A Phase 3, Randomized, Placebo-controlled Clinical Study to Evaluate the Efficacy, Immunogenicity and Safety of the 9vHPV Vaccine in Japanese Males, 16 to 26 Years of Age.
Phase: PHASE3
Conditions: Warts, Genital, Neoplasms, Anal
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04635423 
Document Date: 
24-Sep-2024
A Phase 3, randomized, placebo-controlled clinical study to 
evaluate the efficacy, immunogenicity and safety of the 9vHPV 
vaccine in Japanese males, 16 to 26 years of age.

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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, randomized, placebo-controlled clinical study to evaluate the 
efficacy, immunogenicity and safety of the 9vHPV vaccine in Japanese males, 16 to 26 years 
of age.
Protocol Number: 064-03
Compound Number: V503
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT04635423 
EU CT
Not applicable
EudraCT
2020-001047-67
JRCT
jRCT2031200217
WHO
Not applicable
UTN
Not applicable
IND
Not applicable
Approval Date: 24 September 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 3
24-SEP-2024
The overall rationale for this amendment is to 
add a database lock for the final efficacy 
analysis to account for cases that accrued after 
the data used for the primary efficacy analysis 
but before the final immunogenicity and safety 
assessments. The final database lock for the base 
study will occur after all immunogenicity and 
safety data of the base study are available.
Amendment 2
05-DEC-2023
The overall rationale for this amendment is to 
add an extension study to give participants in the 
placebo group a 3-dose series of the 9vHPV 
vaccine and give participants who did not 
complete 3-dose regimen of 9vHPV vaccine the 
opportunity to finish the series after completion 
of the base study.
Amendment 1
19-SEP-2022
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA.
Original Protocol
13-AUG-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendment:
The overall rationale for this amendment is to add a database lock for the final efficacy analysis to account for cases that accrued after 
the data used for the primary efficacy analysis but before the final immunogenicity and safety assessments. The final database lock for 
the base study will occur after all immunogenicity and safety data are available.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
4.1 Overall Design
Added the description of an additional database lock after the 
final efficacy sample assessment in the base study.
To conduct the final efficacy analysis earlier 
than the final database lock of the base study.
Section Number and Name
Description of Change
Brief Rationale
Additional Changes
8.5.4 Regulatory Reporting Requirements for SAE
Added note for EU reporting requirements.
To comply with EU CTR regulations.
9.1 Statistical Analysis Plan Summary
Added the description of an additional database lock after the 
final efficacy sample assessment in the base study.
To conduct the final efficacy analysis earlier 
than the final database lock of the base study.
9.2 Responsibility for Analyses/In-house Blinding
Added the description of an additional database lock after the 
final efficacy sample assessment in the base study.
Refer to Section 9.1 rationale.
9.6 Statistical Methods
Added the description of an additional database lock after the 
final efficacy sample assessment in the base study.
Refer to Section 9.1 rationale.
10.1.3 Data Protection
Added note on global privacy compliance.
To clarify adherence to global privacy 
compliance.
10.1.8 Data Quality Assurance
Added note for document retention period in the EU
Refer to Section 8.5.4 rationale.
Throughout Protocol
Minor administrative, formatting, editorial, grammatical, 
and/or typographical changes were made throughout the 
document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................20
1.3.1
Scheduled Visits for Base Study..................................................................20
1.3.2
Scheduled Visits for Study Extension (Placebo Group)..............................24
1.3.3
Scheduled Visits for Study Extension (9vHPV Group)...............................25
2
INTRODUCTION..........................................................................................................26
2.1
Study Rationale....................................................................................................26
2.2
Background ..........................................................................................................27
2.2.1
Pharmaceutical and Therapeutic Background .............................................27
2.2.1.1
Disease Burden and Epidemiology for HPV-related anogenital 
disease................................................................................................27
2.2.2
Preclinical and Clinical Studies ...................................................................28
2.2.2.1
Completed Clinical Studies................................................................28
2.2.2.2
On-going Clinical Studies in Japan....................................................29
2.2.2.3
Real-world Evidence Studies.............................................................29
2.3
Benefit/Risk Assessment......................................................................................29
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................30
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................35
4.2.1
Rationale for Endpoints ...............................................................................35
4.2.1.1
Efficacy Endpoints.............................................................................35
4.2.1.2
Immunogenicity Endpoints................................................................36
4.2.1.3
Safety Endpoints................................................................................36
4.2.1.4
Future Biomedical Research..............................................................36
4.2.2
Rationale for the Use of Placebo .................................................................37
4.3
Justification for Dose...........................................................................................37
4.4
Beginning and End-of-Study Definition ............................................................37
4.4.1
Clinical Criteria for Early Study Termination .............................................37
5
STUDY POPULATION ................................................................................................38
5.1
Inclusion Criteria.................................................................................................38
5.1.1
Base Study ...................................................................................................38
5.1.2
Extension Study ...........................................................................................39
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5.2
Exclusion Criteria................................................................................................39
5.2.1
Base Study ...................................................................................................39
5.2.2
Extension Study ...........................................................................................41
5.3
Lifestyle Considerations......................................................................................41
5.3.1
Activity Restrictions ....................................................................................41
5.4
Screen Failures.....................................................................................................42
5.5
Participant Replacement Strategy......................................................................42
6
STUDY INTERVENTION............................................................................................43
6.1
Study Intervention(s) Administered...................................................................43
6.1.1
Drug Device Combination Product/Combination Medicinal Product.........45
6.2
Preparation/Handling/Storage/Accountability .................................................45
6.2.1
Dose Preparation..........................................................................................45
6.2.2
Handling, Storage, and Accountability........................................................45
6.3
Measures to Minimize Bias: Randomization and Blinding..............................46
6.3.1
Intervention Assignment..............................................................................46
6.3.2
Stratification.................................................................................................46
6.3.3
Blinding........................................................................................................46
6.4
Study Intervention Compliance..........................................................................47
6.5
Concomitant Therapy..........................................................................................47
6.5.1
Rescue Medications and Supportive Care ...................................................47
6.6
Dose Modification ................................................................................................48
6.7
Intervention After the End of the Study............................................................48
6.8
Clinical Supplies Disclosure................................................................................48
6.9
Standard Policies..................................................................................................48
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................49
7.1
Discontinuation of Study Intervention...............................................................49
7.2
Participant Withdrawal From the Study...........................................................49
7.3
Lost to Follow-up .................................................................................................50
8
STUDY ASSESSMENTS AND PROCEDURES........................................................51
8.1
Administrative and General Procedures ...........................................................52
8.1.1
Informed Consent.........................................................................................52
8.1.1.1
General Informed Consent.................................................................52
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................52
8.1.2
Inclusion/Exclusion Criteria ........................................................................52
8.1.3
Participant Identification Card.....................................................................53
8.1.4
Medical History ...........................................................................................53
8.1.5
Sexual History, Demographics, Substance Use...........................................53
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8.1.6
Prior and Concomitant Medications Review...............................................53
8.1.6.1
Prior Medications...............................................................................53
8.1.6.2
Concomitant Medications..................................................................54
8.1.7
Assignment of Screening Number...............................................................54
8.1.8
Assignment of Treatment/Randomization Number.....................................54
8.1.9
Study Intervention Administration ..............................................................55
8.1.9.1
Study Intervention Administration in Base Study .............................55
8.1.9.2
Study Intervention Administration in Extension Study.....................56
8.1.9.3
Timing of Dose Administration.........................................................57
8.1.10
Discontinuation and Withdrawal .................................................................57
8.1.10.1
Withdrawal From Future Biomedical Research ................................58
8.1.11
Participant Blinding/Unblinding..................................................................58
8.1.12
Calibration of Equipment.............................................................................59
8.1.13
Optional Testing for Sexually Transmitted Infections.................................59
8.1.14
Sexual Activity.............................................................................................59
8.2
Genital Examination and Efficacy Assessments (Base Study).........................60
8.2.1
Anogenital Physical Examination................................................................60
8.2.2
External Genital Examination......................................................................60
8.2.2.1
Procedure for Penile and Scrotal Examination ..................................60
8.2.2.2
Procedure for Perineal/Perianal Examination....................................61
8.2.3
Efficacy Assessments...................................................................................61
8.2.3.1
Collection of Swabs for HPV PCR....................................................62
8.2.3.1.1
Penile/Glans Penis File and Wetted Swab for HPV PCR........62
8.2.3.1.2
Scrotal File and Wetted Swab for HPV PCR...........................63
8.2.3.1.3
Perineal/Perianal File and Wetted Swab for HPV PCR...........64
8.2.3.1.4
Intra-anal Wetted Swab for HPV PCR ....................................64
8.2.3.2
External Genital Lesion Biopsy.........................................................65
8.2.3.2.1
External Genital Lesion Biopsy at Study Site..........................65
8.2.3.2.2
Preparation and Disposition of Thin Sections from Tissue 
Specimens ................................................................................67
8.2.3.2.3
Specimens Taken Outside the Context of the Study................67
8.2.3.3
HPV DNA PCR Assay.......................................................................68
8.3
Immunogenicity Assessments (Base Study).......................................................68
8.3.1
Blood Sample Collection for Serum Anti-HPV Antibody Testing .............68
8.3.2
Competitive Luminex Immunoassay...........................................................69
8.4
Safety Assessments...............................................................................................69
8.4.1
Physical Examinations.................................................................................70
8.4.2
Oral Temperature Measurements.................................................................70
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8.4.3
Clinical Safety Laboratory Assessments .....................................................70
8.4.4
Vaccination Report Card..............................................................................70
8.4.5
Postvaccination Observation Period (30 Minutes) ......................................71
8.5
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................72
8.5.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................72
8.5.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......74
8.5.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...74
8.5.4
Regulatory Reporting Requirements for SAE .............................................75
8.5.5
Pregnancy and Exposure During Breastfeeding ..........................................75
8.5.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................75
8.5.7
Events of Clinical Interest............................................................................75
8.6
Treatment of Overdose........................................................................................75
8.7
Pharmacokinetics.................................................................................................76
8.8
Pharmacodynamics..............................................................................................76
8.9
Biomarkers ...........................................................................................................76
8.10
Future Biomedical Research Sample Collection...............................................76
8.11
Health Economics Medical Resource Utilization and Health Economics.......76
8.12
Visit Requirements...............................................................................................76
8.12.1
Visit Requirements in Base Study ...............................................................76
8.12.1.1
Screening Visit...................................................................................76
8.12.1.2
Prerequisites for Vaccination Visit (Day 1, Month 2, and Month 
6) ........................................................................................................77
8.12.1.3
Prerequisites for Anogenital Sample Collection Visits .....................77
8.12.1.4
Early Termination Procedures ...........................................................77
8.12.2
Visit Requirements in Extension Study.......................................................78
8.12.2.1
Prerequisites for Vaccination Visit (Extension Visit 1, Extension 
Visit 2a/2b, and Extension Visit 3)....................................................78
8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................78
9
KEY STATISTICAL CONSIDERATIONS ...............................................................79
9.1
Statistical Analysis Plan Summary.....................................................................79
9.2
Responsibility for Analyses/In-house Blinding .................................................81
9.3
Hypotheses/Estimation ........................................................................................81
9.4
Analysis Endpoints...............................................................................................82
9.4.1
Efficacy Endpoints.......................................................................................82
9.4.2
Immunogenicity Endpoints..........................................................................83
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9.4.3
Safety Endpoints..........................................................................................83
9.5
Analysis Populations............................................................................................83
9.5.1
Efficacy Analysis Populations.....................................................................83
9.5.2
Immunogenicity Analysis Populations ........................................................84
9.5.3
Safety Analysis Population..........................................................................85
9.6
Statistical Methods...............................................................................................86
9.6.1
Statistical Methods for Efficacy Analyses...................................................86
9.6.2
Statistical Methods for Immunogenicity Analyses......................................88
9.6.2.1
Estimation of GMTs ..........................................................................88
9.6.2.2
Estimation of Percent Seroconversion...............................................88
9.6.3
Statistical Methods for Safety Analyses ......................................................88
9.6.4
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................90
9.7
Interim Analyses ..................................................................................................90
9.8
Multiplicity ...........................................................................................................90
9.9
Sample Size and Power Calculations .................................................................90
9.9.1
Sample Size and Power for Testing the Primary Efficacy Hypothesis........90
9.9.2
Sample Size and Power for Testing the Secondary Efficacy Hypothesis....91
9.9.3
Sample Size and Power for Safety Analysis................................................92
9.10
Subgroup Analyses...............................................................................................92
9.11
Compliance (Medication Adherence).................................................................93
9.12
Extent of Exposure...............................................................................................93
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................94
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........94
10.1.1
Code of Conduct for Clinical Trials.............................................................94
10.1.2
Financial Disclosure.....................................................................................96
10.1.3
Data Protection.............................................................................................97
10.1.3.1
Confidentiality of Data ......................................................................97
10.1.3.2
Confidentiality of Participant Records...............................................97
10.1.3.3
Confidentiality of IRB/IEC Information............................................97
10.1.4
Committees Structure...................................................................................98
10.1.4.1
Clinical Adjudication Committee (CAC) ..........................................98
10.1.5
Publication Policy........................................................................................98
10.1.6
Compliance with Study Registration and Results Posting Requirements ...98
10.1.7
Compliance with Law, Audit, and Debarment ............................................99
10.1.8
Data Quality Assurance ...............................................................................99
10.1.9
Source Documents .....................................................................................100
10.1.10
Study and Site Closure...............................................................................101
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10.2
Appendix 2: Clinical Laboratory Tests............................................................102
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................103
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................103
10.3.2
Definition of AE ........................................................................................103
10.3.3
Definition of SAE ......................................................................................104
10.3.4
Additional Events Reported.......................................................................105
10.3.5
Recording AE and SAE .............................................................................106
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................108
10.4
Appendix 4: Combination Medicinal Products: Complaints, Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up.110
10.4.1
Definitions..................................................................................................110
10.4.2
Recording, Assessing Causality, and Follow-up of Complaints, 
PQCs/Malfunctions....................................................................................110
10.5
Appendix 5: Contraceptive Guidance..............................................................112
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................113
10.7
Appendix 7: Country-specific Requirements..................................................117
10.8
Appendix 8: Abbreviations ...............................................................................118
11
REFERENCES.............................................................................................................120
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LIST OF TABLES
Table 1
Study Interventions......................................................................................44
Table 2
Blood Collection Volumes...........................................................................51
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ............................................................................74
Table 4
Acceptable Day Ranges for Vaccination Visits...........................................85
Table 5
Acceptable Day Ranges for Collection of Serum Samples .........................85
Table 6
Analysis Strategy for Efficacy Variable ......................................................87
Table 7
Analysis Strategy for Safety Parameters......................................................89
Table 8
Decision Rule and Corresponding Type 1 Error rate and Power for 
Testing the Primary Efficacy Hypothesis....................................................91
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LIST OF FIGURES
Figure 1
Study Design (Base Study)..........................................................................18
Figure 2
Study Design (Extension Study)..................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, randomized, placebo-controlled clinical study to evaluate the 
efficacy, immunogenicity and safety of the 9vHPV vaccine in Japanese males, 16 to 26 years 
of age.
