A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator Controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Children With Sickle Cell Disease (PNEU-SICKLE)
Phase: PHASE3
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03731182  
Document Date: 
06-Sep-2018
A Phase 3, Multicenter, Randomized, Double-blind, Active 
Comparator-controlled Study to Evaluate the Safety, Tolerability, 
and Immunogenicity of V114 in Children with Sickle Cell Disease 
(PNEU–SICKLE)

PRODUCT: V114
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PROTOCOL/AMENDMENT NO.: 023-00
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06-SEP-2018
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 Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in 
Children with Sickle Cell Disease (PNEU–SICKLE)
Protocol Number: 023-00
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
14115
2018-001152-35 
Approval Date: 06-September-2018
 
 
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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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PRODUCT: V114
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Table of Contents
1
PROTOCOL SUMMARY ............................................................................................10
1.1
Synopsis.................................................................................................................10
1.2
Schema ..................................................................................................................13
1.3
Schedule of Activities (SoA) ................................................................................14
2
INTRODUCTION..........................................................................................................16
2.1
Study Rationale....................................................................................................16
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......................................................................................18
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS ................................................19
4
STUDY DESIGN............................................................................................................20
4.1
Overall Design ......................................................................................................20
4.2
Scientific Rationale for Study Design.................................................................20
4.2.1
Rationale for Endpoints ...............................................................................21
4.2.1.1
Immunogenicity Endpoints................................................................21
4.2.1.2
Safety Endpoints ................................................................................21
4.2.1.3
Future Biomedical Research..............................................................22
4.2.2
Rationale for the Use of Comparator...........................................................22
4.3
Justification for Dose ...........................................................................................22
4.4
Beginning and End of Study Definition .............................................................22
4.4.1
Clinical Criteria for Early Study Termination .............................................23
5
STUDY POPULATION ................................................................................................23
5.1
Inclusion Criteria.................................................................................................23
5.2
Exclusion Criteria ................................................................................................24
5.3
Lifestyle Considerations ......................................................................................26
5.4
Screen Failures.....................................................................................................26
5.5
Participant Replacement Strategy......................................................................26
6
STUDY INTERVENTION............................................................................................26
6.1
Study Intervention(s) Administered...................................................................27
6.2
Preparation/Handling/Storage/Accountability .................................................28
6.2.1
Dose Preparation..........................................................................................28
6.2.2
Handling, Storage, and Accountability........................................................28
6.3
Measures to Minimize Bias: Randomization and Blinding..............................28
6.3.1
Intervention Assignment..............................................................................28
 
 
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6.3.2
Stratification.................................................................................................28
6.3.3
Blinding........................................................................................................29
6.4
Study Intervention Compliance..........................................................................29
6.5
Concomitant Therapy..........................................................................................29
6.5.1
Rescue Medications and Supportive Care ...................................................30
6.6
Dose Modification (Escalation/Titration/Other)...............................................30
6.7
Intervention After the End of the Study............................................................30
6.8
Clinical Supplies Disclosure................................................................................30
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................31
7.1
Discontinuation of Study Intervention...............................................................31
7.2
Participant Withdrawal From the Study...........................................................31
7.3
Lost to Follow-up .................................................................................................31
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................32
8.1
Administrative and General Procedures ...........................................................33
8.1.1
Informed Consent/Assent.............................................................................33
8.1.1.1
General Informed Consent/Assent.....................................................33
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................34
8.1.2
Inclusion/Exclusion Criteria ........................................................................34
8.1.3
Participant Identification Card.....................................................................34
8.1.4
Medical History ...........................................................................................34
8.1.5
Prior and Concomitant Medications Review ...............................................35
8.1.5.1
Prior Medications...............................................................................35
8.1.5.2
Concomitant Medications ..................................................................35
8.1.6
Assignment of Screening Number...............................................................35
8.1.7
Assignment of Treatment/Randomization Number .....................................35
8.1.8
Study Intervention Administration ..............................................................36
8.1.8.1
Timing of Dose Administration.........................................................37
8.1.9
Electronic Vaccination Report Card ............................................................37
8.1.10
Telephone Contact Guide for Day 15 Postdose ...........................................37
8.1.11
Telephone Contact Questionnaire................................................................37
8.1.12
Discontinuation and Withdrawal .................................................................38
8.1.12.1
Withdrawal From Future Biomedical Research ................................38
8.1.13
Participant Blinding/Unblinding..................................................................38
8.1.14
Calibration of Equipment.............................................................................39
8.2
Immunogenicity Assessments .............................................................................39
8.2.1
Multiplex Opsonophagocytic Assay............................................................40
 
 
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8.2.2
Pneumococcal Electrochemiluminescence ..................................................40
8.3
Safety Assessments...............................................................................................40
8.3.1
Physical Examinations.................................................................................41
8.3.2
Pregnancy Test.............................................................................................41
8.3.3
Body Temperature Measurement.................................................................41
8.3.4
Safety Assessments and Use of the eVRC...................................................41
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
Planned Genetic Analysis Sample Collection ....................................................46
8.10
Biomarkers ...........................................................................................................46
8.11
Medical Resource Utilization and Health Economics.......................................47
8.12
Visit Requirements...............................................................................................47
8.12.1
Screening......................................................................................................47
8.12.2
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 .................................................49
9.3
Hypotheses/Estimation ........................................................................................49
9.4
Analysis Endpoints...............................................................................................49
9.4.1
Immunogenicity Endpoints..........................................................................49
9.4.2
Safety Endpoints ..........................................................................................50
9.5
Analysis Populations............................................................................................50
9.5.1
Immunogenicity Analysis Populations ........................................................50
9.5.2
Safety Analysis Populations ........................................................................51
 
 
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9.6
Statistical Methods...............................................................................................51
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................51
9.6.2
Statistical Methods for Safety Analyses ......................................................52
9.6.3
Demographic and Baseline Characteristics .................................................54
9.7
Interim Analyses ..................................................................................................54
9.8
Multiplicity ...........................................................................................................55
9.9
Sample Size and Power Calculations .................................................................55
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................55
9.9.2
Sample Size and Power for Safety Analyses ...............................................55
9.10
Subgroup Analyses...............................................................................................56
9.11
Compliance (Medication Adherence).................................................................56
9.12
Extent of Exposure...............................................................................................56
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................57
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........57
10.1.1
Code of Conduct for Clinical Trials.............................................................57
10.1.2
Financial Disclosure.....................................................................................59
10.1.3
Data Protection.............................................................................................59
10.1.3.1
Confidentiality of Data ......................................................................60
10.1.3.2
Confidentiality of Participant Records...............................................60
10.1.3.3
Confidentiality of IRB/IEC Information............................................60
10.1.4
Committees Structure...................................................................................60
10.1.4.1
Scientific Advisory Committee..........................................................60
10.1.4.2
Executive Oversight Committee........................................................60
10.1.4.3
External Data Monitoring Committee ...............................................61
10.1.5
Publication Policy........................................................................................61
10.1.6
Compliance with Study Registration and Results Posting Requirements ...61
10.1.7
Compliance with Law, Audit, and Debarment ............................................62
10.1.8
Data Quality Assurance ...............................................................................62
10.1.9
Source Documents .......................................................................................63
10.1.10
Study and Site Closure.................................................................................64
10.2
Appendix 2: Clinical Laboratory Tests..............................................................65
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................66
10.3.1
Definition of AE ..........................................................................................66
10.3.2
Definition of SAE ........................................................................................67
10.3.3
Additional Events Reported.........................................................................68
10.3.4
Recording AE and SAE ...............................................................................68
 
 
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................72
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................74
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................75
10.5.1
Definitions....................................................................................................75
10.5.2
Contraception Requirements........................................................................75
10.5.3
Pregnancy Testing........................................................................................76
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................77
10.7
Appendix 7: Country-specific Requirements ....................................................82
10.8
Appendix 8: Abbreviations .................................................................................83
11
REFERENCES...............................................................................................................84
 
 
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PRODUCT: V114
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LIST OF TABLES
Table 1
Study Interventions ..........................................................................................27
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Types ...33
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................44
Table 4
Analysis Strategy for Immunogenicity Variables............................................52
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination ...........53
Table 6
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying 
Standard Deviations.........................................................................................55
Table 7
Protocol-required Safety Laboratory Assessments..........................................65
Table 8
Contraceptive Methods ....................................................................................76
 
 
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PRODUCT: V114
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LIST OF FIGURES
Figure 1
V114-023 Study Design.............................................................................13
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in 
Children with Sickle Cell Disease (PNEU–SICKLE)
Short Title: Safety and Immunogenicity of V114 in Children with Sickle Cell Disease
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-023 (PNEU–SICKLE)
Hypotheses, Objectives, and Endpoints:
There is no formal hypothesis testing in this study.
The following objectives and endpoints will be evaluated in participants from 5 years to 17 
years of age (inclusive) with SCD:
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 14 postvaccination
- Solicited systemic AEs from Day 1 through 
Day 14 postvaccination
- Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation
- Objective: To evaluate the anti-pneumococcal 
polysaccharide (PnPs) serotype-specific 
Immunoglobulin G (IgG) Geometric Mean 
Concentrations (GMCs) at 30 days 
postvaccination (Day 30) for each vaccination 
group.
- Anti-PnPs serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
Day 30
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the anti-PnPs 
serotype-specific opsonophagocytic activity 
(OPA) Geometric Mean Titers (GMTs) at 30 
days postvaccination (Day 30) for each 
vaccination group. 
- Anti-PnPs serotype-specific OPA responses 
for the 15 serotypes contained in V114 at 
Day 30
- Objective: To evaluate the anti-PnPs 
serotype-specific Geometric Mean Fold Rises 
(GMFRs) from prevaccination (Day 1) to 30 
days postvaccination (Day 30) for both OPA 
and IgG responses for each vaccination group.
- Anti-PnPs serotype-specific OPA and IgG 
responses for the 15 serotypes contained in 
V114 at Day 1 and Day 30
 
 
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PRODUCT: V114
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Children with sickle cell disease
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
Care Provider
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 19 months from the time the first participant 
signs the informed consent/assent 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 100 participants will be randomized, with approximately 67 participants in 
the V114 intervention group and 33 participants in the Prevnar 13TM intervention group.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination 
Regimen
Use
V114
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
IB = Investigator’s Brochure; IM = intramuscular
Total 
Number
2 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. 
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: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The key components of the study design are depicted in Figure 1.
Figure 1
V114-023 Study Design
 
 
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1.3
Schedule of Activities (SoA)
Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
Comments
Scheduled Time: 
Day 1
Day 15
Day 30
Month 6
Visit Window:
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 and General Procedures
Screening Procedures
Informed Consent/Assent
X
Consent/assent must be obtained before any study procedures.
Informed Consent/Assent for Future 
Biomedical Research
X
Consent/assent for future biomedical research is optional and 
must be obtained before the collection of saliva DNA samples.
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Medical History
X
The participant’s medical history for the 5 years prior to study 
entry will be reviewed.
Post-enrollment Procedures
Assignment of Randomization Number
X
Prior/Concomitant Medication and 
Nonstudy Vaccination Review
X
X
X
See Section 8.1.5.for details.
V114 or Prevnar 13™ Administration 
(Blinded) 
X
At Visit 1 (Day 1), participants will receive either a single dose 
of V114 or a single dose of Prevnar 13™. 
Provide eVRC 
X
All participants will be provided an eVRC at Visit 1 (Day 1) to 
record AEs and body temperature measurements. Instructions 
for using the eVRC will be reviewed with the participant or 
participant’s legally acceptable representative.
Review eVRC data with participant or
participant’s legally acceptable 
representative
X
X
Collect eVRC from participant or 
participant’s legally acceptable 
representative
X
Complete the Telephone Contact 
Questionnaire
X
The Telephone Contact Questionnaire will be provided by the 
Sponsor. 
Safety Procedures
Complete Physical Examination 
X
To be performed by the investigator or medically qualified 
designee before study vaccine is administered.
 
