A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 When Administered Concomitantly With Influenza Vaccine in Healthy Adults 50 Years of Age or Older (PNEU-FLU)
Phase: PHASE3
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03615482 
Document Date: 
01-JUN-2018
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of V114 When Administered Concomitantly with 
Influenza Vaccine in Healthy Adults 50 Years of Age or Older 
(PNEUFLU)

PRODUCT: V114 
1
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 When Administered 
Concomitantly with Influenza Vaccine in Healthy Adults 50 Years of Age or Older (PNEU-
FLU)
Protocol Number: 021-01
Compound Number: V114
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
14977
Approval Date: 01-JUN-2018
 
 
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PRODUCT: V114 
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PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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PRODUCT: V114 
3
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 01
Overall Rationale for the Amendments:
The primary purpose of this amendment is to remove the collection of medical device incidents from the protocol (removal of Section 
6.1.1, Section 8.4.8, and Appendix 4). The implementation of the FDA guidance for reporting events related to combination products 
has been delayed until January 2020. Therefore, the current protocol is not within the scope of medical device reporting requirements. 
Other clarifications and editorial revisions were also made as shown in the Summary of Changes Table below.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
2.2.1  V114 and Pneumococcal Disease
Licensure dates for Prevnar 13™ were 
added to the third paragraph.
Revisions were made in the fourth 
paragraph to better align with the cited 
literature.
Revisions made for accuracy.
5.2  Exclusion Criteria
The number of exclusion criterion 23 has 
been corrected to 22.
Correction of a typographical error.
6.1.1  Medical Devices
8.4.8  Medical Device Incidents (Including 
Malfunctions)
10.4  Appendix 4: Medical Device Incidents: 
Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Sections removed.
The implementation of the FDA 
guidance for reporting events related to 
combination products has been delayed 
until January 2020. Therefore, the 
current protocol is not within the scope 
of medical device reporting 
requirements.
 
 
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PRODUCT: V114 
4
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Section # and Name
Description of Change 
Brief Rationale 
6.5  Concomitant Therapy
Concomitant corticosteroid rules were 
updated to align with other protocols in the 
V114 program.
Updates necessary for program 
consistency.
8.1.10  Telephone Contact Questionnaire
1.3  Schedule of Activities (SoA)
The text in Section 8.1.10 was revised as 
follows:
Original: All participants to collect 
additional information based on a will be 
contacted by telephone at Month 7 to 
complete the Telephone Contact 
Questionnaire provided by the Sponsor.  
Data to be reported from on this discussion 
questionnaire will include SAEs and/or any 
updates to previously reported safety 
information.
Revised: Site personnel will contact study 
participants 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.
The revised text was also added to the 
SoA.
Revisions were made to clarify the 
process for administering the telephone 
contact questionnaire.
 
 
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PRODUCT: V114 
5
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Section # and Name
Description of Change 
Brief Rationale 
8.4.1  Time Period and Frequency for 
Collecting AE, SAE, and Other Reportable 
Safety Event Information
The following text was deleted from the 
second paragraph in this section:
All AEs, SAEs, and other reportable safety 
events must be reported by the investigator 
from the day of allocation/randomization to 
the first vaccination and from the day of 
each vaccination through 14 days (42 days 
for live attenuated vaccines) 
postvaccination.  SAEs must also be 
reported throughout the duration of the 
individual’s participation in the study, 
regardless of whether or not related to the 
Sponsor’s product.
Live attenuated vaccines are not 
provided as part of the study.
8.5  Treatment of Overdose
The definition of overdose was revised as 
follows:
Original: In this study, an overdose is any 
dose higher than 1 dose of any individual 
study vaccine during the individual’s 
participation in the study.
Revised: In this study, an overdose is the 
administration of more than 1 dose of any 
individual study vaccine in any 24-hour 
period.
Revisions made for accuracy.
 
 
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PRODUCT: V114 
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PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Section # and Name
Description of Change 
Brief Rationale 
9.6.2  Statistical Methods for Safety 
Analyses, Table 5
Tier 2 safety endpoint was revised as 
follows (changes in bold):
“Any SAE and vaccine-related AE” was 
changed to “Any vaccine-related SAE”
Table was revised to align with safety 
analysis plan and text under Tier 2 
Events.
Throughout
Editorial revisions
Changes are minor and have not been 
summarized individually.
 
 
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PRODUCT: V114 
7
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA) ................................................................................20
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................23
2.2
Background ..........................................................................................................24
2.2.1
V114 and Pneumococcal Disease ................................................................24
2.2.1.1
Influenza Disease...............................................................................25
2.2.2
Preclinical and Clinical Studies ...................................................................25
2.2.3
Information on Other Study-related Therapy ..............................................26
2.2.3.1
Seasonal Inactivated Quadrivalent Influenza Vaccine ......................26
2.3
Benefit/Risk Assessment......................................................................................26
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................27
4
STUDY DESIGN............................................................................................................29
4.1
Overall Design ......................................................................................................29
4.2
Scientific Rationale for Study Design.................................................................30
4.2.1
Rationale for Endpoints ...............................................................................30
4.2.1.1
Immunogenicity Endpoints................................................................30
4.2.1.1.1
Pneumococcal Immunogenicity Endpoints..............................30
4.2.1.1.2
Influenza Immunogenicity Endpoints......................................31
4.2.1.2
Safety Endpoints ................................................................................31
4.2.1.3
Future Biomedical Research..............................................................32
4.2.2
Rationale for the Use of Comparator/Placebo .............................................32
4.3
Justification for Dose ...........................................................................................32
4.4
Beginning and End of Study Definition .............................................................32
4.4.1
Clinical Criteria for Early Study Termination .............................................32
5
STUDY POPULATION ................................................................................................33
5.1
Inclusion Criteria.................................................................................................33
5.2
Exclusion Criteria ................................................................................................33
5.3
Lifestyle Considerations ......................................................................................35
5.4
Screen Failures.....................................................................................................35
5.5
Participant Replacement Strategy......................................................................35
6
STUDY INTERVENTION............................................................................................36
 
 
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PRODUCT: V114 
8
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
6.1
Study Intervention(s) Administered...................................................................36
6.2
Preparation/Handling/Storage/Accountability .................................................38
6.2.1
Dose Preparation..........................................................................................38
6.2.2
Handling, Storage, and Accountability........................................................38
6.3
Measures to Minimize Bias: Randomization and Blinding..............................38
6.3.1
Intervention Assignment..............................................................................38
6.3.2
Stratification.................................................................................................39
6.3.3
Blinding........................................................................................................39
6.4
Study Intervention Compliance..........................................................................39
6.5
Concomitant Therapy..........................................................................................40
6.6
Dose Modification (Escalation/Titration/Other)...............................................40
6.7
Intervention After the End of the Study............................................................40
6.8
Clinical Supplies Disclosure................................................................................41
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................41
7.1
Discontinuation of Study Intervention...............................................................41
7.2
Participant Withdrawal From the Study...........................................................42
7.3
Lost to Follow-up .................................................................................................42
8
STUDY ASSESSMENTS AND PROCEDURES........................................................43
8.1
Administrative and General Procedures ...........................................................44
8.1.1
Informed Consent.........................................................................................44
8.1.1.1
General Informed Consent.................................................................44
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................45
8.1.1.3
Consent and Collection of Blood Samples for Optional Assay 
Development......................................................................................45
8.1.2
Inclusion/Exclusion Criteria ........................................................................45
8.1.3
Participant Identification Card.....................................................................45
8.1.4
Medical History ...........................................................................................45
8.1.5
Prior and Concomitant Medications Review ...............................................46
8.1.5.1
Prior Medications...............................................................................46
8.1.5.2
Concomitant Medications ..................................................................46
8.1.6
Assignment of Screening Number...............................................................46
8.1.7
Assignment of Treatment/Randomization Number .....................................46
8.1.8
Study Intervention Administration ..............................................................46
8.1.8.1
Timing of Dose Administration.........................................................47
8.1.9
Electronic Vaccination Report Card ............................................................47
8.1.10
Telephone Contact Questionnaire................................................................48
 
 
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PRODUCT: V114 
9
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
8.1.11
Discontinuation and Withdrawal .................................................................48
8.1.11.1
Withdrawal From Future Biomedical Research ................................48
8.1.12
Participant Blinding/Unblinding..................................................................49
8.1.13
Calibration of Equipment.............................................................................49
8.2
Immunogenicity Assessments .............................................................................50
8.2.1
Multiplex Opsonophagocytic Assay (MOPA).............................................50
8.2.2
Electrochemiluminescence (ECL) ...............................................................50
8.2.3
Hemagglutination Inhibition (HAI) Assay ..................................................51
8.3
Safety Assessments...............................................................................................51
8.3.1
Physical Examinations.................................................................................51
8.3.2
Pregnancy Test.............................................................................................51
8.3.3
Body Temperature Measurement.................................................................52
8.3.4
Safety Assessments and Use of the eVRC...................................................52
8.3.5
Clinical Laboratory Assessments.................................................................52
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................53
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................53
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......55
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...55
8.4.4
Regulatory Reporting Requirements for SAE .............................................55
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................55
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................56
8.4.7
Events of Clinical Interest (ECIs) ................................................................56
8.5
Treatment of Overdose........................................................................................56
8.6
Pharmacokinetics.................................................................................................56
8.7
Pharmacodynamics..............................................................................................56
8.8
Future Biomedical Research Sample Collection...............................................56
8.9
Planned Genetic Analysis Sample Collection ....................................................56
8.10
Optional Assay Development Blood Sample Collection ...................................57
8.11
Biomarkers ...........................................................................................................57
8.12
Medical Resource Utilization and Health Economics.......................................57
8.13
Visit Requirements...............................................................................................57
8.13.1
Screening......................................................................................................57
8.13.2
Treatment Period/Vaccination Visit ............................................................57
8.13.3
Discontinued Participants Continuing to be Monitored in the Study ..........57
9
STATISTICAL ANALYSIS PLAN .............................................................................58
 
 
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PRODUCT: V114 
10
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
9.1
Statistical Analysis Plan Summary.....................................................................58
9.2
Responsibility for Analyses/In-house Blinding .................................................60
9.3
Hypotheses/Estimation ........................................................................................60
9.4
Analysis Endpoints...............................................................................................60
9.4.1
Immunogenicity Endpoints..........................................................................60
9.4.2
Safety Endpoints ..........................................................................................61
9.5
Analysis Populations............................................................................................62
9.5.1
Immunogenicity Analysis Populations ........................................................62
9.5.2
Safety Analysis Populations ........................................................................63
9.6
Statistical Methods...............................................................................................63
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................63
9.6.2
Statistical Methods for Safety Analyses ......................................................66
9.6.3
Demographic and Baseline Characteristics .................................................69
9.7
Interim Analyses ..................................................................................................69
9.8
Multiplicity ...........................................................................................................69
9.9
Sample Size and Power Calculations .................................................................70
9.9.1
Sample Size and Power for Immunogenicity Analyses ...............................70
9.9.2
Sample Size and Power for Safety Analyses ...............................................70
9.10
Subgroup Analyses...............................................................................................71
9.11
Compliance (Medication Adherence).................................................................71
9.12
Extent of Exposure...............................................................................................71
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................72
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........72
10.1.1
Code of Conduct for Clinical Trials.............................................................72
10.1.2
Financial Disclosure.....................................................................................74
10.1.3
Data Protection.............................................................................................74
10.1.3.1
Confidentiality of Data ......................................................................75
10.1.3.2
Confidentiality of Participant Records...............................................75
10.1.3.3
Confidentiality of IRB/IEC Information............................................75
10.1.4
Committees Structure...................................................................................75
10.1.4.1
Scientific Advisory Committee..........................................................75
10.1.4.2
Executive Oversight Committee........................................................75
10.1.4.3
External Data Monitoring Committee ...............................................76
10.1.5
Publication Policy........................................................................................76
10.1.6
Compliance with Study Registration and Results Posting Requirements ...76
10.1.7
Compliance with Law, Audit, and Debarment ............................................77
10.1.8
Data Quality Assurance ...............................................................................77
 
