................63
8.11
Medical Resource Utilization and Health Economics.......................................63
8.12
Visit Requirements...............................................................................................63
8.12.1
Screening......................................................................................................63
8.12.2
Treatment Period/Vaccination Visit ............................................................63
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8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................63
9
KEY STATISTICAL CONSIDERATIONS ...............................................................64
9.1
Statistical Analysis Plan Summary.....................................................................64
9.2
Responsibility for Analyses/In-house Blinding .................................................65
9.3
Hypotheses/Estimation ........................................................................................66
9.4
Analysis Endpoints...............................................................................................66
9.4.1
Immunogenicity Endpoints..........................................................................66
9.4.2
Safety Endpoints..........................................................................................67
9.5
Analysis Populations............................................................................................67
9.5.1
Immunogenicity Analysis Populations ........................................................67
9.5.2
Safety Analysis Populations ........................................................................68
9.6
Statistical Methods...............................................................................................68
9.6.1
Statistical Methods for Immunogenicity Analyses......................................68
9.6.2
Statistical Methods for Safety Analyses ......................................................71
9.6.2.1
Overall Safety Assessment ................................................................71
9.6.3
Demographic and Baseline Characteristics .................................................73
9.7
Interim Analyses ..................................................................................................73
9.8
Multiplicity ...........................................................................................................73
9.9
Sample Size and Power Calculations .................................................................74
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................74
9.9.2
Sample Size and Power for Safety Analyses ...............................................74
9.10
Subgroup Analyses...............................................................................................75
9.11
Compliance (Medication Adherence).................................................................76
9.12
Extent of Exposure...............................................................................................76
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................77
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........77
10.1.1
Code of Conduct for Clinical Trials.............................................................77
10.1.2
Financial Disclosure.....................................................................................80
10.1.3
Data Protection.............................................................................................81
10.1.3.1
Confidentiality of Data ......................................................................81
10.1.3.2
Confidentiality of Participant Records...............................................81
10.1.3.3
Confidentiality of IRB/IEC Information............................................81
10.1.4
Committees Structure...................................................................................82
10.1.4.1
Executive Oversight Committee........................................................82
10.1.4.2
External Data Monitoring Committee ...............................................82
10.1.4.3
Scientific Advisory Committee (SAC)..............................................82
10.1.5
Publication Policy........................................................................................82
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10.1.6
Compliance with Study Registration and Results Posting Requirements ...83
10.1.7
Compliance with Law, Audit, and Debarment ............................................83
10.1.8
Data Quality Assurance ...............................................................................84
10.1.9
Source Documents .......................................................................................84
10.1.10
Study and Site Closure.................................................................................85
10.2
Appendix 2: Clinical Laboratory Tests..............................................................86
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................87
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................87
10.3.2
Definition of AE ..........................................................................................87
10.3.3
Definition of SAE ........................................................................................88
10.3.4
Additional Events Reported.........................................................................89
10.3.5
Recording AE and SAE ...............................................................................89
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................94
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................95
10.5
Appendix 5: Contraceptive Guidance................................................................96
10.5.1
Definitions....................................................................................................96
10.5.2
Contraceptive Requirements........................................................................97
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................98
10.7
Appendix 7: Country-specific Requirements..................................................102
10.8
Appendix 8: Abbreviations ...............................................................................103
11
REFERENCES.............................................................................................................106
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LIST OF TABLES
Table 1
Study Interventions......................................................................................40
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample 
Type .............................................................................................................49
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................59
Table 4
Solicited Adverse Events .............................................................................62
Table 5
Analysis Strategy for Immunogenicity Variables........................................70
Table 6
Analysis Strategy for Safety Parameters......................................................72
Table 7
Differences in Incidence of AE Rates Between the 2 Vaccination 
Groups That Can Be Detected With an Approximate 80% Probability 
(Assuming 2-sided 5% Alpha-level With 500 Participants in Each 
Group)..........................................................................................................75
Table 8
Protocol-required Safety Laboratory Assessments......................................86
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LIST OF FIGURES
Figure 1
V116-005 Study Design...............................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Double-blind, Placebo-Controlled Clinical Study to 
Evaluate the Safety, Tolerability, and Immunogenicity of V116 When Administered 
Concomitantly with Influenza Vaccine in Adults 50 Years of Age or Older
Short Title: Safety and immunogenicity of V116 administered with influenza vaccine
Acronym: STRIDE-5
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Objectives and endpoints will be evaluated in adults ≥50 years of age who are administered 
V116 concomitantly with QIV or V116 administered sequentially with QIV.
Primary Objective
Primary Endpoint
•
To evaluate the safety and tolerability of 
V116 when administered concomitantly 
with quadrivalent influenza vaccine 
(QIV) compared with V116 
administered sequentially with QIV as 
assessed by the proportion of 
participants with adverse events (AEs).
•
Solicited injection-site AEs from Day 1 
through Day 5 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 5 postvaccination
•
Vaccine-related Serious Adverse Events 
(SAEs) from Day 1 through the duration 
of participation in the study
•
To compare the serotype-specific 
opsonophagocytic activity (OPA) 
Geometric Mean Titers (GMTs) at 30 
days postvaccination with V116 
administered concomitantly with QIV 
compared with V116 administered 
sequentially with QIV.
•
Hypothesis (H1): V116 administered 
concomitantly with QIV is noninferior 
to V116 administered sequentially with 
QIV as assessed by serotype-specific 
OPA GMTs at 30 days postvaccination 
with V116.
•
Serotype-specific OPA responses
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•
(The statistical criterion for 
noninferiority requires the lower bound 
of the 2-sided 95% confidence interval 
[CI] of the OPA GMT ratio 
[concomitant group/sequential group] to 
be >0.50).
•
To compare the strain-specific 
hemagglutination inhibition (HAI) 
GMTs at 30 days postvaccination with 
QIV administered concomitantly with 
V116 compared with QIV administered 
sequentially with V116.
•
Hypothesis (H2): QIV administered 
concomitantly with V116 is noninferior 
to QIV administered sequentially with 
V116 as assessed by strain-specific HAI 
GMTs at 30 days postvaccination with 
QIV.
(The statistical criterion for 
noninferiority requires the lower bound 
of the 2-sided 95% CI of the HAI GMT 
ratio [concomitant group/sequential 
group] to be greater than 0.67)
•
Strain-specific HAI responses
Secondary Objectives
Secondary Endpoints
•
To evaluate serotype-specific 
Immunoglobulin G (IgG) Geometric 
Mean Concentrations (GMCs) at 30 
days postvaccination with V116 
administered concomitantly with QIV 
compared with V116 administered 
sequentially with QIV.
•
Serotype-specific IgG responses
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•
Within each vaccination group, to 
evaluate the serotype-specific 
Geometric Mean Fold Rises (GMFRs) 
and the proportion of participants who 
achieve a serotype-specific ≥4-fold rise
from baseline to 30 days 
postvaccination with V116 for both 
OPA and IgG responses for participants 
administered V116 concomitantly with 
QIV and participants administered V116 
sequentially with QIV.
•
Serotype-specific OPA and IgG 
responses
•
Within each vaccination group, to 
evaluate the strain-specific (1) GMFRs 
from baseline to 30 days 
postvaccination with QIV, (2) 
proportions of participants with an HAI 
titer ≥1:40 at 30 days postvaccination 
with QIV, and (3) proportions of 
participants that seroconvert at 30 days 
postvaccination with QIV for 
participants administered QIV 
concomitantly with V116 and 
participants administered QIV 
sequentially with V116.
•
Strain-specific HAI responses
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal infection
Population
Adults ≥50 years of age
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
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 9 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
For purposes of analysis and reporting, the 
overall study ends when the Sponsor 
receives the last laboratory result or at the 
time of final contact with the last 
participant, whichever comes last
Number of Participants:
Approximately 1000 participants will be randomized, with approximately 500 participants in 
each intervention group.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Concomitant
Group
Pneumococcal 
21-valent 
conjugate 
vaccine
4 µg of each 
PnPs antigen 
(3, 6A, 7F, 8, 
9N, 10A, 
11A, 12F, 
15A, 15C, 
16F, 17F, 
19A, 20, 
22F, 23A, 
23B, 24F, 31, 
33F, and 
35B)
0.5 mL
IM
Single dose 
at Visit 1
(Day 1)
Test 
Product
Concomitant
Group
Quadrivalent
influenza
vaccine
Refer to 
product
labeling
0.5 mL
IM
Single dose
at Visit 1
(Day 1)
Test 
Product
Concomitant
Group
Placebo
(sterile saline)
N/A
0.5 mL
IM
Single dose
at Visit 3
(Day 30)
Placebo
Sequential 
Group
Quadrivalent 
influenza 
vaccine
Refer to 
product
labeling
0.5 mL
IM
Single dose
at Visit 1
(Day 1)
Test 
Product
Sequential 
Group
Placebo (sterile 
saline)
N/A
0.5 mL
IM
Single dose
at Visit 1
(Day 1)
Placebo
Sequential 
Group
Pneumococcal
21-valent 
conjugate 
vaccine
4 µg of each 
PnPs antigen 
(3, 6A, 7F, 8, 
9N, 10A, 
11A, 12F, 
15A, 15C, 
16F, 17F, 
19A, 20, 
22F, 23A, 
23B, 24F, 31, 
33F, and 
35B)
0.5 mL
IM
Single dose
at Visit 3
(Day 30)
Test 
Product
Admin=administration; IM=intramuscular; NA=not applicable; PnPs=pneumococcal polysaccharide; QIV=quadrivalent influenza vaccine; 
V116=Pneumococcal 21-valent conjugate vaccine
Other current or former name(s) or alias(es) for study intervention(s) are as follows: V116, 
polyvalent pneumococcal conjugate vaccine (pPCV).
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Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
for approximately 7 months from the time 
the participant provides documented 
informed consent through the final contact.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: Yes
A list of abbreviations is in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
V116-005 Study Design
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1.3
Schedule of Activities
Study Period:
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
6
7
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Site Visit
Telephone 
Contact
Telephone 
Contact
Study Day:
Day 1
Day 7
Day 30
Day 36
Day 59
Day 120
Day 210
Visit Window:
Day 7 to 
Day 10
after Visit 1
Day 30 
to Day 
44 after 
Visit 1
Day 7 to 
Day 10 
After Visit 
3
Day 30 to 
Day 44 
After Visit 
3
Day 76 to 
Day 104 
After Visit 
3
Day 166 to 
Day 194 
After Visit 
3
Administrative Procedures
Screening Procedures
Informed Consent
X
Must be obtained before any study 
procedures are conducted. 
