Clinical trial NCT03950856
Conditions: Pneumococcal Infections Pneumonia, Pneumococcal
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-06-12; Completion date: 2020-04-03
Enrollment: 2340 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives are to evaluate the safety and tolerability of V114 and to compare the serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) across 3 different lots of V114. The primary hypothesis is that all 3 lots of V114 are equivalent as measured by the serotype-specific OPA GMTs for 15 serotypes in V114 at 30 days postvaccination.

Detailed description:

Arms: arm 1: Single intramuscular (IM) dose at 0.5 mL of V114 Lot 1 pneumococcal conjugate vaccine at Visit 1 (Day 1) arm 2: Single IM dose at 0.5 mL of V114 Lot 2 pneumococcal conjugate vaccine at Visit 1 (Day 1) arm 3: Single IM dose at 0.5 mL of V114 Lot 3 pneumococcal conjugate vaccine at Visit 1 (Day 1) arm 4: Single IM dose at 0.5 mL of Prevnar 13™ at Visit 1 (Day 1)
Interventions: intervention 1: V114 intervention 2: Prevnar 13™
Intervention descriptions: intervention 1: 15-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F in each 0.5 mL dose. intervention 2: 13-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F in each 0.5. mL dose.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03950856 
Document Date: 
09-Jan-2019
A Phase 3, Multicenter, Randomized, Double-blind, Active
Comparator-controlled, Lot-to-Lot Consistency Study to Evaluate 
the Safety, Tolerability, and Immunogenicity of V114 in Healthy 
Adults 50 Years of Age or Older (PNEU-TRUE)


PRODUCT: V114  
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09-JAN-2019
Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active 
Comparator-controlled, Lot-to-Lot Consistency Study to Evaluate the Safety, Tolerability, 
and Immunogenicity of V114 in Healthy Adults 50 Years of Age or Older (PNEU-TRUE)
Protocol Number: 020-00
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
EudraCT
14977
2018-004266-33
Approval Date: 09 January 2019
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Original Protocol
09-JAN-2019
Not applicable
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................14
1.3
Schedule of Activities (SoA) ................................................................................15
2
INTRODUCTION..........................................................................................................17
2.1
Study Rationale....................................................................................................17
2.2
Background ..........................................................................................................17
2.2.1
V114 and Pneumococcal Disease ................................................................17
2.2.2
Preclinical and Clinical Studies ...................................................................18
2.2.3
Information on Other Study-Related Therapy.............................................18
2.3
Benefit/Risk Assessment......................................................................................19
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS ................................................19
4
STUDY DESIGN............................................................................................................21
4.1
Overall Design ......................................................................................................21
4.2
Scientific Rationale for Study Design.................................................................21
4.2.1
Rationale for Endpoints ...............................................................................22
4.2.1.1
Immunogenicity Endpoints................................................................22
4.2.1.2
Safety Endpoints ................................................................................23
4.2.1.3
Pharmacokinetic Endpoints ...............................................................23
4.2.1.4
Pharmacodynamic Endpoints.............................................................23
4.2.1.5
Future Biomedical Research..............................................................23
4.2.2
Rationale for the Use of Comparator/Placebo .............................................23
4.3
Justification for Dose ...........................................................................................24
4.4
Beginning and End of Study Definition .............................................................24
4.4.1
Clinical Criteria for Early Study Termination .............................................24
5
STUDY POPULATION ................................................................................................24
5.1
Inclusion Criteria.................................................................................................24
5.2
Exclusion Criteria ................................................................................................25
5.3
Lifestyle Considerations ......................................................................................27
5.4
Screen Failures.....................................................................................................27
5.5
Participant Replacement Strategy......................................................................27
6
STUDY INTERVENTION............................................................................................27
6.1
Study Intervention(s) Administered...................................................................27
 
 
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6.2
Preparation/Handling/Storage/Accountability .................................................29
6.2.1
Dose Preparation..........................................................................................29
6.2.2
Handling, Storage, and Accountability........................................................29
6.3
Measures to Minimize Bias: Randomization and Blinding..............................30
6.3.1
Intervention Assignment..............................................................................30
6.3.2
Stratification.................................................................................................30
6.3.3
Blinding........................................................................................................30
6.4
Study Intervention Compliance..........................................................................31
6.5
Concomitant Therapy..........................................................................................31
6.5.1
Rescue Medications and Supportive Care ...................................................32
6.6
Dose Modification (Escalation/Titration/Other)...............................................32
6.7
Intervention After the End of the Study............................................................32
6.8
Clinical Supplies Disclosure................................................................................32
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................32
7.1
Discontinuation of Study Intervention...............................................................32
7.2
Participant Withdrawal From the Study...........................................................32
7.3
Lost to Follow-up .................................................................................................33
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................33
8.1
Administrative and General Procedures ...........................................................34
8.1.1
Informed Consent.........................................................................................34
8.1.1.1
General Informed Consent.................................................................34
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................35
8.1.2
Inclusion/Exclusion Criteria ........................................................................35
8.1.3
Participant Identification Card.....................................................................35
8.1.4
Medical History ...........................................................................................35
8.1.5
Prior and Concomitant Medications Review ...............................................36
8.1.5.1
Prior Medications...............................................................................36
8.1.5.2
Concomitant Medications ..................................................................36
8.1.6
Assignment of Screening Number...............................................................36
8.1.7
Assignment of Treatment/Randomization Number .....................................36
8.1.8
Study Intervention Administration ..............................................................36
8.1.8.1
Timing of Dose Administration.........................................................37
8.1.9
Electronic Vaccination Report Card (eVRC) ..............................................37
8.1.10
Telephone Contact Questionnaire................................................................38
8.1.11
Discontinuation and Withdrawal .................................................................38
8.1.11.1
Withdrawal From Future Biomedical Research ................................38
 
 
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8.1.12
Participant Blinding/Unblinding..................................................................39
8.1.13
Calibration of Equipment.............................................................................39
8.2
Immunogenicity Assessments .............................................................................40
8.2.1
Multiplex Opsonophagocytic Assay (MOPA).............................................40
8.2.2
Electrochemiluminescence (ECL) ...............................................................40
8.3
Safety Assessments...............................................................................................41
8.3.1
Physical Examination...................................................................................41
8.3.2
Pregnancy Test.............................................................................................41
8.3.3
Body Temperature Measurement.................................................................41
8.3.4
Safety Assessments and Use of the eVRC...................................................42
8.3.5
Clinical Laboratory Assessments.................................................................42
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................42
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................43
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......44
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...45
8.4.4
Regulatory Reporting Requirements for SAE .............................................45
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................45
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................45
8.4.7
Events of Clinical Interest (ECIs) ................................................................46
8.5
Treatment of Overdose........................................................................................46
8.6
Pharmacokinetics.................................................................................................46
8.7
Pharmacodynamics..............................................................................................46
8.8
Future Biomedical Research Sample Collection...............................................46
8.9
Medical Resource Utilization and Health Economics.......................................46
8.10
Visit Requirements...............................................................................................46
8.10.1
Screening......................................................................................................46
8.10.2
Treatment Period/Vaccination Visit ............................................................47
9
STATISTICAL ANALYSIS PLAN .............................................................................47
9.1
Statistical Analysis Plan Summary.....................................................................47
9.2
Responsibility for Analyses/In-house Blinding .................................................48
9.3
Hypotheses/Estimation ........................................................................................49
9.4
Analysis Endpoints...............................................................................................49
9.4.1
Immunogenicity Endpoints..........................................................................49
9.4.2
Safety Endpoints ..........................................................................................49
9.5
Analysis Populations............................................................................................50
 