 
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PRODUCT: V114 
11
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
10.1.9
Source Documents .......................................................................................78
10.1.10
Study and Site Closure.................................................................................78
10.2
Appendix 2: Clinical Laboratory Tests..............................................................79
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................80
10.3.1
Definition of AE ..........................................................................................80
10.3.2
Definition of SAE ........................................................................................81
10.3.3
Additional Events Reported.........................................................................82
10.3.4
Recording AE and SAE ...............................................................................82
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................87
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................89
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................90
10.5.1
Definitions....................................................................................................90
10.5.2
Contraception Requirements........................................................................90
10.5.3
Pregnancy Testing........................................................................................92
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................93
10.7
Appendix 7: Country-specific Requirements ....................................................98
10.8
Appendix 8: Abbreviations .................................................................................99
11
REFERENCES.............................................................................................................101
 
 
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PRODUCT: V114 
12
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
LIST OF TABLES
Table 1
Study Interventions ..........................................................................................37
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Types ...44
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................54
Table 4
Analysis Strategy for Immunogenicity Variables............................................65
Table 5
Analysis Strategy for Safety Parameters Following Any Vaccination ............67
Table 6
Differences in Incidence of AE Rates between the 2 Vaccination Groups 
That Can be Detected With an ~80% Probability (Assuming 2-sided 5% 
alpha level with 600 Participants in each Group) ............................................71
Table 7
Protocol-Required Safety Laboratory Assessments.........................................79
Table 8
Contraceptive Methods ....................................................................................91
 
 
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PRODUCT: V114 
13
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
LIST OF FIGURES
Figure 1
V114-021 Study Design.............................................................................19
 
 
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PRODUCT: V114 
14
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 When Administered 
Concomitantly with Influenza Vaccine in Healthy Adults 50 Years of Age or Older (PNEU-
FLU)
Short Title: Safety and Immunogenicity of V114 Administered Concomitantly with 
Influenza Vaccine
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-021 (PNEU – FLU)
Hypotheses, Objectives, and Endpoints:
The following objectives and endpoints will be evaluated in healthy adults ≥50 years of age.
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability of V114 and quadrivalent 
influenza vaccine (QIV) when administered 
concomitantly compared with V114 and QIV 
when administered nonconcomitantly with 
respect to the proportion of participants with 
adverse events (AEs).
Following any vaccination:
- Solicited injection-site AEs from Day 1 
through Day 5 postvaccination 
- Solicited systemic AEs from Day 1 through 
Day 14 postvaccination 
- Vaccine-related serious adverse events 
(SAEs) from Day 1 through Month 7
- Objective: To compare the serotype-
specific opsonophagocytic activity (OPA) 
Geometric Mean Titers (GMTs) at 30 days 
postvaccination with V114 administered 
concomitantly with QIV versus V114 
administered nonconcomitantly with QIV. 
Hypothesis (H1): V114 administered 
concomitantly with QIV is noninferior to 
V114 administered nonconcomitantly with 
QIV as measured by serotype-specific OPA 
GMTs at 30 days postvaccination with V114. 
(the statistical criterion for noninferiority 
requires the lower bound of the 2-sided 95% 
confidence interval [CI] of the OPA GMT 
ratio [concomitant/nonconcomitant] to be
greater than 0.50)
- Serotype-specific OPA responses for the 15 
serotypes in V114 at 30 days postvaccination 
with V114
 
 
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PRODUCT: V114 
15
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
- Objective: To compare the strain-specific 
hemagglutination inhibition (HAI) GMTs at 
30 days postvaccination with QIV 
administered concomitantly with V114 
versus QIV administered nonconcomitantly 
with V114. 
Hypothesis (H2): QIV administered 
concomitantly with V114 is noninferior to 
QIV administered nonconcomitantly with 
V114 as measured 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/nonconcomitant] to be greater 
than 0.50)
- Strain-specific HAI responses for the 
4 strains in QIV at 30 days postvaccination 
with QIV
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the serotype-specific 
Immunoglobulin G (IgG) Geometric Mean 
Concentrations (GMCs) at 30 days 
postvaccination with V114 administered 
concomitantly with QIV compared with 
V114 administered nonconcomitantly with 
QIV.
- Serotype-specific IgG responses for the 15 
serotypes in V114 at 30 days postvaccination 
with V114
- Objective: Within each vaccination group, 
to evaluate the serotype-specific Geometric 
Mean Fold Rises (GMFRs) and proportions 
of participants with a ≥4-fold rise from 
baseline (prevaccination with V114) to 30 
days postvaccination with V114 for both 
OPA and IgG responses for participants 
administered V114 concomitantly with QIV 
and participants administered V114 
nonconcomitantly with QIV.
- Serotype-specific OPA and IgG responses 
for the 15 serotypes in V114 at 
prevaccination with V114 and 30 days 
postvaccination with V114
 
 
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PRODUCT: V114 
16
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
- Objective: Within each vaccination group, 
to evaluate the strain-specific 
(1) GMFRs from baseline (prevaccination 
with QIV) 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 V114 and participants 
administered QIV nonconcomitantly with 
V114.
- Strain-specific HAI responses for the 4 
strains in QIV at prevaccination with QIV 
and 30 days postvaccination with QIV
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Healthy adults, 50 years of age or older
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Participant
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 9 to 10 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last serology assay 
result.
 
 
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PRODUCT: V114 
17
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Number of Participants:
Approximately 1200 participants will be randomized, with approximately 600 participants in 
each intervention group. 
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Vaccination 
Regimen
Use
Concomitant 
Group
V114
Refer to IB
Single Dose
IM
Left arm
Single Dose at 
Visit 1 (Day 1) Experimental
QIV
Refer to 
product 
labeling
Single Dose
IM
Right arm
Single Dose at 
Visit 1 (Day 1) Experimental
Placebo
NA
Single Dose
IM
Left arm
Single Dose at 
Visit 2 (Day 30) Experimental
Nonconcomitant
Group
Placebo
NA
Single Dose
IM
Left arm
Single Dose at 
Visit 1 (Day 1) Experimental
QIV
Refer to 
product 
labeling
Single Dose
IM
Right arm
Single Dose at 
Visit 1 (Day 1) Experimental
V114
Refer to IB
Single Dose
IM
Left arm
Single Dose at 
Visit 2 (Day 30) Experimental
IB = Investigator’s Brochure; IM = intramuscular; NA = not applicable; QIV = quadrivalent influenza 
vaccine (seasonal inactivated).
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 7 months from 
the time the participant signs the Informed Consent Form (ICF) through the final 
contact. 
 
 
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PRODUCT: V114 
18
PROTOCOL/AMENDMENT NO.: 021-01
V114-021-01-FINAL PROTOCOL
01-JUN-2018
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The study design is depicted in Figure 1.
INCL/EXCL = Inclusion/Exclusion
PE = Physical Examination
eVRC = electronic Vaccination Report Card
Note: V114 and placebo are administered under double-blind conditions.
* Randomization is stratified by age and history of prior PNEUMOVAX™23 vaccination.
Figure 1
V114-021 Study Design
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Intervention
Follow-up
Comments
Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
3
Telephone 
Contact
Scheduled Time: 
Day 1
Day 15
Day 30
Day 45
Day 60
Month 7
Visit Window:
Day 15 to 
Day 19
after Visit 
1a
Day 30 to
Day 44 
after Visit 
1a
Day 15 to 
Day 19
after Visit 
2b
Day 30 to 
Day 44
after Visit 
2b
Day 166 to 
Day 194 
after Visit 
2b
Administrative and General Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study procedures.
Informed Consent for Optional 
Assay Development Blood Samples 
(Selected Study Sites Only)
X
Consent for optional assay development blood samples must be 
obtained before any of these samples are collected from a 
participant.
Informed Consent for Future 
Biomedical Research
X
Consent for future biomedical research samples must be obtained 
before the blood sample (DNA sample) is collected.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Medical History
X
The participant’s medical history for the 5 years prior to study 
entry will be reviewed. History of tobacco use will also be 
collected for all participants.
Post-Enrollment Procedures
Assignment of Randomization 
Number
X
Participant Identification Card
X
Prior/Concomitant Medication and 
Nonstudy Vaccination Review
X
X
X
X
X
V114 or Placebo Administration 
(Blinded) – Left Arm
X
X
At Visit 1 (Day 1), participants will receive a single dose of either 
(blinded) V114 or placebo; at Visit 2, participants will receive a 
single dose (blinded) of the other (ie, placebo or V114, 
respectively).
Seasonal Inactivated Quadrivalent
Influenza Vaccine (QIV)
Administration (Open-label) –
Right Arm
X
At Visit 1 (Day 1), participants will receive a single dose of QIV.
 
 
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Study Period
Intervention
Follow-up
Comments
Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
3
Telephone 
Contact
Scheduled Time: 
Day 1
Day 15
Day 30
Day 45
Day 60
Month 7
Visit Window:
Day 15 to 
Day 19
after Visit 
1a
Day 30 to
Day 44 
after Visit 
1a
Day 15 to 
Day 19
after Visit 
2b
Day 30 to 
Day 44
after Visit 
2b
Day 166 to 
Day 194 
after Visit 
2b
Provide electronic Vaccination 
Report Card (eVRC)
X
Participants will be provided an eVRC at Visit 1 (Day 1) to record 
adverse events (AEs) and body temperature measurements. 
Instructions for using the eVRC will be reviewed with the 
participant.
Review eVRC Data with Participant 
X
X
X
X
Collect eVRC from Participant
X
Complete Telephone Contact 
Questionnaire
X
Site personnel will contact study participants to collect additional 
information based on a Telephone Contact Questionnaire 
provided by the Sponsor. Data to be reported from this discussion 
will include serious adverse events (SAEs) and/or any updates to 
previously reported safety information.
Safety Procedures
Complete Physical Examination 
X
To be performed by the investigator or medically qualified 
designee before vaccine is administered.
Directed Physical Examination
X
To be performed by the investigator or medically qualified 
designee before vaccine is administered.
Pregnancy Test – if applicable
X
X
A pregnancy test consistent with local requirements (sensitive to 
at least 25 IU beta human chorionic gonadotropin, β-hCG) must 
be performed before administration of study vaccine in females 
who are of reproductive potential. Urine or serum tests can be 
used, and results must be negative before vaccination can occur.
Body Temperature Measurement 
Before Vaccination
X
X
Each participant's body temperature must be taken before 
vaccination. Participants who present with fever (oral or tympanic 
temperature ≥100.4°F [≥38.0°C]; axillary or temporal temperature 
≥99.4°F [≥37.4°C]; or rectal temperature ≥101.4°F [≥38.6°C]) 
will have the vaccination delayed until fever is resolved for 72 
hours.
30-Minute Postvaccination 
Observation Period
X
X
To be performed by blinded study site personnel only.
 