Informed Consent for Optional 
Assay Development Blood Samples
X
Must be obtained before any sample 
collection.
Informed Consent for FBR
X
Must be obtained before any sample 
collection.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Medical History
X
Postrandomization Procedures
Assignment of Randomization 
Number
X
Participant Identification Card
X
Prior/Concomitant Medication and 
Nonstudy Vaccination Review
X
X
X
X
X 
QIV Administration (Open-label) 
(Right Arm)
X
V116 or Placebo Administration 
(blinded) (Left Arm)
X
X
Provide Electronic Device or 
Configure Participant’s Own 
Electronic Device for eVRC Data 
Collection
X
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Study Period:
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
6
7
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Site Visit
Telephone 
Contact
Telephone 
Contact
Study Day:
Day 1
Day 7
Day 30
Day 36
Day 59
Day 120
Day 210
Visit Window:
Day 7 to 
Day 10
after Visit 1
Day 30 
to Day 
44 after 
Visit 1
Day 7 to 
Day 10 
After Visit 
3
Day 30 to 
Day 44 
After Visit 
3
Day 76 to 
Day 104 
After Visit 
3
Day 166 to 
Day 194 
After Visit 
3
Review eVRC Data With 
Participant
X
X
X
X
Collect Electronic Device From 
Participants Who Received an 
Electronic Device
X
Complete Telephone Contact 
Questionnaire
X
X
Safety Procedures
Complete Physical Examination
X
Performed by investigator or 
medically qualified designee at 
screening and before vaccination.
Directed Physical Examination
X
Performed by investigator or 
medically qualified designee before 
vaccination.
Pregnancy Test (if applicable)
X
X
Females of reproductive potential 
must have a negative urine or serum 
test (consistent with local 
requirements and sensitive to ≤25 IU 
hCG) result before vaccination.
Body Temperature Measurement
X
X
Measured before vaccination. 
Participants with febrile illness within 
72 hours before vaccination must be 
rescheduled.
Postvaccination Observation Period
X
X
Observed by blinded study-site 
personnel for at least 30 minutes 
postvaccination.
AE Monitoring
X
X
X
X
X
X
X
Nonserious AEs collected through 
Day 30 postvaccination. SAEs and 
deaths collected through duration of 
study participation.
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Study Period:
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
6
7
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Site Visit
Telephone 
Contact
Telephone 
Contact
Study Day:
Day 1
Day 7
Day 30
Day 36
Day 59
Day 120
Day 210
Visit Window:
Day 7 to 
Day 10
after Visit 1
Day 30 
to Day 
44 after 
Visit 1
Day 7 to 
Day 10 
After Visit 
3
Day 30 to 
Day 44 
After Visit 
3
Day 76 to 
Day 104 
After Visit 
3
Day 166 to 
Day 194 
After Visit 
3
Immunogenicity Procedures
Serum for Pneumococcal 
Immunogenicity Assays
X
X
X
Visit 1 and Visit 3 samples should be 
collected before vaccination.
Serum for Influenza 
Immunogenicity Assays
X
X
Visit 1 and Visit 3 samples should be 
collected before vaccination.
Future Biomedical Research
Blood (DNA) for Future 
Biomedical Research
X
For participants who provided FBR 
consent. Should be collected before 
vaccination at Visit 1, or at a later date 
as long as FBR consent is obtained 
prior to collection.
Assay Development Samples
Serum for Optional Assay 
Development
X
X
X
For participants who provided consent 
for optional assay development. Visit 
1 and Visit 3 samples should be 
collected before vaccination.
AE=adverse event; DNA=deoxyribonucleic acid; eVRC=electronic vaccination report card; hCG=human chorionic gonadotropin; FBR=future biomedical research; 
ID=identification; IU=international units; QIV=quadrivalent influenza vaccine; SAE=serious adverse event.
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2
INTRODUCTION
The Sponsor is developing an investigational polyvalent pneumococcal 21-valent conjugate 
vaccine (V116) for the prevention of pneumococcal disease caused by the serotypes in the 
vaccine.
2.1
Study Rationale
Streptococcus pneumoniae is a major cause of vaccine-preventable disease worldwide. It is 
associated with considerable morbidity and mortality, with the highest burden seen in 
children <5 years and adults >70 years of age [Troeger, C., et al 2018]. PCV vaccination has 
reduced the incidence of disease caused by vaccine serotypes in the age groups being 
vaccinated (primarily children <5 years of age in most countries) and has had an indirect 
effect in other age groups.
However, an unmet medical need exists as increases in IPD due to serotypes not included in 
licensed PCVs have been observed in several countries, especially in adults.
V116 is an investigational PCV designed to address this unmet medical need and includes 
S pneumoniae serotypes not included in licensed PCVs, which account for the majority of 
IPD in adults.
Pneumococcal pneumonia is a frequent complication of influenza, and simultaneous 
vaccination against both in at-risk individuals has been shown to reduce rates of 
hospitalization and mortality [Dominguez, A., et al 2013] [Zhang, Y. Y., et al 2016]. 
Concomitant administration of PCV13, PCV15, and influenza vaccine results in robust 
immune responses for both pneumococcal and influenza antigens and can be a strategy to 
increase vaccination rates [Gilchrist, S. A., et al 2012] [Frenck, R. W. Jr., et al 2012] 
[Schwarz, T. F., et al 2011] [Schwarz, T. F. 2013] [Kobayashi, M., et al 2022].
In the US, ACIP guidelines recommend that immunocompetent at-risk individuals and 
high-risk individuals 19 to 64 years of age, as well as adults ≥65 years of age receive PCV15 
followed by PPSV23, or PCV20 alone [Kobayashi, M., et al 2022]. PCV13 is approved for 
adults 18 years of age and older for the prevention of pneumococcal pneumonia and invasive 
disease caused by the 13 pneumococcal serotypes contained in the vaccine.
To allow a comprehensive assessment of the concomitant administration of V116 and 
influenza vaccine this study will enroll participants with and without prior PPSV23 and/or 
PCV13 vaccination. In accordance with recommendations regarding the interval between 
vaccination with PPSV23 and PCV13, participants who have received a prior pneumococcal 
vaccine must have received PPSV23 and/or PCV13 at least 12 months prior to study 
enrollment.
This clinical study will evaluate the safety, tolerability, and immunogenicity of V116 when 
administered concomitantly with influenza vaccine in participants ≥50 years of age. This 
population is at elevated risk for pneumococcal disease and associated morbidity and 
mortality due to age-related physiological changes in the respiratory system, age-related 
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immunosenescence, and an increased incidence of other medical conditions associated with 
increased risk for pneumococcal disease [Drijkoningen, J. J 2014] [Janssens, J. P. 2004].
2.2
Background
To date, a Phase 1/2 study (V116-001) and a Phase 1 study in Japan (V116-002) have been
conducted with V116. Results from the Phase 1 part of V116-001 were used to select the 
optimal vaccine formulation for subsequent development. Results from both studies showed 
that V116 is immunogenic and has acceptable safety and tolerability in healthy adults.
Refer to the IB for detailed background information on V116.
2.2.1
Pharmaceutical and Therapeutic Background
Pneumococcal disease (ie, disease caused by S pneumoniae) is one of the single largest 
vaccine-preventable causes of death in children and older adults (≥65 years of age) 
worldwide. PCV use in children has decreased the incidence of disease caused by vaccine 
serotypes and has led to indirect protection in unvaccinated individuals from other age 
groups. This has resulted in a decrease in hospital admissions for pneumococcal disease in 
adults ≥65 years of age, including estimated decreases of 29% and 34% in admissions due to 
IPD and noninvasive pneumococcal pneumonia, respectively [Simonsen, L., et al 2014]. In 
some countries, including the US, the decrease in pneumococcal disease in children 
vaccinated with PCV has led to the recommendation to vaccinate adults with PCVs. 
However, current surveillance does not definitively indicate that the use of PCVs in adults 
results in a similar reduction in pneumococcal disease [Matanock, A. 2018]. The residual 
burden of disease in the US is estimated as 24 cases of IPD per 100,000 in adults ≥65 years 
of age, and surveillance data estimates serotypes included in currently licensed PCVs account 
for approximately 23% to 50% of these cases [Centre for Disease Control and Prevention 
2016] [Centers for Disease Control and Prevention 2019] [Kobayashi, M. 2021].
The residual burden of disease in adults reflects the difference in serotype distribution in 
adults compared with that in infants and children. An increasing incidence of disease due to 
serotypes not included in the licensed PCVs has been observed, particularly in adults [Miller, 
Elizabeth, et al 2011] [Moore, M. R., et al 2015] [Pilishvili, T. 2015] [van der Linden, M., et 
al 2015] [Golden, A. R., et al 2016]. Increases in IPD cases due to nonvaccine serotypes (3, 
7F, and 19A after implementation of Prevnar™; 22F and 33F following widespread usage of 
Prevnar 13™) have been observed in both pediatric and adult (≥65 years of age) populations 
in the US [Hicks, L. A., et al 2007] [Pilishvili, Tamara, et al 2010] [Waight, P. A., et al 2015] 
[Moore, M. R., et al 2015] [Demczuk, W. H. B., et al 2013]. Similarly, due to the limited 
serotype coverage of the currently licensed vaccines in the EU, serotype replacement due to 
nonvaccine serotypes is being observed in older adults and may decrease the potential 
additional benefit of vaccination with currently available PCVs [European Center for Disease 
Prevention and Control 2018].
Serotypes were selected for inclusion in V116 based on available global epidemiology data 
with a primary focus on data from older adults (≥65 years of age) in the US and EU, regions 
with an established pediatric vaccination program. Based on 2018 surveillance data in US 
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adults ≥65 years of age, the serotypes selected for inclusion in V116 account for 
approximately 83% of all cases of IPD, 25% to 30% of which are accounted for by the 
serotypes unique to V116 (US CDC ABCs unpublished data 2014 to 2018) [Centre for 
Disease Control and Prevention 2018].
V116 includes serotypes not currently contained in any licensed pneumococcal vaccine. 
V116 being developed to support an indication for active immunization for the prevention of 
invasive disease and pneumonia caused by S pneumoniae serotypes 3, 6A, 6C, 7F, 8, 9N, 
10A, 11A, 12F, 15A, 15B, 15C, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, and 35B in 
adults 18 years of age and older. Note that serotype 15C represents deOAc15B as the 
molecular structures for deOAc15B and 15C are similar. Throughout this protocol, serotype 
20 refers to serotype 20A.
2.2.2
Information on Other Study-related Therapy
2.2.2.1
Quadrivalent Influenza Vaccine
Refer to approved labeling for detailed background information on the QIV used in this 
study.