Short Title: Phase 3 study for efficacy against anogenital persistent infection, 
immunogenicity, and safety of the 9vHPV vaccine in Japanese males
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives and endpoints will be evaluated in Japanese males, 16 to 26 years 
of age.
Primary Objective
Primary Endpoint
Objective: To demonstrate that a 3-dose regimen of the 9vHPV 
vaccine will reduce the combined incidence of HPV 
6/11/16/18-related anogenital (external genital and intra-anal) 
persistent infection detected in samples from two or more 
consecutive visits 6 months (± 1-month window) or longer 
apart compared with placebo in participants who are 
seronegative at Day 1 and PCR-negative Day 1 through Month 
7 to the relevant HPV type.
Hypothesis: Administration of a 3-dose regimen of the 9vHPV 
vaccine reduces the combined incidence of HPV 6/11/16/18-
related anogenital persistent infection detected in samples from 
two or more consecutive visits 6 months (± 1-month window) 
or longer apart compared with placebo (The statistical criterion 
for success requires that the lower bound of the 2-sided 95% CI 
of vaccine efficacy is >0%).
HPV 6/11/16/18-related 
anogenital persistent 
infection
Objective: To evaluate the safety and tolerability of the 9vHPV 
vaccine.
-Solicited injection-site 
adverse events (AEs)
-Systemic AEs
-Serious adverse events 
(SAEs)
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Secondary Objectives
Secondary Endpoints
Objective: To demonstrate that a 3-dose regimen of the 9vHPV 
vaccine will reduce the combined incidence of HPV 
31/33/45/52/58-related anogenital persistent infection detected 
in samples from two or more consecutive visits 6 months (± 1-
month window) or longer apart compared with placebo in 
participants who are seronegative at Day 1 and PCR-negative 
Day 1 through Month 7 to the relevant HPV type.
Hypothesis: Administration of a 3-dose regimen of the 9vHPV 
vaccine reduces the combined incidence of HPV 
31/33/45/52/58-related anogenital persistent infection detected 
in samples from two or more consecutive visits 6 months (± 1-
month window) or longer apart compared with placebo (The 
statistical criterion for success requires that the lower bound of 
the 2-sided 95% CI of vaccine efficacy is >0%).
HPV 31/33/45/52/58-
related anogenital 
persistent infection
Objective: To summarize antibody responses [Geometric Mean 
Titer (GMT) and percent seroconversion] to each of HPV 6, 11, 
16, 18, 31, 33, 45, 52, and 58 at Month 7 in participants who 
are seronegative at Day 1 and PCR-negative Day 1 through 
Month 7 to the relevant HPV type, by all participants, 
heterosexual males (HM) group and males who have sex with 
males (MSM) group, respectively.
Serum antibody titer to 
each of HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 
58
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Papilloma viral infection
Population
Japanese males, 16 to 26 years of age
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo 
Study Blinding
Double-blind with in-house blinding 
Blinding Roles
Participants or Subjects 
Investigator 
Sponsor 
Outcomes Assessor 
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Estimated Duration of 
Study
The Sponsor estimates that the study will require approximately 
up to 7 years from the time the first participant (or their legally 
acceptable representative) provides documented informed consent 
until the last participant’s last study-related contact.
The base study of this study is a case-driven study and primary 
efficacy analysis will be conducted after at least 17 primary 
efficacy endpoint cases and at least 17 secondary efficacy 
endpoint cases are collected. After completion of the base study, 
the participants in the placebo group and participants who did not 
complete 3-dose regimen of 9vHPV vaccine will be offered an 
opportunity to start or complete a 3-dose series of 9vHPV vaccine 
in the extension study.
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 1050 participants will be randomized in 1:1 ratio to receive the 9vHPV 
vaccine or placebo. The targeted enrollment for MSM is approximately 10% of all 
participants.
Intervention Groups and Duration:
Arm 
Name
Intervention 
Name
Unit Dose Strength(s)
Dosage 
Level(s)
Route of 
Administration
Vaccination 
Regimen
Use
The 
9vHPV 
vaccine
V503
(9vHPV 
vaccine)
HPV
6/11/16/18/31/33/45/52/58 
L1 VLP:
30/40/60/40/20/20/20/20/20 
mcg per dose
0.5 mL
IM
Day 1, Month 
2, Month 6
Test 
Product
Placebo
Saline for 
injection
0.9% sodium chloride
0.5 mL
IM
Day 1, Month 
2, Month 6
Placebo
The 
9vHPV 
vaccine
(Extension 
Study)
V503
(9vHPV 
vaccine)
HPV
6/11/16/18/31/33/45/52/58 
L1 VLP:
30/40/60/40/20/20/20/20/20 
mcg per dose
0.5 mL
IM
1 dose in Ext:
Ext 1
OR
2 doses in Ext:
Ext 1 and 
Month 4 in Ext
Test 
Product
Placebo
(Extension 
Study)
V503
(9vHPV 
vaccine)
HPV
6/11/16/18/31/33/45/52/58 
L1 VLP:
30/40/60/40/20/20/20/20/20 
mcg per dose
0.5 mL
IM
Ext 1, Month 2 
in Ext, Month 
6 in Ext
Test 
Product
9vHPV = 9-valent human papillomavirus; IM = Intramuscular; VLP = virus-like particle
Other current or former name(s) or alias(es) for study intervention(s) are as follows: the 
9vHPV vaccine, SILGARD®9, GARDASIL®9 and V503.
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Total Number of Intervention Groups/Arms
2 intervention groups
Duration of Participation
Each participant will participate in the base 
study for up to 61 months from the time the 
participant (or their legally acceptable 
representative) provides documented 
informed consent through the final contact. 
Each participant will receive 3 doses of the 
9vHPV vaccine or placebo intramuscularly 
at Day 1, Month 2, and Month 6. After the 
completion of vaccination, each participant 
will be followed every 6 months. This is a 
case-driven study, and participants will 
continue in the study until at least 17 
primary efficacy endpoint cases and at least 
17 secondary efficacy endpoint cases are 
collected. After at least 17 primary efficacy 
endpoint cases and at least 17 secondary 
efficacy endpoint cases have accrued, the 
initial database lock and unblinding will be 
performed and notified to the study sites. 
Following notification, participants 
remaining in the study (ie, who have not yet 
completed a Final Visit) will proceed to the 
Final Visit in the base study promptly (as 
shown in Section 1.3, and Section 8.12.1.4).
Sponsor will notify the participants’ 
vaccination assignment after the initial 
database lock. After unblinding the 
participants’ vaccination assignment, 
eligible participants will be offered and 
consented to enter an extension study, 
which could last up to 9 months. 
Participants in the placebo group will 
receive a 3-dose series of the 9vHPV 
vaccine. Participants who did not complete 
a 3-dose series in the base study will be 
eligible to receive 1 to 2 doses of 9vHPV 
depending on the doses they had completed. 
Participants will have a safety phone call 1 
month after their last dose in the extension 
study.
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Study Governance Committees:
Executive Oversight Committee
No 
Data Monitoring Committee
No 
Clinical Adjudication Committee
Yes 
Steering Committee
No 
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: Yes 
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1 (Base Study) and Figure 2 (Extension Study).
Figure 1
Study Design (Base Study)
9vHPV = 9-valent human papillomavirus; D = Day; HPV = human papillomavirus; M = Month; PCR = polymerase chain 
reaction
After at least 17 primary efficacy endpoint cases and at least 17 secondary efficacy endpoint cases have accrued, initial 
database lock and unblinding will be performed and notified to the study sites. Following notification, participants 
remaining in the study (ie, who have not yet completed a Final Visit) will proceed to the Final Visit in the base study
promptly. Under that scenario, participants who have not yet completed a Final Visit will complete the specified procedures 
in Final Visit in this Schedule of Activities. (See Section 1.3 and Section 8.12.1.4).
1 After initial database lock and unblinding, examination and sample collection for efficacy assessment should not be 
conducted.
2 Even after initial database lock and unblinding, serum sample will be collected. At the Final Visit, serum sample should be 
collected within the specific day ranges from Day 913 to Day 1277 only from the participant who have not yet completed 
Month 36.
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Figure 2
Study Design (Extension Study)
9vHPV = 9-valent human papillomavirus
1 Participants who did not complete the 3-dose regimen of 9vHPV vaccine in the base study will be eligible to receive the 
remaining doses from the series (ie, if they already received 2 doses in the base study, they will receive 1 dose in the 
extension study and a safety phone call 1 month after the last dose; if they already received 1 dose in base study, they will 
receive 2 doses which are 4 months apart in the extension study and a safety phone call 1 month after the last dose). For 
those who do not require a dose at the Extension Visit 2b, the visit will not be conducted.
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1.3
Schedule of Activities
1.3.1
Scheduled Visits for Base Study
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Notes
Scheduled Day/Month
Day 
1
Month
2
6
7
12
18
24
30
36
42
48
54
60
(Final 
Visit)
Visit Window1
± 3
Weeks
± 4
Weeks
3 to 7
Weeks 
Postdose 3
± 1 month
To calculate visit windows, assume 
1 month=30 days and 1 week=7 days
Administrative Procedures
Obtain Informed Consent
X
Obtain Informed Consent for 
Future Biomedical Research
X
Participation in future biomedical 
research is optional and consent must be 
obtained before collection of blood 
(DNA) samples.
Review Inclusion/Exclusion 
Criteria
X
Assign Participant 
Identification Card
X
Collect Lifetime Medical 
History (includes substance 
usage)
X
Substances: Alcohol, tobacco
Update Medical History (new 
conditions not already 
recorded as medical history or 
AEs)
X
X
X
X
X
X
X
X
X
X
X
X
Collect Lifetime Sexual 
History
X
Collect Sexual Activity
X
X
X
X
X
X
X
X
X
X
X
X
Sexual activity will not be collected after 
initial database lock and unblinding.
Review Prior/Concomitant 
Medication and Non-study 
Vaccination Review
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 6.5 for prerequisites for 
medications and non-study vaccines
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Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Notes
Scheduled Day/Month
Day 
1
Month
2
6
7
12
18
24
30
36
42
48
54
60
(Final 
Visit)
Visit Window1
± 3
Weeks
± 4
Weeks
3 to 7
Weeks 
Postdose 3
± 1 month
To calculate visit windows, assume 
1 month=30 days and 1 week=7 days
Clinical and Laboratory Procedures
Measure Oral Temperature 
X
X
X
Prior to each vaccination. Participants 
who have a fever (defined as an oral 
temperature of ≥37.5°C) within the 24-
hour period prior to vaccination must be 
rescheduled.
Record Height and Weight
X
Prior to vaccination. 