 
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9.5.1
Immunogenicity Analysis Populations ........................................................50
9.5.2
Safety Analysis Populations ........................................................................50
9.6
Statistical Methods...............................................................................................51
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................51
9.6.2
Statistical Methods for Safety Analyses ......................................................53
9.6.3
Demographic and Baseline Characteristics and Other Analysis..................55
9.7
Interim Analyses ..................................................................................................56
9.8
Multiplicity ...........................................................................................................56
9.9
Sample Size and Power Calculations .................................................................56
9.9.1
Sample Size and Power for Immunogenicity Analyses ...............................56
9.9.2
Sample Size and Power for Safety Analyses ...............................................57
9.10
Subgroup Analyses...............................................................................................58
9.11
Compliance (Medication Adherence).................................................................59
9.12
Extent of Exposure...............................................................................................59
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................60
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........60
10.1.1
Code of Conduct for Clinical Trials.............................................................60
10.1.2
Financial Disclosure.....................................................................................62
10.1.3
Data Protection.............................................................................................62
10.1.3.1
Confidentiality of Data ......................................................................63
10.1.3.2
Confidentiality of Participant Records...............................................63
10.1.3.3
Confidentiality of IRB/IEC Information............................................63
10.1.4
Committees Structure...................................................................................63
10.1.4.1
Scientific Advisory Committee..........................................................63
10.1.4.2
Executive Oversight Committee........................................................63
10.1.4.3
External Data Monitoring Committee ...............................................64
10.1.5
Publication Policy........................................................................................64
10.1.6
Compliance with Study Registration and Results Posting Requirements ...64
10.1.7
Compliance with Law, Audit, and Debarment ............................................65
10.1.8
Data Quality Assurance ...............................................................................65
10.1.9
Source Documents .......................................................................................66
10.1.10
Study and Site Closure.................................................................................67
10.2
Appendix 2: Clinical Laboratory Tests..............................................................68
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................69
10.3.1
Definition of AE ..........................................................................................69
10.3.2
Definition of SAE ........................................................................................70
 
 
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10.3.3
Additional Events Reported.........................................................................71
10.3.4
Recording AE and SAE ...............................................................................71
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................77
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................78
10.5
Appendix 5: Contraceptive Guidance................................................................79
10.5.1
Definitions....................................................................................................79
10.5.2
Contraception Requirements........................................................................80
10.5.3
Pregnancy Testing........................................................................................81
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................82
10.7
Appendix 7: Country-specific Requirements ....................................................87
10.8
Appendix 8: Abbreviations .................................................................................88
11
REFERENCES...............................................................................................................90
 
 
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LIST OF TABLES
Table 1
Study Interventions ..........................................................................................28
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Type ....34
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................44
Table 4
Analysis Strategy for Immunogenicity Variables............................................53
Table 5
Analysis Strategy for Safety Parameters..........................................................55
Table 6
Differences in the Incidence of Adverse Event Rates Between the 
2 Vaccination Groups That Can be Detected With an Approximately 80% 
Probability........................................................................................................58
 
 
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PRODUCT: V114  
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LIST OF FIGURES
Figure 1
V114-020 Study Design.............................................................................14
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active 
Comparator-controlled, Lot-to-Lot Consistency Study to Evaluate the Safety, Tolerability, 
and Immunogenicity of V114 in Healthy Adults 50 Years of Age or Older (PNEU-TRUE)
Short Title: Lot-to-lot consistency of V114 in healthy adults
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-020 (PNEU-TRUE)
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In healthy adults ≥50 years of age enrolled in the study:
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
- Solicited injection-site AEs from Day 1 
through Day 5 postvaccination
- Solicited systemic AEs from Day 1 through 
Day 14 postvaccination
- Vaccine-related serious adverse events 
(SAEs) from Day 1 to Month 6 
postvaccination
- Objective: To compare the 
serotype-specific opsonophagocytic activity 
(OPA) geometric mean titers (GMTs) at 
30 days postvaccination (Day 30) across 
3 different lots of V114.
Hypothesis: All 3 lots of V114 are equivalent 
as measured by the serotype-specific OPA 
GMTs for 15 serotypes in V114 at 30 days 
postvaccination.
(The statistical criterion for equivalence 
requires the bounds of the 95% confidence 
interval [CI] of the GMT ratio for each 
pairwise V114 lot-to-lot comparison of the 
OPA GMT ratio to be within 0.5 to 2.0)
- Serotype-specific OPA responses for the 
15 serotypes in V114 at Day 30
 
 
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Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the serotype-specific 
Immunoglobulin G (IgG) geometric mean 
concentrations (GMCs) at 30 days post 
vaccination (Day 30) compared across the 
3 different lots of V114 and combined lots of 
V114 compared to Prevnar 13™.
- Serotype-specific IgG responses for the 
15 serotypes in V114 at Day 30
- Objective: To evaluate the serotype-specific 
geometric mean fold rises (GMFRs) and 
proportions of participants with a ≥4-fold rise 
from prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for both OPA and 
IgG responses separately across 3 different 
lots of V114.
- Serotype-specific OPA and IgG responses 
for the 15 serotypes in V114 at Day 1 and 
Day 30
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Adults 50 years of age and older
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active Control Without Placebo
Study Blinding
Double-blind with in-house blinding
Masking
Participant or Subject
Investigator
Sponsor
 
 
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Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 11 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result or 
at the time of final contact with the last participant, 
whichever comes last.
Number of Participants:
Approximately 2220 participants will be randomized, with approximately 667 participants in 
each V114 intervention group and 220 participants in the Prevnar 13™intervention group.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination 
Regimen
Use
V114 Lot 1
V114
Refer to IB
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
V114 Lot 2
V114
Refer to IB
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
V114 Lot 3
V114
Refer to IB
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
Prevnar 13™
Prevnar 13™
Refer to 
product 
labeling
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Experimental
Abbreviations: Admin. = administration; IB = Investigator’s Brochure; IM = intramuscular.
Total 
Number
4 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 6 months from 
the time the participant signs the Informed Consent Form (ICF) through the 
final contact.
 
 
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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.
1.2
Schema
The key components of the study design are depicted in Figure 1.
Figure 1
V114-020 Study Design
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Intervention
Notes
Visit Number
1
Telephone 
Contact
2
Telephone 
Contact
Scheduled Time
Day 1
Day 15
Day 30
Month 6
Visit Windows
Day 15 to 
Day 19 after 
Visit 1
Day 30 to 
Day 44 after 
Visit 1
Day 166 to 
Day 194 
After Visit 1
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study procedures.
Informed Consent for Future Biomedical Research
X
Participation in future biomedical research is optional and 
consent must be obtained before the blood sample (DNA 
sample) is collected.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Review of prior medications/vaccinations, a complete physical 
examination, and temperature measurement are required at 
Visit 1 to determine eligibility.
Medical History
X
The participant’s relevant medical history for the 5 years prior 
to study entry will be reviewed. History of tobacco use will 
also be collected for all participants.
Post-Randomization Procedures
Assignment of Randomization Number
X
Participant Identification Card
X
Prior/Concomitant Medication and Non-Study 
Vaccination Review
X
X
X
V114/Prevnar 13™Administration (Blinded)
X
Participants will receive either a single dose of V114 or a 
single dose of Prevnar 13™.
Provide electronic Vaccination Report Card (eVRC)
X
Participants will be provided an eVRC to record adverse events 
(AEs) and body temperature measurements (see Section 8.3.4 
for details).
Review eVRC Data With Participant
X
X
See Section 8.1.9 for details.
Collect eVRC From Participant
X
Complete Telephone Contact Questionnaire
X
See Section 8.1.10 for details.
 