In the US, annual influenza vaccination is recommended for all individuals ≥6 months of age 
[Grohskopf, L. A., et al 2017].
2.2.2.2
Pneumococcal Vaccination Guidelines
Many countries have implemented age-based and/or risk-based recommendations for 
pneumococcal vaccination. Age-based recommendations typically start at 65 years of age due 
to the increased risk of pneumococcal disease associated with age.
Prior to 2014, the US ACIP recommended that all adults ≥65 years of age receive a single 
dose of PPSV23. In 2014, ACIP recommended the sequential vaccination regimen of PCV13 
followed by PPSV23 for all adults ≥65 years of age, with the intent to reevaluate this 
recommendation. The guideline was updated in 2019 to remove the recommendation for 
routine use of PCV13 among adults ≥65 years and continued to recommend a routine single 
dose of PPSV23 for adults aged ≥65 years[Matanock, A., et al 2019]. The ACIP updated the 
guidelines in 2021 to recommend that adults ≥65 years of age should receive either PCV15 
followed by PPSV23 or PCV20 alone [Kobayashi, M., et al 2022].
Risk-based recommendations generally include individuals with an increased risk of 
pneumococcal disease who are categorized as immunocompetent at-risk or as high-risk.
Conditions associated with immunocompetent at-risk include, but are not limited to, chronic 
heart disease, chronic lung disease (including chronic obstructive pulmonary disease, 
emphysema, and asthma), diabetes mellitus, alcoholism, chronic liver disease (including 
cirrhosis), and cigarette smoking. Conditions associated with high-risk include, but are not 
limited to, congenital or acquired asplenia, sickle cell disease/other hemoglobinopathies, 
chronic renal failure, congenital or acquired immunodeficiencies, generalized malignancy, 
hematologic malignancy, HIV infection, nephrotic syndrome, solid organ transplant, and 
hematopoietic stem cell transplant [Kobayashi, M., et al 2022]. In the US, recommendations 
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for immunocompetent at-risk individuals 19 to 64 years of age previously included a single 
dose of PPSV23, with the exception of individuals with cochlear implants or cerebrospinal 
fluid leaks, who should receive PCV13 followed by PPSV23. High-risk individuals were 
recommended to receive 1 dose of PCV13 followed by 1 dose of PPSV23 ≥8 weeks later, 
and an additional dose of PPSV23 ≥5 years later [Matanock, A., et al 2019]. Similar to the 
age-based recommendations, the ACIP guidelines were updated in 2021 and now recommend 
that immunocompetent at-risk individuals and high-risk individuals 19 to 64 years of age 
receive PCV15 followed by PPSV23 or PCV20 alone [Kobayashi, M., et al 2022].
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Despite the public health impact of currently available pneumococcal vaccines, 
pneumococcal disease in adults remains a significant unmet medical need. S pneumoniae is a 
major cause of vaccine-preventable disease worldwide, resulting in considerable morbidity 
and mortality [Troeger, C., et al 2018].
Vaccination with PCVs has reduced the incidence of disease caused by vaccine serotypes in 
the population targeted by the vaccination (primarily children <5 years of age in most 
countries) and has had an indirect effect in other age groups. However, in several countries, 
infant vaccination with PCVs has also led to increases in IPD due to serotypes not included 
in the licensed PCVs, particularly in adults. This has resulted in an unmet medical need in 
this population.
V116 is designed to provide significantly broader pneumococcal disease coverage in adults 
as compared with currently licensed pneumococcal vaccines and is anticipated to have a 
generally comparable safety profile. No clinically important safety findings have been 
identified to date based on data from early phase clinical studies with V116.
The benefit-risk profile for V116 supports continued evaluation.
While the impact of concomitant administration of V116 and QIV on the immune response to 
both vaccines is unknown and will be evaluated in this study, participants in both vaccination 
groups are expected to be sufficiently covered by the QIV for the 2022/2023 influenza season 
through participation in this study based on the experience of concomitant administration of 
PCV13 or PCV15 and influenza vaccines [Severance, R., et al 2021] [Frenck, R. W. Jr., et al 
2012] [Schwarz, T. F., et al 2011] [Schwarz, T. F. 2013].
Previous studies have shown the additive benefit of concomitant administration of 
pneumococcal vaccines and influenza vaccine in elderly populations. The concomitant 
administration of PCVs with influenza vaccine is supported by the results of clinical studies 
with other PCVs [Yin, M., et al 2018]. While reduced immune responses to pneumococcal 
vaccines have been observed when administered concomitantly with influenza vaccine, the 
clinical significance of this trend is unknown [Frenck, R. W. Jr., et al 2012] [Schwarz, T. F., 
et al 2011] [Schwarz, T. F. 2013] [Song, J. Y., et al 2017].
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Objectives and endpoints will be evaluated in adults ≥50 years of age who are administered 
V116 concomitantly with QIV or V116 administered sequentially with QIV.
Primary Objective
Primary Endpoint
•
To evaluate the safety and tolerability of 
V116 when administered concomitantly 
with quadrivalent influenza vaccine 
(QIV) compared with V116 
administered sequentially with QIV as 
assessed by the proportion of 
participants with adverse events (AEs).
•
Solicited injection-site AEs from Day 1 
through Day 5 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 5 postvaccination
•
Vaccine-related Serious Adverse Events 
(SAEs) from Day 1 through the duration 
of participation in the study
•
To compare the serotype-specific 
opsonophagocytic activity (OPA) 
Geometric Mean Titers (GMTs) at 30 
days postvaccination with V116 
administered concomitantly with QIV 
compared with V116 administered 
sequentially with QIV.
Hypothesis (H1): V116 administered 
concomitantly with QIV is noninferior 
to V116 administered sequentially with 
QIV as assessed by serotype-specific 
OPA GMTs at 30 days postvaccination 
with V116.
•
(The statistical criterion for 
noninferiority requires the lower bound 
of the 2-sided 95% confidence interval 
[CI] of the OPA GMT ratio 
[concomitant group/sequential group] to 
be >0.50).
•
Serotype-specific OPA responses
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•
To compare the strain-specific 
hemagglutination inhibition (HAI) 
GMTs at 30 days postvaccination with 
QIV administered concomitantly with 
V116 compared with QIV administered 
sequentially with V116.
•
Hypothesis (H2): QIV administered 
concomitantly with V116 is noninferior 
to QIV administered sequentially with 
V116 as assessed by strain-specific HAI 
GMTs at 30 days postvaccination with 
QIV.
(The statistical criterion for 
noninferiority requires the lower bound 
of the 2-sided 95% CI of the HAI GMT 
ratio [concomitant group/sequential 
group] to be greater than 0.67)
•
Strain-specific HAI responses
Secondary Objectives
Secondary Endpoints
•
To evaluate serotype-specific 
Immunoglobulin G (IgG) Geometric 
Mean Concentrations (GMCs) at 30 
days postvaccination with V116 
administered concomitantly with QIV 
compared with V116 administered 
sequentially with QIV.
•
Serotype-specific IgG responses
•
Within each vaccination group, to 
evaluate the serotype-specific 
Geometric Mean Fold Rises (GMFRs) 
and the proportion of participants who 
achieve a serotype-specific ≥4-fold rise 
from baseline to 30 days 
postvaccination with V116 for both 
OPA and IgG responses for participants 
administered V116 concomitantly with 
QIV and participants administered V116 
sequentially with QIV.
•
Serotype-specific OPA and IgG 
responses
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•
Within each vaccination group, to 
evaluate the strain-specific (1) GMFRs 
from baseline to 30 days 
postvaccination with QIV, (2) 
proportions of participants with an HAI 
titer ≥1:40 at 30 days postvaccination 
with QIV, and (3) proportions of 
participants that seroconvert at 30 days 
postvaccination with QIV for 
participants administered QIV 
concomitantly with V116 and 
participants administered QIV 
sequentially with V116.
•
Strain-specific HAI responses
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
•
To evaluate the cross-reactive immune 
responses to serotypes within a 
serogroup at 30 days postvaccination 
with V116 administered concomitantly 
with QIV compared with V116 
administered sequentially with QIV.
•
Serotype-specific OPA and IgG 
responses
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multisite, double-blind study of 
V116 in adults ≥50 years of age who receive V116 administered concomitantly with QIV or 
V116 administered sequentially with QIV.
Approximately 1000 participants will be randomly assigned in a 1:1 ratio to receive either 
V116 administered concomitantly with QIV or V116 administered sequentially with QIV. 
Randomization will be stratified by participant age at enrollment (50 to 64 years, 65 to 
74 years, 75 to 84 years, and ≥85 years) and by pneumococcal vaccination status 
(PCV13- and PPSV23-naïve, prior receipt of PCV13 only, prior receipt of PPSV23 only, and
prior receipt of both PCV13 and PPSV23). At least 50% of participants will be ≥65 years of 
age and at least 50% of participants will be naïve to PCV13 and PPSV23.
An eVRC will be used by all participants to record solicited injection-site AEs, solicited 
systemic AEs, and daily body temperature from Day 1 through Day 5 postvaccination. 
Unsolicited AEs will be collected through Day 30 postvaccination. All participants will be 
provided an electronic device or have their own electronic device configured, if compatible, 
to complete the eVRC.
Information for SAEs and deaths, regardless of whether the events are considered to be 
vaccine-related by the investigator, will be collected through completion of participation in 
the study.
An external DMC will conduct a periodic review of safety and tolerability data for the V116 
Phase 3 program. A description of the structure and function of the DMC, along with the 
timing and content of the safety reviews, will be outlined in the DMC charter. Information 
regarding the composition of the DMC is provided in Appendix 1.
Blood samples for immunogenicity assays will be drawn on Day 1 and at 30 days after each 
vaccination.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will evaluate the safety, tolerability, and immunogenicity of V116 in adults 
≥50 years of age. The population enrolled in this study is at increased risk for pneumococcal 
disease and its associated morbidity and mortality as the incidence of IPD is directly related 
to age, with over half of all cases occurring in adults ≥50 years of age [Drijkoningen, J. J 
2014].
Adults with stable chronic medical conditions will be included in this study. These 
individuals are generally categorized as being immunocompetent at-risk, reflecting the 
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understanding that while they are at an increased risk of pneumococcal disease, their immune 
responses are not impacted by the chronic medical condition [Curcio, D., et al 2015] 
[Weycker, D., et al 2010] [van Hoek, A. J., et al 2012].
The concomitant and sequential administration of V116 and QIV in this study allows for 
meaningful comparisons of safety, tolerability, and immunogenicity between the 
2 vaccination regimens.