Physical Examination 
(optional, per investigator’s 
discretion; perform if needed 
to assess inclusion/exclusion 
criteria)
X
Anogenital Physical 
Examination
X
Prior to vaccination
Genitourinary examination 
for external genital lesions
X
X
X
X
X
X
X
X
X
X
X
Prior to vaccination on Day 1
Examination will not be required after 
initial database lock and unblinding.
Penile/glans penis file and 
wetted swab for HPV PCR
X
X
X
X
X
X
X
X
X
X
X
Prior to vaccination on Day 1
Sample should not be collected after 
initial database lock and unblinding.
Scrotal file and wetted swab 
for HPV PCR
X
X
X
X
X
X
X
X
X
X
X
Prior to vaccination on Day 1
Sample should not be collected after 
initial database lock and unblinding.
Perianal examination for 
external genital lesions
X
X
X
X
X
X
X
X
X
X
X
Prior to vaccination on Day 1
Examination will not be required after 
initial database lock and unblinding.
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Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Notes
Scheduled Day/Month
Day 
1
Month
2
6
7
12
18
24
30
36
42
48
54
60
(Final 
Visit)
Visit Window1
± 3
Weeks
± 4
Weeks
3 to 7
Weeks 
Postdose 3
± 1 month
To calculate visit windows, assume 
1 month=30 days and 1 week=7 days
Perineal/perianal file and 
wetted swab for HPV PCR
X
X
X
X
X
X
X
X
X
X
X
Prior to vaccination on Day 1
Sample should not be collected after 
initial database lock and unblinding.
Intra-anal wetted swab for 
HPV PCR
X
X
X
X
X
X
X
X
X
X
X
Prior to vaccination on Day 1
Sample should not be collected after 
initial database lock and unblinding.
External genital lesion biopsy 
(if indicated)
X
X
X
X
X
X
X
X
X
X
X
X
Processed and analyzed at Central 
Laboratory
Sample should not be collected after 
initial database lock and unblinding.
Sexually Transmitted 
Infection (STI) Testing (local 
laboratory testing, at the 
discretion of the investigator 
if clinically indicated)
X
X
X
X
X
X
X
X
X
X
X
X
X
Optional at any visit
Blood Sample Collection 
(Serum for anti-HPV)
X
X
X
(X)2
Prior to vaccination on Day 1
Sample should be collected even after 
initial database lock and unblinding.
Blood Sample Collection 
(DNA) for Future Biomedical 
Research
X
Prior to vaccination from enrolled 
participants only (optional). 
Vaccine 
Allocation/Randomization 
X
9vHPV Vaccine/Placebo 
Administration
X
X
X
30-minute postvaccination 
observation period
X
X
X
Provide Vaccination Report 
Card (VRC)
X
X
X
See Section 8.4.4 for data collected in 
VRC.
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Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Notes
Scheduled Day/Month
Day 
1
Month
2
6
7
12
18
24
30
36
42
48
54
60
(Final 
Visit)
Visit Window1
± 3
Weeks
± 4
Weeks
3 to 7
Weeks 
Postdose 3
± 1 month
To calculate visit windows, assume 
1 month=30 days and 1 week=7 days
Review and Collect VRC
X
X
X
Telephone contacts after 15 days from 
Day 1, Month 2 and Month 6, 
respectively to remind the participants.
Monitor Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Once at least 17 primary efficacy endpoint cases and at least 17 secondary efficacy endpoint cases have been observed, initial database lock and unblinding will be performed 
and notified to the study sites. Following notification, participants remaining in the study (ie, who have not yet completed a Final Visit) will proceed to a Final Visit in the base 
study promptly. Under that scenario, participants who have not yet completed a Final Visit will complete the specified procedures in Final Visit in this Schedule of Activities. 
Details are shown in Section 8.12.1.4.
1
At or later than Visit 5, any visit outside of visit window must occur at least 4 months after the previous visit (ie, the minimum length of time between samples to be 
counted as a case of persistent infection, see Section 9.4.1). Regarding protocol study visit windows, the following situations require consultation between the investigator 
and the Sponsor and written documentation of the collaborative decision: the study site is considering skipping a visit.
2
When the cases would accrue earlier, participants who have not yet completed Month 36 should schedule a Final Visit with collection of serum sample within the specific 
day ranges from Day 913 to Day 1277, if possible. At the Final Visit, serum sample should not be collected from the participants who have already completed Month 36 
or outside of the day ranges from Day 913 to Day 1277.
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1.3.2
Scheduled Visits for Study Extension (Placebo Group)
Visit Number
Extension Visit 
1
Extension 
Visit 2a
Extension 
Visit 3
Ext Final 
Status
Notes
Scheduled Day/Month
First Visit of 
Extension 
Study
2
(Extension)
6
(Extension)
1 month after 
last dose in 
Extension
Visit Window
± 3
Weeks
± 4
Weeks
± 1
Week
To calculate visit windows, assume 1 month=30 days and 
1 week=7 days
Obtain Informed Consent
X
Review Inclusion/Exclusion Criteria
X
Measure Oral Temperature 
X
X
X
Prior to each vaccination. Participants who have a fever 
(defined as an oral temperature of ≥37.5°C) within the 24-
hour period prior to vaccination must be rescheduled.
9vHPV Vaccine Administration
X
X
X
The first vaccination in the extension study is 
recommended to occur the same day as the Final Visit of 
base study, if possible.
30-minute postvaccination observation 
period
X
X
X
SAEs and Deaths
X
X
X
X
(Phone call)
SAEs and deaths, regardless of causality, will be reported 
from the time of first vaccination through 1 month after the 
participant’s last vaccination in the extension study.
9vHPV = 9-valent human papillomavirus; SAE=serious adverse event
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1.3.3
Scheduled Visits for Study Extension (9vHPV Group)
Visit Number
Extension Visit 
1
Extension 
Visit 2b
Ext Final 
Status
Notes
Scheduled Day/Month
First Visit of 
Extension 
Study
4
(Extension)
1 month after 
last dose in 
Extension
For those who do not require a dose at the Extension Visit 2b, the visit will 
not be conducted.
Visit Window
± 3
Weeks
± 1
Week
To calculate visit windows, assume 1 month=30 days and 1 week=7 days
Obtain Informed Consent
X
Review Inclusion/Exclusion Criteria
X
Measure Oral Temperature 
X
X
Prior to each vaccination. Participants who have a fever (defined as an oral 
temperature of ≥37.5°C) within the 24-hour period prior to vaccination 
must be rescheduled.
9vHPV Vaccine Administration a
X
X
The first vaccination in the extension study is recommended to occur the 
same day as the Final Visit of base study, if possible.
30-minute postvaccination 
observation period
X
X
SAEs and Deaths
X
X
X
(Phone call)
SAEs and deaths, regardless of causality, will be reported from the time of 
first vaccination through 1 month after the participant’s last vaccination in 
the extension study.
9vHPV = 9-valent human papillomavirus; SAE=serious adverse event
a Participants who did not complete the 3-dose regimen of 9vHPV vaccine in the base study will be eligible to receive the remaining doses from the series (ie, if they already 
received 2 doses in the base study, they will receive 1 dose in the extension study and a safety phone call 1 month after the last dose; if they already received 1 dose in base study, 
they will receive 2 doses which are 4 months apart in the extension study and a safety phone call 1 month after the last dose).
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2
INTRODUCTION
2.1
Study Rationale
HPV infection causes benign and malignant dysplastic disease, localized primarily in the 
anogenital area and upper airway, in both males and females [Paavonen, J. 2007] [Madkan, 
V.K., et al 2007] [Stamataki, S., et al 2007]. Persistent HPV infection significantly increases 
the risk of developing cervical, anogenital, and oropharyngeal cancers [Forman, D., et al 
2012]. HPV disease is frequently multicentric (i.e., affecting more than one anatomic site). 
Individuals with genital warts due to HPV infection have an elevated long-term risk of 
developing anogenital and head and neck cancers [Blomberg, M., et al 2012].
Global clinical studies have demonstrated that the quadrivalent HPV (qHPV) vaccine reduces 
the incidence of external genital and intra-anal persistent infection, anal precancers, and 
anogenital warts caused by HPV types 6, 11, 16 and 18 in males [Giuliano, A.R., et al 2011] 
[Palefsky, J.M., et al 2011][Ferris, D.G., et al 2017]. The results of Protocol V501-122, a 
local Phase 3 study, demonstrated that qHPV vaccine also prevents external genital and intra-
anal persistent infection caused by HPV types 6, 11, 16, and 18 in Japanese males [Mikamo 
H., et al 2019]. 
The 9vHPV vaccine was developed to cover the 4 HPV types included in the qHPV vaccine 
and an additional 5 high-risk HPV types (31, 33, 45, 52, 58). HPV 6 and 11 are responsible 
for approximately 90% of global genital wart cases [Pitisuttithum, P., et al 2015][Garland, 
S.M., et al 2009], and HPV types 16, 18, 31, 33, 45, 52, and 58 are responsible for 
approximately 90% globally of cervical cancers and HPV-related vulvar, vaginal, and anal 
cancers [Serrano, B., et al 2012] [de Sanjosé, S., et al 2013] [Alemany, L., et al 2015] 
[Alemany, L., et al 2014] [Lacey, C.J.N., et al 2006] [de Sanjosé, S., et al 2019]. The 9vHPV 
vaccine was initially licensed in the USA in December 2014 and, as of February 2020, is 
licensed in more than 80 countries or regions under the name GARDASIL®9. In Japan, the 
9vHPV vaccine was approved for female as SILGARD®9 Aqueous Suspension for 
Intramuscular Injection Syringes in July 2020.
HPV vaccination contributes to reducing the burden of HPV diseases in males. The 9vHPV 
vaccine is approved to prevent vaccine type HPV-related genital warts and anal cancer and 
its precancers in males in other countries. In contrast to cervical cancer in females, there is no 
widespread screening program in any country for detection of HPV related anal cancers in 
males, making prophylactic vaccination is the only realistic preventive measure for HPV 
diseases in males, in both developed and developing countries. An additional potential 
benefit of HPV vaccination in males is the generation of herd protection, which in turn could 
lead to a substantial reduction of HPV diseases in both males and females [Baseman, J.G., et 
al 2005]. Previous public health experience has shown that gender-restricted vaccination 
programs are substantially less effective than universal vaccination. It is likely that the most 
effective means to reduce the burden of HPV disease using a safe and effective prophylactic 
vaccine is to vaccinate both males and females. In fact, gender neutral vaccination of HPV 
vaccine is increasing internationally, as over 40 countries or regions have adopted this
approach as of March 2020.  
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This study will evaluate the efficacy, immunogenicity and safety of the 9vHPV vaccine in 
Japanese males, 16 to 26 years of age, in order to pursue indications for prevention of anal 
cancer and its precancerous or dysplastic lesions caused by 9vHPV types in both males and 
females, and genital warts in males in Japan. The scientific rationale for the study design is 
described in Section 4.2.
2.2
Background
Refer to the IB/approved labeling for detailed background information on the 9vHPV vaccine 
(V503).
2.2.1
Pharmaceutical and Therapeutic Background
The 9vHPV vaccine is an aluminum-adjuvanted recombinant protein vaccine prepared from 
the highly purified virus-like particles (VLPs) of the recombinant major capsid (L1) protein 
of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. 
The 9vHPV vaccine is currently indicated for the prevention of cervical, vulvar, vaginal, and 
anal cancers, and precancerous or dysplastic lesions, genital warts, and infection caused by 
the 9 HPV types targeted by the vaccine in many countries. In Japan, the 9vHPV vaccine was 
approved for the prevention of cervical, vulvar, and vaginal cancers and precancers, and 
genital warts caused by 9-valent HPV types in women.
2.2.1.1
Disease Burden and Epidemiology for HPV-related anogenital disease
The average lifetime probability of acquiring HPV among those with at least 1 opposite sex 
partner is estimated to be greater than 80% [Chesson, H.W., et al 2014]. HPV infection is 
transmitted via contact with an infected individual or a contaminated object and occurs most 
often during sexual activity. About sixty percent of sexual partners of infected individuals 
develop lesions a few weeks to 8 months after exposure [Oriel, J.D. 1971]. HPV is often 
acquired immediately after sexual debut and is strongly correlated with the number of 
lifetime sexual partners [Xi, L.F. and Koutsky, L.A. 1997][Koutsky, L. 1997]. Males and 
females in their late teens and early twenties are at the highest risk for HPV infection, as 
early sexual activity is accompanied with a higher likelihood of having multiple sexual 
partners, increasing the risk of exposure to the virus.