 
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Study Period
Intervention
Follow-up
Comments
Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
3
Telephone 
Contact
Scheduled Time: 
Day 1
Day 15
Day 30
Day 45
Day 60
Month 7
Visit Window:
Day 15 to 
Day 19
after Visit 
1a
Day 30 to
Day 44 
after Visit 
1a
Day 15 to 
Day 19
after Visit 
2b
Day 30 to 
Day 44
after Visit 
2b
Day 166 to 
Day 194 
after Visit 
2b
AE Monitoring
X
X
X
X
X
X
AEs (serious and nonserious) are to be reported from Days 1 
through 14 following each vaccination. SAEs and deaths are to be 
reported throughout the duration of an individual’s study 
participation.
Immunogenicity Procedures
Serum for Pneumococcal 
Immunogenicity Assay (Including 
Retention Serum)
X
X
X
Blood samples must be collected before study vaccination when
applicable. After completion of opsonophagocytic activity (OPA)
and electrochemiluminescence (ECL) testing, serum samples will 
be stored to conduct any additional study-related testing as 
required by regulatory agencies or the Sponsor. Leftover sera 
from the study may be used for the development and/or validation 
of pneumococcal assays after completion of all study-related 
immunogenicity testing; this applies only to sera received from 
randomized study participants who provided consent for future 
biomedical research.
Serum for Influenza 
Immunogenicity Assay (Including 
Retention Serum)
X
X
Blood samples must be collected before study vaccination where 
applicable. After completion of hemagglutination inhibition 
(HAI) testing, serum samples will be stored to conduct any 
additional study-related testing as required by regulatory agencies 
or the Sponsor. Leftover sera from the study may be used for the 
development and/or validation of pneumococcal assays after 
completion of all study-related immunogenicity testing; this 
applies only to sera received from randomized study participants 
who provided consent for future biomedical research.
Future Biomedical Research
Blood (DNA) for Future 
Biomedical Research
X
Collected from randomized participants who provided consent for 
future biomedical research (Section 8.8).
Assay Development Samples
Serum for Optional Assay 
Development
(Selected Study Sites Only)
X
X
Collected from randomized participants (target of approximately 
120 participants) who provided consent for Assay Development
Sample collection (Section 8.10).
a When scheduling the Telephone Contact (Day 15) and Visit 2 (Day 30), the visit window “Day 1” is the date of Visit 1.
b When scheduling the Telephone Contact (Day 45), Visit 3 (Day 60), and the Follow-up Telephone Contact (Month 7), the visit window “Day 1” is the date of Visit 2.
 
 
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2
INTRODUCTION
Merck Sharp & Dohme Corp. (MSD) is developing an investigational 15-valent 
pneumococcal conjugate vaccine (PCV) (referred to as V114) for prevention of 
pneumococcal disease caused by the serotypes contained in the vaccine. V114 contains the 
13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) present in the licensed 
vaccine Prevnar 13™ (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197
protein], Wyeth Pharmaceuticals, a subsidiary of Pfizer, Inc., Philadelphia, PA), plus 
2 additional serotypes (22F, 33F).
2.1
Study Rationale
This clinical study will evaluate the safety, tolerability, and immunogenicity of V114 when 
administered concomitantly with influenza vaccine in healthy participants ≥50 years of age.
This population is at elevated risk for pneumococcal disease and its associated morbidity and 
mortality [Drijkoningen, J. J 2014] [Matias, G., et al 2014], as well as the morbidity and 
mortality associated with influenza infection. 
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 Prevnar 13™ 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].
Individuals in the target age population of this study may have received prior vaccination 
with PNEUMOVAX™23, a pneumococcal vaccine containing the polysaccharides of 23 
pneumococcal 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) and no adjuvant or carrier proteins. In the United States,
PNEUMOVAX™23 is recommended for immunocompetent adults 19 to 64 years of age 
who have certain chronic medical conditions, including chronic heart disease, chronic liver 
disease, chronic lung disease, diabetes mellitus, smoking and alcohol abuse. In order to allow 
a comprehensive assessment of the concomitant administration of V114 and influenza 
vaccine in pneumococcal vaccine-naïve adults, this study will enroll participants with and 
without prior PNEUMOVAX™23 vaccination. In accordance with recommendations
regarding the interval between vaccinations with PNEUMOVAX™23 and a PCV, 
participants must have received PNEUMOVAX™23 at least 12 months prior to study 
enrollment. 
This study is designed to evaluate the safety and tolerability of a single dose of V114 when 
administered concomitantly and nonconcomitantly (ie, 30 days after) with influenza vaccine. 
It will also evaluate whether V114 can be administered concomitantly with influenza vaccine 
without impairing the antibody response to the 15 serotypes contained in V114 and to the 
4 influenza viruses contained in the seasonal inactivated quadrivalent influenza vaccine 
 
 
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(QIV). This study will also contribute to the overall safety database and immunogenicity data 
for V114 to support initial licensure in adults.
2.2
Background
2.2.1
V114 and Pneumococcal Disease
Refer to the Investigator’s Brochure (IB) for V114 for more detailed background, including 
information on pneumococcal disease burden.
Streptococcus pneumoniae is a significant cause of disease worldwide, with clinical 
manifestations including pneumonia, meningitis, otitis media, sinusitis, and sepsis. Adults 
with comorbid conditions, in particular immunocompromised individuals, have a higher 
incidence of invasive pneumococcal disease (IPD) morbidity and mortality in all age groups 
compared to adults without the comorbid conditions [Lexau, C. A., et al 2005]. 
Currently licensed PCVs (eg, Prevnar™, Synflorix™, and Prevnar 13™) were first 
implemented in infant immunization programs in many countries worldwide. Prevnar™ was 
first licensed in 2000 and later replaced by Prevnar 13™ in 2009 for the European Union and
in 2010 for the United States. Although Prevnar 13™ is indicated for children and adults, 
Synflorix™ is only indicated for children up to 5 years of age. Widespread use of PCVs has 
reduced the burden of pneumococcal disease caused by the serotypes contained in the 
vaccines in children who were targeted by the vaccination programs and unvaccinated 
individuals from other age groups (herd protection) [Centers for Disease Control and 
Prevention 2008] [Ruckinger, S., et al 2009] [Farrell, D. J, et al 2007] [Pilishvili, Tamara, et 
al 2010] [Lexau, C. A., et al 2005] [Metlay, J. P., et al 2006] [Whitney, Cynthia G., et al 
2003] [Moore, M. R., et al 2015] [Lepoutre, A., et al 2015] [Weiss, S., et al 2015] 
[Martinelli, D., et al 2014] [Guevara, M., et al 2016] [Waight, P. A., et al 2015] [Jokinen, J., 
et al 2015] [Palmu, A. A., et al 2015] [Wagenvoort, G. H., et al 2016]. Prevnar 13™ was also 
shown to be efficacious against vaccine-type nonbacteremic pneumococcal pneumonia and 
IPD in adults ≥65 years of age [Bonten, M. J., et al 2015]. These study results were the basis 
of the recommendation from the Advisory Committee on Immunization Practices for the 
sequential administration of Prevnar 13™ followed at least 12 months later by 
PNEUMOVAX™23 in adults ≥65 years of age [Tomczyk, S., et al 2014] [Kobayashi, M., et 
al 2015].
Although cases of IPD have decreased following implementation of PCVs, an increase in 
IPD caused by serotypes not covered by currently available vaccines has been observed. 
V114 contains 2 additional serotypes (22F, 33F) compared with Prevnar 13™. The selection 
of 22F and 33F was primarily based on epidemiological importance of these 2 additional 
serotypes. Recent data from the United States suggest that 22F is the most common serotype 
not included in Prevnar 13™ in adults ≥18 years of age, causing 13% of IPD cases. Serotype 
33F is associated with an additional 5% of IPD cases [Moore, M. R., et al 2015]. Data from 
the United Kingdom also showed that, in 2013/2014, 22F and 33F are frequent serotypes in 
adults ≥65 years of age, accounting for approximately 10% and 4% of IPD cases in that age 
group, respectively [Waight, P. A., et al 2015]. Data from 2014 reported in the 2016 annual 
 
 
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epidemiological report on IPD by the European Centre for Disease Prevention and Control 
showed that both serotypes 22F and 33F are among the most common serotypes causing IPD 
[European Centre for Disease Prevention and Control 2016].
The serotypes included in V114 will provide broad coverage of the leading serotypes 
associated with pneumococcal disease worldwide. V114 is designed to meet continuing 
medical and public health needs for PCVs globally, as well as to address the emergence of 
pneumococcal disease caused by serotypes not contained in currently licensed PCVs. V114 is 
designed to offer broader serotype coverage than Prevnar 13™ against pneumococcal disease 
in both pediatric and adult populations.
2.2.1.1
Influenza Disease
Influenza occurs annually, typically circulating in the United States in late fall through early 
spring, in epidemic outbreaks of varying severity. The majority of influenza cases are not 
associated with any significant complications. However, the risk for complications, such as 
pneumonia, hospitalization, and death are higher for individuals ≥65 years of age, young 
children, and persons of any age with certain underlying health conditions [Grohskopf, L. A., 
et al 2016]. 
Annual mean rates of hospitalizations due to influenza in the United States between 1993 and 
2008 were 63.5 per 100,000 person-years. The highest rates were observed in adults ≥65 
years of age (309 per 100,000 person-years) [Zhou, H., et al 2012]. In the United States
alone, influenza infection has been responsible for 3,000 to 49,000 deaths each season (from 
the 1976-77 through the 2005-06 seasons) [Centers for Disease Control and Prevention 
(CDC) 2010] and 55,000 to 431,000 hospitalizations annually (from the 1979-80 through 
2000-01 seasons) [Thompson, W. W., et al 2004]. 
Influenza illness may be prevented through vaccination. Antibody responses are often lower 
in individuals ≥65 years of age than in younger adults, and some studies have shown 
statistically significant decline in titers in individuals ≥65 years of age during the first 6 
months postvaccination [Kunzel, W., et al 1996] [Song, J. Y., et al 2010]. While vaccine 
effectiveness can vary, recent studies showed that vaccination reduces the risk of influenza 
illness by about 40% to 60% among the overall population during seasons when most 
circulating influenza viruses are like the vaccine viruses [Grohskopf, L. A., et al 2015]. 
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
V114.
 
 
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2.2.3
Information on Other Study-related Therapy
2.2.3.1
Seasonal Inactivated Quadrivalent Influenza Vaccine
Refer to approved labeling for Fluarix Quadrivalent for detailed background information on 
the QIV used in this study.
The QIV protects against the influenza viruses that research indicates will be most common 
during the upcoming season, and includes antigens from influenza A (H1N1) virus, influenza 
A (H3N2) virus, influenza B/Victoria virus, and influenza B/Yamagata virus. 
In the United States, annual influenza vaccination is recommended for all individuals ≥6 
months of age [Grohskopf, L. A., et al 2017]. Most countries in the European Union 
recommend annual influenza vaccination for individuals at risk for influenza associated 
morbidity and mortality, such as children, older adults, pregnant women and individuals with 
chronic diseases, and for health care workers [ECDC 2017].
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
intervention during participation, as clinical studies are designed to provide information 
about the safety and effectiveness of an investigational vaccine.
While the impact of concomitant administration of V114 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 2018/2019 influenza season
through participation in this study based on the experience of concomitant administration of 
Prevnar 13™ and influenza vaccines [Frenck, R. W. Jr., et al 2012] [Schwarz, T. F., et al 
2011] [Schwarz, T. F. 2013].
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and the Informed Consent Form (ICF).
 