To demonstrate that concomitant administration of V116 and QIV does not adversely affect 
the antibody response to or safety profile of either vaccine, blinding is being maintained 
through the use of a placebo. A saline placebo will be used to maintain blinded vaccine 
administration on Day 1 and Day 30. Both groups of randomized participants will receive 
V116 in the study.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
4.2.1.1.1
Pneumococcal Immunogenicity Endpoints
The immunogenicity endpoints and the associated statistical criteria are consistent with 
previous studies evaluating PCVs.
Sera from participants will be used to assess vaccine-induced, anti-PnPs serotype-specific 
OPA and IgG responses using the validated MOPA and Pn ECL assay, respectively. 
Immunogenicity endpoints will be evaluated for all serotypes included in V116 and for 
cross-reactive serotypes within a serogroup.
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; therefore, it is 
considered an important immunologic surrogate for protection against IPD in adults. It is 
noted that IgG antibody concentration and OPA titer threshold values that correlate with 
protection in adults have not been defined; however, the OPA responses are considered an 
accepted endpoint for the evaluation of novel pneumococcal vaccines in adults.
OPA GMTs, IgG GMCs, GMFRs, and the differences in proportions of participants with 
4-fold rises in OPA and IgG responses are acceptable assessments used to evaluate novel 
PCVs.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1.
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4.2.1.1.2
Influenza Immunogenicity Endpoints
Antibodies that block the binding of the hemagglutinin antigen of the influenza virus to host 
receptors contribute to natural or vaccine-induced immunity against a homologous or related 
influenza virus. These antibodies are generally considered to be correlates of protective 
immunity against influenza [Zakay-Rones, Z. 2010] [Reber, A. 2013]. The HAI assay detects 
antibodies that bind around the globular head of the hemagglutinin molecule, inhibiting the 
interaction of the virus with host cells. It has been shown that serum HAI titers are inversely 
correlated with the frequency of clinical influenza in vaccinated individuals. However, no 
defined serum antibody threshold exists and the relationship between HAI responses and 
protection is influenced by preexisting immunity and age [Reber, A. 2013].
HAI responses are part of the criteria that regulatory agencies use for the evaluation and the 
licensure of influenza vaccines [Food and Drug Administration (CDER) 2007] [European 
Medicines Agency 2016], with postvaccination GMTs, seroconversion, and seroprotection 
rates as recommended endpoints.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1.
4.2.1.2
Safety Endpoints
Safety information will be collected from all participants on an eVRC. The eVRC used to 
record AEs during the postvaccination periods (Section 8.1.9) is structured as recommended 
in the final US FDA Patient-reported Outcome Guidance [U.S. Food and Drug 
Administration 2009].
The safety endpoints (ie, AEs and temperature) evaluated in this study are consistent with 
previous studies of V116 and published data from marketed PCVs. Detailed information for 
the safety endpoints evaluated in this study can be found in Section 9.4.2.
Definitions and reporting requirements for AEs are provided in Appendix 3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
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4.2.2
Rationale for the Use of Comparator/Placebo
Placebo is used in this study to maintain blinding to the concomitant and sequential group 
assignment. The placebo is sterile saline for injection.
4.3
Justification for Dose
The V116 dose of 4 µg/each PnPs was selected based on review of safety and 
immunogenicity data from the Phase 1 and Phase 2 studies. In Phase 1, 2 doses of V116 were 
evaluated: a single dose containing 2 µg/each PnPs and a single dose of 4 µg/each PnPs. 
Based on the data from Phase 1, the V116 dose of 4 µg/each PnPs was selected for further 
evaluation in Phase 2. Results from Phase 2 showed that the V116 dose of 4 µg/each PnPs is 
well tolerated and generates serotype-specific immune responses. These data support the 
selection of the V116 dose of 4 µg/each PnPs for further development in Phase 3.
Refer to the IB for detailed background information on V116.
The dose of QIV selected for use in this study is consistent with the approved dosing and 
product labeling.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
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 meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1. The participant may have underlying chronic conditions if they are assessed to be in 
stable condition as per the investigator’s judgment.
Demographics
2. Is male or female, ≥50 years of age, at the time of informed consent.
Female Participants
3. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses an acceptable contraceptive method, 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 weeks 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. Contraceptive use by 
women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies.
-
Has 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 in Section 8.3.2.
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-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
4. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide documented informed consent for 
FBR and/or assay development sample collection. However, the participant may 
participate in the study without participating in FBR or assay development sample 
collection.
Additional Categories
5. The participant has the ability to complete eVRC data collection without assistance based 
on the judgment of the investigator.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
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 V116 or any influenza vaccine, 
including diphtheria toxoid.
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 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 <72 hours before receipt of study vaccine.
6. Has a known malignancy that is progressing or has required active treatment <3 years 
before enrollment. 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.
Prior/Concomitant Therapy
7. Is expected to receive any pneumococcal vaccine during the study outside of the protocol.
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8. Received any pneumococcal vaccine <12 months prior to enrollment (including PCV13 
followed by PPSV23 and PPSV23 followed by PCV13).
9. Had prior administration of PCV15 or PCV20.
10. Received any influenza vaccine <6 months prior to enrollment or is expected to receive 
any influenza vaccine during the study outside of the protocol.
11. *Received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for 
≥14 consecutive days and has not completed intervention ≥14 days before receipt of 
study vaccine. Note: physiologic replacement doses (prednisone equivalent of 
approximately 5 mg/day), topical, ophthalmic, intra-articular or soft-tissue (eg, bursa, 
tendon steroid injections), and inhaled/nebulized steroids are permitted.
12. Is currently receiving immunosuppressive therapy, including chemotherapeutic agents or 
other immunotherapies/immunomodulators used to treat cancer or other conditions, and 
interventions associated with organ or bone marrow transplantation, or autoimmune 
disease.
13. *Received any nonlive vaccine ≤14 days before receipt of study vaccine or is scheduled 
to receive any nonlive vaccine ≤30 days after receipt of study vaccine.
Exception: SARS-CoV-2 mRNA or SARS-CoV-2 protein subunit vaccines may be 
administered but must be given ≥7 days before or ≥15 days after receipt of study vaccine.
14. *Received any live virus vaccine ≤30 days before receipt of study vaccine or is scheduled 
to receive any live virus vaccine ≤30 days after receipt of study vaccine.
15. Received a blood transfusion or blood products, including immunoglobulin ≤6 months 
before receipt of study vaccine or is scheduled to receive a blood transfusion or blood 
product before the Day 30 postvaccination blood draw is complete. Autologous blood 
transfusions are not considered an exclusion criterion.
Prior/Concurrent Clinical Study Experience
16. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
Diagnostic Assessments
Not applicable
Other Exclusions
17. 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.
18. 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.
19. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
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For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the 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.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (V116, QIV, placebo) 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. Country-specific 
differences are noted in Appendix 7.
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Table 1
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin.
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Concomitant
Group
Experimental Pneumococcal 
21-valent 
conjugate 
vaccine
Biological/Vaccine Injection, 
Solution
4 µg of 
each PnPs 
antigen (3, 
6A, 7F, 8, 
9N, 10A, 
11A, 12F, 
15A, 15C, 
16F, 17F, 
19A, 20, 
22F, 23A, 
23B, 24F, 
31, 33F, 
and 35B)
0.5 mL
IM
Single dose at 
Visit 1
(Day 1)
Test 
Product
IMP
Central
Concomitant
Group
Experimental Quadrivalent
influenza
vaccine
Biological/Vaccine Injection, 
Suspension
Refer to 
product
labeling
0.5 mL
IM
Single dose
at Visit 1
(Day 1)
Test 
Product
IMP
Central 
or
Local
Concomitant
Group
Experimental Placebo
(sterile saline)
Biological/Vaccine Injection, 
Solution
N/A
0.5 mL
IM
Single dose
at Visit 3
(Day 30)
Placebo IMP
Central
Sequential 
Group
Experimental Quadrivalent 
influenza 
vaccine
Biological/Vaccine Injection, 
Suspension
Refer to 
product
labeling
0.5 mL
IM
Single dose
at Visit 1
(Day 1)
Test 
Product
IMP
Central 
or
Local
Sequential 
Group
Experimental Placebo 
(sterile saline)
Biological/Vaccine Injection, 
Solution
N/A
0.5 mL
IM
Single dose
at Visit 1
(Day 1)
Placebo IMP
Central
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Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin.
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Sequential 
Group
Experimental Pneumococcal
21-valent 
conjugate 
vaccine
Biological/Vaccine Injection, 
Solution
4 µg of 
each PnPs 
antigen (3, 
6A, 7F, 8, 
9N, 10A, 
11A, 12F, 
15A, 15C, 
16F, 17F, 
19A, 20, 
22F, 23A, 
23B, 24F, 
31, 33F, 
and 35B)
0.5 mL
IM
Single dose
at Visit 3
(Day 30)
Test 
Product
IMP
Central
Admin=administration; IM=intramuscular; IMP=investigational medicinal product; N/A=not applicable; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
PnPs=pneumococcal polysaccharide
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number. However, central sourcing is 
preferable.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
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 vaccines will be prepared by an unblinded member of the 
study-site staff.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention 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 V116 
administered concomitantly with QIV or V116 administered sequentially with QIV.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
•
Participant age at time of randomization:
-
50 to 64 years of age
-
65 to 74 years of age
-
75 to 84 years of age
-
≥85 years of age
At least 50% of participants will be ≥65 years of age.
•
Prior pneumococcal vaccination status:
-
PCV13- and PPSV23-naïve
-
Prior receipt of PCV13 only
-
Prior receipt of PPSV23 only
-
Prior receipt of PCV13 and PPSV23
At least 50% of participants will be naïve to PCV13 and PPSV23.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. V116 and placebo 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) 
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who are involved in the clinical evaluation of the participants are unaware of the intervention 
assignments.
Because V116 and placebo have a different appearance, an unblinded pharmacist (or 
qualified study-site personnel) will be responsible for receiving, maintaining, preparing 
and/or dispensing, and administering these study vaccines (Section 8.1.8). Although QIV is 
provided open label in this study, it will also be prepared and/or dispensed and administered 
by the unblinded study-site personnel for consistency.
To avoid bias, contact between the unblinded study-site personnel and study participants is 
strictly prohibited for any study-related procedures/assessments other than administration of 
study vaccines. Blinded site personnel will be responsible for all other study 
procedures/assessments specified in Section 1.3.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) directly involved with the conduct of this 
study will remain blinded to the participant-level intervention assignment.