 
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Visit Number:
1
Telephone 
Contact
2
Telephone 
Contact
Comments
Scheduled Time: 
Day 1
Day 15
Day 30
Month 6
Visit Window:
Day 15 to 
Day 19 after 
Visit 1
Day 30 to 
Day 44 after 
Visit 1
Day 166 to 
Day 194 after 
Visit 1
Pregnancy Test – if applicable
X
A pregnancy test consistent with local requirements must be 
performed before administration of the study vaccine in women 
of child-bearing potential. Urine or serum tests can be used, and 
results must be negative before vaccination can occur.
Body Temperature Measurement 
X
Each participant’s body temperature must be taken before 
vaccination (see Section 8.3.3 for details on the method of 
temperature collection). 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.
AE Monitoring
X
X
X
X
Nonserious AEs are to be reported from Days 1 through 14 
postvaccination. SAEs and deaths are to be reported throughout 
the duration of the participant’s study participation.
Immunogenicity Procedures
Serum for immunogenicity assays 
(including retention serum)
X
X
Blood samples must be collected before study vaccination when 
applicable.
Future Biomedical Research
Saliva (DNA) for Future Biomedical 
Research
X
Collected from randomized participants who provided 
consent/assent for Future Biomedical Research (See 
Section 8.8).
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic Vaccination Report Card; SAE = serious adverse event.
 
 
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2
INTRODUCTION
Merck Sharp & Dohme Corp. (MSD) is developing an investigational 15-valent 
pneumococcal conjugate vaccine (PCV) (referred to as V114) for prevention of 
pneumococcal disease caused by the serotypes contained in the vaccine. V114 contains the 
13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 23F) present in the licensed 
vaccine Prevnar 13™ (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197
protein], Wyeth Pharmaceuticals, a subsidiary of Pfizer, Inc., Philadelphia, PA), plus 2 
additional serotypes (22F, 33F). 
2.1
Study Rationale
Sickle cell disease (SCD) is a group of disorders caused by abnormal hemoglobin which can 
deform or “sickle” red blood cells and lead to end-organ damage. Children with SCD have an 
increased risk of invasive disease caused by encapsulated bacteria, such as Streptococcus 
pneumoniae, secondary to splenic dysfunction and abnormalities of innate immunity. Early 
interventions with vaccinations against encapsulated bacteria have significantly reduced the 
mortality of SCD in the United States and Europe [Quinn, C. T., et al 2010] [Telfer, P., et al 
2007].   
Immunization guidelines recommend that infants and children with SCD follow the same 
PCV schedule as healthy infants and children up to 5 years of age, including catch up 
vaccination. Children with SCD 2 to 18 years of age, without a history of immunization with 
the 13-valent Prevnar 13™are recommended to receive catch up immunization with
Prevnar 13™, regardless of previous immunization with other PCVs containing fewer 
pneumococcal polysaccharide (PnPs) serotypes. In addition, it is recommended that children 
with SCD receive 2 doses of the 23-valent PnPs vaccine, PNEUMOVAX™23; the first dose 
at 2 years of age and the second dose either at 5 years of age [National Heart, Lung and 
Blood Institute 2014] or at 7 years of age (5 years after first dose) [Centers for Disease 
Control and Prevention (CDC) 2013].
This clinical study is designed to describe the safety, tolerability, and immunogenicity of 
V114 compared with Prevnar 13™ in children with SCD 5 to 17 years of age (inclusive) who 
are either PCV naïve or have a history of previous PCV immunization. Because of 
widespread adherence to immunization guidelines for children with SCD, it is anticipated 
that a majority of participants will have been previously vaccinated with a PCV. Safety and 
immunogenicity data collected in this study will support recommendations for V114 catch-up 
vaccination in children who received a PCV containing fewer than 15 serotypes or who are 
PCV naïve. In addition, the data from this study will contribute to the overall safety database 
and immunogenicity profile of V114 in children.
 
 
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2.2
Background
2.2.1
V114 and Pneumococcal Disease 
Refer to the Investigator’s Brochure (IB) for V114 for detailed background, including 
information on pneumococcal disease burden.
Streptococcus pneumoniae remains a significant cause of disease worldwide, with clinical 
manifestations including meningitis, sepsis, pneumonia, sinusitis and otitis media. Currently, 
many countries worldwide have incorporated licensed PCVs (eg, Prevnar 13™ and/or 
Synflorix™ (pneumococcal polysaccharide conjugate vaccine [adsorbed], GlaxoSmithKline 
Biologicals S.A, Rixensart, Belgium) into their infant immunization programs. Prevnar™ 
was first licensed in 2000 and later replaced by Prevnar 13™ in 2009 (European Union) and 
2010 (United States). Synflorix™ was licensed in the European Union in 2009. Although 
Prevnar 13™ is indicated for children and adults, Synflorix™ is only indicated for children 
up to 5 years of age. Widespread use of PCVs have reduced the burden of pneumococcal 
disease caused by the serotypes contained in the vaccines in children who received the 
vaccines, as well as unvaccinated individuals through 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]. Despite this, an 
increase in the burden of invasive pneumococcal disease (IPD) caused by serotypes not 
contained in currently available vaccines has been observed.
V114 contains all the pneumococcal serotypes contained in Prevnar 13™plus 2 additional 
serotypes (22F, 33F). The selection of 22F and 33F was primarily based on the emergence of 
these 2 serotypes as important causes of IPD in the era of Prevnar™and Prevnar 13™.
Approximately 4 years after inclusion of Prevnar™in the United States infant immunization 
schedule, serotypes 22F and 33F accounted for approximately 13% of IPD cases in children 
<5 years of age (incidence rate of IPD due to 22F and 33F combined of 3.1 cases per 100,000 
person-years [PY]), in contrast to 1.3% of IPD cases in the pre-PCV7 era (incidence rate of 
22F and 33F IPD of 1.2 cases per 100,000 PY) [Hicks, L. A., et al 2007]. By 2013, both 22F 
and 33F were among the leading serotypes causing IPD beyond those already included in 
Prevnar 13™, accounting for approximately 21% of all IPD in children <5 years of age in the 
United States [Moore, M. R., et al 2015]. 
The additional serotypes contained 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.
 
 
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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
Refer to approved labeling for detailed background information on Prevnar 13™.
Prevnar 13™ is a pneumococcal conjugate vaccine that contains the 7 pneumococcal 
serotypes included in Prevnar™ (4, 6B, 9V, 14, 18C, 19F, 23F) plus 6 additional serotypes 
(1, 3, 5, 6A, 7F, and 19A). In many countries, Prevnar 13™is given as a part of routine 
immunization schedules for all infants and children 2 to 59 months of age. Children with 
SCD 2 to 18 years of age, without a history of immunization with Prevnar 13™ are 
recommended to receive catch up immunization with Prevnar 13™, regardless of previous 
immunization with other PCVs containing fewer PnPs serotypes. [Centers for Disease 
Control and Prevention (CDC) 2013].
Prevnar™ and Prevnar 13™ are also known as Prevenar™ and Prevenar 13™ in many 
countries outside of the United States; these vaccines will be 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 
treatment during participation, as clinical studies are designed to provide information about 
the safety and efficacy of an investigational medicine.
This study will evaluate the safety and immunogenicity of V114 in a pediatric SCD 
population who are either PCV naïve or have received previous PCV immunization. For 
those children previously vaccinated with a PCV, an additional PCV dose will likely increase 
pneumococcal antibody titers against serotypes contained in the previous vaccine, but is not 
anticipated to be associated with safety or tolerability issues. This is supported by a previous 
study in which 2 doses of Prevnar 13™were administered 6 months apart in children with 
SCD with no change in the safety profile with the second dose [De Montalembert, M., et al 
2015]. Furthermore, safety and tolerability issues were not identified following the 
widespread practice of catch up Prevnar 13™vaccination in children previously vaccinated 
with Prevnar™.  
Prevnar 13™is the current standard of care for PCVs in many countries worldwide and is the 
active comparator in this study. Approximately 33% of participants will receive Prevnar 13™
in this study. Based on available data, V114 is expected to provide comparable immune 
responses and a comparable safety profile to Prevnar 13™ for the shared pneumococcal 
serotypes while providing additional coverage for the 2 serotypes unique to V114 (22F, 33F).
However, it is unknown if the investigational V114 will have the same benefit/risk profile as 
Prevnar 13™. 
 