 
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3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
The following objectives and endpoints will be evaluated in healthy adults ≥50 years of age.
Objectives
Endpoints
Primary
•
Objective: To evaluate the safety and 
tolerability of V114 and quadrivalent 
influenza vaccine (QIV) when 
administered concomitantly compared 
with V114 and QIV when administered 
nonconcomitantly with respect to the 
proportion of participants with adverse 
events (AEs).
Following any vaccination:
•
Solicited injection-site AEs from Day 1 
through Day 5 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 14 postvaccination 
•
Vaccine-related serious adverse events 
(SAEs) from Day 1 through Month 7

Objective: To compare the serotype-
specific opsonophagocytic activity 
(OPA) Geometric Mean Titers (GMTs) at 
30 days postvaccination with V114 
administered concomitantly with QIV
versus V114 administered 
nonconcomitantly with QIV.
Hypothesis (H1): V114 administered 
concomitantly with QIV is noninferior to 
V114 administered nonconcomitantly 
with QIV as measured by serotype-
specific OPA GMTs at 30 days 
postvaccination with V114.
(the statistical criterion for noninferiority 
requires the lower bound of the 2-sided 
95% confidence interval [CI] of the OPA 
GMT ratio 
[concomitant/nonconcomitant] to be 
greater than 0.50)
•
Serotype-specific OPA responses for the 
15 serotypes in V114 at 30 days 
postvaccination with V114
 
 
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Objectives
Endpoints

Objective: To compare the strain-
specific hemagglutination inhibition 
(HAI) GMTs at 30 days postvaccination 
with QIV administered concomitantly 
with V114 versus QIV administered 
nonconcomitantly with V114. 
Hypothesis (H2): QIV administered 
concomitantly with V114 is noninferior 
to QIV administered nonconcomitantly 
with V114 as measured 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/nonconcomitant] to be 
greater than 0.50)
•
Strain-specific HAI responses for the 
4 strains in QIV at 30 days 
postvaccination with QIV
Secondary
•
Objective: To evaluate the serotype-
specific Immunoglobulin G (IgG)
Geometric Mean Concentrations (GMCs)
at 30 days postvaccination with V114 
administered concomitantly with QIV 
compared with V114 administered
nonconcomitantly with QIV.
•
Serotype-specific IgG responses for the 
15 serotypes in V114 at 30 days 
postvaccination with V114
•
Objective: Within each vaccination 
group, to evaluate the serotype-specific 
Geometric Mean Fold Rises (GMFRs)
and proportions of participants with a ≥4-
fold rise from baseline (prevaccination 
with V114) to 30 days postvaccination
with V114 for both OPA and IgG 
responses for participants administered 
V114 concomitantly with QIV and
participants administered V114 
nonconcomitantly with QIV.
•
Serotype-specific OPA and IgG 
responses for the 15 serotypes in V114 at 
prevaccination with V114 and 30 days 
postvaccination with V114
 
 
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Objectives
Endpoints
•
Objective: Within each vaccination 
group, to evaluate the strain-specific 
(1) GMFRs from baseline
(prevaccination with QIV) 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 
V114 and participants administered QIV 
nonconcomitantly with V114.
•
Strain-specific HAI responses for the 4 
strains in QIV at prevaccination with 
QIV and 30 days postvaccination with 
QIV
4
STUDY DESIGN
4.1
Overall Design
Approximately 1200 participants will be randomly assigned in a 1:1 ratio to receive either 
V114 with concomitant QIV or V114 with nonconcomitant QIV. Randomization will be 
stratified by age (50 to 64 years, 65 to 74 years, and 75 years or older; at least 50% of the 
participants will be 65 years of age or older) and by history of prior PNEUMOVAX™23 
vaccination (yes and no; at least 50% of participants are to be PNEUMOVAX™23-naïve).
Participants enrolled in the concomitant group will receive V114 (blinded) in the left arm and 
QIV (open label) in the right arm on Day 1, and then will receive placebo (blinded) in the left
arm 30 days later at Visit 2 (Day 30). 
Participants enrolled in the nonconcomitant group will receive placebo (blinded) in the left
arm and QIV (open label) in the right arm on Day 1, and then will receive V114 (blinded) in 
the left arm 30 days later at Visit 2 (Day 30).
Participants will be followed for local and systemic AEs through Day 14 following each 
vaccination. Information for SAEs and deaths, regardless of whether the events are 
considered to be vaccine-related by the investigator, will be collected from the time consent 
is signed through completion of participation in the study. An external Data Monitoring 
Committee (DMC) will conduct a periodic review of safety and tolerability data for the adult 
V114 Phase 3 program. A description of the structure, function, and guidelines for decision-
making by 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.
 
 
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Blood samples for immunogenicity assays will be drawn immediately before the first V114 
or placebo vaccination and the QIV vaccination at Visit 1 (Day 1), before vaccination at Visit 
2 (Day 30), and at Visit 3 (Day 60).
After completion of OPA, electrochemiluminescence (ECL), and HAI testing, serum samples 
will be stored to conduct any additional study-related testing as required by regulatory 
agencies or the Sponsor. Leftover sera from the study may be used for the development 
and/or validation of pneumococcal assays after completion of all study-related 
immunogenicity testing; this applies only to sera received from randomized study 
participants who provided consent for future biomedical research.
Adult participants at selected study sites who consent (target of approximately 120 
participants) will have 2 optional additional blood samples drawn (50 mL at each of Visits 1 
and 3) to support further development, validation, and performance of anti-pneumococcal 
antibody assays.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is conducted in a population (healthy adults ≥50 years of age) at elevated risk for 
pneumococcal and influenza disease and associated morbidity and mortality [Drijkoningen, J. 
J 2014]. 
The concomitant and nonconcomitant administration of V114 and QIV in this study allows 
for meaningful comparisons of safety, tolerability, and immunogenicity between the 2 
administration types.
In order to demonstrate that concomitant administration of V114 and QIV does not adversely 
affect the antibody response to or safety profile of either vaccine, concomitant and 
nonconcomitant administration groups are being generated in this study through the use of a 
placebo to V114. A saline placebo is being used to maintain blinded vaccine administration 
on Day 1 and Day 30. Both groups of randomized participants will receive V114 in the study.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
4.2.1.1.1
Pneumococcal Immunogenicity Endpoints
Sera from participants will be used to measure vaccine-induced, serotype-specific OPA and 
IgG responses for all 15 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 
33F) included in V114 using the Multiplexed Opsonophagocytic Assay (MOPA) assay and 
pneumococcal electrochemiluminescence (PnECL) assay.
 
 
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Several studies have shown a positive correlation between serotype-specific IgG antibody 
concentrations and OPA titers in children and adults [Centers for Disease Control and 
Prevention 2010] [Anttila, M., et al 1999] [Romero-Steiner, S., et al 1997]. OPA assesses 
levels of functional antibodies capable of opsonizing pneumococcal capsular polysaccharides 
for presentation to phagocytic cells for engulfment and subsequent killing, and therefore is 
considered an important immunologic surrogate for protection against IPD in adults. It is 
noted that threshold values that correlate with protection in adults have not been defined for 
either assay.
Details on the immunogenicity endpoints evaluated in this study can be found in Section 
9.4.1.
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 to a homologous or related 
influenza virus and 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 demonstrated 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 primary endpoints. 
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in previous studies, published data from marketed PCVs, and feedback 
received from regulatory agencies during product development. The electronic Vaccination 
Report Card (eVRC) used to record AEs during the postvaccination periods, as defined in 
Section 8.1.9, was structured as recommended in the final US Food and Drug Administration 
Patient Reported Outcome Guidance [U.S. Food and Drug Administration 2009]. 
Details on the safety endpoints evaluated in this study can be found in Section 8.3.4 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
 
 
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4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Placebo is used in this study in order to maintain blinding to the concomitant and 
nonconcomitant group assignment. The placebo is sterile saline for injection. 
4.3
Justification for Dose
The dosing regimen of V114 is similar to that used in previous adult V114 clinical studies in 
which 1 dose has resulted in a robust immune response (refer to the V114 IB for more 
detailed information on dose selection).
The dose of QIV for use in this study is the approved dose.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last serology assay result.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
 
 
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5
STUDY POPULATION
Healthy adult males and females (≥50 years of age) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. The participant is in good health. Any underlying chronic illness must be documented to 
be in stable condition.
Demographics
2. Participant is male or female ≥50 years of age.
Female Participants
3. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least 1 of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP who agrees to use 1 of the contraceptive methods as defined in Appendix 
5 during the treatment period and for at least 6 weeks after the last dose of study 
intervention.
Informed Consent
4. The participant provides written informed consent for the study. 
The participant may also provide consent for future biomedical research and/or Assay 
Development Sample collection. However, the participant may participate in the main 
study without participating in future biomedical research or Assay Development Sample 
collection.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. 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 before Visit 1 (Day 1).
2. Known hypersensitivity to any component of pneumococcal polysaccharide vaccine, 
PCV, or any diphtheria toxoid-containing vaccine.
 
 
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3. Known hypersensitivity to any component of influenza vaccines, including egg protein, 
or following a previous dose of any influenza vaccine.
4. 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).
5. Has experienced Guillain-Barré syndrome within 6 weeks of receiving a previous 
influenza vaccination.
6. Coagulation disorder contraindicating intramuscular vaccinations.
7. * Recent febrile illness (defined as oral or tympanic temperature ≥100.4°F [≥38.0°C]; 
axillary or temporal temperature ≥99.4°F [≥37.4°C]; or rectal temperature ≥101.4°F 
[≥38.6°C]) or received antibiotic therapy for any acute illness occurring within 72 hours 
before receipt of study vaccine.
8. History of malignancy ≤5 years prior to signing informed consent, except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer.
9. A WOCBP who has a positive urine or serum pregnancy test before the first vaccination 
at Visit 1 (Day 1). 
Prior/Concomitant Therapy
10. Prior administration of any PCV (eg, Prevnar 13™) or is expected to receive any 
pneumococcal vaccine during the study outside of the protocol.
11. Prior administration of PNEUMOVAX™23 ≤12 months before Visit 1. 
Note: individuals who received PNEUMOVAX™23 >12 months prior to Visit 1 are 
eligible for this study. 
12. Previous receipt of influenza vaccine during the 2018/2019 flu season or expected to
receive any influenza vaccine during the study outside of the protocol.
13. Received systemic corticosteroids (≥20 mg/day prednisone equivalent) for ≥14 
consecutive days and has not completed intervention at least 30 days before study entry. 
14. Received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) within 14 days before vaccination. 
(Note: Topical, ophthalmic, intra-articular or soft-tissue [eg, bursa, tendon steroid
injections], and inhaled/nebulized steroids are permitted).
15. Receiving immunosuppressive therapy, including chemotherapeutic agents used to treat 
cancer or other conditions, and interventions associated with organ or bone marrow 
transplantation, or autoimmune disease. 
16. *Received any non-live vaccine within the 14 days before receipt of any study vaccine or 
is scheduled to receive any non-live vaccine within 30 days following receipt of any 
study vaccine.
 