 
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Study Period
Intervention
Notes
Visit Number
1
Telephone 
Contact
2
Telephone 
Contact
Scheduled Time
Day 1
Day 15
Day 30
Month 6
Visit Windows
Day 15 to 
Day 19 after 
Visit 1
Day 30 to 
Day 44 after 
Visit 1
Day 166 to 
Day 194 
After Visit 1
Safety Procedures
Complete Physical Examination
X
To be performed by the investigator or medically qualified 
designee before vaccine is administered.
Pregnancy Test – if applicable
X
A pregnancy test consistent with local requirements (sensitive 
to at least 25 IU beta human chorionic gonadotropin [β-hCG]) 
must be performed before administration of study vaccine in 
females who are of reproductive potential (see Section 8.3.2 for 
details).
Body Temperature Measurement
X
Each participant’s body temperature must be taken before 
vaccination (see Section 8.3.3 for details). Participants who 
have febrile illness occurring at or within 72 hours of Visit 1 
must be rescheduled (see Section 5.2 for details).
30-Minute Postvaccination Observation Period
X
To be performed by blinded study site personnel only.
Adverse Event (AE) Monitoring
X
X
X
X
Nonserious AEs are to be reported from Days 1 through 
14 following vaccination. Serious AEs (SAEs) and deaths are 
to be reported throughout the duration of an individual’s study 
participation (see Section 8.4.1 for details).
Immunogenicity Procedures
Serum for immunogenicity assays (including 
retention serum)
X
X
Day 1 blood samples must be collected before vaccination (see 
Section 4.1 and Section 8.8 for details).
Future Biomedical Research
Blood (DNA) for Future Biomedical Research
X
Sample will be collected from randomized participants who 
provided consent for future biomedical research (see 
Section 8.8). The sample should be obtained only at Visit 1 
(Day 1) before vaccine is administered (or with the next 
scheduled blood draw) as the last sample drawn, or at a later 
date as soon as the informed consent is obtained.
 
 
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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 the prevention of 
pneumococcal disease caused by the serotypes in the vaccine. V114 contains the 13 serotypes 
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 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 and 33F).
2.1
Study Rationale
This study is conducted in healthy, pneumococcal vaccine naïve adults ≥50 years of age to 
demonstrate the consistency of 3 different lots of V114 with respect to the safety, tolerability, 
and immunogenicity of V114. This study will contribute to the overall safety database and 
immunogenicity profile of 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 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 (US). Although Prevnar 13™ is indicated for both 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 US Advisory Committee on Immunization Practices for the 
sequential administration of Prevnar 13™ followed at least 12 months later by 
 
 
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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 vaccine campaigns with 
PCVs, an increase in IPD caused by serotypes not covered by currently available PCVs has 
been observed. V114 contains 2 additional serotypes (22F and 33F) compared with 
Prevnar 13™, and the selection of 22F and 33F was primarily based on epidemiological 
importance of these 2 additional serotypes. By 2012 to 2013 in the US, 22F was the most 
common serotype not included in Prevnar 13™ in adults ≥18 years of age, causing 13% of 
IPD cases. Serotype 33F was 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 
were among the leading 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 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 additional serotypes included in V114 will provide broader coverage against the leading 
serotypes associated with pneumococcal disease worldwide. V114 is designed to meet 
continuing medical and public health needs for PCVs globally, as well as address the 
emergence of pneumococcal disease caused by serotypes not contained in currently licensed 
PCVs.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
V114.
2.2.3
Information on Other Study-Related Therapy
Prevnar 13™
Refer to approved labeling for detailed background information on Prevnar 13™.
Prevnar 13™ contains all of the pneumococcal serotypes included in Prevnar™ (4, 6B, 9V, 
14, 18C, 19F, and 23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A).
The adult indication was approved based on immune responses elicited by Prevnar 13™ in 
comparison with PNEUMOVAX™23. A placebo-controlled clinical efficacy study
(Community Acquired Pneumonia Immunization Trial in Adults [CAPiTA]) evaluated the 
efficacy of Prevnar 13™ against pneumococcal pneumonia and IPD in immunocompetent 
adults ≥65 years of age. Results from CAPiTA showed that Prevnar 13™ was 45.6% 
(95% confidence interval [CI]: 21.8% to 62.5%) efficacious against vaccine-type 
nonbacteremic pneumococcal pneumonia and 75.0% (95% CI: 41.4% to 90.8%) efficacious 
against vaccine-type IPD in adults ≥65 years of age [Bonten, M. J., et al 2015].
 
 
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Prevnar™ and Prevnar 13™ are also known as Prevenar™ and Prevenar 13™ in many 
countries outside of the US. These vaccines are referred to as Prevnar™ and Prevnar 13™ 
throughout this document.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
vaccination with V114 during participation, as clinical studies are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Approximately 220 participants will receive Prevnar 13™, the standard of care, as the active 
comparator in this study. V114 is expected to provide comparable immune responses to 
Prevnar 13™for the shared serotypes while providing additional coverage for the 2 serotypes 
(22F and 33F) unique to V114. It is unknown if the investigational V114 will have the same 
clinical benefit as Prevnar 13™.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In healthy adults ≥50 years of age enrolled in the study:
Objectives
Endpoints
Primary

Objective: To evaluate the safety and 
tolerability of V114 with respect to 
the proportion of participants with 
adverse events (AEs).

Solicited injection-site AEs from 
Day 1 through Day 5 postvaccination

Solicited systemic AEs from Day 1 
through Day 14 postvaccination

Vaccine-related serious adverse 
events (SAEs) from Day 1 to 
Month 6 postvaccination
 
 
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Objectives
Endpoints

Objective: To compare the 
serotype-specific opsonophagocytic 
activity (OPA) geometric mean titers 
(GMTs) at 30 days postvaccination 
(Day 30) across 3 different lots of 
V114.
Hypothesis: All 3 lots of V114 are 
equivalent as measured by the 
serotype-specific OPA GMTs for 
15 serotypes in V114 at 30 days 
postvaccination.
(The statistical criterion for 
equivalence requires the bounds of 
the 95% confidence interval [CI] of 
the GMT ratio for each pairwise 
V114 lot-to-lot comparison of the 
OPA GMT ratio to be within 0.5 to
2.0)

Serotype-specific OPA responses for 
the 15 serotypes in V114 at Day 30
Secondary

Objective: To evaluate the 
serotype-specific Immunoglobulin G 
(IgG) geometric mean concentrations 
(GMCs) at 30 days post vaccination 
(Day 30) compared across the 
3 different lots of V114 and combined 
lots of V114 compared to 
Prevnar 13™.

Serotype-specific IgG responses for 
the 15 serotypes in V114 at Day 30

Objective: To evaluate the 
serotype-specific geometric mean fold 
rises (GMFRs) and proportions of 
participants with a ≥4-fold rise from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for both 
OPA and IgG responses separately 
across 3 different lots of V114.