 
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent/assent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no formal hypothesis testing in this study.
The following objectives and endpoints will be evaluated in participants from 5 years to 17 
years of age (inclusive) with SCD:
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 14 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 14 postvaccination
•
Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation
•
Objective: To evaluate the 
anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G 
(IgG) Geometric Mean Concentrations 
(GMCs) at 30 days postvaccination
(Day 30) for each vaccination group.
•
Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes contained 
in V114 at Day 30
Secondary
•
Objective: To evaluate the anti-PnPs 
serotype-specific opsonophagocytic 
activity (OPA) Geometric Mean Titers 
(GMTs) at 30 days postvaccination
(Day 30) for each vaccination group.
•
Anti-PnPs serotype-specific OPA
responses for the 15 serotypes contained 
in V114 at Day 30
•
Objective: To evaluate the anti-PnPs 
serotype-specific Geometric Mean Fold 
Rises (GMFRs) from prevaccination 
(Day 1) to 30 days postvaccination
(Day 30) for both OPA and IgG 
responses for each vaccination group.
•
Anti-PnPs serotype-specific OPA and 
IgG responses for the 15 serotypes 
contained in V114 at Day 1 and Day 30
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active comparator-controlled, parallel-group, multi-site, double-blind
(with in-house blinding), study of V114 in participants 5 to 17 years of age (inclusive) with 
SCD. Approximately 100 participants will be randomly assigned in a 2:1 ratio to receive 
either V114 (67 participants) or Prevnar 13™ (33 participants) on Visit 1 (Day 1).
Participants will be followed for local and systemic AEs through Day 14 following 
vaccination. Information for serious adverse events (SAEs) and deaths, regardless of whether 
the events are considered to be vaccine-related by the investigator, will be collected from the 
time consent/assent 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 this study, as well as all studies in the pediatric V114 Phase 3 program. A description 
of the structure, function, and guidelines for decision-making by the DMC, along with the 
timing and content of the safety reviews will be outlined in the DMC charter. Information 
regarding the composition of the DMC is provided in Appendix 1.
To obtain baseline pneumococcal antibody titers, blood samples for immunogenicity assays 
will be drawn immediately before V114 or Prevnar 13™ vaccination at Visit 1 (Day 1). An 
additional blood draw for immunogenicity testing (including OPA and 
electrochemiluminescence [ECL] testing to measure V114 or Prevnar 13™-induced 
pneumococcal-specific immune responses) will occur at Visit 2 (Day 30). 
After completion of immunogenicity testing, serum samples will be stored to conduct any 
additional study-related testing as required by regulatory agencies or the Sponsor. For 
randomized study participants who provided consent/assent for future biomedical research, 
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.  
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 clinical study is designed to describe the safety, tolerability, and immunogenicity of 
V114 compared with Prevnar 13™ in children with SCD 5 to 17 years of age (inclusive) who 
are either PCV naïve or have a history of previous PCV immunization. The primary and 
secondary immunogenicity endpoints (IgG and OPA) measure anti-pneumococcal serotype-
specific antibody responses, which are known to be associated with protection from IPD. 
Injection-site reactions and systemic symptoms following vaccination will be solicited for 14 
days. Participants will be followed for 6 months following immunization for reports of SAEs 
or death. The duration of the safety follow-up period is consistent with previous studies 
evaluating the immunogenicity and safety of PCVs in children with SCD. The
immunogenicity and safety objectives are descriptive and do not test formal hypotheses.
 
 
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V114 has the potential to offer additional protection against IPD caused by 2 PnPs serotypes 
not contained in Prevnar 13™ in addition to boosting immune responses to serotypes shared 
with Prevnar 13™. Safety and immunogenicity data collected in this study will support 
recommendations for V114 catch-up vaccination in children with SCD who received a PCV 
containing fewer than 15 serotypes or who are PCV-naïve.  
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Sera from participants will be used to measure vaccine-induced, serotype-specific IgG and 
OPA 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 pneumococcal electrochemiluminescence (PnECL) 
assay and multiplexed opsonophagocytic assay (MOPA). Anti-PnPs serotype-specific IgG 
responses will be measured at baseline and at 30 days following the dose of V114 or
Prevnar 13™.
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. It is noted that 
threshold values that correlate with protection in children with SCD have not been defined 
for either assay.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1.
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in previous studies, published data from marketed PCVs, and feedback 
received from regulatory agencies during product development. The electronic Vaccination 
Report Card (eVRC) used to record AEs during the postvaccination periods, as defined in 
Section 8.1.9, was structured as recommended in the final Food and Drug Administration 
Patient Reported Outcome Guidance [U.S. Food and Drug Administration 2009]. 
Details on the safety endpoints evaluated in this study can be found in Section 8.3.4 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
 
 
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4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
Placebo-controlled clinical studies for new PCVs are no longer acceptable given the proven 
clinical efficacy, public health impact, and widespread use of licensed PCVs worldwide. 
Prevnar 13™ is currently the most widely recommended vaccine for the prevention of 
pneumococcal disease in infants and children in many countries worldwide, includes the 
largest number of serotypes, and will be used as the active comparator in this study.
Refer to approved labeling for detailed background information on Prevnar 13™.
4.3
Justification for Dose
The dosing regimen of V114 is similar to that used in previous V114 adult and pediatric 
Phase 2 clinical studies in which 1 dose administered to adults resulted in a robust immune 
response and had an acceptable safety and tolerability profile. 
The dose of Prevnar 13™ for use in this study is the approved dose.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form. 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
 
 
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.     
5
STUDY POPULATION
Male/Female participants with SCD between the ages of 5 and 17 years (inclusive) 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
To be eligible for inclusion in this study, the participant must:
1. Have a documented diagnosis of SCD in their medical record.
Demographics
2. Be male or female, from 5 years to 17 years of age (inclusive), at the time of obtaining
the informed consent/assent.
Female Participants
3. Not be pregnant (Appendix 5) or breastfeeding, and at least 1 of the following conditions 
applies:
a.
Not be a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP must agree to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 6 weeks after the last dose of study intervention.
Informed Consent/Assent
4. Have a legally acceptable representative who understands the study procedures, alternate 
treatments available, and risks involved with the study and voluntarily agrees to 
participate by giving written informed consent/assent. The legally acceptable 
representative may also provide consent/assent for future biomedical research. However, 
the participant may participate in the main study without participating in future 
biomedical research.
 
 
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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 conjugate vaccine
(PCV), or any diphtheria toxoid-containing vaccine.
3. Has a known or suspected impairment of immunological function.
4. Has a history of congenital or acquired immunodeficiency.
5. Has a documented human immunodeficiency virus (HIV) infection.
6. Has a history of autoimmune disease (including but not limited to systemic lupus 
erythematosus, antiphospholipid syndrome, Behcet’s disease, autoimmune thyroid 
disease, polymyositis and dermatomyositis, scleroderma, or type 1 diabetes mellitus).
7. Has a known coagulation disorder contraindicating intramuscular vaccination.
8. *Has had a recent febrile illness (defined as oral or tympanic temperature ≥38.1°C 
[≥100.5°F]; axillary or temporal temperature ≥37.8°C [≥100.0°F]) or received antibiotic 
therapy for any acute illness occurring within 72 hours before receipt of study vaccine.
9. Has a history of malignancy ≤5 years prior to signing informed consent/assent, except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
10. Is a WOCBP who has a positive urine or serum pregnancy test before the first 
vaccination at Visit 1 (Day 1).
Prior/Concomitant Therapy
11. Has received any PCV or PnPs vaccine <3 years before Visit 1 (Day 1).
12. Is 5 years of age and has received <3 doses of PCV.
13. *Meets one or more of the following systemic corticosteroid exclusion criteria:
a.
Has received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for 
≥14 consecutive days and has not completed treatment at least 30 days before study 
vaccination.
 
 
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b. Has received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) within 14 days before study 
vaccination.  
c.
Is expected to require systemic corticosteroids within 30 days after study vaccination.
Note: Topical, ophthalmic, intra-articular or soft-tissue (eg, bursa, tendon steroid 
injections), and inhaled/nebulized steroids are permitted.
14. 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.
Note: Hydroxyurea is permitted.
15. *Has received any non-live vaccine within the 14 days before receipt of the study vaccine 
or is scheduled to receive any non-live vaccine within 30 days following receipt of the
study vaccine. Exceptions: Inactivated influenza vaccine may be administered but must 
be given at least 7 days before receipt of the study vaccine or at least 15 days after receipt 
of the study vaccine. PNEUMOVAX™23 may be administered after the blood draw at 
Visit 2 (Day 30).
16. *Has received any live vaccine within 30 days before receipt of the study vaccine or is 
scheduled to receive any live vaccine within 30 days following receipt of the study 
vaccine.
17. Has received immunoglobulin within 6 months before receipt of study vaccine.
Prior/Concurrent Clinical Study Experience
18. Has participated in another clinical study of an investigational product within 2 months 
before the beginning or anytime during the duration of the current clinical study. 
Participants enrolled in observational studies may be included; these will be reviewed on 
a case-by-case basis for approval by the Sponsor.
Other Exclusions
19. Has a recent history (within the last year) of more than 3 inpatient hospitalizations. 
20. Is, at the time of signing informed consent/assent, a user of recreational or illicit drugs or 
has had a recent history (within the last year) of drug or alcohol abuse or dependence as 
assessed by the study investigator.
21. Has a history or current evidence of any condition, therapy, lab abnormality or other
circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study in the opinion of the Investigator.
 
 
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22. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, 
Visit 1 may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent 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 and Prevnar 13™) will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
 
 
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
V114
Experimental
V114
Biological/
Vaccine
Sterile Suspension
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
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.
Definitions of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) are based on guidance issued by the European Commission. 
Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon local country operational requirements. 
If local sourcing, every attempt should be made to source these supplies from a single lot/batch number where possible (eg, not 
applicable in the case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
 
 
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6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 2:1 ratio to V114 or Prevnar 13™, respectively.
6.3.2
Stratification
No stratification will be used in this study.
 
 
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6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevnar 13™will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study site personnel. The 
participant and the investigator who is involved in the clinical evaluation of the participants 
will remain blinded to the group assignments.
Because V114 and Prevnar 13™ differ in appearance, a member of the study site staff will be 
unblinded for the purposes of receiving, maintaining, preparing, and administering these 
study vaccines. Procedures for handling, preparing, and administering the unblinded vaccines 
are located in the Investigator Trial File Binder.
In order to avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel will not be present in the examination room when study vaccines are administered. 
Contact between participants and unblinded study personnel after vaccination administration 
is strictly prohibited. Blinded site personnel will be responsible for all safety and 
immunogenicity follow-up procedures after vaccine administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) and Merck Research Laboratories employees 
directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified plan for V114 or Prevnar 13™ vaccination 
indicated in Section 1.3 require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (see Section 5.2 for details). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
 
 
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individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate electronic Case Report Form (eCRF). It is important to record the use of any
analgesic or antipyretic use that occurs on the day of vaccination on the eVRC and 
appropriate eCRF.
During influenza season, it is anticipated that participants may be given an influenza vaccine. 
Influenza vaccine should be administered either 7 days prior to or 15 days after the 
administration of the study vaccine. In addition, PNEUMOVAX™23 may be administered 
after the blood draw at Visit 2 (Day 30) outside of the study.
Documentation of which arm was used for the administration of V114 or Prevnar 13™
should be recorded on the appropriate eCRF. This information should also be recorded on the 
eVRC to inform the parent or legally acceptable representative of the appropriate limb to 
monitor for AEs related to the V114 or Prevnar 13™. 
No other investigational compound or device may be administered at any time during this 
study without prior approval by the Sponsor.
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 as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.13). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.13 for a description of the method of unblinding a participant during the
study, should such action be warranted.
 