 
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17. *Received any live vaccine within 30 days before receipt of any study vaccine or is 
scheduled to receive any live vaccine within 30 days following receipt of any study 
vaccine.
18. Received a blood transfusion or blood products, including immunoglobulin within the 6 
months before receipt of study vaccine or is scheduled to receive a blood transfusion or 
blood product within 30 days of receipt of study vaccine. Autologous blood transfusions 
are not considered an exclusion criterion.
Prior/Concurrent Clinical Study Experience
19. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
Other Exclusions 
20. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history (within the last year) of drug or alcohol abuse or dependence as 
assessed by the study investigator.
21. Has history or current evidence of any condition, therapy, lab 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.
22. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, the 
Day 1 Visit may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who 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 (V114, placebo, and QIV) 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
 
 
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The study interventions to be used in this study are outlined in Table 1.
Table 1
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength
Dosage 
Level
Route of 
Admin
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Concomitant 
Group
Experimental
V114
Biological/
Vaccine
Sterile suspension 
(prefilled syringe)
Refer to IB
0.5 mL
IM
Left arm
Single Dose at Visit
1 (Day 1)
Experimental
IMP
Central
Concomitant 
Group
Experimental
QIVa
Biological/
Vaccine
Sterile solution 
(prefilled syringe)
Refer to product 
labeling
0.5 mL
IM
Right arm
Single Dose at Visit
1 (Day 1)
Experimental
IMP
Central
Concomitant 
Group
Experimental
Placebo
(Sterile Saline)
Biological/
Vaccine
Ampule
N/A
0.5 mL
IM
Left arm
Single Dose at Visit
2 (Day 30)
Experimental
IMP
Central
Nonconcomitant 
Group
Experimental
Placebo 
(Sterile Saline)
Biological/
Vaccine
Ampule
N/A
0.5 mL
IM
Left arm
Single Dose at Visit
1 (Day 1)
Experimental
IMP
Central
Nonconcomitant 
Group
Experimental
QIVa
Biological/
Vaccine
Sterile solution 
(prefilled syringe)
Refer to product 
labeling
0.5 mL
IM
Right arm
Single Dose at Visit
1 (Day 1)
Experimental
IMP
Central
Nonconcomitant 
Group
Experimental
V114
Biological/
Vaccine
Sterile suspension 
(prefilled syringe)
Refer to IB
0.5 mL
IM
Left arm
Single Dose at Visit
2 (Day 30)
Experimental
IMP
Central
a Fluarix Quadrivalent (Influenza Vaccine) 
Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; IMP = investigational medicinal product; NIMP = non-investigational medicinal 
product; QIV = quadrivalent influenza vaccine (seasonal inactivated).
The definition of IMP and NIMP is based on guidance issued by the European Commission. Regional and/or country differences of the definition of IMP/NIMP 
may exist. In these circumstances, local legislation is followed.
All supplies indicated in Table 1 will be provided per the “Sourcing” column depending upon local country operational requirements. 
Every attempt should be made to source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
 
 
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6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to receive either V114 concomitantly with QIV or V114 
nonconcomitantly with QIV.
 
 
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6.3.2
Stratification
Treatment allocation/randomization will be stratified according to the following factors at 
time of randomization:

Age (50 to 64 years of age, 65 to 74 years of age, and ≥75 years of age). At least 50% 
of the participants will be ≥65 years of age.

History of prior PNEUMOVAX™23 vaccination (Yes and No). At least 50% of 
participants will be PNEUMOVAX™23-naïve. 
6.3.3
Blinding
A double-blinding technique will be used. V114 and placebo will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study site personnel. The 
participant and the investigator who is involved in the clinical evaluation of the participants 
will remain blinded to the group assignments.
Because the V114 and placebo have a different appearance, a member of the study site staff 
will be unblinded for the purposes of receiving, maintaining, preparing and/or dispensing, 
and administering these study vaccines. QIV will also be prepared and/or dispensed and 
administered by unblinded study site staff for consistency even though it will be provided 
open-label in this study. In order to avoid bias, the unblinded study personnel will have no 
further contact with study participants for any study-related procedures/assessments after 
administration of study vaccines, which includes all safety follow up procedures. 
Additionally, blinded site personnel will not be present in the exam room when study 
vaccines are administered. Contact between participants and unblinded study personnel after 
vaccination administration is strictly prohibited. 
Blinded site personnel will be responsible for all safety and immunogenicity follow-up 
procedures after vaccine administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) and Merck Research Laboratories employees 
directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
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 plan for V114 or placebo and QIV vaccinations at 
Visit 1 (Day 1) and placebo or V114 vaccination at Visit 2 (Day 30) require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
 
 
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6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medication or vaccination 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.
Listed below (items 1 to 4) are specific restrictions for concomitant therapy or vaccination 
during the course of the study: 
1. Any administration of a nonstudy pneumococcal vaccine is prohibited during the 
study.
2. Live and non-live vaccines may only be administered prior to or following the receipt 
of study vaccine according to the time frames specified in exclusion criteria 
(Section 5.2).
Vaccines should not be given within 30 days after receipt of study vaccine. 
Participants should not receive an influenza vaccine during the 2018/2019 flu season 
outside of the study.
3. Participants should not receive systemic corticosteroids (≥20 mg/day prednisone 
equivalent for ≥14 consecutive days) starting from 30 days prior to through 30 days 
following each study vaccination. Note: Topical, ophthalmic, intra-articular or soft-
tissue (eg, bursa, tendon steroid injections), and inhaled/nebulized steroids are 
permitted.
4. Participants should not receive systemic corticosteroids exceeding physiologic 
replacement doses (prednisone equivalent dose >5 mg/day) within 14 days before any 
vaccination. Note: Topical, ophthalmic, intra-articular or soft-tissue (eg, bursa, tendon 
steroid injections), and inhaled/nebulized steroids are permitted.
Any deviation from the above requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
 
 
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6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided open label; therefore, an unblinded 
pharmacist or unblinded qualified study site personnel will be used to maintain the blinding 
of study staff who are directly involved in the clinical evaluation of participants in the study. 
Study intervention identity (name, strength, or potency) is included in the label text; 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). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.12 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccinations
will still continue to participate in the study as specified in Section 1.3 and Section 8.13.3, 
unless the participant withdraws consent (Section 7.2).
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.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant requests to discontinue study intervention.
 
 
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•
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 
with placebo/V114 vaccine at Visit 2 (Day 30).
For participants who are discontinued from study intervention but continue to be monitored 
in the study, see Section 1.3 and Section 8.13.3 for those procedures to be completed at each 
specified visit.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.11. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
 
 
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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 or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Study 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.
•
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.
Table 2 shows the approximate blood volumes drawn by study visit and by sample type. The 
maximum amount of blood collected from each participant at each study visit for 
immunogenicity assessments will not exceed 40 mL and the total amount of blood for the 
entire study will not exceed 120 mL. For those participants that consent to future biomedical 
research, an additional blood sample of approximately 8.5 mL will be taken. For those at 
selected study sites who consent to provide optional assay development blood samples (target 
of approximately 120 participants), additional blood samples of approximately 50 mL will be 
taken at Visit 1 (Day 1) and Visit 3 (Day 60).
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 Types
Study Visit
Visit 1
Day 1
Visit 2
Day 30
Visit 3
Day 60
Blood parameter
Approximate Blood Volume (mL)
Serum for immunogenicity assays (including retention serum)
40 mL
40 mL
40 mL
Blood (DNA) for future biomedical research
8.5 mL
N/A
N/A
Optional assay development blood samples a
50 mL
N/A
50 mL
Expected totala
48.5 mL
40 mL
40 mL
a Optional assay development blood samples will be obtained from a total of only approximately 120 
participants and therefore the volumes associated with these samples are not included in the Expected total 
values. For participants who consent to provide optional assay development blood samples, the total blood 
volumes drawn will be approximately 98.5 mL, 40 mL, and 90 mL at Visit 1, Visit 2, and Visit 3, respectively.
DNA = deoxyribonucleic acid
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant prior to participating in a clinical 
study or future biomedical research . If there are changes to the participant’s status during the 
study (eg, health or age of majority requirements), the investigator or medically qualified 
designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant should be 
informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent form or addendum to 
the original consent form that captures the participant’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
 
 
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
8.1.1.3
Consent and Collection of Blood Samples for Optional Assay Development
At selected study sites (target of approximately 120 participants), the investigator or 
medically qualified designee will explain the consent for the optional assay development 
blood samples to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the optional assay development blood 
samples collection. A copy of the informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
If the participant meets any of the exclusion criteria with an asterisk (*), Visit 1 (Day 1) may 
be rescheduled for a time when these criteria are not met.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee before 
vaccination at Visit 1 (Day 1). The participant’s medical history for the 5 years prior to Visit 
1 (Day 1) will be obtained to ensure that the participant satisfies the inclusion and exclusion 
criteria of the study. History of tobacco use will also be collected for all participants.
 
 
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations and 
medications taken by the participant within 30 days before the first dose of study vaccine at 
Visit 1 (Day 1).
Any history of prior PNEUMOVAX™23 vaccination will be reviewed and recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
New and/or concomitant medications taken after Visit 1 (Day 1) and nonstudy vaccines 
received since Visit 1 will be recorded with the eVRC as specified in Section 8.3.4.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.13.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
V114 or placebo will be administered at Visit 1 (Day 1) and placebo or V114 will be 
administered at Visit 2 (Day 30). QIV will be administered at Visit 1 (Day 1).
V114 should be removed from the refrigerator no more than 1 hour before vaccination. The 
time of removal and time of vaccination should be documented in the participant’s chart.
 
 
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Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer V114 or placebo and QIV at the study site. QIV will be administered open-
label.
Prior to administration of V114, the unblinded pharmacist should shake the product 
vigorously to obtain a homogenous white suspension. If white-colored insoluble particle 
appears, the unblinded pharmacist should use rapid, horizontal hand shaking for 5 to 10 
seconds while holding the syringe in between the thumb and index finger until complete 
resuspension. This action should be repeated, as necessary. If appearance is otherwise, the 
vaccine should not be administered. The vaccine should not be used if the vaccine cannot be 
resuspended.
For QIV, study personnel should follow the preparation and administration instructions for 
Fluarix Quadrivalent (influenza vaccine) as specified in the product label. 
Study vaccine will be administered as a single 0.5-mL intramuscular injection in the deltoid 
region of the participant’s arm. Vaccination information, such as Component Identification 
Number and time of vaccination, must be recorded on the appropriate electronic case report 
form (eCRF) per the Data Entry Guidelines.
All safety and immunogenicity assessments will be conducted by blinded personnel, and the 
participant will be blinded to the intervention (ie, V114 then placebo vs placebo then V114).
8.1.8.1
Timing of Dose Administration
Vaccinations may be administered at any time of day, and without regard to timing of meals. 
Each participant's body temperature must be taken before each vaccine administration. 
Individuals who present with fever (oral or tympanic temperature ≥100.4°F [≥38.0°C]; 
axillary or temporal temperature ≥99.4°F [≥37.4°C]; or rectal temperature ≥101.4°F 
[≥38.6°C]) will have the vaccination delayed until fever is resolved for at least 72 hours.
The collection of blood samples and administration of pregnancy tests (if applicable) must be 
done before each vaccine administration. 
All participants will be observed for 30 minutes after each vaccination for any immediate 
reactions. This observation must be performed by blinded site personnel for all study 
vaccines (Section 1.3 and Section 6.3.3).
8.1.9
Electronic Vaccination Report Card
The eVRC was developed to be administered electronically via a hand-held device. This item 
was structured as recommended in the final Food and Drug Administration Patient Reported 
Outcome Guidance [U.S. Food and Drug Administration 2009]. The investigator or delegate 
will train the participant in the use of the eVRC at Visit 1 (Day 1). 
 