Serotype-specific OPA and IgG 
responses for the 15 serotypes in 
V114 at Day 1 and Day 30
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, parallel-group, multi-site, double-blind/mask study 
of V114 in adults 50 years of age or older.
Approximately 2220 participants will be randomized in a 3:3:3:1 ratio to 1 of 4 vaccination 
groups (approximately 667 participants per V114 arm and 220 participants in the 
Prevnar 13™ arm): V114 Lot 1, V114 Lot 2, V114 Lot 3, and Prevnar 13™. Randomization 
will be stratified by participant age at enrollment (50 to 64 years, 65 to 74 years, and 
≥75 years). Approximately 50% of the participants will be ≥65 years of age.
Participants will be followed for solicited injection-site AEs from Day 1 through Day 5 
postvaccination and solicited systemic AEs from Day 1 through Day 14 postvaccination. In 
addition, participants will be followed for non-solicited injection-site and systemic AEs 
through Day 14 postvaccination. Information for SAEs and deaths, regardless of whether the 
events are considered to be vaccine related by the investigator, will be collected from the 
time consent is signed through completion of participation in the study. 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 and function of the DMC, 
along with the timing and content of the safety reviews will be outlined in the DMC charter. 
Information regarding the composition of the DMC is provided in Appendix 1.
Blood samples for immunogenicity assays will be drawn immediately before V114 or 
Prevnar 13™ vaccination at Visit 1 (Day 1) and at 30 days postvaccination at Visit 2 
(Day 30).
After completion of 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 study participants who provided consent for future 
biomedical research.
In countries that recommend sequential administration of Prevnar 13™ followed at least 
12 months later by PNEUMOVAX™23, PNEUMOVAX™23 will be administered outside 
of this study protocol.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will serve as a lot-to-lot consistency study for licensure of V114. This study is 
conducted to demonstrate the consistency of the antibody response to 3 different 
 
 
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manufactured lots of V114 in a population (ie, healthy adults ≥50 years of age) at elevated 
risk for pneumococcal disease and its associated morbidity and mortality. Prevnar 13™was 
included as the active comparator in this study to better characterize the safety profile of 
V114.
The incidence of IPD is directly related to age, with over half of all cases occurring in adults 
50 years of age or older [Drijkoningen, J. J 2014]. The population of subjects included in this 
study (healthy adults ≥50 years of age) is consistent with the indication of pneumococcal 
vaccines, including Prevnar 13™, in healthy adults.
Demonstration of lot-to-lot consistency is often required by some national regulatory 
agencies prior to licensure of investigational vaccines. The objective of a clinical lot-to-lot 
consistency study is to show consistency of manufacturing and clinical performance of the 
final product by demonstrating that 3 consecutively manufactured final formulated clinical 
lots of the vaccine display comparable safety profiles and elicit equivalent immune 
responses. The sample size of this study will allow for a high statistical probability to 
demonstrate consistency of the immune response across 3 lots of V114, while also bolstering 
the size of the overall safety database of the clinical development program.
Participants will be stratified by age group based on observations from previous V114 adult 
studies, where individuals ≥75 years of age showed lower post-vaccination immunogenicity 
responses (based on OPA response) for several serotypes compared with individuals 50 to 
64 and 65 to 74 years of age.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints and associated comparative statistical criteria are consistent 
with previous studies evaluating PCVs.
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, 
and 33F) included in V114 using the Multiplexed Opsonophagocytic Assay (MOPA) and 
pneumococcal electrochemiluminescence (PnECL) assay.
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; however, the OPA functional assay is considered a preferred endpoint in adults.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1.
 
 
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4.2.1.2
Safety Endpoints
The safety endpoints (ie, AEs and temperature) 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.
4.2.1.3
Pharmacokinetic Endpoints
Pharmacokinetic (PK) parameters will not be evaluated in this study.
4.2.1.4
Pharmacodynamic Endpoints
Pharmacodynamic parameters will not be evaluated in this study.
4.2.1.5
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-controlled clinical studies for new PCVs are no longer feasible given the proven 
clinical efficacy and widespread use of licensed PCVs worldwide. Prevnar 13™ is currently 
a recommended vaccine for the prevention of pneumococcal disease in the US and is also 
 
 
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used in many other countries worldwide. It will be used as the active comparator in this study
and will allow for an unbiased assessment of safety.
4.3
Justification for Dose
The concentrations of pneumococcal polysaccharide and adjuvant in V114 have been 
established in previous clinical studies. 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).
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy male and female participants ≥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
A participant will be eligible for inclusion in the study if the participant:
1. In the opinion of the investigator, is in good health. Any underlying chronic condition 
must be documented to be stable according to the investigator’s judgment.
Demographics
2. Is male or female ≥50 years of age at the time of signing the informed consent.
 
 
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Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
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. Provides written informed consent for the study. The participant may also provide 
consent for future biomedical research. However, the participant may participate in the 
main study without participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or 
positive culture at another sterile site) or known history of other culture-positive 
pneumococcal disease within 3 years of Visit 1 (Day 1).
2. Has a known hypersensitivity to any component of pneumococcal polysaccharide 
vaccine, PCV, or any diphtheria toxoid-containing vaccine.
3. Has a known or suspected impairment of immunological function including, but not 
limited to, a history of congenital or acquired immunodeficiency, documented human 
immunodeficiency virus (HIV) infection, functional or anatomic asplenia, or history of 
autoimmune disease (including but not limited to the autoimmune conditions outlined in 
the Investigator Trial File Binder for this study).
4. Has a coagulation disorder contraindicating intramuscular vaccinations.
5. *Had a recent febrile illness (defined as oral or tympanic temperature ≥100.4°F 
[≥38.0°C] or axillary or temporal temperature ≥99.4°F [≥37.4°C]) or received antibiotic 
therapy for any acute illness occurring within 72 hours before receipt of study vaccine.
 
 
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6. Has a 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.
7. A WOCBP has a positive urine or serum pregnancy test before the first vaccination at 
Visit 1 (Day 1).
Prior/Concomitant Therapy
8. Has received any pneumococcal vaccine or is expected to receive any pneumococcal 
vaccine during the study outside of the protocol.
9. Has received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for 
≥14 consecutive days and has not completed intervention at least 30 days before study 
entry.
10. Has 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).
11. Is receiving immunosuppressive therapy, including chemotherapeutic agents used to treat 
cancer or other conditions, and interventions associated with organ or bone marrow 
transplantation, or autoimmune disease.
12. *Has received any non-live vaccine 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. Exception: Inactivated influenza vaccine may be administered but 
must be given at least 7 days before receipt of any study vaccine or at least 15 days after 
receipt of any study vaccine.
13. *Has 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.
14. Has 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
15. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
 
 
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Other Exclusions
16. In the opinion of the investigator, has a history of clinically relevant drug or alcohol 
abuse that would interfere with participation in protocol-specified activities.
17. Has history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study.
18. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, the 
Day 1 Visit may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
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.
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, Prevnar 13™] will be packaged to support enrollment . Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
 