 
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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 or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.12. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
 
 
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
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, and assent if applicable, be obtained from 
the participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
Table 2 shows the approximate blood volumes drawn by study visit and by sample type. The 
maximum amount of blood collected from each participant for study procedures at each 
study visit will not exceed 10 mL and the total amount of blood for the entire study collected 
during planned study visits will not exceed 20 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Types
Study Visit
Visit 1
(Day 1)
Visit 2
(Day 30)
Blood parameter
Approximate Blood Volume (mL)
Serum for immunogenicity assays (including retention serum)
10 mL
10 mL
Expected total (mL)
10 mL
10 mL
N/A = not applicable
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative 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/assent is in place.
8.1.1.1
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form, 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 or his/her legally acceptable representative should 
be informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent/assent form or 
addendum to the original consent form that captures the participant’s dated signature or by 
the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
 
 
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant, answer all of his/her questions, and obtain written informed 
consent/assent before performing any procedure related to the future biomedical research 
substudy. A copy of the informed consent/assent 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. The investigator should 
consult with the Sponsor’s Clinical Director for any questions about participant eligibility.
If the participant meets any of the exclusion criteria with an asterisk (*), Visit 1 (Day 1) may 
be rescheduled for a time when these criteria are not met.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent/assent. 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. The participant’s medical history for the 5 years prior to Visit 1 will be 
obtained to ensure that the participant satisfies the inclusion and exclusion criteria of the 
study.
 
 
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations and 
medications taken by the participant within 30 days before the first dose of study vaccine at 
Visit 1.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate eCRF. 
It is important to record the use of any analgesic or antipyretic use that occurs on the day of 
vaccination on the eVRC and appropriate eCRF. Concomitant medications taken after Visit 1 
and nonstudy vaccines received since Visit 1 will be recorded with the eVRC as specified in 
Section 8.3.4.
Other vaccinations administered during the study should be recorded on the appropriate 
eCRF. Injectable vaccines should not be administered in the same limb as V114 or 
Prevnar 13™. Documentation of which limb was used for the administration of V114 or 
Prevnar 13™ should be recorded on the eVRC (Section 8.3.4) and appropriate eCRF. 
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.12.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
 
 
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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 the study vaccine. 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 labels.
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.
If the V114 is provided as a syringe: Prior to administration of study vaccine, the unblinded 
pharmacist should shake 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. 
If V114 is provided as a vial: Prior to administration of study vaccine, the unblinded 
pharmacist should use rapid, horizontal hand-shaking for up to 5 seconds while holding the 
vial in between the thumb and index finger to obtain a homogenous white suspension. 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 in the deltoid 
region of the participant’s arm. Prevnar 13™ will be supplied as a pre-filled syringe.
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 and/or participant’s parent/guardian will be blinded to 
the study vaccine received by the participant. Vaccination information, such as Component 
Identification Number and time of vaccination, must be recorded on the appropriate eCRF as 
per the Data Entry Guidelines.
 
 
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8.1.8.1
Timing of Dose Administration
V114 or Prevnar 13™ will be administered as indicated in Section 1.3. All participants will 
be observed for 30 minutes postvaccination 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).
Participants must be afebrile for at least 72 hours prior to vaccination. 
Blood samples must be collected and pregnancy tests (in WOCBP) must be administered
before study vaccination.
8.1.9
Electronic Vaccination Report Card
The eVRC was developed to be administered electronically via a hand-held device. This item 
was structured as recommended in the final Food and Drug Administration Patient Reported 
Outcome Guidance [U.S. Food and Drug Administration 2009]. The investigator or delegate 
will train the participant or participant’s legally acceptable representative in the use of the 
eVRC as indicated in Section 1.3.
Body temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or vaccinations will be recorded on the eVRC as 
described in Section 1.3 and Section 8.3.4. The investigator or delegate will review the data 
captured on the eVRC with the participant or participant’s legally acceptable representative
as indicated in Section 1.3.
For the AEs outlined above, the investigator will use the information provided by the 
participant or participant’s legally acceptable representative both on the eVRC, and verbally 
at the time of eVRC review, to apply the appropriate assessment of intensity as described in 
Appendix 3.
8.1.10
Telephone Contact Guide for Day 15 Postdose
Site personnel will contact study participants on Day 15 postdose to review eVRC data with 
the participant or participant’s legally acceptable representative. The Day 15 Postdose 
Telephone Contact Guide will be provided by the Sponsor. This guide is designed to assist 
site personnel to collect any updates or edits to data previously entered on the eVRC from the
participant or participant’s legally acceptable representative. Any differences between eVRC 
data and the clinical database must be clearly explained in the participant’s source 
documentation with an indication of where the information was obtained (eg, from the 
Day 15 Postdose Telephone Contact with the participant or participant’s legally acceptable 
representative).
8.1.11
Telephone Contact Questionnaire
Site personnel will contact study participants or the participant’s legally acceptable 
representative approximately 6 months after administration of study vaccine to collect 
 
 
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additional information based on a Telephone Contact Questionnaire provided by the Sponsor. 
Data to be reported from this discussion will include SAEs and/or any updates to previously 
reported safety information.
8.1.12
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the protocol-specified 
vaccinations should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (Visit 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.
8.1.12.1
Withdrawal From Future Biomedical Research
A Participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate). A participant’s consent 
may be withdrawn at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.13
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
 
 
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investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (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 that is part of the study design has taken place, the principal 
investigator, site personnel, and Sponsor personnel may be unblinded so that the appropriate 
follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced OPA and IgG 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.
 
 
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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
The MOPA, developed and published by Professor Moon Nahm (Director of the United 
States World Health Organization pneumococcal serology reference laboratory and National 
Institutes of Health pneumococcal reference laboratories), is a multiplexed OPA assay 
capable of measuring 4 serotypes at a time, against a total of 16 serotypes of pneumococci 
[Burton, Robert L. and Nahm, Moon H. 2006]. The OPA is an antibody-mediated killing 
assay that measures the ability of human serum to kill S. pneumoniae serotypes with the help 
of complement and phagocytic effector cells. The ability of the assay to simultaneously test 
4 serotypes/run reduces the amount of serum needed for testing. The assay readout is the 
opsonization index, which is the reciprocal of the highest dilution that gives ≥50% bacterial 
killing, as determined by comparison to assay background controls. The Sponsor 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 
pre-specified acceptance criteria for each of the parameters.
8.2.2
Pneumococcal Electrochemiluminescence
The Sponsor has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 PnPs 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 the assay including 
precision, ruggedness, relative accuracy, dilutional linearity, selectivity, and specificity. The 
validation results were evaluated against pre-specified acceptance criteria for each of the 
parameters.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
 
 
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination with V114 or Prevnar 13™ 
as indicated in Section 1.3. 
Investigators should pay special attention to clinical signs related to previous illnesses.
8.3.2
Pregnancy Test
A pregnancy test consistent with local requirements (sensitive to at least 25 IU beta human 
chorionic gonadotropin [β-hCG]) must be performed before vaccination 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
Pre-vaccination body temperature will be taken by study staff as indicated in Section 1.3.
Participants who have febrile illness (oral temperature ≥38.1°C [≥100.5°F] or axillary 
temperature ≥37.8°C [≥100.0°F]) occurring at or within 72 hours of Visit 1 must be 
rescheduled. Oral is the preferred method of obtaining participant’s temperature. Axillary 
(underarm) is an acceptable method but temperature needs to be confirmed by oral
measurement if fever is detected. If an axillary temperature is reported to be ≥37.8°C 
(≥100.0°F), an oral temperature must be taken. In this case, both axillary and oral
temperatures must be recorded on the eVRC. Temperature readings should be taken at 
approximately the same time each day. Use of temporal or tympanic thermometers to collect 
temperature for this study is prohibited.
The participant or the participant’s legally acceptable representative will be asked to record a 
body temperature reading on the eVRC from Day 1 through Day 7 postvaccination. 
Temperature measurement must be recorded in the eVRC if fever is suspected during Day 8 
through Day 14 postvaccination.
8.3.4
Safety Assessments and Use of the eVRC
All participants will be observed for 30 minutes after each vaccination for any immediate 
reactions. If any immediate AEs are observed during this period, the time at which the event 
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event, must be recorded on the appropriate eCRF.
The participant or the participant’s legally acceptable representative will use the eVRC 
(Section 8.1.9) to document the following information:
•
Body temperatures measured Day 1 (day of vaccination) through Day 7 postvaccination; 
Day 8 through Day 14 postvaccination if fever is suspected
•
Solicited injection-site AEs (redness, swelling, tenderness, and hard lump) Day 1 through 
Day 14 postvaccination
 
 
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•
Solicited systemic AEs (muscle pain, joint pain, headache, tiredness, and hives or welts) 
Day 1 through Day 14 postvaccination
•
Any other injection-site or systemic AEs Day 1 through Day 14 postvaccination
•
The arm that was used for the administration of V114 or Prevnar 13™ (Note: the study 
will report injection-site AEs from V114 or Prevnar 13™; the location of V114 or 
Prevnar 13™ administration can be used by the participant or participant’s legally 
acceptable representative to monitor the appropriate limb for injection-site AEs related to 
V114 or Prevnar 13™)
•
Use of any analgesic or antipyretic on the day of vaccination
•
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 Section 1.3.
•
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.
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.
 