Anogenital Warts 
Anogenital warts are generally benign, exophytic, hyperkeratotic lesions on the penile shaft 
(most common site of lesions), scrotum, perineum, and anus in males. In general, the lesions 
do not cause any physical discomfort [Chuang, T.Y., et al 1984]. Some patients experience 
itching, burning, bleeding, moisture, irritation or soreness, especially with lesions in the 
perianal region. Patients are often distressed by the lesions’ appearance. Genital warts 
(condyloma acuminata) are caused by HPV-6 or -11 account for approximately 75 to 90% of 
cases in both males and females [Aubin, F., et al 2008][Garland, S.M., et al 2009][Chan, 
P.K.S., et al 2009][Yanofsky, V.R., et al 2012]. The incubation period following exposures is 
3 weeks to 8 months [Yanofsky, V.R., et al 2012]. Treatment consists of chemical or physical 
ablation and is often unsuccessful. Recurrence rates are high [Stone, K.M. 1995]. In Japan, 
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genital warts are categorized as one of the sentinel reporting diseases of Category V 
Infectious Diseases by The Law Concerning the Prevention of Infectious Diseases and 
Medical Care for Patients of Infections (Infectious Diseases Control Law). According to the 
Infectious Diseases Weekly Report based on Infectious Diseases Control Law, the total 
reported number of genital warts cases in 2019 was 6263 (males: 4113, females: 2150) 
[MHLW. 2019]. The prevalence of genital warts in Japan peaks at ages 25 to 29 years in 
males and 20 to 24 years in females [NIID. 2018].
Anal Cancer
Triggered by HPV infection, anal cancer develops through persistent infections and precursor 
lesions [Valvo, F., et al 2019]. The association between anal cancer and HPV infection is 
strongly suggested by the results of clinical trials. In a report by de Martel et al., HPV-DNA 
was demonstrated in 35,000 of 40,000 worldwide cases of anal cancer [de Martel, C., et al 
2017]. Similarly, HPV-DNA was detected in 88.3% of anal cancers in a large-scale global 
study [Alemany, L., et al 2015]. Of the HPV types detected in invasive anal cancer in males, 
HPV type 16 (73.4%) was most common, followed by type 18 (5.2%), and type 6, 11, 31, 33 
and 45 were also detected [De Vuyst H., et al 2009]. HPV type 16 and 18 were also detected 
in anal adenocarcinoma [Herfs, M., et al 2018]. In Japan, though HPV type distribution data 
is limited, 952 new anal cancer cases occurred in 2015 based on national cancer incidence 
data from the National Cancer Registration and Statistics Cancer Information Service of the 
National Cancer Research Center [National Cancer Center. 2015]. In addition, Daling et al. 
reported that HPVs were detected in 78.0% and 97.7% anal cancer of HM and MSM, 
respectively [Daling, J.R., et al 2004].
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
the 9vHPV vaccine.
2.2.2.1
Completed Clinical Studies
The qHPV vaccine was highly effective in preventing HPV 6, 11, 16, or 18-type related 
persistent infection and external genital lesions [genital warts, penile/perianal/perineal 
intraepithelial neoplasia (PIN)] in male participants, 16-26 years old, and anal diseases 
(AIN/anal cancer) in MSM participants in a global Phase 3 study (V501-020). Long term 
follow-up data in 2 additional global studies (V501-020-21 and V501-018-11) showed the 
protective effectiveness of qHPV vaccine in boys and males, 9 to 26 years of age persisted 
for approximately 10 years after the first vaccination. Similarly, the results of Protocol V501-
122 demonstrated that qHPV vaccine prevents persistent anogenital infections associated 
with HPV types 6, 11, 16 and 18 in Japanese males (16-26 years of age). qHPV vaccine was 
generally well-tolerated both in non-Japanese and Japanese males in these studies.
The efficacy, immunogenicity and safety of the 9vHPV vaccine (V503) was demonstrated in 
a global Phase 3 study in females (16-26 years old, including Japanese females) in Protocol 
V503-001. The 9vHPV vaccine prevented infection and disease caused by the vaccine type 
HPV and was generally well-tolerated [Joura, E.A., et al 2015] [Huh, W.K., et al 2017]. In 
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addition, an open-label, Japan local Phase 3 study was also conducted. The safety, 
tolerability, and immunogenicity of the 9vHPV vaccine in Japanese girls (9-15 years old) 
was demonstrated in Protocol V503-008 [Iwata, S., et al 2017]. At Month 7 (after 1 month 
post dose 3), 100% of the participants exhibited seroconversion for each type of HPV with a 
3-dose regimen of the 9vHPV vaccine. The immunogenicity in this population was similar to 
that observed in Japanese females aged 16-26 years in V503-001.
2.2.2.2
On-going Clinical Studies in Japan
For the 9vHPV vaccine in males, a global Phase 3 study (Protocol V503-049) is currently 
being conducted to evaluate the efficacy, immunogenicity, and safety of the 9vHPV vaccine 
in the prevention of oral persistent infection caused by any of the high-risk HPV types 
covered by the vaccine. This study also includes Japanese adult males, 20 to 45 years of age. 
In addition, a local phase 3 study (Protocol V503-066) is also currently being conducted to 
evaluate the immunogenicity and safety of the 9vHPV vaccine following 3-dose in Japanese 
boys aged 9 to 15 years as well as that following 2-dose in Japanese boys and girls aged 9 to 
14 years.
2.2.2.3
Real-world Evidence Studies
A recent study of a nationally representative sample of males and females in the USA found 
a reduction in the prevalence of HPV types 6/11/16/18 infections in genital sites among 
vaccinated participants that completed the National Health and Nutrition Examination 
Survey. There were a reduced prevalence of HPV types 6/11/16/18 infections at the genital 
site among vaccinated females (RR 0.2 [0.1 to 0.3]) and males (RR 0.7 [0.1 to 5.4]) 
compared with non-vaccinated participants [Brouwer, A.F., et al 2019].
2.3
Benefit/Risk Assessment
The 9vHPV vaccine has been shown to be beneficial and efficacious in preventing persistent 
genital HPV infection and disease associated with the 9 HPV types (6, 11, 16, 18, 31, 33, 45, 
52, and 58). The frequency, severity, and magnitude of AEs identified in previous studies and 
post marketing surveillance support a favorable benefit-risk for the 9vHPV vaccine in this 
study population. 
Approximately 50% of participants receive placebo in the base study. After the base study is 
completed, recipients of placebo and participants who did not complete their 3-dose series of 
9vHPV vaccine in the base study will be offered vaccination with the 9vHPV vaccine in an 
extension study as allowed by local regulations and IRBs.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives and endpoints will be evaluated in Japanese males, 16 to 26 years 
of age.
Primary Objective
Primary Endpoint
Objective: To demonstrate that a 3-dose regimen of the 
9vHPV vaccine will reduce the combined incidence of 
HPV 6/11/16/18-related anogenital (external genital and 
intra-anal) persistent infection detected in samples from 
two or more consecutive visits 6 months (± 1-month 
window) or longer apart compared with placebo in 
participants who are seronegative at Day 1 and PCR-
negative Day 1 through Month 7 to the relevant HPV 
type.
Hypothesis: Administration of a 3-dose regimen of the 
9vHPV vaccine reduces the combined incidence of HPV 
6/11/16/18-related anogenital persistent infection 
detected in samples from two or more consecutive visits 
6 months (± 1-month window) or longer apart compared 
with placebo (The statistical criterion for success 
requires that the lower bound of the 2-sided 95% CI of 
vaccine efficacy is >0%).
HPV 6/11/16/18-related 
anogenital persistent infection
Objective: To evaluate the safety and tolerability of the 
9vHPV vaccine.
-Solicited injection-site adverse 
events (AEs)
-Systemic AEs
-Serious adverse events (SAEs)
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Secondary Objectives
Secondary Endpoints
Objective: To demonstrate that a 3-dose regimen of the 
9vHPV vaccine will reduce the combined incidence of 
HPV 31/33/45/52/58-related anogenital persistent 
infection detected in samples from two or more 
consecutive visits 6 months (± 1-month window) or 
longer apart compared with placebo in participants who 
are seronegative at Day 1 and PCR-negative Day 1 
through Month 7 to the relevant HPV type.
Hypothesis: Administration of a 3-dose regimen of the 
9vHPV vaccine reduces the combined incidence of HPV 
31/33/45/52/58-related anogenital persistent infection 
detected in samples from two or more consecutive visits 
6 months (± 1-month window) or longer apart compared 
with placebo (The statistical criterion for success 
requires that the lower bound of the 2-sided 95% CI of 
vaccine efficacy is >0%).
HPV 31/33/45/52/58-related 
anogenital persistent infection
Objective: To summarize antibody responses 
[Geometric Mean Titer (GMT) and percent 
seroconversion] to each of HPV 6, 11, 16, 18, 31, 33, 
45, 52, and 58 at Month 7 in participants who are 
seronegative at Day 1 and PCR-negative Day 1 through 
Month 7 to the relevant HPV type, by all participants, 
heterosexual males (HM) group and males who have 
sex with males (MSM) group, respectively.
Serum antibody titer to each of 
HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58
Tertiary/Exploratory Objectives
Tertiary/Exploratory 
Endpoints
Objective: To evaluate that a 3-dose regimen of the 
9vHPV vaccine will reduce the combined incidence of 
HPV 6/11/16/18/31/33/45/52/58-related anogenital 
persistent infection detected in samples from two or 
more consecutive visits 6 months (± 1-month window) 
or longer apart compared with placebo in participants 
who are seronegative at Day 1 and PCR-negative Day 1 
through Month 7 to the relevant HPV type.
HPV 
6/11/16/18/31/33/45/52/58-
related anogenital persistent 
infection
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Objective: To evaluate that a 3-dose regimen of the 
9vHPV vaccine will reduce the combined incidence of 
HPV 6/11/16/18/31/33/45/52/58-related genital warts, 
PIN, penile, perianal or perineal cancer compared with 
placebo in participants who are seronegative at Day 1 
and PCR-negative Day 1 through Month 7 to the 
relevant HPV type.
HPV 
6/11/16/18/31/33/45/52/58-
related genital warts, PIN, 
penile, perianal or perineal 
cancer
Objective: To evaluate that a 3-dose regimen of the 
9vHPV vaccine will reduce the combined incidence of 
HPV 6/11/16/18/31/33/45/52/58-related intra-anal 
persistent infection detected in samples from two or 
more consecutive visits 6 months (± 1-month window) 
or longer apart compared with placebo in participants 
who are seronegative at Day 1 and PCR-negative Day 1 
through Month 7 to the relevant HPV type.
HPV 
6/11/16/18/31/33/45/52/58-
related intra-anal persistent 
infection
Objective: To evaluate that a 3-dose regimen of the 
9vHPV vaccine will reduce the combined incidence of 
HPV 6/11/16/18/31/33/45/52/58-related anogenital 
persistent infection detected in samples from three or 
more consecutive visits 6 months (± 1-month window) 
or longer apart (i.e., at least 12 months persistent 
infection) compared with placebo in participants who 
are seronegative at Day 1 and PCR-negative Day 1 
through Month 7 to the relevant HPV type.
HPV 
6/11/16/18/31/33/45/52/58-
related anogenital persistent 
infection
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4
STUDY DESIGN
4.1
Overall Design
Base Study
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind study of the 
9vHPV vaccine (V503) in Japanese males, 16 to 26 years of age.
This study will evaluate the efficacy, immunogenicity and safety of the 9vHPV vaccine in 
Japanese males. In this study, approximately 1050 Japanese male participants (including a 
target enrollment of approximately 10% MSM) will be randomized in a 1:1 ratio with 
stratification by HM and MSM to receive 3 doses of either the 9vHPV vaccine or placebo 
(saline solution) on Day 1, Month 2, and Month 6. 
Penile/glans penis, scrotal, perineal/perianal, and intra-anal samples will be collected by a 
wetted swab specimen for HPV PCR testing at Day 1, Month 7, 12, and every 6 months 
thereafter up to a maximum of approximately Month 60. These swabs will be tested for 
detection of HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 by PCR assay. 
PCR analysis of the swabs will be used to identify participants who have an active HPV 
infection at enrollment and to determine persistent HPV infection endpoints.
A detailed genitourinary and perianal inspection will be performed at Day 1, Month 7, 12, 
and every 6 months thereafter up to a maximum of approximately Month 60. If a lesion 
observed at Day 1 is assessed to be possibly, probably, or definitely HPV-related or of 
unknown etiology, then the participant should be excluded from the study. All new (after 
Day 1) genitourinary and perianal lesions judged by the investigator to be possibly, probably, 
or definitely HPV-related, or any lesion whose etiology is not known will be biopsied. If 
multiple lesions are observed (after Day 1), then lesions of each representative morphology 
will be biopsied. If more than one anatomic location is affected, then a lesion from each 
location will be biopsied. 
Tissue samples obtained from biopsy will be analyzed by HPV Thinsection PCR assay and 
by a consensus diagnosis from the HPV Vaccine Program Pathology Panel to determine 
clinical disease efficacy endpoints.
Blood samples will be collected immediately before vaccination on Day 1, Month 7, and 
Month 36 (or Final Visit) to evaluate HPV antibody responses. 
Participants will be followed for solicited injection-site AEs Days 1 through Days 5 
following each vaccination, and any other injection-site AEs and systemic AEs Days 1 
through Days 15 following each vaccination. Any SAEs regardless of causality will be 
recorded from the time of randomization through 6 months postdose 3. Vaccine-related SAEs 
and deaths will be collected throughout the study. New medical conditions (defined as 
incident medical conditions occurring outside of Days 1 to Days 15 period following each 
vaccination and not considered SAEs) will be recorded for all participants at each study visit 
throughout the study.