See Section 8.1.12 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (see Section 5.2). 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.
It is important to record the use of any analgesic or antipyretic medication that occurs on the 
day of vaccination on the eVRC and appropriate eCRF.
Listed below are specific restrictions for concomitant therapy or vaccination:
•
Administration of a nonstudy pneumococcal vaccine and/or a nonstudy influenza vaccine 
is prohibited during the study.
•
Nonstudy vaccines may only be administered before or after the receipt of study vaccines 
according to the time frames specified in the Exclusion Criteria (Section 5.2).
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•
Receipt of systemic corticosteroids (prednisone equivalent ≥20 mg/day) for
≥14 consecutive days is prohibited from 14 days before any vaccination through 30 days 
following any vaccination. Note: physiologic replacement doses (prednisone equivalent 
of approximately 5 mg/day), 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.
Use of prior and concomitant medications/vaccinations should be recorded as described in 
Section 8.1.5.
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 after the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.12). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention 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 8.1.12 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified vaccination 
regimen will still continue to participate in the study as specified in Section 1.3 and 
Section 8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.11 and 
Section 8.12.3.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance, which in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive urine or serum pregnancy test before vaccination 
at Visit 3.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
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Section 8.1.11. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the pre-
specified statistical data handling and analysis guidelines.
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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 providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant at each visit will not exceed 
99 mL, and the total amount of blood collected over the duration of the study will not exceed 
258.5 mL (Table 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Type
Visit 1
Visit 3
Visit 5
Total
Parameter
Approximate Blood Volume
Pneumococcal 
Immunogenicity 
assessment
30 mL
30 mL
30 mL
90 mL
Influenza 
Immunogenicity 
assessment
20 mL
20 mL
N/A
40 mL
DNA for Future 
Biomedical Researcha
8.5 mL
N/A
N/A
8.5 mL
Assay developmenta
40 mL
40 mL
40 mL
120 mL
Expected total
98.5 mL
90 mL
70 mL
258.5 mL
DNA=deoxyribonucleic acid; N/A=not applicable.
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 informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
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Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.1.3
Consent and Collection of Specimens for Optional Assay Development
The investigator or medically qualified designee will explain the consent for the optional 
assay development blood samples to the participant, or the participant’s legally acceptable 
representative, answer all of their questions, and obtain documented 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 documented 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 health care 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 before Visit 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 must review and record the following in the 
participant’s source documents and on the appropriate eCRF before vaccination at Visit 1:
•
Prior vaccinations and medication taken by the participant within 30 days before study 
vaccination at Visit 1.
•
History of prior pneumococcal vaccination regardless of timing before Visit 1.
•
Any analgesic or antipyretic medication taken on the day of vaccination before 
vaccination.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
Any analgesic or antipyretic medication taken must be recorded on the eVRC and 
appropriate eCRF.
The participant will use their eVRC (Section 8.1.9) to record new and/or concomitant 
medications taken and nonstudy vaccines received from the day of each vaccination through 
30 days 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 before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused 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 reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Unblinded study personnel will prepare and administer all study vaccines (Section 6.3.3). 
The unblinded study personnel who administer study vaccines should not have contact with 
participants for any other study-related procedures/assessments.
Blinded site personnel will not be present in the examination room when study vaccines are 
administered.
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.
Study vaccine will be administered according to the schedule specified in Section 1.3. V116 
or placebo should be administered as a single IM injection in the deltoid region of the 
participant’s left arm, while QIV should be administered as a single IM injection in the 
deltoid region of the participant’s right arm. QIV will be administered open label. Adequate 
treatment provision, including epinephrine and equipment for maintaining an airway, should 
be available for immediate use should an anaphylactic or anaphylactoid reaction occur
[Centers for Disease Control and Prevention 2015].
8.1.8.1
Timing of Dose Administration
Study vaccines will be administered as indicated in Section 1.3. Vaccinations may be 
administered at any time of day and without regard to timing of meals.
All participants will be observed for at least 30 minutes after vaccination for any immediate 
reactions (Section 8.3.4). This observation must be performed by blinded site personnel 
(Section 6.3.3).
Participants must not have a fever reported within 72 hours before vaccination (Section 1.3 
and Section 8.3.3).
Administration of pregnancy tests (if applicable) must be performed before vaccine 
administration.
The collection of blood samples should be performed before vaccine administration.
8.1.9
Electronic Vaccination Report Card
The eVRC is structured as recommended in the final US FDA Patient-reported Outcome 
Guidance [U.S. Food and Drug Administration 2009].
The participant will use the eVRC to record body temperature (Section 8.3.3), solicited 
injection-site AEs, and solicited systemic AEs (Section 8.4.8.1). Unsolicited AEs 
(Section 8.4.8.2), concomitant medications (including use of any analgesic or antipyretic 
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medication), and nonstudy vaccinations (Section 8.1.5.2) will also be reported. Participants 
will be provided an electronic device or have their own electronic device configured, if 
compatible, to complete the eVRC.
The investigator or delegate will review the data captured on the eVRC with the participant 
as indicated in Section 1.3. Any differences between data reported by the participant on the 
eVRC and data entered into the clinical database must be clearly explained in the 
participant’s source documents.
8.1.10
Telephone Contact Questionnaire
Site personnel will contact the participant (or the participant’s legally acceptable 
representative, as applicable) as indicated in Section 1.3 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.
8.1.11
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the vaccination 
regimen should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.12.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
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8.1.12
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before 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 grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If 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. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure pneumococcal vaccine-induced OPA and IgG 
responses and QIV-induced HAI responses. These endpoints will be tested for all 
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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 Pn ECL assay to assess the concentration 
of binding antibodies to capsular polysaccharide of S pneumoniae.
The HAI assay will be used to measure influenza vaccine-induced antibodies that inhibit 
hemagglutination. The HAI results reflect the degree of hemagglutination inhibition.
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 requested by 
regulatory agencies or the Sponsor. For participants who provide optional consent for FBR, 
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 immunogenicity testing.
8.2.1
Multiplex Opsonophagocytic Assay (MOPA)
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 
[Burton, Robert L. and Nahm, Moon H. 2006]. The ability of the assay to simultaneously test 
4 serotypes at a time reduces the amount of serum needed for testing. The assay readout is 
the opsonization index, which is the reciprocal of the highest dilution that gives ≥50% 
bacterial killing, as determined by comparison to assay background controls. The Sponsor 
has developed and optimized the MOPA in a high-throughput microcolony platform, which 
not only covers all 21 serotypes in V116, but also includes serotypes 6C and 15B so that 
antibodies induced by vaccine serotypes 6A and 15C but cross-reactive to serotypes 6C and 
15B, respectively, can be measured. The assay has been validated for 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 (Pn ECL)
The Sponsor has developed, optimized, and validated a multiplex, ECL-based detection 
method for the quantitation of IgG serotype-specific antibodies. This multiplexed ECL assay 
not only detects all 21 serotypes contained in V116, but also detects serotypes 6C and 15B so 
that antibodies induced by vaccine serotypes 6A and 15C, but cross-reactive to serotypes 6C 
and 15B, respectively, can be measured. The ECL assay is based on the Meso-Scale 
Discovery technology, which employs disposable multispot microtiter plates. Briefly, PnPs 
are bound to the surface of 96-well 10 plex carbon microplates, and serum containing 
purported anti-PnPs antibodies is added. The anti-PnPs antibodies bind to the coated plates 
and form an antibody-antigen complex. The bound antibody-antigen complex can be detected 
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using a ruthenium labeled anti-human IgG. Plates are read by measure of the 
chemiluminescent signal emitted from the ruthenium tag upon electrochemical stimulation 
initiated at the electrode surfaces of the microplates.
 
 
ssay validation studies showed excellent 
performance operating characteristics for precision (intra- and inter-assay), dilutability, 
ruggedness (to different plate lots and analysts), relative accuracy, and specificity.
8.2.3
Hemagglutination Inhibition (HAI) Assay
The HAI assay is based on the WHO established method as described in the WHO Manual 
for the Laboratory Diagnosis and Virological Surveillance of Influenza [WHO Global 
Influenza Surveillance Network 2011]. The HAI assay relies on the tendency of influenza 
virus to bind to red blood cells, causing them to agglutinate. It is a traditional method to 
measure vaccine-induced antibodies to influenza that bind to the hemagglutinin molecule, 
thereby inhibiting hemagglutination. The HAI test is generally performed using microtiter 
plates. Nonspecific inhibitors of hemagglutination that occur naturally in sera are removed 
prior to testing. Serially diluted serum is then mixed with standardized quantities of 
hemagglutinin antigens compatible with the strains included in the seasonal vaccine 
formulation. After addition of red blood cells, the degree of inhibition of agglutination 
compared with strain-specific reference sera is assessed. The HAI titer is the inverse of the 
highest dilution of serum exhibiting complete inhibition of hemagglutination.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination and a brief directed physical examination will be 
conducted by an investigator or medically qualified designee (consistent with local 
requirements) per institutional standard before vaccination as indicated in Section 1.3. The 
directed physical examination should focus on examining systems related to any ongoing
conditions and/or follow-up on previously reported AEs.
Findings related to the physical examinations should be documented in the source 
documents. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.3.2
Pregnancy Testing
A pregnancy test consistent with local requirements (sensitive to at least 25 IU hCG) must be 
performed before vaccination in WOCBP as described in Section 1.3.
CCI
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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.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
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.
8.3.3
Body Temperature Measurements
Each participant’s body temperature must be taken by study-site staff before vaccination as 
described in Section 1.3. The prevaccination temperature should be documented in the 
participant’s source documents. Participants who have febrile illness (defined as oral or 
tympanic temperature ≥100.4°F [≥38.0°C]; axillary or temporal temperature ≥99.4°F 
[≥37.4°C]) <72 hours before vaccination must be rescheduled.
Participants will also record oral body temperature measurements using the eVRC 
(Section 8.1.9) from Day 1 to Day 5 after each vaccination.
8.3.4
Postvaccination Observation Period
All participants will be observed for at least 30 minutes after vaccination for any immediate 
reactions. If any immediate AEs are observed during this period, the time at which the event 
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event must be recorded on the appropriate 
eCRF.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).
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•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 to 44 days after the last dose of study intervention, 
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 need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before randomization, must be reported by the 
investigator if they cause the participant to be excluded from the study, or are the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, placebo, 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 after the first vaccination and from the time of each subsequent vaccination through 
30 days postvaccination.
All pregnancies and lactation exposure during breastfeeding must be reported by the 
investigator from the day of randomization through 6 weeks postvaccination.