 
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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.
Not required
Not 
applicable
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
 
 
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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.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
All reports of overdose must be reported by the investigator within 5 calendar days to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in 
the electronic data collection (EDC) data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant’s legally acceptable representative signs the future biomedical research 
consent and the participant assents if applicable, the following specimens will be obtained as 
part of future biomedical research:
•
Saliva DNA for future research
•
Leftover study serum after completion of immunogenicity testing stored for future 
research
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
 
 
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8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study. 
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Screening procedures will be conducted at Visit 1 (Day 1) as outlined in Section 1.3.
8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental Statistical Analysis Plan and referenced in the 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 through Section 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active 
Comparator-controlled Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of V114 in Children with Sickle Cell Disease 
(PNEU-SICKLE).
Intervention Assignment
Participants will be randomly assigned in a 2:1 ratio to V114 or 
Prevnar 13™, respectively.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
 
 
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Primary Endpoint(s)
Immunogenicity:
Anti-PnPs Serotype-specific IgG GMCs at 30 days postvaccination 
(Day 30)
Safety:

Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling,  tenderness/pain, and hard 
lump/induration) from Day 1 through Day 14 following V114 or
Prevnar 13™ 

Proportion of participants with solicited systemic AEs (muscle 
pain/myalgia, joint pain/arthralgia, headache, tiredness/fatigue, and 
hives or welts/urticarial) from Day 1 through Day 14 following 
V114 or Prevnar 13™

Proportion of participants with vaccine-related SAEs from Day 1 
through completion of study participation following V114 or 
Prevnar 13™
Key Secondary Endpoints
Immunogenicity:

Anti-PnPs serotype-specific OPA GMTs for the 15 serotypes 
contained in V114 at 30 days postvaccination (Day 30)

Anti-PnPs serotype-specific GMFR from prevaccination (Day 1) to 
30 days postvaccination for both OPA and IgG responses
Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes contained in V114 separately. To address the 
primary immunogenicity objective, evaluation of the IgG GMCs at
30 days postvaccination with V114 or Prevnar 13™ will include 
descriptive summaries. The point estimates will be calculated by 
exponentiating the estimates of the mean of the natural log values and the 
within-group CIs will be derived by exponentiating the CIs of the mean 
of the natural log values based on the t-distribution. A similar statistical 
approach will be used to evaluate the OPA GMTs at 30 days 
postvaccination with V114 or Prevnar 13™ (Day 30).
Statistical Methods for Key 
Safety Analyses
The analysis strategy for safety parameters following vaccination is 
described in Section 9.6.2. Safety parameters will be summarized via 
descriptive statistics. In addition, for select safety parameters, 95% 
within-group CIs will be provided.
Interim Analyses
To support the periodic review of safety and tolerability data across the      
V114 Phase 3 program, an external unblinded statistician will provide 
unblinded interim safety summaries to an independent 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
No multiplicity adjustment is planned.
 
 
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Sample Size and Power 
Immunogenicity:
The planned sample size is 100 participants. Participants are to be 
randomly assigned in 2:1 ratio to V114 or Prevnar 13™, respectively 
(resulting in approximately 67 participants in the V114 group and 
33 participants in the Prevnar 13™ group). It is assumed that 
approximately 54 participants in the V114 group and 26 in the 
Prevnar 13™ group will be evaluable for the PP immunogenicity 
analyses at Day 30 (80% evaluability rate). There are no hypotheses to 
be evaluated for primary objectives. Section 9.9.1 provides information 
about the expected variability of IgG GMCs given the sample size.  
Safety:
Section 9.9.2 provides information about the ability of this study to 
estimate the incidence of AEs within the V114 group.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented using an IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study, and no formal 
hypothesis testing will be performed.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be summarized are listed below.
9.4.1
Immunogenicity Endpoints
A description of immunogenicity assessments is presented in Section 8.2.
Immune responses will be measured for each of the following serotypes contained in V114: 
1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F.
The primary immunogenicity analysis endpoints are the anti-PnPs serotype-specific IgG 
GMCs at 30 days postvaccination with V114 or Prevnar 13™.
 
 
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The secondary immunogenicity analysis endpoints include:

Anti-PnPs serotype-specific OPA GMTs at 30 days postvaccination

Anti-PnPs serotype-specific GMFR from prevaccination (Day 1) to 30 days
postvaccination for both OPA and IgG responses
9.4.2
Safety Endpoints
A description of safety measures is presented in Section 8.3 and Section 8.4. The analysis of 
safety results is described in Section 9.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements following V114 or Prevnar 13™.
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration) from Day 1 through Day 14
postvaccination with V114 or Prevnar 13™

Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue, and hives or welts/urticaria) from
Day 1 through Day 14 postvaccination with V114 or Prevnar 13™

Proportions of participants with the broad AE categories consisting of any AE, a 
vaccine-related AE, a SAE, an AE which is both vaccine-related and serious, and 
discontinuation due to an AE and the proportion of participants who died

Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 7 postvaccination with 
V114 or Prevnar 13™
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this study. The PP population consists of all randomized participants without 
deviations from the protocol that may substantially affect the results of the immunogenicity 
endpoint. 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 (ie, 
participants who were cross-treated)
 
 
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
Receipt of a prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant from the 
PP population for specific immunogenicity analyses (depending on the time point) include:

Receipt of a prohibited medication or prohibited vaccine prior to a blood sample 
collection 

Collection of a blood sample outside of the pre-specified window (as described in 
Section 1.3)
The final determination on protocol deviations, and thereby the composition of the 
PP population, will be made prior to the final unblinding of the database. Participants will be 
included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the PP population.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed 
for the primary immunogenicity endpoint(s). The FAS population consists of all randomized 
participants who received the study vaccination and have at least 1 serology result. 
Participants will be included in the vaccination group to which they are randomized for the 
analysis of immunogenicity data using the FAS population.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 1 dose of study 
vaccination. Participants will be included in the group corresponding to the study vaccination 
they actually received for the analysis of safety data using the APaT population. This will be 
the group to which they are randomized except for participants who take incorrect study 
vaccination; such participants will be included in the treatment group corresponding to the 
study vaccination actually received.
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. 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. Methods related to exploratory objectives will be further 
described in the supplemental statistical analysis plan.
Immunogenicity analyses will be conducted for each of the 15 pneumococcal serotypes 
contained in V114 separately. To address the primary immunogenicity objective, evaluation 
 
 
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of the serotype-specific IgG GMCs at 30 days postvaccination will include descriptive 
summaries and within-group 95% confidence intervals (CIs) to be calculated for each 
vaccination group. Point estimates for the IgG GMCs will be calculated by exponentiating 
the estimates of the mean of the natural log values. The within-group CIs will be derived by 
exponentiating the CIs of the mean of the natural log values based on the t-distribution.
A similar statistical approach will be used to evaluate serotype-specific OPA GMTs at 
30 days postvaccination for each vaccination group. Point estimates of serotype-specific 
GMFR and its associated 95% CI will be calculated based on the t-distribution of natural 
log-transformed fold rise.
Reverse cumulative distribution curves for OPA titers and IgG concentrations will be 
graphically displayed by serotype at Day 30.
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 4.
Table 4
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Anti-PnPs IgG GMCs at Day 30
P
Descriptive 
Statistics
(estimate, 95%
CI)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoints
Anti-PnPs OPA GMTs at Day 30
P
Descriptive 
Statistics 
(estimate, 95%
CI)
PP
Missing data 
will not be 
imputed
GMFR from Day 1 to Day 30 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.
CI = confidence interval; FAS = Full Analysis Set; GMC = Geometric Mean Concentration; 
GMFR = Geometric Mean Fold Rise; GMT = Geometric Mean Titer; IgG = immunoglobulin G; 
OPA = opsonophagocytic activity; PnPs = pneumococcal polysaccharide; 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.
 
 
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The analysis strategy for safety parameters following each vaccination is summarized in 
Table 5. The proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration Day 1 to Day 14 postvaccination) and 
solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, 
tiredness/fatigue, and hives or welts/urticarial from Day 1 to Day 14 postvaccination) will be 
provided along with the corresponding within-group 95% CIs (based on the exact binomial 
method proposed by Clopper and Pearson [Collett, D. 1999]. In addition, the broad AE 
categories consisting of the proportion of participants with any AE, a vaccine-related AE, an
SAE, an AE which is both vaccine-related and serious, discontinuation due to an AE, and the 
proportion of participants who died will be summarized in the same manner. The proportion 
of participants with maximum temperature measurements meeting the Brighton 
Collaboration cut points (from Day 1 through Day 7) will also be provided along with the 
corresponding within-group 95% CIs. Point estimates by vaccination group will be provided 
for all other safety parameters (specific AE terms and system organ class terms).
The analysis of safety parameters will be evaluated following administration of V114 or 
Prevnar 13™(Day 30). Descriptive summaries of AEs following administration of V114 or 
Prevnar 13™ will include non-serious AEs within 14 days of vaccination and SAEs 
occurring Day 1 through completion of study participation (end of the study).
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination
Safety Endpoint
95% CI for Within-Group 
Comparison
Descriptive Statistics
Injection-site redness/erythema (Days 1 to 14)†
X
X
Injection-site swelling (Days 1 to 14)†
X
X
Injection-site tenderness/pain (Days 1 to 14)†
X
X
Injection-site hard lump/induration (Days 1 to 14)
X
X
Muscle pain/myalgia (Days 1 to 14)†
X
X
Joint pain/arthralgia (Days 1 to 14)†
X
X
Headache (Days 1 to 14)†
X
X
Tiredness/fatigue (Days 1 to 14)†
X
X
Hives or welts/urticaria (Days 1 to 14)
X
X
Any AE‡
X
X
Any vaccine-related AE‡
X
X
Any SAE‡
X
X
Any vaccine-related SAE‡
X
X
Discontinuation due to AE‡
X
X
Death‡
X
X
Maximum temperature measurements meeting the 
Brighton Collaboration cut points (Days 1 to 7)
X
X
Specific AEs by SOCs and PT
X
† Includes solicited events only.
‡ These endpoints are broad adverse event categories. For example, descriptive statistics for the safety endpoint of “Any AE” 
will provide the number and percentage of participants with at least 1 AE.
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = System Organ 
Class; X = results will be provided.
 
 
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Safety analyses will be based on the observed data (ie, with no imputation of missing data).
9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed by the use of summary tables. No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, race, and gender), baseline characteristics, 
prior and concomitant vaccinations and therapies will be summarized by vaccination group 
either by descriptive statistics or categorical tables.
9.7
Interim Analyses
A periodic review of safety and tolerability data across the V114 Phase 3 pediatric program 
will be conducted by an independent, unblinded, external DMC. A description of the 
structure, function, and guidelines for decision-making by the DMC, along with the timing 
and content of the safety reviews will be outlined in the DMC charter. Information regarding 
the composition of the DMC is provided in Appendix 1. There are no plans to conduct an 
interim analysis of unblinded immunogenicity data in this study. However, unblinded 
immunogenicity data will be made available to the DMC upon request to enable a 
benefit-risk assessment.
Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
intervention assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician performing 
interim analyses.
The DMC will serve as the primary reviewer of the results of the safety interim analyses and 
will make recommendations for discontinuation of the study or protocol modifications to an 
executive committee of the Sponsor (see Appendix 1 for details on the Committees Structure 
for this study). If the DMC recommends modifications to the design of the protocol or 
discontinuation of the study, this Executive Oversight Committee (EOC) of the Sponsor (and 
potentially other limited Sponsor personnel) may be unblinded to results at the intervention 
level in order to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented by the external 
unblinded statistician. Additional logistical details will be provided in the DMC Charter.
Intervention-level results from the safety interim analysis will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
interim analyses.
 