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The primary analysis is case driven. The database will be locked, and the primary analysis 
will be conducted after at least 17 primary efficacy endpoint cases and at least 17 secondary 
efficacy endpoint cases have been observed in the base study. There is no interim analysis 
planned in this study. These efficacy results as well as immunogenicity and safety results 
based on data in the initial database lock for the primary analysis will be reported as the 
primary CSR. All participants will be unblinded after the primary efficacy analysis database 
lock. Once a participant is unblinded, no further efficacy samples will be collected from the 
participant. 
Once at least 17 primary endpoint cases and at least 17 secondary efficacy endpoint cases are 
accrued, each participant will proceed to the Final Visit promptly without completing any 
other scheduled visits in order to complete the base study (as shown in Section 1.3, and 
Section 8.12.1.4). Additional database locks will be executed, including a second database 
lock after the completion of the final efficacy sample assessment for the purpose of the final 
efficacy analysis and a final database lock of the base study after the last participant’s Final 
Visit in the base study for the final immunogenicity and safety analysis, respectively.
Cumulative data collected from the initiation of the study will be summarized separately and 
a report will be written after each database lock. The base study will end after the last 
participant completes their Final Visit in the base study.
Extension Study
After accrual of at least 17 primary endpoint cases and at least 17 secondary efficacy 
endpoint cases in the base study have been achieved and the database has been locked for the 
primary efficacy analysis, participants will be unblinded to determine eligibility for 
subsequent vaccination with 9vHPV vaccine in the extension study. 
The participants’ vaccination group assignment in the base study will be communicated to 
the investigator by the Sponsor for the purpose of determining participant eligibility for 
receiving 9vHPV vaccine in the extension study. The investigator will be responsible for 
notifying each participant regarding his original vaccination group assignment and 
determining who is eligible to participate in the extension study. In the event that this 
communication results in the return of a participant who did not complete the base study (eg, 
lost to follow-up), this participant may be offered vaccine.
Eligible participants will be reconsented for the extension study and follow the procedures 
outlined in Section 1.3.2 and Section 1.3.3. If possible, it is recommended that the first 
vaccination in the extension study is administered on the same day as the Final Visit of the 
base study. Participants in the placebo group will receive a 3-dose series with the 9vHPV 
vaccine as allowed by local regulations and IRBs. Participants in the active group who did 
not complete the 3-dose series in the base study will be eligible to receive 1 to 2 doses in the 
extension study depending on the doses they had completed. SAEs and deaths will be 
collected throughout the extension study. Safety data from the extension study will be 
summarized in a separate report.
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Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is designed to evaluate the 9vHPV vaccine efficacy against HPV 6/11/16/18-
related anogenital persistent infection and HPV 31/33/45/52/58-related anogenital persistent 
infection, respectively. The qHPV vaccine efficacy findings associated with the 4 HPV types 
in V501-020 will be extrapolated to the 9vHPV vaccine, via the demonstration of the 
efficacy similarities against HPV type 6, 11, 16 or 18-related anogenital persistent infection 
in V501-122 with qHPV vaccine. Considering the comparison between this study data and 
previous study data (V501-122), 16 to 26 years old in both HM and MSM are selected as this 
study population in a manner consistent with Protocol V501-122. The enrollment of 
approximately 10% MSM participant will be targeted in this study. Please note “10%” is a 
target number considering the challenging nature of MSM enrollment in Japan from 
operational aspect. In addition, participants will be enrolled regardless of the history of 
circumcision. This study targeted young males with a maximum of 5 female (HM) and/or 
male (MSM) sexual partners in order to minimize the proportion of enrolled subjects who
were HPV positive at baseline. In addition, in order to obtain a cohort with a reasonable risk 
of becoming infected after the vaccination series was completed, virgins were excluded from 
the study, with the exception of MSMs who identified themselves as a male who has had sex 
with males or must have engaged in oral sex with another male within the last year.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Efficacy endpoints based on precancerous lesions (high-grade intraepithelial dysplasia) were 
used in clinical studies with the qHPV and the 9vHPV vaccines to demonstrate protection 
from cervical, vulvar, vaginal, and anal cancers and precancers caused by vaccine HPV 
types. Results from efficacy clinical trials of the qHPV vaccine have shown that participants 
with HPV 16/18-related persistent infection were at a greater risk of HPV 16/18-related high-
grade cervical dysplasia. In contrast, participants without persistent infection were unlikely to 
develop HPV 16/18-related high-grade cervical disease [Radley, D., et al 2016]. Similar 
results were observed in the pivotal study of the 9vHPV vaccine (Protocol V503-001) for the 
endpoints of HPV 31/33/45/52/58-related persistent infection and HPV 31/33/45/52/58-
related high-grade disease (MSD unpublished data). This suggests that HPV 
16/18/31/33/45/52/58-related persistent infection is appropriate as a surrogate endpoint for 
HPV 16/18/31/33/45/52/58-related high-grade cervical disease. Although HPV infection has 
been primarily studied in the context of cervical cancer, the results are considered applicable 
to other squamous epithelial cancers (including cancers of vulva, vagina, anal canal, oral 
cavity, pharynx, and larynx), that are susceptible to infection by high-risk HPV types 
[Gillison, M.L., et al 2012].
The primary efficacy endpoint is the incidence of HPV 6-, 11-, 16- or 18-related anogenital 
persistent infection. This endpoint was chosen based on the finding from two previous 
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studies of qHPV vaccine. One is the Japanese Phase 3 study that demonstrated the efficacy of 
qHPV vaccine against HPV 6-, 11-, 16- or 18-related anogenital persistent infection in 
Japanese males (Protocol V501-122). The other is the previous global Phase 3 study (V501-
020) that qHPV vaccine showed prophylactic efficacy against HPV 6-, 11-, 16- or 18-related 
AIN and genital warts as well as HPV 6-, 11-, 16- or 18-related persistent infection in 16- to 
26-year-old males, suggesting HPV related anogenital persistent infection is a predictor of 
HPV related anogenital diseases in males. For the purpose of bridging qHPV vaccine 
efficacy against HPV 6-, 11-, 16- or 18-related AIN and genital warts to 16- to 26-year-old 
Japanese males who received the 9vHPV vaccine, the incidence of HPV 6-, 11-, 16- or 18-
related anogenital persistent infection was selected as the primary efficacy endpoint in this 
study as well as in V501-122. 
As the secondary endpoint, the incidence of the other 5 types of HPV (31-, 33-, 45-, 52- or 
58)-related anogenital persistent infection will also be assessed similarity with the 9vHPV 
vaccine efficacy finding associated with the 5 HPV types in V503-001 that was global Phase 
3 study in 16- to 26-year-old females including Japanese females.
4.2.1.2
Immunogenicity Endpoints
Humoral immune responses to HPV vaccination will be evaluated based on previously 
established methods including MSD’s Competitive Luminex Immunoassay (cLIA) as the 
primary immunoassay [Roberts, C., et al 2014]. The assay has been used in previous clinical 
studies within the 9vHPV vaccine program. Details on the immunogenicity endpoints 
evaluated in this study can be found in Section 8.3 and Section 9.4.2.
4.2.1.3
Safety Endpoints
Safety assessments in this study are consistent with those used in previous studies of the 
9vHPV vaccine and qHPV vaccine. In the base study, the paper vaccination report card 
(VRC) will be used to record AEs during the postvaccination periods. Details for the VRC 
are provided in Section 8.4.4.
Details on the safety endpoints evaluated in this study can be found in Section 8.4 and 
Section 9.4.3. 
Details on AEs, including definitions and reporting requirements, can be found in Appendix 
3.
4.2.1.4
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
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more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
In Japan at the start of the study, qHPV vaccine has been approved and marketed under the 
name of GARDASIL® only for females 9 years of age or older. As there is no active 
comparator for this male study in Japan, placebo (saline solution) will be included to 
demonstrate the vaccine efficacy and to compare the safety profile of the 9vHPV vaccine in 
the base study. Participants randomized in the placebo arm will receive placebo in the base 
study and those who are eligible will be offered a 3-dose series of 9vHPV vaccine in the 
extension study.
4.3
Justification for Dose
The 0.5 mL dose administered as a 3-dose regimen (Day 1, Month 2, Month 6) is based on 
the global efficacy, immunogenicity, and safety clinical studies that supported the licensure 
of the 9vHPV vaccine and is consistent with the approved dosing and product labeling of the 
9vHPV vaccine (SILGARD®9 in Japan, GARDASIL®9 in USA, EU, and other countries).
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). 
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory test result or at the time of final contact with the last participant, whichever 
comes last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Healthy male participants between the ages of 16 and 26 years (inclusive) will be enrolled in 
this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
The history of medical conditions will be based on the self-report or medical chart provided 
by participant. For item with an asterisk (*), if the inclusion criterion is not met, then the Day 
1 visit may be rescheduled for a time when the criterion is met.
5.1.1
Base Study
Type of Participant and Disease Characteristics
1. Is healthy and is judged to be in good physical health based on medical history and 
physical examination.
Demographics
2. Is Japanese male, from 16 years to 26 years of age inclusive, at the time of signing the 
informed consent.
Informed Consent
3. Provides written informed consent/assent for the study by the participant [or, for minor 
participants, if applicable, the parent/legal guardian (legally acceptable representative) 
and the participant]. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Categories
4. Agrees to provide study personnel at the study site with a primary telephone number as 
well as an alternate means of contact, if available (such as an alternate telephone number, 
SNS or e-mail) for follow-up purposes.
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5. Can read, understand, and complete the VRC.
6. *Agrees to refrain from sexual activity (including vaginal and anal penetration and any 
genital contact) for 48 hours prior to any scheduled visit that includes sample collection, 
to avoid detection of viral DNA which has been deposited in the male genital area during 
sexual intercourse and is not the result of ongoing infection.
7. a) For HM: Participants must be a heterosexual male, who has had exclusively female 
sexual partners, and has 1 to 5 lifetime female sexual partners at the time of enrollment.
b) For MSM: Participants must identify themselves as a male who has sex with males, 
must have engaged in either insertive or receptive anal intercourse or oral sex with 
another male sexual partner within the last year, and have 0 to 5 lifetime male and/or 
female sexual partners at the time of enrollment. 
For protocol purposes, a female sexual partner is defined as a female with whom the 
participant has engaged in vaginal intercourse. For protocol purposes, a male sexual 
partner is defined as a male with whom the participant has engaged in insertive or 
receptive anal intercourse.
5.1.2
Extension Study
After initial database lock and unblinding a participant’s vaccination group assignment in the 
base study, the participant will be eligible for inclusion in the extension study if the 
participant still meets Inclusion Criteria #1 and #4, and:
8. Was in the placebo group during the base study; or was in the 9vHPV vaccine group and 
did not complete the vaccination series in the base study.
9. Provides documented informed consent for the extension study.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
The history of medical conditions will be based on the self-report or medical chart provided 
by participant. For items with an asterisk (*), if the exclusion criterion is met, then the Day 1 
visit (or Extension Visit 1) may be rescheduled for a time when the criterion is not met.
5.2.1
Base Study
Medical Conditions
1. Has a history of HPV-related anal lesion (anal intraepithelial neoplasia, anal condyloma 
or anal cancer) or HPV-related head and neck cancer.
2. Has a history of or clinical evidence at the Day 1 external genital examination of HPV-
related external lesion (genital warts, penile/perianal/perineal intraepithelial neoplasia, or 
penile cancer).
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3. Has clinical evidence at the Day 1 external genital examination of gross genital lesion 
suggesting sexually transmitted disease.
4. *Has a fever (defined as oral temperature ≥37.5°C) within the 24-hour period prior to the 
Day 1 visit
5. Has a history of severe allergic reaction (e.g., swelling of the mouth and throat, difficulty 
breathing, hypotension, or shock) that required medical intervention.
6. Is allergic to any vaccine component, including aluminum, yeast, or BENZONASE™
(nuclease, Nycomed [used to remove residual nucleic acids from this and other 
vaccines]). For this exclusion criterion, an allergy to vaccine components is defined as an 
allergic reaction that met the criteria for severe AEs or SAEs defined in Appendix 3.
7. Has known thrombocytopenia or any coagulation disorder that would contraindicate 
intramuscular injections.
8. Is currently immunocompromised or has been diagnosed as having a congenital or 
acquired immunodeficiency, HIV infection, lymphoma, leukemia, systemic lupus 
erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel 
disease, or other auto immune condition.
9. Has a history of splenectomy.
10. Has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance that might confound the results of the study, or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate by judgement of investigator.
11. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history (within the 12 months) of drug or alcohol abuse or dependence at the 
discretion of the investigator. Alcohol abusers are defined as those who drink despite 
recurrent social, interpersonal, and/or legal problems because of alcohol use.