All SAEs must be reported by the investigator throughout the duration of the individual’s 
participation in the study, regardless of whether related to the study intervention.
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 the investigator 
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considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 3
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
– any death until 
participant 
completion of 
study
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
ECI (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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 toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
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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 SAEs) 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.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, 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.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable for this study.
8.4.7
Events of Clinical Interest
There are no ECIs for this study.
8.4.8
Adverse Events on the VRC
Participants will use an eVRC to report solicited and unsolicited AEs.
The definitions of solicited and unsolicited AEs can be found in Appendix 3.
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8.4.8.1
Solicited Adverse Event
Solicited AEs for this study are summarized in Table 4.
Table 4
Solicited Adverse Events
Type of 
Solicited 
Adverse Event
Predefined Solicited Adverse Events (Preferred Term)
Solicited Time 
Period
Injection site

Injection-site pain or tenderness (injection-site pain)

Injection-site redness (injection-site erythema)

Injection-site swelling (injection-site swelling)
Day 1 through 
Day 5 
postvaccination
Systemic

Headache (headache)

Muscle aches all over body (myalgia)

Tiredness (fatigue)
Day 1 through 
Day 5 
postvaccination
8.4.8.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 4 or 
2) predefined in Table 4 but reported at any time outside the solicited period.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study 
vaccine in any 24-hour period.
No specific information is available on the treatment of overdose.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
DNA for future research
•
Leftover study serum after completion of immunogenicity testing stored for future 
research
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8.10
Optional Assay Development Blood Sample Collection
If the participant documented informed consent for the optional assay development blood 
samples, these 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.
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 as outlined in Section 1.3. Potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Section 5.
If Visit 1 is rescheduled (see Section 5.2), a pregnancy test (if applicable); a body 
temperature measurement; and a review of inclusion/exclusion criteria, prior 
medications/vaccinations, and medical history must be repeated before vaccination.
8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
A participant who discontinues from study intervention will continue to participate in 
protocol-specified activities as outlined in Section 1.3, including blood draws for 
immunogenicity testing and AE monitoring activities, as long as the participant does not 
withdraw consent.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study. The 
protocol will be amended if, after the study has begun, but prior to any unblinding/final 
database lock, changes are made to primary and/or key secondary hypotheses or the 
statistical methods related to those hypotheses (consistent with ICH Guideline E9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in an sSAP and referenced in 
the CSR for the study. Post-hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3 Randomized, Double-blind, Placebo-Controlled Clinical 
Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 
When Administered Concomitantly with Influenza Vaccine in Adults 50 
Years of Age or Older.
Treatment Assignment
Approximately 1000 participants will be randomly assigned in a 1:1 ratio 
to receive either V116 concomitantly with QIV or V116 sequentially 
with QIV. Randomization will be stratified based on the participant’s age 
(50 to 64 years, 65 to 74 years, 75 to 84 years, and ≥85 years) and prior 
pneumococcal vaccination status (PCV13- and PPSV23-naïve, prior 
receipt of PCV13 only, prior receipt of PPSV23 only, and prior receipt of 
PCV13 and PPSV23) at the time of randomization.
Analysis Populations
Immunogenicity: PP population
Safety: APaT population
Primary Endpoint(s)
Immunogenicity:

Serotype-specific OPA GMTs at 30 days postvaccination with V116

Strain-specific HAI GMTs at 30 days postvaccination with QIV
Safety:

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 aches 
all over body/myalgia, 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
Key Secondary Endpoints

Serotype-specific IgG GMCs at 30 days postvaccination with V116
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Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 21 
pneumococcal serotypes in V116 and each of the 4 influenza strains in 
QIV separately. For the primary immunogenicity objectives:
H1: The concomitant group will be considered noninferior to the 
sequential group if the lower bound of the 2-sided 95% CI of the OPA 
GMT ratio (GMT1/GMT2) for each of the 21 serotypes is >0.50, where 
GMT1 is the serotype-specific OPA GMT for the concomitant group and 
GMT2 is the serotype-specific OPA GMT for the sequential group.
H2: The concomitant group will be considered noninferior to the 
sequential group if the lower bound of the 2-sided 95% CI of the HAI 
GMT ratio (GMT1/GMT2) for each of the 4 strains is >0.67, where 
GMT1 is the strain-specific HAI GMT for the concomitant group and 
GMT2 is the strain-specific HAI GMT for the sequential group.
For the hypotheses H1 and H2, estimation of serotype-specific OPA 
GMT ratios for each of the 21 serotypes in V116 and strain-specific HAI 
GMT ratios for each of the 4 strains in QIV, 95% CIs, and p-values will 
be calculated using the cLDA method [Liang, K-Y and Zeger, S. L. 
2000].
Statistical Methods for Key 
Safety Analyses
For overall safety evaluation, safety parameters will be summarized via 
descriptive statistics. For selected safety parameters, between-group 95% 
CIs will be provided for the percentage of participants using the M&N 
method [Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
To support the periodic review of safety and tolerability data across the 
adult V116 Phase 3 program, an external unblinded statistician will 
provide unblinded interim safety summaries to an independent external 
DMC for their review. Unblinded immunogenicity data will be made 
available to the DMC upon request to enable a benefit-risk assessment.
Multiplicity
This study will be considered to have met its primary immunogenicity 
objectives if noninferiority is demonstrated with respect to OPA GMTs 
for the 21 serotypes in V116 and HAI GMTs for the 4 influenza strains 
in QIV at a 1-sided 2.5% alpha-level. Since comparisons are made 
individually for each of the 21 serotypes and the 4 influenza strains, this 
approach controls the 1-sided type 1 error rate at 0.025, and no 
multiplicity adjustment is required.
Sample Size and Power
This study will randomize approximately 500 participants into the 
concomitant group and 500 participants into the sequential group and has 
approximately 90% power to demonstrate noninferiority of OPA GMT 
ratio for the 21 pneumococcal serotypes included in V116 and 
noninferiority of HAI GMT ratio for the 4 influenza strains in QIV at an 
overall 1-sided 2.5% alpha-level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
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The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented using an IRT system.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety endpoints that will be evaluated for within- and/or 
between-intervention differences are listed below.
9.4.1
Immunogenicity Endpoints
OPA and IgG responses will be measured for all 21 serotypes contained in V116 (3, 6A, 7F, 
8, 9N, 10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, and 35B), 
and 2 cross-reactive serotypes (6C and 15B).
HAI responses will be measured for all 4 influenza strains contained in QIV.
The primary immunogenicity endpoints include:
•
Serotype-specific OPA GMTs at 30 days postvaccination with V116.
•
Strain-specific HAI GMTs at 30 days postvaccination with QIV.
The secondary immunogenicity endpoints include:
•
Serotype-specific IgG GMCs at 30 days postvaccination with V116.
•
Serotype-specific GMFRs and proportions of participants with a ≥4-fold rise from 
baseline (prevaccination with V116) to 30 days postvaccination with V116 for both OPA 
and IgG responses.
•
Strain-specific HAI GMFRs from baseline (prevaccination with QIV) to 30 days 
postvaccination with QIV.
•
Strain-specific proportions of participants with a HAI titer ≥1:40 at 30 days 
postvaccination with QIV.
•
Strain-specific proportions of participants that seroconvert at 30 days postvaccination 
with QIV for HAI responses. Seroconversion for HAI responses is defined as achieving 
either (1) a ≥4-fold rise in HAI titer from baseline (prevaccination with QIV) to 30 days 
postvaccination with QIV among participants who are seropositive at baseline (HAI titer 
≥1:10) or (2) a HAI titer of ≥1:40 at 30 days postvaccination with QIV among 
participants who are seronegative at baseline (HAI titer < 1:10).
The exploratory immunogenicity endpoints include the summaries of the cross-reactive 
immune responses to serotypes within a serogroup using serotype-specific OPA and IgG 
responses at 30 days postvaccination with V116.
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9.4.2
Safety Endpoints
The safety endpoints for overall safety assessment that address the primary objectives 
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 aches all over 
body/myalgia, 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 endpoints for overall safety assessment include:
•
Proportion of participants with the broad AE categories consisting of any AE, any 
unsolicited AE, and any vaccine-related AE from Day 1 through Day 30 postvaccination.
•
Proportion of participants with the broad AE categories consisting of any SAE, any 
vaccine-related SAE, discontinuation due to an AE, 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 all randomized participants without 
deviations from the protocol that may substantially affect the results of the immunogenicity 
endpoint(s). Potential deviations that may result in the exclusion of a participant from the PP 
population for all immunogenicity analyses include:
•
Failure to receive the assigned regimen as per randomization schedule at Visit 1 (Day 1).
•
Receipt of a prohibited medication or prohibited vaccine prior to study vaccination.
Additional potential deviations that may result in the exclusion of a participant from the PP 
population for specific immunogenicity analyses (depending on the time point) include:
•
Failure to receive study vaccine at Visit 3 (Day 30).
•
Failure to receive correct clinical material as per randomization schedule at Visit 3 (Day 
30).
•
Receipt of a prohibited medication or prohibited vaccine prior to a blood sample 
collection.
•
Collection of a blood sample outside of the pre-specified window.
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The final determination on protocol deviations that impact the immunogenicity analysis, and 
thereby the composition of the PP population, will be made prior to the final unblinding of 
the database and will be documented in a separate memo. Participants will be included in the 
vaccination group to which they are randomized for the analysis of immunogenicity data 
using the PP population.
A supportive analysis using the FAS population will also be performed for the primary 
immunogenicity endpoint. The FAS population consists of all randomized participants who 
received at least 1 study 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.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study vaccination. Participants will be included in 
the group corresponding to the study vaccination they actually received for the analysis of 
safety data using the APaT population. If a participant receives incorrect study vaccines 
resulting in a regimen that does not belong to either of the 2 designed regimens in the study, 
this participant’s data will be excluded from the APaT population and summarized 
separately.
At least 1 temperature measurement obtained subsequent to study intervention is required for 
inclusion in the analysis of temperature.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives. Methods related to exploratory objectives will be described in 
the sSAP.
Immunogenicity analyses will be conducted for each of the 21 pneumococcal serotypes in 
V116 and each of the 4 influenza strains in QIV separately.