 
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9.8
Multiplicity
No adjustment will be made for multiplicity.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. The planned sample size is 100 participants. Participants are to be 
randomly assigned in 2:1 ratio to V114 (67 participants) or Prevnar 13™(33 participants). It 
is assumed that approximately 54 participants in the V114 group and 26 in the Prevnar 13™
group will be evaluable for PP immunogenicity analyses at Day 30 (based on an 80% 
evaluability rate).
The width of the within-group 95% CIs for the serotype-specific IgG GMCs depends on the 
sample size, variability of the natural log concentrations, and the magnitude of the IgG GMC. 
In Table 6, 95% CIs for various hypothetical IgG GMCs at 30 days postvaccination and 
various hypothetical standard deviation estimates for the natural log titers are displayed.
Table 6
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying 
Standard Deviations 
Standard 
Deviation 
of Natural 
Log 
Titers†
Observed Serotype-specific IgG GMC†
1
5
10
V114
Prevnar 13™
V114
Prevnar 13™
V114
Prevnar 13™
1.0
(0.76, 1.31)
(0.67, 1.50)
(3.81, 6.57)
(3.34, 7.49)
(7.61, 13.14)
(6.68, 14.98)
1.5
(0.66, 1.51)
(0.55, 1.83)
(3.32, 7.53)
(2.73, 9.16)
(6.64, 15.06)
(5.46, 18.33)
2.0
(0.58, 1.73)
(0.45, 2.24)
(2.90, 8.63)
(2.23, 11.22)
(5.79, 17.26)
(4.46, 22.43)
† The estimates of the standard deviation and IgG GMC ratio are representative of those observed in a previous 
MSD study.
Based on 54 evaluable participants in the V114 group and 26 evaluable participants in the Prevnar 13™ group.
CI = confidence interval; GMC = Geometric Mean Concentration.
9.9.2
Sample Size and Power for Safety Analyses
The sample size was selected to achieve a reasonably sized safety database in this population 
exposed to V114. The probability of observing at least 1 SAE in this study depends on the 
number of participants vaccinated and the underlying percentage of participants with a SAE 
in the study population. Calculations below assume that 100% of the randomized participants 
will be evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE 
among 67 participants in the V114 group if the underlying incidence of a SAE is 2.4% (1 of 
every 42 participants receiving the vaccine). There is a 50% chance of observing at least 
1 SAE among 67 participants in the V114 group if the underlying incidence of a SAE is 1.0% 
(1 of 97 every participants receiving the vaccine). If no SAEs are observed among the 
67 participants in the V114 group, this study will provide 97.5% confidence that the 
 
 
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underlying percentage of participants with a SAE is <5.4 % (1 in every 19 participants) in the 
V114 group.  
9.10
Subgroup Analyses
Subgroup analyses (eg, sex = female vs male) will be performed for the primary 
immunogenicity endpoint and selected safety endpoints (summary of AEs). Details of 
subgroup analyses will be documented in the supplemental Statistical Analysis Plan.
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 
each vaccination will be summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V114 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.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF 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 (see Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
 
 
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of 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

The tests detailed in Table 7 will be performed according to local requirements.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 7
Protocol-required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Other Screening Tests

Serum or urine β-hCG pregnancy test (as needed for 
WOCBP)
β-hCG = β human chorionic gonadotropin; WOCBP = woman/women of childbearing potential.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, 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, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
 
 
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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.
 
 
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
•
Injection site redness or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
 
 
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•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
 
 
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-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal 
sequence of the AE onset relative to the administration of the Sponsor’s 
product is reasonable. The AE is more likely explained by the Sponsor’s 
product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
 
 
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•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the 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.
 
 
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•
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 and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
•
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
10.5.2
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
1 of the contraception methods described in Table 8 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
 
 
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Table 8
Contraceptive Methods
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
●Male or female condom with or without spermicide
●Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●Combined (estrogen- and progestogen- containing) hormonal contraceptionb
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●Progestogen only hormonal contraceptionb
○
Oral
○
Injectable
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen- only contraceptive implantb
●Intrauterine hormone-releasing systemb
●Intrauterine device 
●Bilateral tubal occlusion
●Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.
●Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.
a.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
b.
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable hormonal 
contraceptives are limited to those which inhibit ovulation.
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
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 principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation,
the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
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
CI
confidence interval
CRF
case report form 
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
eVRC
electronic Vaccination Report Card
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
FAS
full analysis set
GCP
Good Clinical Practice 
GMC
geometric mean concentration
GMFRs
geometric mean fold rises
GMT
geometric mean titers
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IPD
invasive pneumococcal disease
IRB
Institutional Review Board 
IRT
interactive response technology
MSD
Merck Sharp & Dohme Corp.
MOPA
multiplexed opsonophagocytic assay
OPA
opsonophagocytic activity 
PCV
pneumococcal conjugate disease
PnECL
pneumococcal electrochemiluminescence
PnPs
pneumococcal polysaccharide 
PP
per protocol
PY
person-years
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SCD
sickle cell disease
SoA
schedule of activities
WOCBP
woman/women of childbearing potential 
 
 
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11
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epidemiology of invasive pneumococcal disease 
among older adults in the era of pediatric 
pneumococcal conjugate vaccine. JAMA 
2005;294(16):2043-51.
03RBPW
[Martinelli, D., et al 2014]
Martinelli D, Pedalino B, Cappelli MG, Caputi 
G, Sallustio A, Fortunato F, et al Towards the 
13-valent pneumococcal conjugate universal 
vaccination: effectiveness in the transition era 
between PCV7 and PCV13 in Italy, 2010-2013. 
Hum Vaccin Immunother. 2014;10(1):33-9.
04KW8B
[Metlay, J. P., et al 2006]
Metlay JP, Fishman NO, Joffe M, Edelstein PH. 
Impact of pediatric vaccination with 
pneumococcal conjugate vaccine on the risk of 
bacteremic pneumococcal pneumonia in adults. 
Vaccine 2006;24:468-75.
03RC46
[Moore, M. R., et al 2015]
Moore MR, Link-Gelles R, Schaffner W, 
Lynfield R, Lexau C, Bennett NM, et al. Effect 
of use of 13-valent pneumococcal conjugate 
vaccine in children on invasive pneumococcal 
disease in children and adults in the USA: 
analysis of multisite, population-based 
surveillance. Lancet Infect Dis. 2015 Feb 3. 
[Epub ahead of print].
043MRP
 
 
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PRODUCT: V114
87
PROTOCOL/AMENDMENT NO.: 023-00 
V114-023-00 FINAL PROTOCOL
06-SEP-2018
[National Heart, Lung and 
Blood Institute 2014]
National Heart, Lung and Blood Institute. 
Evidence-based management of sickle cell 
disease: expert panel report, 2014: guide to 
recommendations. Bethesda (MD): National 
Institutes of Health; 2014. 45 p.
04ZJ5Q
[Palmu, A. A., et al 2015]
Palmu AA, Kilpi TM, Rinta-Kokko H, Nohynek 
H, Toropainen M, Nuorti JP, et al. 
Pneumococcal conjugate vaccine and clinically 
suspected invasive pneumococcal disease. 
Pediatrics. 2015 Jul;136(1):e22-7.
04KVRL
[Pilishvili, Tamara, et al 2010]
Pilishvili T, Lexau C, Farley MM, Hadler J, 
Harrison LH, Bennett NM, et al. Sustained 
reductions in invasive pneumococcal disease in 
the era of conjugate vaccine. J Infect Dis 
2010;201(1):32-41.
03R5S4
[Quinn, C. T., et al 2010]
Quinn CT, Rogers ZR, McCavit TL, Buchanan 
GR. Improved survival of children and 
adolescents with sickle cell disease. Blood. 2010 
Apr 29;115(17):3447-52.
04ZH6N
[Romero-Steiner, S., et al 
1997]
Romero-Steiner S, Libutti D, Pais LB, Dykes J, 
Anderson P, Whitin JC, et al. Standardization of 
an opsonophagocytic assay for the measurement 
of functional antibody activity against 
streptococcus pneumoniae using differentiated 
HL-60 cells. Clin Diagn Lab Immunol 
1997;4(4):415-22.
03NWQ5
[Ruckinger, S., et al 2009]
Ruckinger S, van der Linden M, Reinert RR, 
von Kries R, Burckhardt F, Siedler A. Reduction 
in the incidence of invasive pneumococcal 
disease after general vaccination with 7-valent 
pneumococcal conjugate vaccine in Germany. 
Vaccine 2009;27:4136-41.
03QYQQ
[Telfer, P., et al 2007]
Telfer P, Coen P, Chakravorty S, Wilkey O, 
Evans J, Newell H, et al. Clinical outcomes in 
children with sickle cell disease living in 
England: a neonatal cohort in East London. 
Haematologica. 2007;92(07):905-12.
04ZH6P
 
 
050KMD
 
 
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PRODUCT: V114
88
PROTOCOL/AMENDMENT NO.: 023-00 
V114-023-00 FINAL PROTOCOL
06-SEP-2018
[U.S. Food and Drug 
Administration 2009]
U.S. Food and Drug Administration (CDER, 
CBER, CDRH). Guidance for industry patient-
reported outcome measures: use in medical 
product development to support labeling claims 
[Internet]. Washington: U.S. Department of 
Health and Human Services; 2009. Available 
from: 
https://www.fda.gov/downloads/drugs/guidances
/ucm193282.pdf
04MG9J
[Wagenvoort, G. H., et al 
2016]
Wagenvoort GH, Knol MJ, de Melker HE, 
Vlaminckx BJ, van der Ende A, Rozenbaum  
MH, et al.  Risk and outcomes of invasive 
pneumococcal disease in adults with underlying 
conditions in the post-PCV7 era, The 
Netherlands. Vaccine. 2016 Jan 12;34(3):334-
40.
04KTDB
[Waight, P. A., et al 2015]
Waight PA, Andrews NJ, Ladhani SN, Sheppard 
CL, Slack MP, Miller E. Effect of the 13-valent 
pneumococcal conjugate vaccine on invasive 
pneumococcal disease in England and Wales 4 
years after its introduction: an observational 
cohort study. Lancet Infect Dis. 2015 
May;15(5):535-43.
04KTF2
[Weiss, S., et al 2015]
Weiss S, Falkenhorst G, van der Linden M, 
Imohl M, von Kries R. Impact of 10-  and 13-
valent pneumococcal conjugate vaccines on 
incidence of invasive pneumococcal disease in 
children aged under 16 years in Germany, 2009 
to 2012. Euro Surveill. 2015 Mar 
12;20(10):21057.
04KTFC
[Whitney, Cynthia G., et al 
2003]
Whitney CG, Farley MM, Hadler J, Harrison 
LH, Bennett NM, Lynfield R, et al. Decline in 
invasive pneumococcal disease after the 
introduction of protein-polysaccharide conjugate 
vaccine. N Engl J Med 2003;348(18):1737-46.
03QT0D
 