Prior/Concomitant Therapy
12. Has received within 12 months prior to enrollment, is receiving, or plans to receive 
during Day 1 through Month 7 of the study, the following immunosuppressive therapies: 
radiation therapy, cyclophosphamide, azathioprine, methotrexate, any chemotherapy, 
cyclosporin, leflunomide, TNF-α antagonists, monoclonal antibody therapies (including 
rituximab), intravenous gamma globulin (IVIG), antilymphocyte sera, or other therapy 
known to interfere with the immune response. Regarding systemic corticosteroids, a 
participant will be excluded if he is currently receiving steroid therapy, has recently 
(defined as within 2 weeks of Day 1 vaccination) received such therapy, or has received 2 
or more courses of high-dose corticosteroids (≥20 mg/day of prednisone orally or 
parenterally) lasting at least 1 week in duration in the year prior to Day 1 vaccination. 
Participants using inhaled, nasal, or topical steroids are considered eligible for the study.
13. Has received within the 3 months prior to the Day 1 vaccination, is receiving, or plans to 
receive during Day 1 through Month 7 of the study, any immune globulin product 
(including Rho(D) human immune globulin [Benesis™]) or blood-derived product other 
than IVIG.
14. *Has received inactivated or recombinant vaccines within 14 days prior to Day 1 
vaccination or receipt of live vaccines within 28 days prior to Day 1 vaccination.
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15. Has previously received a marketed HPV vaccine, or has participated in a clinical trial for 
any HPV vaccine (receiving either active agent or placebo).
Prior/Concurrent Clinical Study Experience
16. Is concurrently enrolled in other clinical studies of investigational agents or studies 
involving collection of genital specimens.
Diagnostic Assessments
None.
Other Exclusions
17. *Has engaged in sexual activity within 48 hours prior to Day 1 (this may result in the 
detection of viral DNA that has been deposited in the male genital area during sexual 
intercourse and is not the result of ongoing infection).
Sexual activity is defined as:
•
Penile penetrative vaginal intercourse with female partner
•
Penile penetrative or receptive anal intercourse with male or female partner
•
Any oral/genital contact, or genital/genital contact
18. *Has shaved their genital region and/or applied any post-shave lotion or lubricants within 
24 hours prior to the visit.
19. Is unlikely to adhere to the study procedures, keep appointments, or is planning to 
permanently relocate from the area prior to the completion of the study or to leave for an 
extended period when study visits would need to be scheduled.
20. 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.
5.2.2
Extension Study
The participant must be excluded from the extension study if the participant meets Exclusion 
Criteria #4*, #5, #6, #7, #10, #16, or #19.
5.3
Lifestyle Considerations
5.3.1
Activity Restrictions
Participants will refrain from sexual activity (including vaginal and anal penetration and any 
genital contact, stated in 5.2 Exclusion Criteria) for 48 hours prior to any scheduled visit that 
includes efficacy sample collection.
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study vaccination OR withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm 
Type
Interventi
on Name
Interventi
on Type
Dose 
Formul
ation
Unit Dose Strength(s) Dosage 
Level(s)
Route of 
Adminis
tration
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
The 
9vHPV 
vaccine
Experim
ental
V503
(9vHPV 
vaccine)
Biological
/Vaccine
Suspensi
on
HPV
6/11/16/18/31/33/45/5
2/58 L1 VLP:
30/40/60/40/20/20/20/
20/20 mcg per dose
0.5 mL
IM
Day 1, Month 2, 
Month 6
Test 
Product
IMP
Provided 
centrally by 
Sponsor
Placebo
Placebo 
Compara
tor
Saline for 
injection
Biological
/Vaccine
Solution
0.9% sodium chloride
0.5 mL
IM
Day 1, Month 2, 
Month 6
Placebo
IMP
Provided 
Centrally by 
Sponsor
The 
9vHPV 
vaccine 
(Extension 
Study)
Experim
ental
V503 
(9vHPV 
vaccine)
Biological
/Vaccine
Suspensi
on
HPV 
6/11/16/18/31/33/ 
45/52/58 L1 VLP: 
30/40/60/40/20/20/ 
20/20/20 mcg per dose
0.5 mL
IM
1 dose in Ext:
Ext 1
OR
2 doses in Ext:
Ext 1 and Month 
4 in Ext
Test 
Product
IMP
Provided 
Centrally by 
Sponsor
Placebo
(Extension 
Study)
Experim
ental
V503 
(9vHPV 
vaccine)
Biological
/Vaccine
Suspensi
on
HPV 
6/11/16/18/31/33/ 
45/52/58 L1 VLP: 
30/40/60/40/20/20/ 
20/20/20 mcg per dose
0.5 mL
IM
Ext 1, Month 2 in 
Ext, Month 6 in 
Ext
Test 
Product
IMP
Provided 
Centrally by 
Sponsor
9vHPV = 9-valent human papillomavirus; AXMP = Auxiliary Medicinal Product; HPV = human papillomavirus; IM = Intramuscular; VLP = virus-like particle.
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In 
these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
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 8.1.9 for details regarding administration of the study intervention.
6.1.1
Drug Device Combination Product/Combination Medicinal Product
In the extension study, combination medicinal product(s) (MSD marketed/MSD investigation 
medicinal product and medical device or non-MSD marketed/non-MSD investigational 
product and medical device) provided for use in this study are GARDASIL®9 syringes. Refer 
to Appendix 4 for instruction on reporting events associated with these combination 
medicinal products.
Instructions for combination medicinal product use are provided separately.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3. Information on preparation and administration of study vaccine and placebo is 
provided in Section 6.3.3 and Section 8.1.9.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization of the base study will occur centrally using an IRT system. There 
are 2 study intervention arms. Participants will be assigned randomly in a 1:1 ratio to receive 
the 9vHPV vaccine or placebo.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. HM or MSM
Even though randomization will be stratified by HM and MSM, the test of the primary and 
secondary efficacy hypotheses will not be stratified by HM and MSM. Stratification is 
intended to support immunogenicity analysis within HM and MSM, to avoid unbalanced 
allocation between the vaccination groups particularly in the MSM cohort.
6.3.3
Blinding
In the base study, a double-blinding technique will be used. the 9vHPV vaccine (V503) and 
placebo will be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or 
qualified study-site personnel. The participant, the investigator, and Sponsor personnel or 
delegate(s) who are involved in clinical evaluation of the participants are unaware of the 
intervention assignments.
After accrual of at least 17 primary endpoint cases and at least 17 secondary efficacy 
endpoint cases in the base study have been achieved and the database has been locked for the 
primary efficacy analysis, vaccination assignment will be unblinded for all participants. The 
participants’ vaccination group assignment in the base study will be communicated to the 
investigator by the Sponsor for the purpose of determining participant eligibility for receiving 
9vHPV vaccine in the extension study. By receiving the vaccination allocation for the 
participants, the relevant investigator, study-site personnel, and the participant will be 
unblinded to study vaccination assignment. After this point of time, only the central 
laboratory personnel and the pathology panel will remain blinded to the primary vaccination 
group assignment. 
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study should such action be warranted.
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In the extension study, administration of the 9vHPV vaccine will be conducted as open label; 
therefore, the Sponsor, investigator, and participant will know the vaccine administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan specified 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
In the base study, medications or vaccinations specifically prohibited in the exclusion criteria 
are not allowed during time periods specified by this protocol for that medication or 
vaccination (Section 5.2). If there is a clinical indication for any medications or vaccinations 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
Listed below are specific restrictions for concomitant therapy or vaccination during the base 
study:
•
See the exclusion criteria for specific restriction for prior and concomitant medications at 
Day 1 (Section 5.2) and prerequisites for other vaccination visits (Section 8.12.1.2).
•
If possible, participants should not receive “Special medications” (corticosteroids, 
immunosuppressive therapies, immune globulin products, and blood-derived products) 
from Day 1 through Month 7, non-study inactivated or recombinant vaccines from 14 
days prior to each study vaccination through 14 days after each study vaccination, or non-
study live vaccines from 28 days prior to each study vaccination through 14 days after 
each study vaccination.
•
“Non-study HPV vaccine” must not be used at any time during the study.
•
Participants may receive allergen desensitization therapy and tuberculin skin testing 
while participating in the base study.
Use of prior and concomitant medications/vaccination should be recorded for the base study 
as described in Section 8.1.6.
In the extension study, dosage or interval of vaccinations for concomitant therapy or other 
vaccination will not be specified, but will be in accordance with the local approved label for 
each drug or vaccine and judgement by the investigators.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
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6.6
Dose Modification
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study. After the base study is 
completed, recipients of placebo and participants who did not complete their 3-dose series of 
9vHPV vaccine in the base study will be offered vaccination with the 9vHPV vaccine in the 
extension study as allowed by local regulations and IRBs.
6.8
Clinical Supplies Disclosure
The base 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 8.1.11). The 
Sponsor will not provide random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified vaccination 
regimen will continue to participate in the study as specified in Section 1.3 and Section 
8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10 and Section 
8.12.3.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, see Section 1.3 and Section 8.12.3 for those procedures to be completed at each 
specified visit.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.10. The procedures to be performed should a participant repeatedly fail to return 
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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 (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The total volume of blood collected for immunogenicity testing and blood (DNA) for 
future biomedical research is outlined in Table 2. The maximum amount of blood 
collected from each participant over the duration of the study will not exceed 
approximately 38.5 mL.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
Table 2
Blood Collection Volumes
Day 1
Month 7
Month 36 (or Final Visit)
Anti-HPV Immunogenicity Testing
10 mL
10 mL
10 mL
Blood (DNA) for Future 
Biomedical Research
8.5 mL
-
-
Total Volume
18.5 mL
10 mL
10 mL
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
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.
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator. At Visit 1 (Day 1) in the base study, 
the participant’s lifetime medical history of genitourinary or HPV-related diagnoses will be 
collected. Other medical history for the year prior to Visit 1 will be collected. 
After the Day 1 visit, any new medical history that has not been previously documented (ie, 
incident medical conditions occurring outside of Days 1 to Days 15 period postvaccination 
and not considered SAEs) will be collected throughout the base study. In the extension study, 
any new medical history will not be collected.
8.1.5
Sexual History, Demographics, Substance Use
A sexual history will be obtained by the investigator or qualified designee. At Visit 1 (Day 
1), the participant’s lifetime number of female and/or male sexual partners and age of first 
sexual intercourse will be collected. After Visit 1, the participant’s sexual activity including 
the number of new females and/or males with which the participant engaged in sexual 
intercourse (for females, insertive vaginal intercourse; for males insertive or receptive anal 
intercourse) will be collected throughout the base study. In the extension study, any sexual 
activity will not be collected.
Other documentation, such as lifetime sexual history, demographics, and substance use 
(alcohol and tobacco) will be collected in the data collection system, as discussed in the 
electronic Case Report Form (eCRF) entry guidelines.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medications or vaccinations on Day 1 
of the base study. A participant receiving any of the prior medications or vaccinations 
prohibited in the exclusion criteria (Section 5.2) should not be enrolled into the study. During 
the base study, prior and concomitant medicines or vaccinations should be documented in the 
data collection system per the following timeframe.
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
“Special medications” (corticosteroids, immunosuppressive therapies as defined in 
the exclusion criteria, immune globulin products, and blood-derived products) from 3 
days prior to Day 1 through Month 7.

“Other medications” from 3 days prior to each study vaccination through 14 days 
after each study vaccination.

“Non-study inactivated or recombinant vaccines” from 14 days prior to each study 
vaccination through 14 days after each study vaccination.

“Non-study live vaccines” from 28 days prior to each study vaccination through 14 
days after each study vaccination.

“Non-study HPV vaccine” must not be used at any time during the study. However, 
for the specific case where a participant mistakenly receives any non-study HPV 
vaccines, the non-study HPV vaccine must be reported on the appropriate eCRF, 
regardless of when the non-study vaccine was received during the study.
8.1.6.2
Concomitant Medications
During the base study, the investigator or qualified designee will record medication, if any, 
taken by the participant during the study time frames specified in Section 8.1.6.1. The non-
study HPV vaccine must be recorded in the extension study, if used.
Participants may receive allergen desensitization therapy and tuberculin skin testing while 
participating in the base study.
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any individual 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 in Section 8.12.1.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
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8.1.9
Study Intervention Administration
8.1.9.1
Study Intervention Administration in Base Study
Study vaccine should be prepared and administered by the Unblinded Study Personnel who 
are not involved in clinical evaluation of the participants.
Preparation of Study Vaccine/Placebo by Unblinded Study Personnel
The study vaccine and placebo must be stored at 2.0°C to 8.0°C. Do NOT freeze the study 
vaccine/placebo. Protect the study vaccine/placebo from light. The study vaccine must be 
used as supplied (no dilution before administration). The vaccine vial should be thoroughly 
mixed before administration by gently rolling the vial between the palms of both hands for 
30 seconds before withdrawing the 0.5 ml dose of vaccine from the single-dose vial using a 
sterile needle and syringe. The study vaccine should be a whitish, semi-translucent 
suspension when thoroughly mixed. The normal saline placebo should be a clear, 
colorless liquid. If the appearance of vaccine or placebo is otherwise, do not administer, and 
contact the Sponsor immediately.