 
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Temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or vaccinations will be recorded on the eVRC as 
described in Section 1.3 and Section 8.3.4. The investigator or delegate will review the data 
captured on the eVRC with the participant at Telephone Contact (Day 15), Visit 2 (Day 30), 
Telephone Contact (Day 45), and Visit 3 (Day 60).
For the AEs outlined above, the investigator will use the information provided by the 
participant both on the eVRC, and verbally at the time of eVRC review, to apply the 
appropriate assessment of intensity and toxicity as described in Appendix 3.
8.1.10
Telephone Contact Questionnaire
Site personnel will contact study participants 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 prior to completion of the protocol-specified
vaccinations should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (Visit 3 [Day 60]) should be performed if the participant 
can attend during the Day 30 window or the Day 60 window. If the participant withdraws at 
any other time, the Month 7 Telephone Contact activities should be performed (at the time of 
withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
 
 
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8.1.12
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal 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 should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
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 is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
 
 
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8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced OPA and IgG for serotypes 
included in V114. These endpoints will be tested for all blood draws. 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 GMTs. 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.
Measurement of serotype-specific IgG will be measured using the PnECL v2.0 assay to 
assess the concentration of binding antibodies to capsular polysaccharide of S. pneumoniae 
for the serotypes included in the study vaccines.
The HAI assay will be used to measure influenza vaccine-induced antibodies which inhibit 
hemagglutination. The HAI results reflect the degree of hemagglutination inhibition.
8.2.1
Multiplex Opsonophagocytic Assay (MOPA)
The MOPA, developed and published by Professor Moon Nahm (Director of the United 
States World Health Organization pneumococcal serology reference laboratory and National 
Institutes of Health pneumococcal reference laboratories), is a multiplexed OPA assay 
capable of measuring 4 serotypes at a time, against a total of 16 serotypes of pneumococci 
[Burton, Robert L. and Nahm, Moon H. 2006]. The OPA is an antibody-mediated killing 
assay that measures the ability of human serum to kill S. pneumoniae serotypes with the help 
of complement and phagocytic effector cells. The ability of the assay to simultaneously test 4 
serotypes/run reduces the amount of serum needed for testing. The assay readout is the 
opsonization index, which is the reciprocal of the highest dilution that gives ≥50% bacterial 
killing, as determined by comparison to assay background controls. MSD has developed and 
optimized the MOPA in a high throughput microcolony platform. The MOPA assay for all 
15 V114 serotypes has undergone validation. The validation study evaluated various 
performance parameters of the assay including precision, relative accuracy/dilutional 
linearity, and specificity. The validation results were evaluated against prespecified 
acceptance criteria for each of the parameters.
8.2.2
Electrochemiluminescence (ECL)
MSD has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 pneumococcal polysaccharide 
serotypes contained in V114. The PnECL v2.0 assay is based on the Meso-Scale Discovery 
technology, which employs disposable multi-spot microtiter plates. The benefits of the ECL 
multiplex technology over the prior enzyme-linked immunosorbent assay methodology 
include speed, equivalent or better sensitivity, increased dynamic range, the ability to 
multiplex, and reduction in required serum sample and reagent volumes. The measurement of 
 
 
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immune responses to the 15 serotypes included in V114 is performed using an assay format
consisting of 2 groups of 7 and 8 serotypes each. The PnECL v2.0 assay for all 15 serotypes 
has undergone validation. The validation study evaluated various performance parameters of 
the assay including precision, ruggedness, relative accuracy, dilutional linearity, selectivity, 
and specificity. The validation results were evaluated against pre-specified acceptance 
criteria for each of the parameters.
8.2.3
Hemagglutination Inhibition (HAI) Assay
The HAI assay is based on the World Health Organization (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 (RBCs), causing them to agglutinate. It 
is a traditional method to measure vaccine-induced antibodies to hemagglutinin that bind to
the hemagglutinin molecule, thereby inhibiting hemagglutination. The HAI test is generally 
performed using microtiter plates. In a first step, 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 RBCs, the degree of inhibition of 
agglutination compared to strain-specific reference sera is being 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. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood/tissue volumes drawn by visit and by 
sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 1 (Day 1). A 
directed physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 2 (Day 30). 
Investigators should pay special attention to clinical signs related to previous illnesses.
8.3.2
Pregnancy Test
A pregnancy test consistent with local requirements (sensitive to at least 25 IU beta human 
chorionic gonadotropin [β-hCG]) must be performed before vaccination at Visit 1 (Day 1) 
and Visit 2 (Day 30) in WOCBP as described in Section 1.3. Urine or serum tests can be 
used, and results must be negative before vaccination can occur.
 
 
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8.3.3
Body Temperature Measurement
Each participant's body temperature must be taken before vaccination, as described in 
Section 1.3.
Oral body temperatures will also be documented by participants using their eVRC during the 
eVRC-specified postvaccination follow-up period (Section 8.3.4).
For this study, any oral or tympanic temperature ≥100.4°F (≥38.0°C), axillary or temporal 
temperature ≥99.4°F (≥37.4°C), or rectal temperature ≥101.4°F (≥38.6°C) will be considered 
an AE of fever. All fevers must be reported Day 1 through Day 14, unless the fever is a 
symptom of another reported AE.
8.3.4
Safety Assessments and Use of the eVRC
All participants will be observed for 30 minutes after each vaccination for any immediate 
reactions. If any immediate AEs are observed during this period, the time at which the event 
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event, must be recorded on the appropriate eCRF.
Participants will use the eVRC (Section 8.1.9) to document the following information:

Oral body temperatures measured Day 1 (day of vaccination) through Day 5 
postvaccination;

Solicited injection-site AEs (redness/erythema, swelling, and tenderness/pain) Day 1 
through Day 5 postvaccination;

Solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, and 
tiredness/fatigue) Day 1 through Day 14 postvaccination;

Any other injection-site or systemic AEs Day 1 through Day 14 postvaccination; and

Concomitant medications and nonstudy vaccinations Day 1 to Day 14 postvaccination
8.3.5
Clinical 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.
•
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 (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver or surrogate).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE, as well as other reportable safety events. 
Investigators remain responsible for following up AE, 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 consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the day of allocation/randomization to the first vaccination and from the day of each 
vaccination through 14 days postvaccination.  SAEs must also be reported throughout the 
duration of the individual’s participation in the study, regardless of whether or not related to 
the Sponsor’s product.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
1. A death that occurs prior to the participant completing the study.
OR
2. An SAE that is considered by an investigator who is a qualified physician to be 
vaccine related.
 
 
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Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe to 
Report Event 
and Follow-
up 
Information 
to Sponsor:
Nonserious Adverse 
Event 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion of 
study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Events of Clinical 
Interest
There are no Events of Clinical Interest for this study.
Not 
applicable
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE 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 AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
 
 
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest (ECIs)
There are no events of clinical interest for this study.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study 
vaccine in any 24-hour period.
No specific information is available on the treatment of overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
All reports of overdose must be reported by the investigator within 5 calendar days to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in 
the electronic data collection (EDC) data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
DNA for future research
•
Leftover study serum after completion of immunogenicity testing stored for future 
research
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
 
 
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8.10
Optional Assay Development Blood Sample Collection
Each participant enrolled at the selected study sites will be asked to provide optional assay 
development blood samples until approximately 120 participants have consented.
Each participant providing consent will have a 50-mL sample of blood collected at Visit 1 
(Day 1) and Visit 3 (Day 60) (100 mL total). These additional blood samples will be used to 
establish a proficiency panel for a particular assay, 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
Biomarkers
Biomarkers are not evaluated in this study.
8.12
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.13
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.13.1
Screening
Screening procedures will be conducted at Visit 1 (Day 1) as outlined in Section 1.3.
8.13.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
8.13.3
Discontinued Participants Continuing to be Monitored in the Study
A participant may discontinue from study intervention (ie, vaccination) but continue to 
participate in subsequent protocol visits as outlined in Section 1.3, as long as the participant 
does not withdraw consent. Protocol-specified activities, including blood draws for 
immunogenicity assessments and AE monitoring, should occur at these visits.
 
 
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to unblinding, changes are made to hypotheses, or the statistical 
methods related to those hypotheses, then the protocol will be amended (consistent with ICH 
Guideline E-9). Changes to other nonconfirmatory analyses made after the protocol has been 
finalized, but prior to unblinding/final database lock, will be documented in a Supplemental 
Statistical Analysis Plan and referenced in the Clinical Study Report (CSR) for the study. 
Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of V114 When Administered Concomitantly with 
Influenza Vaccine in Healthy Adults 50 Years of Age or Older (PNEU 
– FLU)
Intervention Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 with 
concomitant QIV or V114 with nonconcomitant QIV, respectively. 
Randomization will be stratified into 6 groups according to the
participant’s age (50 to 64 years, 65 to 74 years, and ≥75 years) and 
history of prior PNEUMOVAX™23 vaccination (Yes and No) at the 
time of randomization as described in Section 6.3.2.
Analysis Populations
Immunogenicity: Per Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:

Serotype-specific OPA GMTs at 30 days postvaccination with 
V114

Strain-specific HAI GMTs at 30 days postvaccination with QIV
Safety: 

Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling, tenderness/pain) from Day 1 through 
Day 5 following any vaccination

Proportion of participants with solicited systemic AEs (muscle 
pain/myalgia, joint pain/arthralgia, headache, and 
tiredness/fatigue) from Day 1 through Day 14 following any 
vaccination

Proportion of participants with vaccine-related SAEs from Day 1 
to Month 7
Key Secondary Endpoints

Serotype-specific IgG GMCs at 30 days postvaccination with
V114
 
 
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Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes in V114 and each of the 4 influenza strains in 
QIV separately. 
The primary objective (to compare the serotype-specific OPA GMTs 
at 30 days postvaccination with V114 between participants 
administered V114 concomitantly with QIV versus participants 
administered V114 nonconcomitantly with QIV) will be assessed via 
the following noninferiority hypotheses:
H0: GMT1/GMT2 ≤0.50 versus 
H1: GMT1/GMT2 >0.50
where GMT1 is the serotype-specific OPA GMT for the concomitant 
group and GMT2 is the serotype-specific OPA GMT for the 
nonconcomitant group. The primary objective (to compare the strain-
specific HAI GMTs at 30 days postvaccination with QIV between 
participants administered QIV concomitantly with V114 versus 
participants administered QIV nonconcomitantly) will be assessed via 
the following noninferiority hypotheses:
H0: GMT1/GMT2 ≤0.50 versus 
H1: GMT1/GMT2 >0.50
where GMT1 is the strain-specific HAI GMT for the concomitant 
group and GMT2 is the strain-specific HAI GMT for the 
nonconcomitant group. The serotype-specific OPA GMTs at 30 days 
postvaccination with V114 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 15 serotypes in 
V114 and strain-specific HAI GMT ratios for each of the 4 strains in 
QIV, respectively. Serotype-specific OPA GMT ratios and strain-
specific HAI GMT ratios estimation, 95% CIs, and results from the
hypothesis tests (i.e., 1-sided p-values) will be calculated using a 
constrained longitudinal data analysis (cLDA) method utilizing data 
from both vaccination groups. Estimation of the serotype-specific IgG 
GMC ratios and 95% CIs will be calculated using the cLDA method.
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 endpoints) and 95% CIs (Tier 1 and Tier 2 endpoints) 
will be provided for between-group differences in the percentage of 
participants with events; these analyses will be performed using the
unstratified Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985].
Interim Analyses
To support the periodic review of safety and tolerability data across the 
V114 Phase 3 program, an external unblinded statistician will provide 
unblinded interim safety summaries to an independent external DMC 
for their review. There are no plans to conduct an interim analysis of 
unblinded immunogenicity data in this study.
Multiplicity
The overall success of the study requires demonstrating success on all 
15 pneumococcal serotypes and all 4 influenza strains included in the 
primary immunogenicity hypotheses. This approach controls the 1-
sided type-I error rate at 0.025, and no multiplicity adjustment is
required.
 