Primary Endpoint/Hypothesis (H1)
The primary objective to compare the serotype-specific OPA GMTs at 30 days 
postvaccination with V116 between participants administered V116 concomitantly with QIV 
versus participants administered V116 sequentially with QIV will be assessed via the 
following noninferiority hypotheses:
H0: GMT1/GMT2 ≤0.50 versus
H1: GMT1/GMT2 >0.50,
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where GMT1 is the serotype-specific OPA GMT for the concomitant group and GMT2 is the 
serotype-specific OPA GMT for the sequential group. A ratio of 0.50 corresponds to a 2.0 
fold decrease of OPA GMT in the concomitant group as compared with the sequential 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 (concomitant group/sequential group) being 
>0.50 and would lead to the conclusion that the OPA responses in the concomitant group are 
noninferior to the sequential group for the 21 pneumococcal serotypes.
Primary Endpoint/Hypothesis (H2)
The primary objective to compare the strain-specific HAI GMTs at 30 days postvaccination 
with QIV between participants administered QIV concomitantly with V116 versus 
participants administered QIV sequentially will be assessed via the following noninferiority 
hypotheses:
H0: GMT1/GMT2 ≤0.67 versus
H1: GMT1/GMT2 >0.67,
where GMT1 is the strain-specific HAI GMT for the concomitant group and GMT2 is the 
strain-specific HAI GMT for the sequential group. A ratio of 0.67 corresponds to a 1.5 fold 
decrease of the HAI GMT in the concomitant group as compared with the sequential 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 (concomitant group/sequential group) being 
>0.67 and would lead to the conclusion that the influenza HAI responses in the concomitant 
group are noninferior to the sequential group for the 4 influenza strains.
To address the 2 primary immunogenicity objectives, the serotype-specific OPA GMTs at 30 
days postvaccination with V116 and strain-specific HAI GMTs at 30 days postvaccination 
with QIV will be compared between intervention groups separately. Comparisons will be 
made through the estimation of serotype-specific OPA GMT ratios for each of the 21 
serotypes in V116 and strain-specific HAI GMT ratios for each of the 4 strains in QIV, 
respectively. Estimation of the ratios, 95% CI, and the hypothesis test (ie, 1-sided p-value) 
will be calculated using the cLDA method proposed by Liang and Zeger [Liang, K-Y and 
Zeger, S. L. 2000] using data from both vaccination groups. In this model, the response 
vector consists of the log transformed antibody titers at baseline and 30 days postvaccination. 
The repeated measures model will include terms for vaccination group, time, the interaction 
of time-by-vaccination group, age stratum (ie, 50 to 64 years, 65 to 74 years, 75 to 84 years, 
and ≥85 years) at baseline, prior pneumococcal vaccination status (ie, PCV13- and PPSV23 
naïve, prior receipt of PCV13 only, prior receipt of PPSV23 only, and prior receipt of PCV13 
and PPSV23), the interaction of age stratum-by-time, and the interaction of prior 
pneumococcal vaccination status-by-time. This model will allow for different baseline means 
for each stratum but restrict the baseline mean within both the age stratum levels and the 
prior pneumococcal vaccination status stratum levels to be the same for both vaccination 
groups. 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 restricted maximum likelihood to make proper 
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statistical inference. This model allows the inclusion of participants who are missing either 
the baseline or postbaseline measurements, thereby increasing efficiency.
Further details of handling sparse data in stratification variables (eg, age and prior 
pneumococcal vaccination status) will be described in the sSAP.
Secondary Endpoints
A similar statistical approach will be used to evaluate the serotype-specific IgG GMCs at 30 
days postvaccination with V116 for participants administered V116 concomitantly with QIV 
and participants administered V116 sequentially with QIV.
Descriptive statistics with point estimates and within-group 95% CIs will be provided for all 
other immunogenicity endpoints. For the continuous endpoints, the point estimates will be 
calculated by exponentiating the estimates of the mean of the natural log values and the 
within-group CIs will be derived by exponentiating the bounds of the CIs of the mean of the 
natural log values based on the t-distribution. For the dichotomous endpoints, the within 
group CIs will be calculated based on the exact method proposed by Clopper and 
Pearson[CLOPPER, C. J. and PEARSON, E. S. 1934].
Reverse Cumulative Distribution Curves for both OPA titers and IgG concentrations at 30 
days postvaccination with V116 will be graphically displayed by serotype. Reverse 
Cumulative Distribution Curves for HAI titers at 30 days postvaccination with QIV will be 
graphically displayed by strain.
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 5.
Table 5
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
OPA GMTs at 30 days postvaccination 
with V116
P
cLDAb
(estimate, 95% CI, p-
value)
PP
Model-based
S
FAS
HAI GMTs at 30 days postvaccination 
with QIV
P
cLDAb
(estimate, 95% CI, 
p-value)
PP
Model-based
S
FAS
Secondary Endpoints
IgG GMCs at 30 days postvaccination 
with V116
P
cLDAb
(estimate, 95% CI)
PP
Model-based
GMFRs and proportions of participants 
with a ≥4-fold rise from baseline 
(prevaccination with V116) to 30 
days postvaccination with V116 for 
both OPA and IgG responses
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data will 
not be imputed
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Endpoint/Variable
(Description, Time Point)
Primary vs 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing Data 
Approach
HAI GMFRs from baseline 
(prevaccination with QIV) to 30 days 
postvaccination with QIV
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data will 
not be imputed
Proportions of participants with HAI 
titer ≥1:40 at 30 days 
postvaccination with QIV
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data will 
not be imputed
Proportions of participants that 
seroconvert at 30 days 
postvaccination with QIV for HAI 
responses
P
Descriptive Statistics
(estimate, 95% CI)
PP
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; HAI=hemagglutination inhibition; 
IgG=immunoglobulin G; OPA=opsonophagocytic activity; PP=per-protocol; QIV=quadrivalent influenza vaccine.
a P=primary approach; S=supportive approach.
b cLDA model with terms for vaccination group, time, the interaction of time-by-vaccination, age stratum at baseline, 
prior pneumococcal vaccination status, age stratum-by-time interaction, and prior pneumococcal vaccination status-
by-time interaction. 
9.6.2
Statistical Methods for Safety Analyses
Safety and Tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and postvaccination temperature measurements.
9.6.2.1
Overall Safety Assessment
The overall safety evaluation will be performed following any vaccination. A participant 
with an AE after the first vaccination, the second vaccination, or both vaccinations will 
contribute a count of one participant for the particular AE. The summary (ie, number and 
percentage) by the concomitant and sequential groups will include participants with any AEs, 
any unsolicited AEs, any vaccine-related AEs, any SAEs, any vaccine-related SAEs, 
discontinuation of vaccine due to an AE, any AEs resulting in death following any 
vaccination. Point estimates and 95% CIs for the between-group differences (the concomitant 
group compared with the sequential group) in the percentages of participants with the event 
will be provided.
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 95% CIs of the differences between intervention groups in the percentages of 
participants with specific AEs will be provided for solicited AEs and AEs that occur in ≥1% 
of participants in any intervention group. Events reported by <1% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful differences.
The number and percentage of participants with maximum temperature measurements 
meeting the Brighton Collaboration cut point [Marcy, S. M., et al 2004] will be provided 
along with point estimates and 95% CIs of between-group differences.
CIs for between-group differences will be calculated using the M&N Method [Miettinen, O. 
and Nurminen, M. 1985]. CIs that are not associated with pre-specified hypotheses are not 
adjusted for multiplicity. Therefore, they should be regarded as helpful descriptive measures 
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for the review of the safety profile and not a formal method for assessing statistical 
significance of between-group differences. Rainfall plots with point estimates and 95% CIs 
will be displayed for AEs that occur in ≥5% of participants in the concomitant or sequential 
group.
The analysis strategy for safety endpoints is summarized in Table 6.
Table 6
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95 % Between-
group CI
Graphical 
Display
Overall Safety 
Assessment
Solicited injection-site AE (Day 1 through Day 5 
postvaccination) a
X
X
Solicited systemic site AE (Day 1 through Day 5 
postvaccination) a
X
X
Any AE b
X
X
Any unsolicited AE b
X
X
Any vaccine-related AE b
X
X
Any SAE b
X
X
Any vaccine-related SAE b
X
X
Discontinuation due to AE b
X
X
Death b
X
X
Specified AEs by SOC and PT c
X
X
X
Maximum temperature (Day 1 through Day 5 
postvaccination) d
X
X
AE=adverse event; CI=confidence interval; PT=preferred term; SAE=serious adverse event; SOC=system organ class.
a
Solicited injection-site AEs include redness/erythema, swelling, and tenderness/pain; solicited systemic AEs include 
muscle aches all over body/myalgia, headache, and tiredness/fatigue.
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
Descriptive statistics, 95% between-group CI, and graphical display will be provided for specific AEs with incidence 
>0%, ≥1%, and ≥5% of participants respectively, in the concomitant and sequential groups.
d
Maximum temperature measurements are categorized by Brighton Collaboration cut points.
In addition to the analyses following any vaccination, a supportive analysis of select safety 
endpoints will be provided after each vaccination. Point estimates by vaccination group will 
be provided for injection-site AEs following V116 and following QIV separately. That is, the 
proportion of participants with injection-site AEs following administration of V116 will 
include AEs reported following V116 administration in the limb corresponding to the 
location of V116 administration. Similarly, the proportion of participants with injection-site 
AEs following administration of QIV will include AEs reported following QIV 
administration in the limb corresponding to the location of QIV administration.
Additionally, the systemic AEs following each vaccination time point for each vaccination 
group will be summarized. That is, descriptive summaries of systemic AEs will include AEs 
reported following administration of:
•
QIV and V116 in the concomitant group at Visit 1 (Day 1).
•
QIV with placebo in the sequential group at Visit 1 (Day 1).
•
Placebo alone in the concomitant group at Visit 3 (Day 30).
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•
V116 alone in the sequential group at Visit 3 (Day 30).
9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed by using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (eg, age, race, ethnicity, sex, and gender), baseline 
characteristics, prior and concomitant vaccinations and medications will be summarized by 
vaccination group either by descriptive statistics or categorical tables.
9.7
Interim Analyses
A periodic review of safety and tolerability data across the V116 Phase 3 adult program will 
be conducted by an independent, unblinded, external DMC. A description of the structure 
and function of the DMC, along with the timing and content of the safety reviews, will be 
outlined in the DMC charter. Information regarding the composition of the DMC is provided 
in Appendix 1. In addition, unblinded immunogenicity data will be made available to the 
DMC upon request to enable a benefit-risk assessment.
The DMC will serve as the primary reviewer of the results of the ongoing safety reviews and 
will make recommendations for discontinuation of the study or protocol modifications to an 
EOC of the Sponsor (see Appendix 1 for details on the Committees Structure for this study). 