 
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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
V114 
Lot 1
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension 
(Prefilled 
Syringe)
Refer to 
IB
0.5 mL
IM
Single dose 
at Visit 1 
(Day 1)
Experimental
IMP
Central
V114 
Lot 2
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension 
(Prefilled 
Syringe)
Refer to 
IB
0.5 mL
IM
Single dose 
at Visit 1 
(Day 1)
Experimental
IMP
Central
V114 
Lot 3
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension 
(Prefilled 
Syringe)
Refer to 
IB
0.5 mL
IM
Single dose 
at Visit 1 
(Day 1)
Experimental
IMP
Central
Prevnar 
13™
Active 
Comparator
Prevnar 13™
Biological/
Vaccine
Sterile 
Suspension 
(Prefilled 
Syringe)
Refer to 
product 
labeling
0.5 mL
IM
Single dose 
at Visit 1 
(Day 1)
Experimental
IMP
Central
Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; IMP = investigational medicinal product; NIMP = non-investigational medicinal 
product.
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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All supplies indicated in Table 1 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.
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.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 4 study intervention arms. Participants will be assigned 
randomly in a 3:3:3:1 ratio to V114 Lot 1, V114 Lot 2, V114 Lot 3, and Prevnar 13™,
respectively, based on their age strata assignments as defined below.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
•
Age at time of randomization:
-
Participants 50 to 64 years of age
-
Participants 65 to 74 years of age
-
Participants ≥75 years of age.
Approximately 50% of the participants will be ≥65 years of age.
6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevnar 13™will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study site personnel. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
Because V114 and Prevnar 13™have a different appearance, a member of the study site staff 
will be unblinded for the purposes of receiving, maintaining, preparing and/or dispensing, 
and administering these study vaccines. Procedures for handling, preparing, and 
administering the unblinded vaccines are located in the Investigator Trial File Binder.
To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel will not be present in the examination room when study vaccines are administered. 
Contact between participants and unblinded study personnel after vaccination administration 
is strictly prohibited. Blinded site personnel will be responsible for all safety and 
immunogenicity follow-up procedures after vaccine administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) and Merck Research Laboratories employees 
 
 
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directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Given that a single dose of V114 or Prevnar 13™will be administered in this study,
intervention compliance will not be assessed.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (see Section 5.2). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
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 non-study 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). 
Exception: Inactivated influenza vaccine may be administered but must be given at least 
7 days before receipt of study vaccine or at least 15 days after receipt of any study 
vaccine.
3. Participants should not receive systemic corticosteroids (prednisone equivalent of 
≥20 mg/day for ≥14 consecutive days) starting from 30 days prior to through 30 days 
following vaccination.
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.
 
 
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6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (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.
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 8.1.10). 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
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
 
 
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.11. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
 
 
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•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant for study procedures at each 
study visit will not exceed 30 mL and the total amount of blood for the entire study collected 
during planned study visits will not exceed 50 mL (Table 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Type
Study Visit
Visit 1
Day 1
Visit 2
Day 30
Total
Parameter
Approximate Blood Volume (mL)
Immunogenicity assays (including retention samples)
20 mL
20 mL
40 mL
DNA for Future Biomedical Research
8.5 mL
N/A
8.5 mL
Expected total (mL)
28.5 mL
20 mL
48.5 mL
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.
 
 
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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.
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.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee before 
vaccination at Visit 1 (Day 1). The participant’s relevant medical history for the 5 years prior 
to Visit 1 (Day 1) will be obtained to ensure that the participant satisfies the inclusion and 
exclusion criteria of the study. History of tobacco use will also be collected.
 
 
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the study vaccination at Visit 1 (Day 1).
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
New and/or concomitant medications taken after Visit 1 (Day 1) and non-study 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.
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
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer V114 or Prevnar 13™. Study vaccines should be prepared and administered 
by appropriately qualified members of the study personnel (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by local/state, 
country, and institutional guidance. Procedures for handling, preparing, and administering the 
unblinded vaccines are provided in the Investigator Trial File Binder. Unblinded study 
personnel should follow the preparation and administration instructions for Prevnar 13™ as 
specified in the product label.
Study vaccines should be removed from the refrigerator no more than 1 hour before 
vaccination. The time of removal and time of vaccination should be documented in the 
participant’s chart.
 
 
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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.
Study vaccine will be administered as a single 0.5-mL intramuscular injection, preferably in 
the deltoid region of the participant’s arm. Adequate treatment provision, including 
epinephrine and equipment for maintaining an airway, should be available for immediate use 
should an anaphylactic or anaphylactoid reaction occur [Centers for Disease Control and 
Prevention 2015].
Unblinded study personnel should not have contact with participants for any study-related 
procedures/assessments after administration of study vaccines, which includes all safety 
follow-up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant will be blinded to the study vaccine received. 
Vaccination information, such as Component Identification Number and time of vaccination, 
must be recorded on the appropriate electronic Case Report Form (eCRF) as per the Data 
Entry Guidelines.
8.1.8.1
Timing of Dose Administration
Vaccinations may be administered at any time of day and without regard to timing of meals.
Each participant's body temperature must be taken before vaccine administration. Individuals 
who present with fever (oral or tympanic temperature ≥100.4°F [≥38.0°C] or axillary or 
temporal temperature ≥99.4°F [≥37.4°C]) will have the vaccination delayed until fever is 
resolved for at least 72 hours.
The collection of blood samples and administration of pregnancy tests (if applicable) must be 
done before each vaccine administration.
All participants will be observed for at least 30 minutes after vaccination for any immediate 
reactions. This observation must be performed by blinded site personnel for all study 
vaccines (Section 1.3 and Section 6.3.3).
8.1.9
Electronic Vaccination Report Card (eVRC)
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).
Temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or vaccinations will be recorded on the eVRC as 
 
 
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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 the Telephone Contact (Day 15) and Visit 2 
(Day 30).
Any differences between eVRC data and the clinical database must be clearly explained in 
the participant’s source documentation.
For the specific AEs collected via the eVRC, 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 the participant approximately 6 months after the last dose of study 
vaccine to collect additional information based on a Telephone Contact Questionnaire 
provided by the Sponsor. Data to be reported from this discussion will include SAEs and/or 
any updates to previously reported safety information.
8.1.11
Discontinuation and Withdrawal
Participants who receive a single-dose intervention cannot discontinue study intervention 
(see Section 7.1).
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (Visit 2) 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 investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
 
 
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8.1.12
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
 
 
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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 and Prevnar 13™. 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.
8.2.1
Multiplex Opsonophagocytic Assay (MOPA)
The MOPA, developed and published by Professor Moon Nahm (Director of the US World 
Health Organization pneumococcal serology reference laboratory and National Institutes of 
Health pneumococcal reference laboratories), 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 micro-colony 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 
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 
 
 
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the assay including precision, ruggedness, relative accuracy, dilutional linearity, selectivity, 
and specificity. The validation results were evaluated against prespecified acceptance criteria 
for each of the parameters.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examination
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 1 (Day 1).
A complete physical examination includes, but is not limited to, assessment of general 
appearance, vital signs (heart rate, respiratory rate, blood pressure, and body temperature),
eyes, throat, mouth, cardiovascular, respiratory, gastrointestinal, skin, neurologic, and 
psychiatric systems, and other organ systems as indicated.
In the source documents, investigators should document physical exam data and the status of 
all active medical conditions.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Pregnancy Test
A pregnancy test consistent with local requirements (sensitive to at least 25 IU beta human 
chorionic gonadotropin [β-hCG]) must be performed before vaccination at Visit 1 (Day 1) in 
WOCBP as described in Section 1.3. Urine or serum tests can be used, and results must be 
negative before vaccination can occur.
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) or axillary or temporal 
temperature ≥99.4°F (≥37.4°C) will be considered an AE of fever. All fevers must be 
reported Day 1 through Day 14, unless the fever is a symptom of another reported AE.
 