 
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Sample Size and Power
Immunogenicity:
This study will randomize approximately 600 participants into the 
concomitant group and 600 participants into the nonconcomitant group 
and has approximately 87% power overall for demonstrating 
noninferiority of OPA GMT ratio for the 15 pneumococcal serotypes 
included in V114 and noninferiority of HAI GMT ratio for the 4 
influenza strains in QIV at an overall 1-sided 2.5% alpha-level. 
Safety: 
Section 9.9.2 provides information about the ability of this study to 
estimate the incidence of AEs within and between the concomitant and 
nonconcomitant group.
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.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented using an IRT.
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 analysis endpoints that will be evaluated for within- and/or
between-intervention differences are listed below.
9.4.1
Immunogenicity Endpoints
A description of immunogenicity assessments is contained in Section 8.2. 
The primary immunogenicity analysis endpoints include: 

Serotype-specific OPA GMTs at 30 days postvaccination with V114

Strain-specific HAI GMTs at 30 days postvaccination with QIV
 
 
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The secondary immunogenicity analysis endpoints include:

Serotype-specific IgG GMCs at 30 days postvaccination with V114

Serotype-specific GMFRs and proportions of participants with a 4-fold rise from 
baseline (prevaccination with V114) to 30 days postvaccination with V114 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)
9.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 8.4. The analysis of safety 
results is described in Section 9.6.2.
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain) from Day 1 through Day 5 following any vaccination

Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue) from Day 1 through Day 14
following any vaccination

Proportions of participants with the broad AE categories consisting of any AE, a 
vaccine-related AE, a SAE, a death, an AE which is both vaccine-related and serious, 
an AE which leads to discontinuation

Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 5 following any 
vaccination
 
 
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9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The Per-Protocol (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 endpoints. Potential deviations that may result in the exclusion of a 
participant from the PP population for all immunogenicity analyses include:

Failure to receive any study vaccine at Visit 1 (Day 1)

Failure to receive correct clinical material as per randomization schedule at Visit 1 
(Day 1) (ie, participants who were cross-treated)

Receipt of a prohibited medication or prohibited vaccine prior to study vaccination
Additional 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 any study vaccine at Visit 2 (Day 30)

Failure to receive correct clinical material as per randomization schedule at Visit 2
(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 (as described in 
Section 1.3)
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. 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 Full Analysis Set (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. 
 
 
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9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (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. This will be 
the group to which they are randomized except for participants who take incorrect study 
vaccination; such participants will be included in the group corresponding to the study 
vaccination actually received. If a participant received the same vaccine at Visit 1 and Visit 2 
due to the incorrect medication administration, resulting in the administration of 2 doses of 
V114 or 2 doses of placebo, this participant’s data would be excluded from APaT and would 
be 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
Statistical testing and inference for immunogenicity and safety analyses are described in 
Section 9.6.1 and Section 9.6.2, respectively. Unless otherwise stated, all statistical tests will 
be conducted at the α=0.05 (2-sided) level. Section 9.6.3 describes how demographic and 
baseline characteristics will be summarized.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives.
Immunogenicity analyses will be conducted for each of the 15 pneumococcal serotypes in 
V114 and each of the 4 influenza strains in QIV separately.
The primary objective (to compare the serotype-specific OPA GMTs at 30 days 
postvaccination with V114 between participants administered V114 concomitantly with QIV 
versus participants administered V114 nonconcomitantly with QIV) will be assessed via the 
following noninferiority hypotheses:
H0: GMT1/GMT2 ≤0.50 versus 
H1: GMT1/GMT2 >0.50,
where GMT1 is the serotype-specific OPA GMT for the concomitant group and GMT2 is the 
serotype-specific OPA GMT for the nonconcomitant group. A ratio of 0.50 corresponds to a 
2.0-fold decrease of OPA GMT in the concomitant group as compared with the 
nonconcomitant group. This same statistical criterion has been previously applied to evaluate 
Prevnar 13™ when administered concomitantly with influenza vaccine [Frenck, R. W. Jr., et 
al 2012] [Schwarz, T. F., et al 2011] [Schwarz, T. F. 2013]. 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/ nonconcomitant) being >0.50 and would lead to the conclusion 
 
 
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that the OPA responses in the concomitant group are noninferior to the nonconcomitant 
group for the 15 pneumococcal serotypes. 
The primary objective (to compare the strain-specific HAI GMTs at 30 days postvaccination 
with QIV between participants administered QIV concomitantly with V114 versus 
participants administered QIV nonconcomitantly) will be assessed via the following 
noninferiority hypotheses:
H0: GMT1/GMT2 ≤0.50 versus 
H1: GMT1/GMT2 >0.50, 
where GMT1 is the strain-specific HAI GMT for the concomitant group and GMT2 is the 
strain-specific HAI GMT for the nonconcomitant group. A ratio of 0.50 corresponds to a 2.0-
fold decrease of HAI GMT in the concomitant group as compared with the nonconcomitant 
group. This same statistical criterion has been previously applied to evaluate influenza 
vaccine when administered concomitantly with Prevnar 13™[Frenck, R. W. Jr., et al 2012] 
[Schwarz, T. F., et al 2011] [Schwarz, T. F. 2013] [U.S. Department of Health & Human
Services 2018]. 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/ nonconcomitant) 
being >0.50 and would lead to the conclusion that the influenza HAI responses in the 
concomitant group are noninferior to the nonconcomitant group for the 4 influenza strains.
To address the 2 primary immunogenicity objectives, the serotype-specific OPA GMTs at 30 
days postvaccination with V114 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 15 
serotypes in V114 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 (i.e., 1-sided p-value) 
will be calculated using a constrained longitudinal data analysis (cLDA) method proposed by 
Liang and Zeger [Liang, K-Y and Zeger, S. L. 2000] utilizing data from both vaccination 
groups. In this model, the response vector consists of the log-transformed baseline and 30 
days postvaccination antibody titers. The repeated-measures model will include terms for 
vaccination group, time, the interaction of time-by-vaccination group (with a restriction of 
the same baseline mean across groups), age stratum (i.e., 50 to 64 years, 65 to 74 years, and 
≥75 years) at baseline, history of prior PNEUMOVAX™23 stratum (i.e., Yes and No), age 
stratum-by-time interaction, and history of prior PNEUMOVAX™23 stratum-by-time
interaction. This model will allow for different baseline means for each stratum, but restrict 
the baseline mean within both the age stratum levels and the history stratum levels to be the 
same for both vaccination groups. An unstructured covariance matrix will be used to model 
the correlation among repeated measurements. The Kenward-Roger adjustment will be used 
with restricted (or residual) maximum likelihood to make proper statistical inference. This 
model allows the inclusion of participants who are missing either the baseline or postbaseline 
measurements, thereby increasing efficiency.
 
 
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A similar statistical approach will be used to evaluate the serotype-specific IgG GMCs at 30 
days postvaccination with V114 for participants administered V114 concomitantly with QIV
and participants administered V114 nonconcomitantly 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 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 V114 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 4.
Table 4
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing 
Data 
Approach
Primary Endpoints
OPA GMTs at 30 days postvaccination with 
V114
P
cLDA§
(estimate, 95% CI)
PP
Model-based
S
FAS
HAI GMTs at 30 days postvaccination with 
QIV
P
cLDA§
(estimate, 95% CI)
PP
Model-based
S
FAS
Secondary Endpoints
IgG GMCs at 30 days postvaccination with
V114
P
cLDA§
(estimate, 95% CI)
PP
Model-based
OPA GMTs and IgG GMCs at baseline
(prevaccination with V114) and 30 days 
postvaccination with V114
P
Descriptive 
Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
GMFRs and %s of participants with a ≥4-
fold rise from baseline (prevaccination with
V114) to 30 days postvaccination with
V114 for both OPA and IgG responses
P
Descriptive 
Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
HAI GMTs at baseline (prevaccination 
with QIV) and 30 days postvaccination
with QIV
P
Descriptive 
Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
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
 
 
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing 
Data 
Approach
%s 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
%s 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
† P = Primary approach; S = Supportive approach.
‡ Statistical models are described in further detail below:
§ Constrained longitudinal data analysis (cLDA) model with terms for vaccination group, time, the interaction 
of time-by-vaccination, age stratum at baseline, history of prior PNEUMOVAX™23 stratum, age stratum-
by-time interaction, and history of prior PNEUMOVAX™23 stratum-by-time interaction.
CI = confidence interval; FAS = Full Analysis Set; GMC = Geometric Mean Concentration; 
GMFR = geometric mean fold rise; GM = Geometric Mean Titer; IgG = Immunoglobulin G; OPA=
opsonophagocytic activity; PP = Per-Protocol; HAI= hemagglutination inhibition; QIV = quadrivalent 
influenza vaccine (seasonal inactivated).
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements.
The analysis of safety results following any vaccination will follow a tiered approach 
(Table 5). The tiers differ with respect to the analyses that will be performed. AEs (specific 
terms as well as system organ class terms) are either pre-specified as “Tier 1” endpoints, or 
will be classified as belonging to "Tier 2" or "Tier 3" based on the number of events 
observed.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance with p-
values and 95% CIs to be provided for between-group differences in the proportion of 
participants with events; these analyses will be performed using the unstratified Miettinen 
and Nurminen (M&N) method [Miettinen, O. and Nurminen, M. 1985], an unconditional, 
asymptotic method. For this protocol, solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain) from Day 1 through Day 5 following any vaccination and solicited 
systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, and tiredness/fatigue) 
from Day 1 through Day 14 following any vaccination are considered Tier 1 events.
 
 
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the unstratified M&N method 
[Miettinen, O. and Nurminen, M. 1985]).
Membership in Tier 2 requires that at least 4 participants in any vaccination group exhibit the 
event. The threshold of at least 4 events was chosen because the 95% CI for the between-
group difference in percent incidence will always include zero when vaccination groups of 
equal size each have less than 4 events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% CIs for Tier 2 events may be 
provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse events.
In addition to individual events that occur in 4 or more participants in any vaccination group, 
the broad AE categories consisting of the proportion of participants with any AE, a vaccine-
related AE, a SAE, an AE which is both vaccine-related and serious, discontinuation due to 
an AE, and the proportion of participants who died will be considered Tier 2 endpoints. The 
proportion of participants with maximum temperature measurements meeting the Brighton 
Collaboration cut points will also be considered Tier 2 endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by vaccination group are provided for Tier 3 safety parameters.
Table 5
Analysis Strategy for Safety Parameters Following Any Vaccination
Safety Tier
Safety Endpoint
p-Value
95% CI for 
Between-Group 
Comparison
Descriptive 
Statistics
Tier 1
Injection-site redness/erythema (Days 1 to 5)
X
X
X
Injection-site swelling (Days 1 to 5)
X
X
X
Injection-site tenderness/pain (Days 1 to 5)
X
X
X
Muscle pain/myalgia (Days 1 to 14)
X
X
X
Joint pain/arthralgia (Days 1 to 14)
X
X
X
Headache (Days 1 to 14)
X
X
X
Tiredness/fatigue (Days 1 to 14)
X
X
X
 
 
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Safety Tier
Safety Endpoint
p-Value
95% CI for 
Between-Group 
Comparison
Descriptive 
Statistics
Tier 2
Any AE†
X
X
Any vaccine-related AE†
X
X
Any SAE†
X
X
Any vaccine-related SAE†
X
X
Discontinuation due to AE†
X
X
Death†
X
X
Maximum temperature measurements meeting the 
Brighton Collaboration cut points (Days 1 to 5) 
X
X
Specific AEs by SOC and PT‡ (incidence ≥4 of 
participants in 1 of the vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PT‡ (incidence <4 of 
participants in all of the vaccination groups)
X
† These endpoints are broad adverse event categories. For example, descriptive statistics for the safety 
endpoint of “Any AE” will provide the number and percentage of participants with at least 1 AE. 
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
AE = adverse event; PT = preferred term; SAE = serious adverse event; SOC = system organ class; X = results 
will be provided.
In addition to the analyses following any vaccination, point estimates by vaccination group 
will be provided for injection-site AEs following V114 and following QIV separately. That 
is, the proportion of participants with injection-site AEs following administration of V114 
will include AEs reported from Day 1 through Day 5 following V114 administration in the 
limb corresponding to the location of V114 administration. Similarly, the proportion of 
participants with injection-site AEs following administration of QIV will include AEs 
reported from Day 1 through Day 5 following QIV administration in the limb corresponding 
to the location of QIV administration.
Additionally, the systemic AEs in the 14 days following each vaccination time point for each 
vaccination group will be summarized. That is, descriptive summaries of systemic AEs will 
include AEs reported from Day 1 through Day 14 following administration of
1. V114 and QIV in the concomitant group at Visit 1 (Day 1)
2. QIV with placebo in the nonconcomitant group at Visit 1 (Day 1)
3. Placebo alone in the concomitant group at Visit 2 (Day 30)
4. V114 alone in the nonconcomitant group at Visit 2 (Day 30)
Safety analyses will be based on the observed data (ie, with no imputation of missing data). 
 