The Unblinded Study Personnel will wrap the prepared syringe with the nontransparent label 
provided by the Sponsor to mask the difference in appearance between vaccine and placebo. 
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].
Study Vaccine Administration by Unblinded Personnel
Study vaccines should be administered by the designated unblinded physician at Day 1, 
Month 2, and Month 6. At each vaccination visit, participants will receive the 9vHPV 
vaccine or placebo as a 0.5 mL intramuscular injection. The deltoid muscle of the 
nondominant arm is the preferred site of vaccination. Study vaccinations should not be 
administered in the buttocks area. Injections should not be given within 2 cm of a tattoo, scar, 
or skin deformation.
Injections should be administered at a 90° angle into the muscle tissue using a needle long 
enough to ensure intramuscular deposition of study vaccine. The study vaccine should be 
administered in the deltoid muscle using preferably a 1.0 mL syringe (the largest allowable 
size is a 3.0 mL syringe) with the following needle length and gauge specifications:
•
1-inch needle, 22 to 23 gauge for participants weighing <200 pounds (<90.9 kg)
•
1½-inch needle, 22 to 23 gauge for participants weighing ≥200 pounds (≥90.9 kg)
•
1½ -inch needle, 22 to 23 gauge for thigh injections
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Observing Participants After Vaccination by Blinded Personnel
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 participants will be observed by Blinded Study Personnel for at 
least 30 minutes after each study vaccination for any untoward effects, including allergic 
reactions. This observation period will be documented in the participant’s study chart.
All safety, efficacy, and immunogenicity assessments will be conducted by blinded 
personnel, and the participant will be blinded to the study vaccine received. Vaccination 
information, such as Component Identification Number and time of vaccination, must be 
recorded on the appropriate eCRF as per the Data Entry Guidelines.
8.1.9.2
Study Intervention Administration in Extension Study
In the extension study, preparation and administration of the 9vHPV vaccine will be 
conducted as open label. Study vaccine should be prepared and administered by 
appropriately qualified members of the Study Personnel. 
Preparation of Study Vaccine
The study vaccine must be stored at 2.0°C to 8.0°C. Do NOT freeze the study vaccine. 
Protect the study vaccine from light. The study vaccine must be used as supplied (no dilution 
before administration). 
The study vaccine will be supplied as a prefilled syringe. The syringe should be shaken 
before use. 
Attach the appropriate needle (as recommended by the product label) by twisting in a 
clockwise direction until the needle fits securely on the syringe. The followings are needle 
length and gauge specifications:
•
1-inch needle, 22 to 23 gauge for participants weighing <200 pounds (<90.9 kg)
•
1½-inch needle, 22 to 23 gauge for participants weighing ≥200 pounds (≥90.9 kg)
•
1½ -inch needle, 22 to 23 gauge for thigh injections
Administer the entire dose as an intramuscular injection per standard protocol.
The study vaccine should be a whitish, semi-translucent suspension when thoroughly 
mixed. If the appearance of vaccine is otherwise, do not administer, and contact the Sponsor 
immediately.
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].
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Study Vaccine Administration
At each vaccination visit in the extension study, participants will receive 9vHPV vaccine as a 
0.5 mL intramuscular injection as specified in Section 1.3.2 and Section 1.3.3. The first 
vaccination in the extension study is recommended to occur the same day as the Final Visit 
of the base study, if possible. The deltoid muscle of the nondominant arm is the preferred site 
of vaccination. Study vaccinations should not be administered in the buttocks area.
Injections should be administered at a 90° angle into the muscle tissue using a needle long 
enough to ensure intramuscular deposition of study vaccine. The study vaccine should be 
administered in the deltoid muscle.
Observing Participants After Vaccination
All participants will be observed by Study Personnel for at least 30 minutes after each study 
vaccination for any untoward effects, including allergic reactions. This observation period 
will be documented in the participant’s study chart.
Vaccination information, such as Component Identification Number and time of vaccination, 
must be recorded on the appropriate eCRF as per the Data Entry Guidelines.
8.1.9.3
Timing of Dose Administration
In the base study, the first dose of study vaccine or placebo will be administered at Day 1, 
which should be the day of randomization. The second and third (final) doses of study 
vaccine or placebo will be administered at Month 2 (± 3 weeks) and Month 6 (± 4 weeks), 
respectively (Section 1.3).
In the extension study, the 3 doses of the 9vHPV vaccine will be administered at the first 
visit of the extension study (Extension Visit 1) and at 2 months and 6 months after Extension 
Visit 1 for the participants in the placebo group (Section 1.3.2). For the participants who did 
not complete the 3-dose regimen of 9vHPV vaccine in the base study, the remaining doses 
from the series (i.e., if they already received 2 doses in the base study, they will receive 1 
dose in the extension study; if they already received 1 dose in base study, they will receive 2 
doses which are 4 months apart in the extension study) will be provided (Section 1.3.3).
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the 3-dose of 
vaccination regimen should be encouraged to continue to be followed for all remaining study 
visits as outlined in the SoA and Section 8.12.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the next study visit (exception: serum sample collection should not be 
performed unless the participant has received all 3 scheduled doses of the study vaccine) 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.
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8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.11
Participant Blinding/Unblinding
The base study is blinded. Participants will be unblinded after the primary efficacy analysis 
database lock to determine eligibility for participation in the extension study.
The following is applicable for the base study:
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
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Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
The Sponsor will remain blinded to participant vaccination allocations until the required 
number of cases of the primary and the secondary efficacy endpoint have been observed and 
the database is unblinded for the primary analyses of efficacy.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
The extension study is unblinded. Participants will be unblinded throughout the extension 
study.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.13
Optional Testing for Sexually Transmitted Infections
Local laboratory testing for sexually transmitted infections (STIs) including chlamydia, 
gonorrhea, herpes simplex virus (HSV), syphilis, hepatitis B, and HIV may be performed at 
any visit during the base study at the discretion of the investigator if clinically indicated. 
Abnormal results should be captured as New Medical History at the next visit. In addition, 
per the exclusion criteria for this study, known HIV-positive participants should not be 
enrolled in the study. 
Any participant who tests positive for an STI during the study will not be discontinued from 
the trial and may participate in all study procedures. These participants will be referred for 
appropriate counseling and treatment outside of the context of the protocol.
8.1.14
Sexual Activity
At every scheduled visit from Visit 2 through the Final Visit in the base study, participants 
will be asked questions regarding sexual activity since last visit. Details such as the date of 
last sexual intercourse, number of new sexual partners and total number of sexual partners, 
etc. will be recorded in the appropriate eCRF. 
Sexual activity of participant is defined as:
•
Penile penetrative vaginal intercourse with female partner
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•
Penile penetrative or receptive anal intercourse with male or female partner
•
Any oral/genital contact, or genital/genital contact
If a participant has engaged in sexual activity 48 hours prior to visit that includes efficacy
sample collection, then the visit will be rescheduled to a later time when this criterion is not 
met. See Section 8.12.1.3 for prerequisites for sample collection. Sexual activity will not be 
collected after participants are unblinded.
8.2
Genital Examination and Efficacy Assessments (Base Study)
8.2.1
Anogenital Physical Examination
An anogenital physical examination will be performed on Day 1 of the base study prior to the 
external genital lesion examination. A physical examination details will be documented in 
the participant’s chart and any medical conditions including will be documented in the data 
collection system. If a lesion observed at Day 1 meets the exclusion criterion 1, then the 
participant should be excluded from the study.
8.2.2
External Genital Examination
In the base study, the external genital lesion examination should be completed prior to 
external genital swab collection, and prior to vaccination on Day 1. If a lesion observed at 
Day 1 meets the exclusion criteria 2 or 3, then the participant should be excluded from the 
study.
Equipment
The minimal equipment needed to perform the genital lesion inspection includes:
•
Good light source
•
Magnifying apparatus (hand-held magnifying glass of 4x to 5x power)
•
Nonsterile gloves
•
Optional: colposcope at low power magnification (2x to 4x)
8.2.2.1
Procedure for Penile and Scrotal Examination
1.
The participant should be lying supine on the examination table.
2.
The examiner should inquire as to whether the participant has shaved their genital region 
and/or applied any post-shave lotion or lubricants within 24 hours prior to the visit.
3.
The examiner should inquire as to whether the participant has noticed any bumps or 
lesions or unusual symptoms (eg, itching, dyspareunia, or dysuria). Begin with the 
inspection of the penile shaft, glans penis and urethral meatus, noting and recording 
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evidence of abnormalities, including any abnormalities of the skin, rashes, minor 
lacerations, or bruises, etc.
4.
The entire penis is to be palpated, region by region, for apparent cutaneous and 
subcutaneous lesions or wart-like growths.
5.
After completing the inspection of the penis, continue with a careful examination is to be 
performed of the scrotum. The testes should be palpated for asymmetry and/or palpable 
lesions.
6.
The examination is to be performed using the hand-held magnifying glass and/or 
colposcope and should include the penile shaft, glans penis, and urethral meatus, and 
scrotum.
7.
At the investigator’s discretion, low power magnification with the colposcope may be 
used for better visualization of an identified lesion.
8.
Acetic acid is not be used routinely. It may be used for confirmation of a suspected 
lesion.
8.2.2.2
Procedure for Perineal/Perianal Examination
1.
The participant should lie on his left lateral side with his knees tucked up toward his 
chest or the prone knee-chest position that allows comfortable access for examination.
2.
The examiner should inquire as to whether the participant has noticed any bumps or 
lesions or unusual symptoms (eg, itching, dyspareunia).
3.
Inspect the anus, perianal and perineal areas for the presence of anogenital warts.
4.
The perianal and perineal regions are to be palpated, for apparent cutaneous and 
subcutaneous lesions or wart-like growths.
5.
The examiner should spread the contiguous skin using his/her thumbs and note the 
condition of the anus.
6.
The examination is to be performed using the hand-held magnifying glass and/or 
colposcope and should include the perianal and anal region.
7.
At the investigator’s discretion, low power magnification with the colposcope may be 
used for better visualization of an identified lesion.
8.
Acetic acid is not be used routinely. It may be used for confirmation of a suspected 
lesion.
8.2.3
Efficacy Assessments
In the base study, penile/glans penis, scrotal, perineal/perianal, and intra-anal swabs will be 
tested for detection of HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 by 
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PCR assay. PCR analysis of the swabs will be used to determine persistent HPV infection 
endpoints.
In addition, all new (after Day 1) genitourinary and perianal lesions judged by the 
investigator to be possibly, probably, or definitely HPV-related, or any lesion whose etiology 
is not known will be biopsied. Tissue samples obtained from biopsy will be analyzed by HPV 
Thinsection PCR assay (detection of HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 
58, and 59) and by a consensus diagnosis from the HPV Vaccine Program Pathology Panel to 
determine clinical disease efficacy endpoints.
Once a participant is unblinded, no further efficacy samples should be collected from the 
participant.
8.2.3.1
Collection of Swabs for HPV PCR
After the completion of external genital lesion examination, one penile/glans swab, one 
scrotal swab, one perineal/perianal swab, and one intra-anal swab will be collected.
Specimen collection supplies provided by the Sponsor/Central Laboratory must be used. 
Details regarding sample handling are provided in the laboratory manual.
8.2.3.1.1
Penile/Glans Penis File and Wetted Swab for HPV PCR
1.
The participant should be lying supine on the examination table. In order to prepare the 
participant for the specimen collection with nail file, the examiner should demonstrate a 
nail file (not kept in sterile condition) prior to the procedure and ask the participant to 
rub it on his hands.
2.
Remove the nail file from the packaging; remove the swab from the packaging, then 
twist the top off of the sterile saline ampule and wet the entire head of the swab with the 
sterile saline, but do not over moisten. If necessary, squeeze the head of the swab to 
remove excess liquid (while maintaining sterility), as too much liquid may wash cells off 
the skin instead of collecting them on the swab. If the swab is dripping saline, it is too 
wet. Only one file and one swab are to be used in the penile sampling.
3.
In circumcised men, the examiner wearing gloves should hold the tip of the penis with 
the thumb and index finger of the non-dominant hand. The file should be held in the 
dominant hand and in a tight up and down motion (or back and forth motion), gently 
move the file over the left and right side of the penile shaft, encompassing the whole 
shaft, and then gently rub the glans. Sufficient pressure should be applied in order to 
cause blanching of the skin. If blanching is not observed, pressure should be increased in 
order to collect the required DNA. Subsequently, the examiner should hold the swab in 
the dominant hand and in a tight up and down motion, gently swab the shaft and glans 
following the same route. As with the file, sufficient pressure should be used with the 
swab to blanch the skin while moving it over the area of loosened cellular debris. The 
swab should also be twisted or rotated in order to increase surface area exposure for 
collection of cellular debris.
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4.