 
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8.3.4
Safety Assessments and Use of the eVRC
All participants will be observed for at least 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
•
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).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study, every attempt should be made to perform repeat assessments 
until the values return to normal or baseline or if a new baseline is established as 
determined by the investigator.
8.4
Adverse Events (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.
 
 
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the 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.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
 
 
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion of 
study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest
There are no ECIs for this study.
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
 
 
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for 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.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
 
 
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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.
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
PK 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
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Screening procedures will be conducted at Visit 1 (Day 1) as outlined in Section 1.3.
 
 
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8.10.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
amended (consistent with International Council for Harmonisation [ICH] Guideline E-9). 
Changes to other non-confirmatory analyses made after the protocol has been finalized, but 
prior to unblinding/final database lock, will be documented in a supplemental Statistical 
Analysis Plan (sSAP) and referenced in the Clinical Study Report for the study. Post hoc 
exploratory analyses will be clearly identified in the Clinical Study Report.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 to Section 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active 
Comparator-controlled, Lot-to-Lot Consistency Study to Evaluate the 
Safety, Tolerability, and Immunogenicity of V114 in Healthy Adults 
50 Years of Age or Older (PNEU-TRUE)
Treatment Assignment
Participants will be randomly assigned in a 3:3:3:1 ratio into 1 of 
4 vaccination groups: V114 Lot 1, V114 Lot 2, V114 Lot 3, or 
Prevnar 13™. Randomization will be stratified into 3 groups based on 
the participant’s age (50 to 64 years of age, 65 to 74 years of age, and 
≥75 years of age) 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 for the 15 serotypes in V114 at 
30 days postvaccination (Day 30)
Safety:

Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling, and tenderness/pain) from Day 1 
through Day 5 postvaccination

Proportion of participants with solicited systemic AEs (muscle 
pain/myalgia, joint pain/arthralgia, headache, and 
tiredness/fatigue) from Day 1 through Day 14 postvaccination

Proportion of participants with vaccine-related SAEs from Day 1 
to Month 6 postvaccination
Key Secondary Endpoints
Immunogenicity:

Serotype-specific IgG GMCs for the 15 serotypes in V114 at 
30 days postvaccination (Day 30)
 
 
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Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 
15 pneumococcal serotypes in V114.
Each possible pairwise comparison of lots will be made (Lot 1 to 
Lot 2, Lot 1 to Lot 3, and Lot 2 to Lot 3). Each pairwise comparison of 
lots will consist of two 1-sided tests at the α=0.025 level. Rejecting the 
null hypothesis of nonequivalence for any test is equivalent to 
requiring the bounds of the 95% CI on the pairwise lot-to-lot 
comparison of the V114 GMT ratios to be between 0.5 and 2.0.
Estimation of the serotype-specific OPA GMT ratios and 95% CIs 
will be conducted using the constrained longitudinal data analysis 
(cLDA) method [Liang, K-Y and Zeger, S. L. 2000].
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-treatment differences in the percentage 
of participants with events; these analyses will be performed using the 
Miettinen and Nurminen (M&N) method [Miettinen, O. and 
Nurminen, M. 1985].
Interim Analyses
To support the periodic review of safety and tolerability data across 
the adult 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. 
However, unblinded immunogenicity data will be made available to 
the DMC upon request to enable a benefit-risk assessment.
Multiplicity
The overall success of the study requires demonstrating success on all 
15 pneumococcal serotypes for all 3 pairwise comparisons for V114 
lots that are evaluated in the primary immunogenicity objective. Since 
comparisons are made individually for each of the 15 serotypes and 
for each pairwise comparison, this approach controls the 2-sided type I 
error rate at 0.05, and no multiplicity adjustment is required.
No multiplicity adjustments will be made for the safety comparisons.
Sample Size and Power
This study will randomize approximately 667 participants into each of 
3 manufactured lots of V114 (Lot 1, Lot 2, and Lot 3) and 
220 participants into the Prevnar 13™group.
This study has >90% power to demonstrate equivalent immunogenicity 
across the 3 V114 lots of the OPA GMT ratio for the 15 serotypes
contained in V114 at an overall α=0.05 (2-sided) level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. This study will be conducted as a 
double-blind study under in-house blinding procedures. The official, final database will not 
be unblinded until medical/scientific review has been performed, protocol deviations have 
been identified, and data have been declared final and complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IRT. Blinding issues 
related to the planned interim analyses are described in Section 9.7.
 
 
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9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be evaluated for within- and/or 
between-intervention differences are listed below.
9.4.1
Immunogenicity Endpoints
The primary immunogenicity analysis endpoints are the serotype-specific OPA GMTs at 
30 days postvaccination (Day 30).
The secondary immunogenicity analysis endpoints include:
•
Serotype-specific IgG GMCs at 30 days postvaccination (Day 30)
•
Serotype-specific GMFRs and proportions of participants with a ≥4-fold rise from 
prevaccination (Day 1) to 30 days postvaccination (Day 30) for both OPA and IgG 
responses
9.4.2
Safety Endpoints
The safety analysis endpoints include:
•
Proportion of participants with solicited injection-site AEs (redness/erythema, swelling, 
and tenderness/pain) from Day 1 through Day 5 postvaccination
•
Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue) from Day 1 through Day 14 
postvaccination 
•
Proportions of participants with the broad AE categories consisting of any AE and any
vaccine-related AE from Day 1 through Day 14 postvaccination.
•
Proportions of participants with the broad AE categories consisting of any SAE, any
vaccine-related SAE, and death from Day 1 through the duration of participation in the 
study. As this is a single-dose study, the broad AE category of discontinuation of study 
intervention due to an AE is not applicable.
•
Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 5 postvaccination.
 
 
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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 endpoint(s). Potential deviations that may result in the exclusion of a 
participant from the PP population for all immunogenicity analyses include:
•
Failure to receive 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 prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant’s 
measurement from a specific time point assessment in the PP population for immunogenicity 
analyses include:
•
Receipt of prohibited medication or prohibited vaccine prior to a blood sample collection
•
Collection of blood sample outside of the prespecified window (as described in 
Section 1.3)
The final determination on protocol deviations, and thereby the composition of the PP 
population, will be made 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 endpoints. The FAS population consists of all randomized 
participants who received at least 1 vaccination and have at least 1 serology result. 
Participants will be included in the vaccination group to which they are randomized for the 
analysis of immunogenicity data using the FAS population.
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 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 treatment group corresponding to the study vaccination 
actually received.
 