 
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9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed by the use of 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, and gender), baseline characteristics, 
prior and concomitant vaccinations and therapies 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 adult V114 Phase 3 program will 
be conducted by an independent, unblinded, external DMC. A description of the structure, 
function, and guidelines for decision-making by 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. There are no plans to conduct an interim 
analysis of unblinded immunogenicity data in this study. However, unblinded 
immunogenicity data will be made available to the DMC upon request to enable a benefit-
risk assessment.
Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
intervention assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician performing 
the interim analysis. The DMC will serve as the primary reviewer of the results of the safety 
interim analyses and will make recommendations for discontinuation of the study or protocol 
modifications to an executive committee 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, this executive committee (and potentially other 
limited Sponsor personnel) may be unblinded to results at the intervention level in order to 
act on these recommendations. The extent to which individuals are unblinded with respect to 
results of interim analyses will be documented by the external unblinded statistician. 
Additional logistical details will be provided in the DMC Charter. 
Intervention-level results from the safety interim analysis 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 
interim analyses.
9.8
Multiplicity
The overall success of the study requires demonstrating success on all 15 pneumococcal 
serotypes and all 4 influenza strains included in the primary immunogenicity hypotheses.
This approach controls the 1-sided type-I error rate at 0.025, and no multiplicity adjustment 
will be required.
 
 
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9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This study will randomize approximately 600 participants into the concomitant group and 
600 participants into the nonconcomitant group and has approximately 87% power for 
demonstrating noninferiority of the serotype-specific OPA GMT ratios for the 15
pneumococcal serotypes included in V114 and >99.9% 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. Because the 2 hypotheses are assumed to be independent 
and the success of the study requires that the statistical criteria be met for both hypotheses, 
the overall power for the primary immunogenicity hypotheses is estimated to be 
approximately 87% (=0.87×>0.999).
The sample size and power calculations are based on the following assumptions:

90% evaluability rate (approximately 540 evaluable participants per treatment group) 
for both primary endpoints (OPA GMT ratios and HAI GMT ratios).

The underlying OPA GMT ratio is 0.80 (concomitant/nonconcomitant) for the 15 
pneumococcal serotypes. The assumption for this ratio is based on results of studies 
evaluating the administration of Prevnar 13™with concomitant influenza vaccines.

The variabilities for OPA titers in both concomitant group and nonconcomitant group 
are the same as that observed in V114-006. The standard deviations of the natural log 
titers for the 15 pneumococcal serotypes in V114 range from 1.33 to 2.24. The lowest 
estimated GMT ratios (concomitant group/nonconcomitant group) that would still 
meet the noninferiority margin range from 0.59 to 0.65. 

The HAI antibody responses are the same as those observed in a prior Merck study.
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 a 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 
600 participants in the concomitant group if the underlying incidence of a SAE is 0.27% (1 
of every 373 participants receiving the vaccine). There is a 50% chance of observing at least 
1 SAE among 600 participants in the concomitant group if the underlying incidence of a SAE
is 0.12% (1 of every 866 participants receiving the vaccine). If no SAEs are observed among 
600 participants in the concomitant group, this study will provide 97.5% confidence that the 
underlying percentage of participants with a SAE is <0.61% (1 in every 163 participants) in 
the concomitant group.
 
 
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Table 6 summarizes the percentage point differences between the 2 vaccination groups that 
could be detected with 80% probability for a variety of hypothetical underlying incidences of 
an AE. These calculations assume 600 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 (1990) [Farrington, C. P. 1990]; no multiplicity adjustments were made.
Table 6
Differences in Incidence of AE Rates between the 2 Vaccination Groups That Can 
be Detected With an ~80% Probability (Assuming 2-sided 5% alpha level with 600 
Participants in each Group)
Incidence of Adverse Event
Risk Difference
Nonconcomitant Group (%)
Concomitant Group (%)
Percentage Points
0.1
1.6
1.5
2.0
5.0
3.0
5.0
9.1
4.1
10.0
15.4
5.4
15.0
21.2
6.2
20.0
26.8
6.8
30.0
37.6
7.6
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
Based on an asymptotic method (Farrington and Manning [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). Examples of possible 
subgroup classification variables include age (50 to 64 years, 65 to 74 years, and ≥75 years)
and history of PNEUMOVAX™23 vaccination (Yes and No). Further details of subgroup 
analyses will be documented in the Supplemental Statistical Analysis Plan.
9.11
Compliance (Medication Adherence)
Given that participants will receive just a single dose of V114 and a single dose of QIV, 
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 V114 and the number and proportion of randomized participants 
administered QIV.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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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 report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (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.
10.1.4.2
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised  of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
DMC regarding the study.
 
 
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10.1.4.3
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.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
 
 
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); and all applicable federal, state and local laws, 
rules and regulations relating to the conduct of the clinical study. The Code of Conduct, a 
collection of goals and considerations that govern the ethical and scientific conduct of 
clinical investigations sponsored by MSD, is provided in this appendix under the Code of 
Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
 
 
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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 will be performed according to local requirements. 

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 7
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Other 
Screening 
Tests
Serum or urine β-hCG pregnancy test (as needed for WOCBP)
β-hCG = β human chorionic gonadotropin; WOCBP = woman/women of 
childbearing potential
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent, or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, 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, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.7 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
 
 
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity/Toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
•
Injection-site redness/erythema or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
•
The investigator will make an assessment of toxicity for each AE and SAE (and other 
reportable event) reported during the study.  A toxicity grade will be assigned to 
injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in the following tables. The toxicity grading scales used in 
this study are adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007.”
 
 
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Injection-Site AE Toxicity Grading Scale
Injection Site Reaction 
to Study 
Vaccine/Placeboa
Grade 1
Grade 2
Grade 3
Grade 4
Injection-site AEs occurring Days 1 through 5 following receipt of study vaccine/placebo
Pain/Tenderness
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or 
interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Erythema/Redness
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or 
exfoliative dermatitis 
or results in ER visit 
or hospitalization
Induration/Swelling
Size measured as 
B
Size measured as
C or D
Size measured as
E→
Necrosis or ER visit 
or hospitalization
Other 
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or 
interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Any injection-site reaction that begins ≥ 6 days after receipt of study vaccine/placebo
Pain/tenderness
Erythema/Redness
Induration/Swelling
Other
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or 
interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Abbreviations: AE = adverse event; ER = emergency room; eVRC = electronic Vaccine Report Card; SAE = serious 
adverse event
a Based upon information provided by the patient on the eVRC and verbally during VRC review. Erythema/Redness and 
Induration/Swelling are specific injection-site AEs with size designations of letters A through E→, based upon a graphic in 
the eVRC.  Size A is not assigned a toxicity grade; however, injection-site AEs that measure size A should be reported as 
adverse experiences.  If the participant has an ER visit or is hospitalized for any injection-site AE, that AE is to be assigned 
a toxicity grade of 4, regardless of the size measured.
Specific Systemic AE Toxicity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
>24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
ER visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference with 
activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference with 
activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Abbreviations: ER = emergency room
 
 
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Other Systemic AE Toxicity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)b
Illness or clinical AE 
(as defined according 
to applicable 
regulations)
No interference with 
activity
Some interference with 
activity not requiring 
medical intervention
Prevents daily activity 
and required medical 
intervention
ER visit or 
hospitalization
Abbreviations: ER = emergency room; eVRC = electronic Vaccine Report Card; SAE = serious adverse event
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
Vital Sign (Temperature) Toxicity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever 
(°C) b
(°F) b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
a Participant should be at rest for all vital sign requirements
b Oral temperature; no recent hot or cold beverages or smoking
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
 
 
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-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study); or (3) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs /worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of the 
AE onset relative to the administration of the Sponsor’s product is reasonable. The 
AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
 
 
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-
Participant did not receive the Sponsor’s product OR temporal sequence of the AE 
onset relative to administration of the Sponsor’s product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product. (Also entered 
for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
 
 
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•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
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
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 follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
10.5.2
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
1 of the contraception methods described in Table 8 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
 
 
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Table 8
Contraceptive Methods
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraceptionb
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●
Progestogen only hormonal contraceptionb
○
Oral
○
Injectable
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implantb
●
Intrauterine hormone-releasing system (IUS)b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner
A vasectomized partner 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.
●
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.
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
b
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation.
 
 
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10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions

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. 

Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2

Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2

DNA: Deoxyribonucleic acid.

RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the body

Other pathways drugs/vaccines may interact with

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
 
 
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3. Summary of Procedures for Future Biomedical Research.

Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy

Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants at a study visit by the 
investigator or his or her designate. Informed consent for future biomedical research 
should be presented to the participants on the visit designated in the SoA. If delayed, 
present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.

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.

Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
 
 
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At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
 
 
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answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
 
 
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12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
13. References

National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618

International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 

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/ 

Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event
APaT
All Participants as Treated
β-hCG
beta-human chorionic gonadotropin
CAPiTA
Community-Acquired Pneumonia Immunization Trial in Adults
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
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECL
electrochemiluminescence
eCRF
electronic case report form
EDC
electronic data collection
EMA
European Medicines Agency
EOC
Executive Oversight Committee
eVRC
Electronic Vaccination Report Card
FAS
Full Analysis Set
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GMC
Geometric Mean Concentration
GMFR
Geometric Mean Fold Rise
GMT
Geometric Mean Titer
HIV
Human Immunodeficiency Virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation Good Clinical Practice
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IMP
investigational medicinal product
IPD
invasive pneumococcal disease
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MOPA
Multiplexed Opsonophagocytic Assay
MSD
Merck Sharp & Dohme Corp.
NIMP
non-investigational medicinal product
OPA
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PnECL
pneumococcal electrochemiluminescence
PP
Per-Protocol
 
 
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Abbreviation
Expanded Term
PT
preferred term
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event
SLAB
supplemental laboratory test
SoA
schedule of activities
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
US
United States
WOCBP
woman/women of childbearing potential
 
 
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11
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103
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PRODUCT: V114 
104
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V114-021-01-FINAL PROTOCOL
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PRODUCT: V114 
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PRODUCT: V114 
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1-JUN-2018
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