If the DMC recommends modifications to the design of the protocol or discontinuation of the 
study, the EOC of the Sponsor (and potentially other limited Sponsor personnel) may be 
unblinded to results at the intervention level to act on these recommendations. The extent to 
which individuals are unblinded with respect to ongoing safety reviews will be documented 
by the external unblinded statistician. Additional logistical details will be provided in the 
DMC charter.
Study enrollment may be ongoing at the time of external DMC review. Blinding to 
intervention assignment will be maintained at all investigational sites. Participant-level 
unblinding will be restricted to an external unblinded statistician performing ongoing safety 
reviews. Intervention-level, ongoing safety reviews will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
safety reviews.
9.8
Multiplicity
The study will have met its primary immunogenicity objectives if noninferiority is 
demonstrated with respect to the OPA GMTs for the 21 serotypes in V116 and the HAI 
GMTs for the 4 influenza strains in QIV at a 1-sided 2.5% alpha-level. All hypotheses will be 
tested individually for each pneumococcal serotype and influenza strain at a 1-sided 
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0.025 alpha-level. This approach controls the 1-sided type 1 error rate at 0.025, and no 
multiplicity adjustment will be required.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This study will randomize approximately 500 participants into the concomitant group and 
500 participants into the sequential group.
Primary Immunogenicity Endpoints/Hypotheses (H1 and H2)
For the primary hypotheses, this study has approximately 90% power for demonstrating 
noninferiority of the serotype-specific OPA GMT ratios for the 21 pneumococcal serotypes 
included in V116 and >99% power for demonstrating noninferiority of the strain-specific 
HAI GMT ratios for the 4 influenza strains in QIV at an overall 1-sided 2.5% alpha-level.
The sample size and power calculations are based on the following assumptions:
•
90% evaluability rate (approximately 450 evaluable participants per treatment group) for 
both primary endpoints (OPA GMT ratios and HAI GMT ratios).
•
The underlying OPA GMT ratio is 
 (concomitant group/sequential group) for the 
21 pneumococcal serotypes. The assumption for this ratio is based on results of studies 
evaluating the administration of PCVs with concomitant influenza vaccines.
•
The variabilities for OPA titers in both concomitant and sequential groups are the same as 
those observed in V116-001 Phase 2. The standard deviations of the natural log titers for 
the 21 pneumococcal serotypes in V116 range from 1.06 to 1.95.
•
The underlying HAI GMT ratio is 
(concomitant group/sequential group) for the 
4 influenza strains. The variabilities for HAI titers in both concomitant and sequential 
groups are the same as that observed in V114-021. The standard deviations of the natural 
log titers for the 4 influenza strains range from 1.08 to 1.41 in the concomitant group.
The 2 hypotheses are assumed to be independent. The overall power for the primary 
immunogenicity hypotheses is estimated to be approximately 90% (=0.909×>0.992) to 
achieve the pre-specified noninferiority statistical criteria for the 21 serotypes in V116 and 
the 4 influenza strains in QIV.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE among 
500 participants in the concomitant group if the underlying incidence of an SAE is 0.32% 
(1 of every 311 participants receiving the vaccine). There is a 50% chance of observing at 
least 1 SAE among 500 participants in the concomitant group if the underlying incidence of 
an SAE is 0.14% (1 of every 721 participants receiving the vaccine). If no SAEs are observed 
CCI
CCI
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among 500 participants in the concomitant group, this study will provide 97.5% confidence 
that the underlying percentage of participants with an SAE is <0.74% (1 in every 
136 participants) in the concomitant group.
The percentage point differences between the 2 vaccination groups that could be detected 
with 80% probability is summarized in Table 7 for a variety of hypothetical underlying 
incidences of an AE. These calculations assume 500 participants in each group and are based 
on a 2-sided 5% alpha-level. The calculations are based on an asymptotic method proposed 
by Farrington and Manning [Farrington, C. P. 1990]; no multiplicity adjustments were made.
Table 7
Differences in Incidence of AE Rates Between the 2 Vaccination Groups That 
Can Be Detected With an Approximate 80% Probability (Assuming 2-sided 5% Alpha-level 
With 500 Participants in Each Group)
Incidence of Adverse Event
Risk Difference
Concomitant Group (%)
N=500
Sequential Group (%)
N=500
Percentage Points
1.8
0.1
1.7
5.3
2.0
3.3
9.6
5.0
4.6
15.9
10.0
5.9
21.9
15.0
6.9
27.5
20.0
7.5
38.4
30.0
8.4
Incidences presented here are hypothetical and do not represent actual adverse experiences in either 
group. The incidences assume a 2-sided 5% alpha-level with 500 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 performed for the primary immunogenicity endpoints and selected 
safety endpoints (summary of AEs and summary of solicited AEs). The following subgroups 
are planned for evaluation:
•
Age (50 to 64 years, 65 to 74 years, 75 to 84 years, and ≥85 years of age)
•
Sex
•
Race
•
Ethnicity
•
Prior pneumococcal vaccination status (PCV13- and PPSV23-naïve, prior receipt of 
PCV13 only, prior receipt of PPSV23 only, and prior receipt of PCV13 and PPSV23)
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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 V116, QIV, and placebo, compliance 
will not be calculated. However, the number and proportion of randomized participants 
receiving each vaccination will be summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V116, QIV, and placebo.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing, and reporting these trials in compliance with 
the highest ethical and scientific standards. Protection of participants in clinical trials 
is the overriding concern in the design and conduct of clinical trials. In all cases, 
MSD clinical trials will be conducted in compliance with local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 
in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
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protection rights of all participants, trial site staff and, where applicable, third 
parties. All trial protocols are and will be assessed for the need and capability to 
enroll underrepresented groups. Participants must meet protocol entry criteria to 
be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. 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.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
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 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
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authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations. Changes to the protocol that are required urgently to eliminate 
an immediate hazard and to protect participant safety may be enacted in anticipation
of ethics committee approval. MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review and medical evaluation to identify 
potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 before 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 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.5
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.
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Authorship will be determined by mutual agreement and in line with ICMJE 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 trials Regulation 536/2014, 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, https://euclinicaltrials.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 trials 
Regulation 536/2014 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 Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH 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 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
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, 
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contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor 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 8 will be performed by the local laboratory.
•
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.
Table 8
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Pregnancy 
Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
hCG=human chorionic gonadotropin; WOCBP=women of childbearing potential
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
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
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 includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting 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.
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•
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.
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting 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/participant’s legally authorized representative who has signed the 
informed consent. Unsolicited AEs include serious and nonserious AEs.
•
Solicited AEs are predefined local (at the injection/administration site) and systemic 
events for which the participant/participant’s legally authorized representative is 
specifically questioned, and which are noted by the participant/participant’s legally 
authorized representative in their VRC.
10.3.3
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.
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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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
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•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of overall intensity grade for each AE and SAE 
(and other reportable event) reported during the study. An overall intensity 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 overall intensity 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” [Food and Drug Administration 2007].
Injection-Site AE Overall Intensity Grading Scale
Injection-Site 
Reaction to Study 
Vaccine/Placebo
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(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
≤5 cm
Size measured as
5.1 to 10 cm
Size measured 
as
>10 cm
Necrosis or 
exfoliative dermatitis 
or results in ER visit 
or hospitalization
Swelling
Size measured as 
≤5 cm
Size measured as
5.1 to 10 cm
Size measured 
as
>10 cm
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
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Injection-Site 
Reaction to Study 
Vaccine/Placebo
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Any injection-site reaction that begins ≥6 days after receipt of study vaccine/placebo
Pain/Tenderness
Erythema/Redness
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
The overall intensity 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” [Food and Drug Administration 2007].
Specific Systemic AE Overall Intensity 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
The overall intensity 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” [Food and Drug Administration 2007].
Other Systemic AE Overall Intensity 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
AE=adverse event; ER=emergency room; eVRC=electronic Vaccine Report Card; SAE=serious adverse event
The overall intensity 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” [Food and Drug Administration 2007].
a
Based upon information provided by the patient on the 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.
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Vital Sign (Temperature) Overall Intensity 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
The overall intensity 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” [Food and Drug Administration 2007].
a
Participant should be at rest for all vital sign requirements.
b
Oral temperature; no recent hot or cold beverages or smoking.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention 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 initialed 
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 on the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? 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 reexposed to the study intervention 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; (2) the study is a single-dose vaccine study; or (3) study 
intervention(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 STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
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RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention 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 their 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 study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
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 their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
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 email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
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, Müllerian 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 non-hormonal 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
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant c
IUSd
Nonhormonal 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 for a male participant 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
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.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Male or female condom with or without spermicide
Cervical cap, diaphragm, or sponge with spermicide
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)
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 contraceptives 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, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
•
Male and female condom should not be used together (due to risk of failure with friction).
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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 Research3, 4
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 Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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.
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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 Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
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 that 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.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using 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 Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, 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 before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
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 Participants3, 4
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.
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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 Population3, 4
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 Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ABCs
Active Bacterial Care Surveillance
ACIP
Advisory Committee on Immunization Practices
AE
adverse event 
APaT
All-Participants-as-Treated
CDC
Centers for Disease Control and Prevention
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 Trial Facilitation Group 
CTR
Clinical Trials Regulation
deOAc
De-O-acylated
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EU
European Union
eVRC
electronic Vaccination Report Card
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation
Expanded Term
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMT
geometric mean concentration
H
hypothesis
HAI
hemagglutination inhibition
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IM
Intramuscular(ly)
IMP
investigational medicinal product
IND
Investigational New Drug 
IPD
Invasive pneumococcal disease
IRB
Institutional Review Board
IRT
interactive response technology
ISO
International Organization for Standardization
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
Lactational amenorrhea method
M&N
Miettinen and Nurminen
MedDRA
Medical Dictionary for Regulatory Activities
MOPA
Mulitplexed Opsonophagocytic Assay
mRNA
messenger RNA
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Abbreviation
Expanded Term
NIMP
noninvestigational medicinal product
NSAE
nonserious adverse event
OPA
opsonophagocytic activity
PCV
Pneumococcal conjugate vaccine
PCV13
Prevnar 13™ (Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 
and 23F)
PCV15
VAXNEUVANCE™ (Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 
19A, 19F, 22F, 23F, and 33F)
PCV20
Prevnar 20™ 
PK
Pharmacokinetics
Pn ECL
Pneumococcal electrochemiluminescence
PnPs
Pneumococcal polysaccharide
PP
per-protocol
PPSV23
PNEUMOVAX™23 (Serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 
11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F)
QIV
quadrivalent influenza vaccine
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
standard deviation
SLAB
supplemental laboratory test(s)
SoA
schedule of activities
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
US
United States
VRC
Vaccination Report Card
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
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11
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