 
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At least 1 temperature measurement obtained subsequent to study intervention is required for 
inclusion in the analyses 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 separately for each of the 15 pneumococcal 
serotypes across the 3 different lots of V114 (Lot 1, Lot 2, and Lot 3).
Primary Endpoint/Hypothesis
The primary objective (to compare the serotype-specific OPA GMTs at 30 days 
postvaccination [Day 30] across the 3 different lots of V114) will be assessed via the primary 
hypothesis.
Each possible pairwise comparison of lots will be made (Lot 1 to Lot 2, Lot 1 to Lot 3, and 
Lot 2 to Lot 3). Each possible pairwise comparison of lots will consist of two 1-sided tests at 
the α=0.025 level. Rejecting the null hypothesis of nonequivalence for any test is equivalent 
to requiring the bounds of the 95% CI on the pairwise lot-to-lot comparison of the V114 
GMT ratios to be between 0.5 and 2.0.
For each of the 15 serotypes in V114 and for each pairwise comparison, OPA GMTs between 
participants administered different lots of V114 at 30 days postvaccination will be compared 
via the following equivalence hypotheses:
H0: GMTx/GMTy < 0.5 or GMTx/GMTy > 2.0 versus
H1: 0.5 ≤ GMTX/GMTy ≤ 2.0
where GMTx is serotype-specific OPA GMT for one of the V114 lots and GMTy is 
serotype-specific OPA GMT for another V114 lot. A ratio between 0.5 and 2.0 corresponds
to ensuring that there’s no more than a 2.0-fold difference between OPA GMTs across any of 
the V114 lots (Lot 1 vs Lot 2, Lot 1 vs Lot 3, and Lot 2 vs Lot 3). Rejecting the null 
hypothesis (H0) at the two 1-sided α=0.025 level corresponds to the bounds of the 95% CI on 
the GMT ratio between each V114 lot (Lot 1/Lot 2, Lot 1/Lot 3, and Lot 2/Lot 3) being 
between 0.5 and 2.0 and would lead to the conclusion that the OPA responses for the 
15 serotypes across the V114 lot are equivalent.
 
 
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Estimation of the GMT ratios and 95% CIs, and the hypothesis test will be conducted using a 
cLDA method proposed by Liang and Zeger [Liang, K-Y and Zeger, S. L. 2000] utilizing 
data from the participants randomized to V114. In this model, the response vector consists of 
the log-transformed antibody titers at baseline (Visit 1 [Day1]) and 30 days postvaccination 
(Visit 2 [Day 30]). The repeated-measures model will include terms for vaccination group 
(V114 Lot 1, V114 Lot 2, and V114 Lot 3), time, the interaction of time-by-vaccination 
group (with a restriction of the same baseline mean across groups), age stratum (ie, 50 to 64 
years, 65 to 74 years, and ≥75 years) at baseline, and age stratum-by-time interaction. This 
model will allow for different baseline means for each stratum, but restrict the baseline mean 
within the age stratum levels to be the same for all V114 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.
Secondary Endpoints
A similar statistical model as used for the primary objective will be used to address the 
secondary objective that evaluates the serotype-specific IgG GMCs at 30 days 
postvaccination compared across 3 different lots of V114 and combined lots of V114 
compared to Prevnar 13™. Given the disparity in sample size across the intervention groups
for the combined lots of V114 versus Prevnar 13™comparison, convergence issues for the 
model are possible due to sensitivity of the model to differences in covariance structure 
between time points across intervention groups. Details of the methods to be used for this 
analysis if any of the models fail to converge will be provided in the sSAP.
Descriptive statistics with point estimates and within-group 95% CIs will be provided for all 
other immunogenicity endpoints. For the continuous endpoints, the point estimates will be 
calculated by exponentiating the estimates of the mean of the natural log values and the 
within-group CIs will be derived by exponentiating the bounds of the CIs of the mean of the 
natural log values based on the t-distribution. For the dichotomous endpoints, the 
within-group CIs will be calculated based on the exact method proposed by Clopper and 
Pearson [CLOPPER, C. J. and PEARSON, E. S. 1934].
Reverse Cumulative Distribution Curves for both OPA titers and IgG concentrations at 
30 days postvaccination with each lot of V114 will be graphically displayed by serotype.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 4.
 
 
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Table 4
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing 
Data 
Approach
Primary Endpoint
OPA GMTs at Day 30
P
cLDA§
(estimate, 95% CI, 
p-values)
PP
Model-based
S
FAS
Secondary Endpoint
IgG GMCs at Day 30
P
cLDA§
(estimate, 95% CI)
PP
Model-based
GMFRs and proportions of participants 
with a ≥4-fold rise from baseline to 
30 days postvaccination for both OPA 
and IgG 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:
§
cLDA model with terms for vaccination group, time, the interaction of time-by-vaccination, age stratum at 
baseline, and age stratum-by-time interaction.
CI = confidence interval; cLDA = constrained longitudinal data analysis; FAS = Full Analysis Set; 
GMC = Geometric Mean Concentration; GMFR = geometric mean fold rise; GMT = Geometric Mean Titer; 
IgG = Immunoglobulin G; OPA= opsonophagocytic activity; PP = Per-Protocol.
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.
Consistency of the safety profile across lots will be assessed via point estimates and 95% CIs
(for select safety endpoints) within each of the V114 vaccination groups (Lot 1, Lot 2, Lot 3). 
Details will be provided in the sSAP. The analysis of safety will then be performed for V114 
overall (combining the Lot 1, Lot 2, and Lot 3 vaccination groups) versus the Prevnar 13™ 
vaccination group following a tiered approach as detailed below (Table 5).
The tiers differ with respect to the analyses that will be performed. AEs (specific terms as 
well as system organ class [SOC] 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.
 
 
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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-treatment differences in the proportion of 
participants with events; these analyses will be performed using the Miettinen and Nurminen 
(M&N) method [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic 
method. For this protocol, solicited injection-site AEs (redness/erythema, swelling, and 
tenderness/pain) from Day 1 through Day 5 postvaccination and solicited systemic AEs 
(muscle pain/myalgia, joint pain/arthralgia, headache, and tiredness/fatigue) from Day 1 
through Day 14 postvaccination are considered Tier 1 events.
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 M&N method) [Miettinen, O. and 
Nurminen, M. 1985].
Membership in Tier 2 requires that at least 36 participants in the V114 combined group 
(combining Lot 1, Lot 2, and Lot 3 vaccination groups) or 4 participants in the Prevnar 13™
group exhibit the event. Because many 95% CIs for Tier 2 events may be provided without
adjustment for multiplicity, the CIs should be regarded as a helpful descriptive measure to be 
used in review, not a formal method for assessing the statistical significance of the 
between-group differences in AEs.
In addition, the broad AE categories consisting of the proportion of participants with any AE, 
a vaccine-related AE, an SAE, a vaccine-related SAE, and death will be considered Tier 2 
endpoints. Nonserious adverse events (NSAEs) will be followed for 14 days postvaccination
and SAEs will be followed for 6 months postvaccination. 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 treatment group are provided for Tier 3 safety parameters.
 
 
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Table 5
Analysis Strategy for Safety Parameters
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
Tier 2
Any AE†
X
X
Any Vaccine-Related AE†
X
X
Any SAE†
X
X
Any Vaccine-Related SAE†
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 
≥36 participants in the combined V114 group 
or ≥4 participants in the Prevnar 13™group)
X
X
Tier 3
Specific AEs by SOC and PT§ (incidence 
<36 participants in the combined V114 group 
and <4 participants in the Prevnar 13™group)
X
†
These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of 
“Any AE” will provide the number and percentage of participants with at least 1 AE.
‡
These analyses will be performed using the M&N method [Miettinen, O. and Nurminen, M. 1985].
§
Includes only those endpoints not prespecified as Tier 1 or not already prespecified as Tier 2 endpoints.
AE = adverse event; CI = confidence interval; M&N = Miettinen and Nurminen; PT = preferred term; 
SAE = serious adverse event; SOC = system organ class; X = results will be provided.
9.6.3
Demographic and Baseline Characteristics and Other Analysis
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants randomized
and discontinued from the study and discontinuation reasons will be displayed. Demographic 
variables (age, race, and gender), baseline characteristics, the number (%) of subjects 
reporting specific prior medications within 14 days prior to the first vaccination, the number 
(%) of subjects reporting specific concomitant medications within 14 days following any 
vaccination, the number (%) of subjects reporting specific prior vaccinations within 30 days 
prior to the first vaccination, and the number (%) of subjects reporting specific concomitant 
vaccinations within 30 days following any vaccination will be summarized by vaccination 
group either by descriptive statistics or categorical tables.
 