 
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Supplemental SAP                                          
                                  30 Sep 2020
Supplemental Statistical Analysis Plan (sSAP)
 
 
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Table of Contents
1. INTRODUCTION .........................................................................................................4
2. SUMMARY OF CHANGES.........................................................................................4
2.1
SUMMARY OF CHANGES FROM PROTOCOL SAP...........................................4
2.2
SUMMARY OF CHANGES FROM PREVIOUS VERSIONS OF THE 
SSAP
..................................................................................................................5
3. ANALYTICAL AND METHODOLOGICAL DETAILS............................................5
3.1
STATISTICAL ANALYSIS PLAN SUMMARY .....................................................5
3.2
RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING..............................6
3.3
HYPOTHESES/ESTIMATION .................................................................................7
3.4
ANALYSIS ENDPOINTS .........................................................................................7
3.4.1
Immunogenicity Endpoints .....................................................................7
3.4.2
Safety Endpoints......................................................................................7
3.5
ANALYSIS POPULATIONS ....................................................................................8
3.5.1
Immunogenicity Analysis Populations....................................................8
3.5.2
Safety Analysis Populations....................................................................8
3.6
STATISTICAL METHODS.......................................................................................9
3.6.1
Statistical Methods for Immunogenicity Analyses .................................9
3.6.2
Statistical Methods for Safety Analyses................................................11
3.6.3
Demographic and Baseline Characteristics...........................................13
3.7
INTERIM ANALYSES............................................................................................13
3.8
MULTIPLICITY.......................................................................................................14
3.9
SAMPLE SIZE AND POWER CALCULATIONS.................................................14
3.9.1
Sample Size and Power for Immunogenicity Analyses ........................14
3.9.2
Sample Size and Power for Safety Analyses.........................................14
3.10
SUBGROUP ANALYSES ....................................................................................15
3.11
COMPLIANCE (MEDICATION ADHERENCE) ...............................................15
3.12
EXTENT OF EXPOSURE ....................................................................................15
4. LIST OF REFERENCES.............................................................................................15
 
 
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List of Tables
Table 1 Analysis Strategy for Immunogenicity Variables.........................................................9
Table 3 Analysis Strategy for Safety Parameters ....................................................................11
Table 4 Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying Standard 
Deviations ........................................................................................................................13
 
 
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1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this sSAP provides additional statistical analysis
details/data derivations and documents modifications or additions to the analysis plan that are 
not “principal” in nature and result from information that was not available at the time of 
protocol finalization.
2. SUMMARY OF CHANGES 
2.1
Summary of Changes from Protocol SAP
A summary of changes is provided in the table below:
Section 
Description of Change
Rationale
Section 3.4.2 Safety 
Endpoints
Added a paragraph to specify the 
timeframe associated with the 
reporting of AEs. 
Revisions made for clarity. 
Section 3.5.1 
Immunogenicity Analysis 
Populations
Updated one sentence in this section 
from “The FAS population consists of 
all randomized participants who 
received the study vaccination and 
have at least 1 serology result” to “The 
FAS population consists of all 
randomized participants who received 
the study vaccination and have at least 
1 serology result at the time point for 
the analysis.”
Revisions made to clarify the 
criteria for inclusion in the FAS
population.
Section 3.6.1 Statistical 
Methods for 
Immunogenicity Analyses
Added a paragraph and a table (Table 
2) to explain how values below the 
LLOQ or above the ULOQ should be 
treated in various analyses.  
Added to provide additional 
statistical analysis details/data 
derivations.
Section 3.6.2 Statistical 
Methods for Safety 
Analyses
Added a paragraph to explain the 
rationale for not including laboratory
AEs in the summary tables.
Added to provide additional
statistical analysis details/data 
derivations.
Section 3.6.2 Statistical 
Methods for Safety 
Analyses
Added a paragraph to describe an 
additional supportive analysis of the 
proportion of participants with 
solicited complaints using the data 
collected directly from participants via 
the VRC.
Added to provide additional 
statistical analysis details/data 
derivations.
Section 3.10 Subgroup 
Analyses 
Added details of subgroup analyses. 
Added to provide additional 
statistical analysis details/data 
derivations.
Throughout
Corrected minor typographical and 
grammatical errors.
Revisions made for accuracy. 
 
 
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2.2
Summary of Changes from Previous Versions of the sSAP
Previous 
Version 
Current 
Version
Section
Description of 
Change
Rationale
None
30 Sep 2020
Not Applicable
Not Applicable
This is the first version of the sSAP.
3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Sections 3.2 through 3.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active
Comparator-controlled Study to Evaluate the Safety, Tolerability, and
Immunogenicity of V114 in Children with Sickle Cell Disease
(PNEU-SICKLE).
Intervention Assignment
Participants will be randomly assigned in a 2:1 ratio to V114 or 
Prevnar 13™, respectively.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:
Anti-PnPs Serotype-specific IgG GMCs at 30 days postvaccination (Day 
30)
Safety:

Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling, tenderness/pain, and hard 
lump/induration) from Day 1 through Day 14 following 
V114 or Prevnar 13™ 

Proportion of participants with solicited systemic AEs 
(muscle pain/myalgia, joint pain/arthralgia, headache, 
tiredness/fatigue, and hives or welts/urticaria) from Day 1 
through Day 14 following V114 or Prevnar 13™

Proportion of participants with vaccine-related SAEs from 
Day 1 through completion of study participation following 
V114 or Prevnar 13™
Key Secondary Endpoint(s)
Immunogenicity:

Anti-PnPs serotype-specific OPA GMTs for the 15 
serotypes contained in V114 at 30 days postvaccination 
(Day 30)

Anti-PnPs serotype-specific GMFR from prevaccination 
(Day 1) to 30 days postvaccination for both OPA and IgG 
responses
Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes contained in V114 separately. To address the 
primary immunogenicity objective, evaluation of the IgG GMCs at
30 days postvaccination with V114 or Prevnar 13™ will include 
 
 
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descriptive summaries. The point estimates will be calculated by 
exponentiating the estimates of the mean of the natural log values and the 
within-group CIs will be derived by exponentiating the CIs of the mean 
of the natural log values based on the t-distribution. A similar statistical 
approach will be used to evaluate the OPA GMTs at 30 days 
postvaccination with V114 or Prevnar 13™ (Day 30).
Statistical Methods for Key 
Safety Analyses
The analysis strategy for safety parameters following vaccination is 
described in Section 3.6.2. Safety parameters will be summarized via 
descriptive statistics. In addition, for select safety parameters, 95% within-
group CIs will be provided.
Interim Analyses
To support the periodic review of safety and tolerability data across the      
V114 Phase 3 program, an external unblinded statistician will provide 
unblinded interim safety summaries to an independent 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
No multiplicity adjustment is planned.
Sample Size and Power
Immunogenicity:
The planned sample size is 100 participants. Participants are to be 
randomly assigned in 2:1 ratio to V114 or Prevnar 13™, respectively 
(resulting in approximately 67 participants in the V114 group and 
33 participants in
the Prevnar 13™ group). It is assumed that 
approximately 54 participants in the V114 group and 26 in the 
Prevnar 13™ group will be evaluable for the PP immunogenicity 
analyses at Day 30 (80% evaluability rate). There are no hypotheses to 
be evaluated for primary objectives. Section 3.9.1 provides information 
about the expected variability of IgG GMCs given the sample size.  
Safety:
Section 3.9.2 provides information about the ability of this study to 
estimate the incidence of AEs within the V114 group.
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented in an IRT.
Blinding issues related to the planned interim analyses are described in Section 3.7. 
 
 
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3.3
HYPOTHESES/ESTIMATION
Objectives of the study are stated in Section 3 of the protocol. This is an estimation study,
and no formal hypothesis testing will be performed.
3.4
ANALYSIS ENDPOINTS
Immunogenicity and safety analysis endpoints that will be summarized are listed below.
3.4.1
Immunogenicity Endpoints
A description of immunogenicity assessments is contained in Section 8.2 of the protocol.
Immune responses will be measured for each of the following serotypes contained in V114:
1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F.
The primary immunogenicity analysis endpoints are the anti-PnPs serotype-specific IgG 
GMCs at 30 days postvaccination with V114 or Prevnar 13™.
The secondary immunogenicity analysis endpoints include:

Anti-PnPs serotype-specific OPA GMTs at 30 days postvaccination

Anti-PnPs serotype-specific GMFR from prevaccination (Day 1) to 30 days 
postvaccination for both OPA and IgG responses
3.4.2
Safety Endpoints
A description of safety measures is presented in Sections 8.3 and 8.4 of the protocol. The 
analysis of safety results is described in Section 3.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements following V114 or Prevnar 13™.
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration) from Day 1 through Day 14 
postvaccination with V114 or Prevnar 13™

Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue, and hives or welts/urticaria) from 
Day 1 through Day 14 postvaccination with V114 or Prevnar 13™

Proportions of participants with the broad AE categories consisting of any AE, a 
vaccine-related AE, a SAE, an AE which is both vaccine-related and serious, 
discontinuation due to an AE, and the proportion of participants who died
 
 
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
Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 7 postvaccination with 
V114 or Prevnar 13™
The timeframe associated with the reporting of AEs is consistent with the collection. 
Nonserious adverse events (NSAEs) are reported from Day 1 through Day 14 following 
vaccination. SAEs are reported from Day 1 through completion of study participation.
3.5
ANALYSIS POPULATIONS
3.5.1
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. 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

Receipt of prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant from the PP
population for specific immunogenicity analyses (depending on the time point for analysis) 
include:

Receipt of prohibited medication or prohibited vaccine prior to a blood sample 
collection

Collection of blood sample outside of the pre-specified window (as described in 
Section 1.3 of the protocol)
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 the study vaccination and have at least 1 serology result at the time 
point for the analysis. Participants will be included in the vaccination group to which they are 
randomized for the analysis of immunogenicity data using the FAS population.
3.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 1 dose of study 
 
 
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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 vaccination group corresponding to the 
study vaccination actually received.
At least 1 temperature measurement obtained subsequent to study intervention is required for 
inclusion in the analysis of temperature.
3.6
STATISTICAL METHODS
Statistical testing and inference for immunogenicity and safety analyses are described in 
Section 3.6.1 and Section 3.6.2, respectively. Section 3.6.3 describes how demographic and 
baseline characteristics will be summarized.
3.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary
immunogenicity objectives.
Immunogenicity analyses will be conducted for each of the 15 pneumococcal serotypes 
contained in V114 separately. To address the primary immunogenicity objective, evaluation 
of the serotype-specific IgG GMCs at 30 days postvaccination will include descriptive 
summaries and within-group 95% confidence intervals (CIs) to be calculated for each 
vaccination group. Point estimates for the IgG GMCs will be calculated by exponentiating 
the estimates of the mean of the natural log values. The within-group CIs will be derived by 
exponentiating the CIs of the mean of the natural log values based on the t-distribution.
A similar statistical approach will be used to evaluate serotype-specific OPA GMTs at 
30 days postvaccination for each vaccination group. Point estimates of serotype-specific 
GMFR and its associated 95% CI will be calculated based on the t-distribution of natural 
log-transformed fold rise.
Reverse cumulative distribution curves for OPA titers and IgG concentrations will be 
graphically displayed by serotype at Day 30.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 1.
 