 
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9.7
Interim Analyses
A periodic review of safety and tolerability data across the V114 Phase 3 adult program will 
be conducted by an independent, unblinded, external DMC. A description of the structure
and function of the DMC, along with the timing and content of the safety review, 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.
The DMC will serve as the primary reviewer of the results of the ongoing safety reviews and 
will make recommendations for discontinuation of the study or protocol modifications to an 
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 Oversight Committee (EOC) of the Sponsor (and 
potentially other limited Sponsor personnel) may be unblinded to results at the intervention 
level to act on these recommendations. The extent to which individuals are unblinded with 
respect to ongoing safety reviews will be documented by the external unblinded statistician. 
Additional logistical details will be provided in the DMC Charter.
Study enrollment is likely to be ongoing at the time of external DMC review. Blinding to 
intervention assignment will be maintained at all investigational sites. Participant-level 
unblinding will be restricted to an external unblinded statistician performing ongoing safety 
reviews. Intervention-level ongoing safety reviews will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
safety reviews.
9.8
Multiplicity
The overall success of the study requires demonstrating success on all 15 pneumococcal 
serotypes for all 3 pairwise comparisons for V114 lots that are evaluated in the primary 
immunogenicity objective. Since comparisons are made individually for each of the 
15 serotypes and for each pairwise comparison, this approach controls the 2-sided type I 
error rate at 0.05, and no multiplicity adjustment is required.
No multiplicity adjustments will be made for the safety comparisons.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This study will randomize approximately 667 participants to receive each of 3 manufactured 
lots of V114 (Lot 1, Lot 2, and Lot 3) and 220 participants to receive Prevnar 13™.
 
 
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For the primary hypothesis, this study has >90% power to demonstrate equivalent 
immunogenicity across the 3 V114 lots. The power and sample size are based on the 
following assumptions:
•
90% evaluability rate (approximately 600 evaluable participants per intervention group)
•
The underlying serotype-specific OPA GMT ratios for each of the 15 pneumococcal 
serotypes is 1.0.
•
The variabilities for OPA titers in the V114 vaccination groups are the same as those 
observed in V114-006. That is, the standard deviations of the natural log titers for the 
15 pneumococcal serotypes range from 1.33 to 2.24.
•
The statistical criterion for equivalence requires the bounds of the 2-sided 95% CI of the 
OPA GMT ratios to be between 0.50 and 2.0.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE among 
2000 participants in V114 group (Lot 1, Lot 2, Lot 3 combined) if the underlying incidence 
of an SAE is 0.08% (1 of every 1243 participants receiving the vaccine). There is a 50% 
chance of observing at least 1 SAE among 2000 participants in the V114 group if the 
underlying incidence of an SAE is 0.03% (1 of every 2885 participants receiving the 
vaccine). If no SAEs are observed among 2000 participants, this study will provide 97.5% 
confidence that the underlying percentage of participants with an SAE is <0.18% (1 in every 
542 participants) in the V114 group (Lot 1, Lot 2, Lot 3 combined).
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.
 
 
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Table 6
Differences in the Incidence of Adverse Event Rates Between the 2 Vaccination 
Groups That Can be Detected With an Approximately 80% Probability 
Incidence of Adverse Event
Risk Difference
V114 (%)
N=2000
Prevnar 13™(%)
N=220
Percentage Points
1.5
0.1
1.4
5.4
2.0
3.4
9.9
5.0
4.9
16.5
10.0
6.5
22.5
15.0
7.5
28.3
20.0
8.3
39.3
30.0
9.3
The incidences presented here are hypothetical and do not represent actual adverse experiences in either group. 
The incidences assume a 2-sided 5% alpha level, with sample sizes of 2000 participants in the V114 group 
(Lot 1, Lot 2, Lot 3 combined) and 220 participants in the Prevnar 13™group. No multiplicity adjustments 
were made.
The calculations are based on an asymptotic method proposed by Farrington and Manning (1990) [Farrington, 
C. P. 1990].
9.10
Subgroup Analyses
To determine whether the intervention effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI for each V114 
vaccination group) will be summarized for the primary immunogenicity endpoint. The 
95% CI will only be calculated if there are more than 10 participants in each vaccination 
group for each subgroup. In addition, a summary of AEs and a summary of solicited AEs will 
be provided for each subgroup (point estimates only) for V114 overall (combining the Lot 1, 
Lot 2, and Lot 3 vaccination groups) and the Prevnar 13™ vaccination groups. The following 
are examples of classification variables:
•
Age category (50 to 64 years, 65 to 74 years, and ≥75 years)
•
Race (eg, White, Black, Asian, and Other)
•
Sex (female, male)
Further details of subgroup analyses will be documented in the sSAP.
 
 
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9.11
Compliance (Medication Adherence)
Given that participants will receive a single dose of V114 or Prevnar 13™, compliance will 
not be calculated. However, the number and proportion of randomized participants receiving 
V114 or Prevnar 13™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 or Prevnar 13™.
 
 
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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 (Institutional 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.
 
 
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (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 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
external 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 Interim 
Analysis) 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 GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical 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.
 
 
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
 
 
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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
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
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.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
 
 
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
•
Injection site erythema/redness or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
•
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.
a Based upon information provided by the participant 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.
 
 
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Specific Systemic AE Toxicity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Headache
No interference 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or some 
interference with 
activity
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity
ER visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
Abbreviations: AE = adverse event; ER = emergency room.
Other Systemic AE Toxicity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)b
Illness or clinical AE 
(as defined 
according to 
applicable 
regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
required medical 
intervention
ER visit or 
hospitalization
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 the eVRC review during the primary 
safety follow-up period. For SAEs reported beyond the primary safety follow-up period, grading will be based upon the 
initial report and/or follow-up of the event.
b AEs resulting in death will be assessed as Grade 4.
Vital Sign (Temperature) Toxicity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever 
(°C)b
(°F)b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
a Participant should be at rest for all vital sign requirements.
b Oral temperature; no recent hot or cold beverages or smoking.
 
 
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
 
 
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-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
 
 
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•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high 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 two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only contraceptive implantc
•
Intrauterine hormone-releasing system (IUS)c (IUS is a progestin-releasing IUD)
•
Intrauterine device (IUD)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen-containing) hormonal contraception
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraception
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)d
a. Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b. Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation
d. A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
-
Male and female condom should not be used together (due to risk of failure with friction).
 
 
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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 expected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways 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.
3.
Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
 
 
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5.
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in 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 investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.
Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.
Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10.
Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.
Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13.
References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-for-
genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.
Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.
Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
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
CRF
Case Report Form
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
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 Harmonization
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IM
intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug
IPD
invasive pneumococcal disease
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
M&N
Miettinen and Nurminen
MOPA
multiplexed opsonophagocytic assay
MSD
Merck Sharp & Dohme Corp.
NIMP
non-investigational medicinal product
NSAE
nonserious adverse event
OPA
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PK
pharmacokinetic
PnECL
pneumococcal electrochemiluminescence
 
 
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Abbreviation
Expanded Term
PP
Per-Protocol
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
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
US
United States
WOCBP
woman/women of childbearing potential
 
 
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11
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