 
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Table 1 Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical 
Method
Analysis 
Population
Missing 
Data 
Approach
Primary Endpoint
Anti-PnPs IgG GMCs at Day 30
P
Descriptive 
Statistics
(estimate, 95%
CI)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoints
Anti-PnPs OPA GMTs at Day 30
P
Descriptive 
Statistics 
(estimate, 95%
CI)
PP
Missing data 
will not be 
imputed
GMFR from Day 1 to Day 30 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.
CI = confidence interval; FAS = Full Analysis Set; GMC = Geometric Mean Concentration; 
GMFR = Geometric Mean Fold Rise; GMT = Geometric Mean Titer; IgG = immunoglobulin G; 
OPA = opsonophagocytic activity; PnPs = pneumococcal polysaccharide; PP = Per-Protocol.
The detectable ranges for OPA and IgG responses differ across serotypes. The limits of 
quantitation define the range of responses over which the assay provides precise and accurate 
measurements. Table 2 gives the limits of quantitation defined for each serotype for OPA and 
IgG responses. For responses smaller than the lower limit of quantitation (LLOQ), half of the 
LLOQ is used for analysis when calculating the OPA GMTs and IgG GMCs. The value of the 
LLOQ is used for analysis when calculating the GMFR for OPA and IgG responses. For OPA 
and IgG responses that are larger than the upper limit of quantitation (ULOQ), a value equal 
to ULOQ + 1 is used for analysis.
 
 
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3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements.
The analysis strategy for safety parameters following each vaccination is summarized in
Table 3. The proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration Day 1 to Day 14 postvaccination) and 
solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, 
tiredness/fatigue, and hives or welts/urticaria from Day 1 to Day 14 postvaccination) will be 
provided along with the corresponding within-group 95% CIs (based on the exact binomial 
method proposed by Clopper and Pearson [Collett, D. 1999]. In addition, the broad AE 
categories consisting of the proportion of participants with any AE, a vaccine-related AE, an
SAE, an AE which is both vaccine-related and serious, discontinuation due to an AE, and the 
proportion of participants who died will be summarized in the same manner. The proportion 
of participants with maximum temperature measurements meeting the Brighton 
Collaboration cut points (from Day 1 through Day 7) will also be provided along with the 
 
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corresponding within-group 95% CIs. Point estimates by vaccination group will be provided 
for all other safety parameters (specific AE terms and system organ class terms).
The analysis of safety parameters will be evaluated following administration of V114 or 
Prevnar 13™ (Day 30). Descriptive summaries of AEs following administration of V114 or 
Prevnar 13™ will include non-serious AEs within 14 days of vaccination and SAEs 
occurring Day 1 through completion of study participation (end of the study).
Table 3 Analysis Strategy for Safety Parameters
Safety Endpoint
95% CI for Within-Group 
Comparison
Descriptive Statistics
Injection-site redness/erythema (Days 1 to 14)†
X
X
Injection-site swelling (Days 1 to 14)†
X
X
Injection-site tenderness/pain (Days 1 to 14)†
X
X
Injection-site hard lump/induration (Days 1 to 14)
X
X
Muscle pain/myalgia (Days 1 to 14)†
X
X
Joint pain/arthralgia (Days 1 to 14)†
X
X
Headache (Days 1 to 14)†
X
X
Tiredness/fatigue (Days 1 to 14)†
X
X
Hives or welts/urticaria (Days 1 to 14)
X
X
Any AE‡
X
X
Any vaccine-related AE‡
X
X
Any SAE‡
X
X
Any vaccine-related SAE‡
X
X
Discontinuation due to AE‡
X
X
Death‡
X
X
Maximum temperature measurements meeting the 
Brighton Collaboration cut points (Days 1 to 7)
X
X
Specific AEs by SOCs and PT
X
† Includes solicited events only.
‡ These endpoints are broad adverse event categories. For example, descriptive statistics for the safety endpoint 
of “Any AE” will provide the number and percentage of participants with at least 1 AE.
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = 
System Organ Class; X = results will be provided.
Safety analyses will be based on the observed data (ie, with no imputation of missing data).
Additionally, laboratory AEs will not be reported in summary tables as laboratory testing is 
not performed as part of the study and, as such, AEs would only be reported spontaneously. A 
listing of laboratory AEs will be provided.
A supportive analysis summarizing the proportion of participants reporting each of the 
solicited complaints on the VRC will be conducted in support of the primary safety analyses 
 
 
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that are based on solicited AEs. This supportive analysis will use the methodology specified 
in Table 3 for solicited AEs. The analysis will be conducted on the subset of the APaT 
population who entered solicited complaints data on the VRC.
3.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed by the use of summary tables. No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (e.g., age, race, and gender), baseline 
characteristics, prior and concomitant vaccinations and therapies will be summarized by 
vaccination group either by descriptive statistics or categorical tables.
3.7
INTERIM ANALYSES
A periodic review of safety and tolerability data across the V114 Phase 3 pediatric program 
will be conducted by an independent, unblinded, external DMC. A description of the 
structure, function, and guidelines for decision-making by the DMC, along with the timing 
and content of the safety reviews will be outlined in the DMC charter. Information regarding 
the composition of the DMC is provided in Appendix 1 of the protocol. There are no plans to 
conduct an interim analysis of unblinded immunogenicity data in this study. However, 
unblinded immunogenicity data from this study and other ongoing V114 clinical studies will 
be made available to the DMC upon request to enable a benefit-risk assessment.
Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
intervention assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician performing 
interim analyses.
The DMC will serve as the primary reviewer of the results of the safety interim analyses and 
will make recommendations for discontinuation of the study or protocol modifications to an 
executive committee of the Sponsor (see Appendix 1 of the protocol 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 in order to act on these recommendations. The extent to which 
individuals are unblinded with respect to results of interim analyses will be documented by 
the external unblinded statistician. Additional logistical details will be provided in the DMC 
Charter.
Intervention-level results from the safety interim analysis will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
interim analyses.
 
 
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3.8
MULTIPLICITY
No adjustment will be made for multiplicity.
3.9
SAMPLE SIZE AND POWER CALCULATIONS
3.9.1
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. The planned sample size is 100 participants. Participants are to be 
randomly assigned in 2:1 ratio to V114 (67 participants) or Prevnar 13™(33 participants). It 
is assumed that approximately 54 participants in the V114 group and 26 in the Prevnar 13™
group will be evaluable for PP immunogenicity analyses at Day 30 (based on an 80% 
evaluability rate).
The width of the within-group 95% CIs for the serotype-specific IgG GMCs depends on the 
sample size, variability of the natural log concentrations, and the magnitude of the IgG GMC. 
In Table 4, 95% CIs for various hypothetical IgG GMCs at 30 days postvaccination and 
various hypothetical standard deviation estimates for the natural log titers are displayed.
Table 4 Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying Standard 
Deviations 
Standard 
Deviation 
of Natural 
Log 
Titers†
Observed Serotype-specific IgG GMC†
1
5
10
V114
Prevnar 13™
V114
Prevnar 13™
V114
Prevnar 13™
1.0
(0.76, 1.31)
(0.67, 1.50)
(3.81, 6.57)
(3.34, 7.49)
(7.61, 13.14)
(6.68, 14.98)
1.5
(0.66, 1.51)
(0.55, 1.83)
(3.32, 7.53)
(2.73, 9.16)
(6.64, 15.06)
(5.46, 18.33)
2.0
(0.58, 1.73)
(0.45, 2.24)
(2.90, 8.63)
(2.23, 11.22)
(5.79, 17.26)
(4.46, 22.43)
†The estimates of the standard deviation and IgG GMC ratio are representative of those observed in a previous 
MSD study.
Based on 54 evaluable participants in the V114 group and 26 evaluable participants in the Prevnar 13™ group.
CI = confidence interval; GMC = Geometric Mean Concentration.
3.9.2
Sample Size and Power for Safety Analyses
The sample size was selected to achieve a reasonably sized safety database in this population 
exposed to V114. The probability of observing at least 1 SAE in this study depends on the 
number of participants vaccinated and the underlying percentage of participants with a SAE 
in the study population. Calculations below assume that 100% of the randomized participants 
will be evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE 
among 67 participants in the V114 group if the underlying incidence of a SAE is 2.4% (1 of 
every 42 participants receiving the vaccine). There is a 50% chance of observing at least 
1 SAE among 67 participants in the V114 group if the underlying incidence of a SAE is 1.0% 
(1 of every 97 participants receiving the vaccine). If no SAEs are observed among the 
67 participants in the V114 group, this study will provide 97.5% confidence that the 
 
 
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underlying percentage of participants with a SAE is <5.4 % (1 in every 19 participants) in the 
V114 group.
3.10
SUBGROUP ANALYSES
An overall summary of AEs and a summary of solicited AEs following vaccination will be 
provided for each subgroup (point estimates only) with more than 10 participants in each 
vaccination group.
To determine whether the intervention effect is consistent across various subgroups, the 
estimate of the within-group intervention effect (with a nominal 95% CI) will be summarized 
for the primary immunogenicity endpoint (IgG GMCs at 30 days postvaccination) for each 
subgroup with more than 10 participants in each vaccination group.
The following subgroups are planned for evaluation:

Age category (5 to 9 years, 10 to 14 years, 15 to 17 years)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Race (American Indian or Alaska Native, Asian, Black or African American, 
Multiple, Native Hawaiian or Other Pacific Islander, White

Sex (Female, Male)
3.11
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 
each vaccination will be summarized (Section 3.12).
3.12
EXTENT OF EXPOSURE
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V114 or Prevnar 13™.
4. LIST OF REFERENCES 
[Collett, D. 1999]
Collett D. Statistical inference for binary data. In: 
Collett D, ed. Modelling Binary Data. New York: 
Chapman & Hall, 1999:17-42.
03NVVC
 
 
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