In uncircumcised men, the examiner wearing gloves should hold the tip of the penis with 
the thumb and index finger of the non-dominant hand. The file should be held in the 
dominant hand and in a tight up and down motion (or back and forth motion), gently 
move the file over the left and right side of the penile shaft, including the outer foreskin. 
The examiner should retract the foreskin and hold the penis with the thumb and the index 
finger, and gently rub the file over the glans. Sufficient pressure should be applied in 
order to cause blanching of the skin. If blanching is not observed, pressure should be 
increased in order to collect the required DNA. Then follow with a wetted swab and rub 
the penile shaft, the outer foreskin, and then retract the foreskin, and swab the glans, 
following the same route as the file. As with the file, sufficient pressure should be used 
with the swab to blanch the skin while moving it over the area of loosened cellular 
debris. The swab should also be twisted or rotated in order to increase surface area 
exposure for collection of cellular debris.
5.
Discard the file in a Biohazard Sharps container.
6.
Place the swab in an STM vial and break the pre-scored handle. Do not add saline to the 
STM vial either before or after swabbing.
7.
Securely cap the collection/transport tube containing the specimen.
8.
Place the appropriate label for the Penile Sample on the STM vial.
8.2.3.1.2
Scrotal File and Wetted Swab for HPV PCR
1.
The participant should be lying supine on the examination table. As same as the 
penile/glans penis sampling, remove the nail file from the packaging; remove the swab 
from the packaging, then twist the top off of the sterile saline ampule and wet the entire 
head of the swab with the sterile saline. Only one file and one swab are to be used in the 
scrotal sampling.
2.
With the non-dominant hand, lift and move the penis off of the scrotum, and gently rub 
the file over the entire scrotum with a tight up and down motion (or back and forth 
motion), moving from left to right. Sufficient pressure should be applied in order to 
cause blanching of the skin. If blanching is not observed, pressure should be increased in 
order to collect the required DNA. It is important to stretch or pull the skin taut in order 
to allow enough pressure to be applied by the nail file. If necessary, the participant can 
assist with this activity by holding the skin at the bottom of the scrotum while the file 
(and subsequently the wetted swab) is moved across the area. The participant should not 
perform the filing or swabbing procedure.
3.
Subsequently, with the non-dominant hand, lift the penis, and gently rub the wetted swab 
over the entire scrotum with a tight up and down motion, moving from left to right. As 
with the file, sufficient pressure should be used with the swab to blanch the skin while 
also be twisted or rotated in order to increase surface area exposure for collection of 
cellular debris. Only one file and one swab are to be used in the scrotal sampling.
4.
Discard the file in a Biohazard Sharps container.
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5.
Place the swab in an STM vial and break the pre-scored handle. Do not add saline to the 
STM vial either before or after swabbing.
6.
Securely cap the collection/transport tube containing the specimen.
7.
Place the appropriate label for the Scrotal Sample on the STM vial.
8.2.3.1.3
Perineal/Perianal File and Wetted Swab for HPV PCR
1.
The participant should lie on his left lateral side with his knees tucked up towards his 
chest or in the prone knee-chest position that allows comfortable access for examination. 
As same as the penile/glans penis sampling, remove the nail file from the packaging. 
Remove the swab from the packaging, then twist the top off of the sterile saline ampule. 
Only one file and one swab are to be used in the perineal/perianal sampling.
2.
If the participant is in the left lateral position, the participant should lift their right leg, so 
that the perineal area is able to be visualized. Gently rub the file over the right and left 
side of the perineal and perianal area. It is important to spread the buttocks apart for 
ample sampling of the perianal region. Sufficient pressure should be applied in order to 
cause blanching of the skin. If blanching is not observed, pressure should be increased in 
order to collect the required DNA. The examiner should gently swab the perineal area. 
Using the non-dominant hand, the examiner should spread the buttocks to better 
visualize the perianal area and the anus. The swab should be held in the dominant hand, 
and starting 3 to 5 cm from the anus, begin swabbing in a circular motion until the 
entrance of the anus is reached. As with the file, sufficient pressure should be used with 
the swab to blanch the skin while moving it over the area of loosened cellular debris. The 
swab should also be twisted or rotated in order to increase surface area exposure for 
collection of cellular debris.
3.
Discard the file in a Biohazard Sharps container. 
4.
Place the swab in an STM vial and break the pre-scored handle. Do not add saline to the 
STM vial either before or after swabbing.
5.
Securely cap the collection/transport tube containing the specimen.
6.
Place the appropriate label for the Perianal Sample on the STM vial.
8.2.3.1.4
Intra-anal Wetted Swab for HPV PCR
1.
As same as the perineal/perianal sampling, the participant should lie on his left lateral 
side with his knees tucked up towards his chest or in the prone knee-chest position that 
allows comfortable access for examination. Remove the swab from the packaging, then 
twist the top off of the sterile saline ampule. Only one swab is to be used in the intra-anal 
sampling.
2.
Using the non-dominant hand, the examiner should spread the buttocks to better 
visualize the anus. The swab should be held in the dominant hand, and once at the 
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entrance to the anus, the contiguous skin should be spread and the swab should be 
inserted into the anus as far as it will go until resistance is met (generally 5-6 cm), 
swabbing the inside of the anal canal in a 360º rotating motion 2 to 3 times. 
3.
Place the swab in an STM vial and break the pre-scored handle. Do not add saline to the 
STM vial either before or after swabbing.
4.
Securely cap the collection/transport tube containing the specimen.
5.
Place the appropriate label for the Intra-anal Sample on the STM vial.
8.2.3.2
External Genital Lesion Biopsy
8.2.3.2.1
External Genital Lesion Biopsy at Study Site
After a thorough examination, the investigator’s clinical impression should be recorded. If a 
lesion, in the investigator’s opinion, is possibly, probably, or definitely HPV infection-related 
or the diagnosis is unknown, it should be biopsied for further evaluation. For multiple 
lesions, select one external lesion to biopsy that is most representative of the morphology or 
anatomic location, and is most accessible. A second biopsy is indicated, if a lesion is 
identified in a separate region (anterior region includes penis and scrotum and posterior 
region includes perineal and perianal region) or a lesion is identified with different 
morphology in the same region. For each biopsy, different instruments are to be used to 
prevent cross-contamination between specimens. At the investigator’s discretion, the 
lesion(s) may be surgically removed (therapeutic excision). In that case, the entire specimen 
must be submitted for analysis. All specimen(s) excised should be submitted to the central 
laboratory designated by the Sponsor for analysis. For the genital wart/lesion biopsy, the 
external genital lesion biopsy kit provided by the Sponsor central laboratory is to be used. 
Slides of the wart/lesion biopsy will be reviewed by a pathologist for the purpose of 
management of the participant. Management of anogenital warts is a study procedure, but the 
decision regarding the modality of therapy will be left to the discretion of the investigator, 
per the site’s standard and practices. Excision of the wart/lesion is the preferred study 
treatment. All excised tissue is to be submitted to the central laboratory for analysis. If more 
than one biopsy is performed, then use separate instruments for each biopsy. Each biopsy 
should be placed in individual formalin containers. Treatment of anogenital warts by topical 
medications or cryotherapy is an acceptable study procedure. A biopsy of the identified 
lesion/lesions (e.g., morphology differs among identified lesions or more than one lesion is 
identified) must be obtained prior to administering treatment.
•
The investigator should provide a clinical impression of the lesion, which should include 
one of the following: condyloma acuminata, other HPV-related lesion (e.g., Bowenoid 
papulosis, Bowen’s disease), or other non-HPV related lesions.
•
The location and anatomical area of each biopsied lesion should be identified and noted 
(as per the lab kit requisition supplied by the Sponsor and should also be recorded in the 
appropriate eCRF).
•
To perform the biopsy, cleanse the biopsy area first with an antiseptic solution.
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•
Using a 25-30 gauge needle and a syringe containing 0.5 to 1 mL of 1% lidocaine or 
lidocaine with epinephrine, infiltrate below the epidermis of the wart. Optionally, a 
topical anesthetic cream may be applied over the biopsy site prior to infiltration with 
lidocaine to decrease the pain associated with needle insertion.
•
Remove the wart tangentially with fine (iris) scissors or a scalpel blade to obtain the 
specimen.
•
A different set of instruments is to be used for each biopsy taken.
•
To promote hemostasis, apply gentle pressure. Styptic may be used. For larger areas, a 
single interrupted suture may be used. Electrocauterization is to be avoided, but the 
decision is left to the discretion of the practitioner. Silver nitrate is to be avoided, as it is 
reported to be more caustic and painful to the participant.
•
Apply topical antibiotic ointment to the area to promote healing (optional).
•
Management of anogenital warts will be left to the discretion of the investigator. 
Excision of the wart is an acceptable study treatment. All excised tissue is to be 
submitted to the central laboratory for analysis.
During genital wart treatment, follow-up biopsies should be obtained if new HPV-related 
lesions of differing morphology, and/or differing location appear. A recurrence is defined as 
the reappearance within 2 months of a lesion of similar morphology in the same anatomical 
location after complete resolution of the initial lesion. Recurring lesions will not be biopsied. 
Otherwise, all new lesions will be biopsied. 
The external genital lesion biopsies will be processed and read by a central laboratory chosen 
by the Sponsor. These specimens will be processed at the central laboratory using study-
specific guidelines. The central laboratory diagnosis will be used for management of 
participants. However, this diagnosis will not be the diagnosis of record in the study. Rather 
all routine slides generated by the central laboratory will be sent to the Pathology Panel. The 
consensus diagnosis of this panel will represent the final diagnosis for study purposes. If the 
diagnosis of the Pathology Panel is worse than the diagnosis of central laboratory, then the 
investigator will be notified of the discrepancy in diagnoses.
External genital lesion specimens will also be used for HPV analysis. HPV analysis will be 
performed on Thinsection microtomy specimens. Each biopsy specimen will be analyzed by 
HPV PCR, regardless of whether an HPV-related histologic diagnosis is made, for the 
purpose of determining the causal HPV type in the lesion. 
Thinsection microtomy biopsy specimens will be tested for detection of HPV types 6, 11, 16, 
18, 31, 33, 45, 52, and 58. In addition to this testing, specimens may be tested for other HPV 
types. 
If a participant has an external genital lesion biopsy taken, that participant may remain in the 
study.
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8.2.3.2.2
Preparation and Disposition of Thin Sections from Tissue Specimens
The following procedures will be performed at the Sponsor-designated central laboratory.  
The procedures will be performed by an experienced, qualified histotechnologist according to 
the Central Laboratory's Standard Operating Procedure.  The histotechnologist will assure 
that the microtome and work areas are clean and free of contaminants.  All Thinsection 
microtomy for PCR will be performed at a time when all other routine work has been 
completed, so that potential contaminations can be minimized.  Prior to sectioning each 
block, a new blade will be installed in the microtome.  The blade will only be positioned so 
that it is at the left margin of the blade surface.  Technicians sectioning study blocks will 
utilize “biologically clean” gloves while handling the blocks (new gloves for each block).  
First, the histotechnologist will face the block by removing two 4-micron sections from the 
face of the block.  These sections will be discarded.  Using sterile plastic forceps, the next 
two 4-micron paraffin sections are collected and floated in a water bath for the preparation of 
one hematoxylin & eosin (H&E) slide (Slide 1, with 2 sections).
Nine additional, consecutive sections will then be cut to be used for Thinsection PCR. There 
will be 9 individual tubes (Tube 1, 2, 3, 4, 5, 6, 7, 8, 9), and one 4-micron section will be 
placed in each tube using a sterile disposable plastic forceps.  The pair of sterile plastic 
forceps used is then discarded after placing the cut section in each tube.  Each tube is then 
placed inside a plastic sleeve and sealed. 
Two additional, consecutive 4-micron sections will then be cut, and the 2 sections floated in 
the water bath for preparation of the second H&E slide both sections to be placed on one 
slide (Slide 2 with 2 sections each).  All H&E slides (Slides 1 and 2) will have a 
histopathologic review by the central laboratory's pathologist.
Slides and tubes should be labeled with participant's allocation number.  The specimen tubes 
are collated with the appropriate specimen requisition and prepared for shipping to the 
SPONSOR-designated Central Laboratory and then in turn, shipped on to MRL.  
The microtome is cleaned in preparation for the next block and the process above is repeated.  
The microtome blade is replaced with a new blade and adjusted for each new biopsy block 
and the same procedure is to be followed.  A new pair of clean gloves and a new pair of 
clean, disposable forceps will be used for each block being sectioned.  The “used” blade may 
be retained for cutting non-PCR blocks.  The total number of sections to be cut from each 
block is 13.  A total of 2 slides and 9 tubes:
1.
Slide 1 (H&E), with 2 sections each, stained.
2.
Tubes 1, 2, 3, 4, 5, 6, 7, 8, 9 (HPV PCR Analysis), one section per tube.
3.
Slide 2 (H&E), with 2 sections each, stained.
8.2.3.2.3
Specimens Taken Outside the Context of the Study
Tissue biopsies collected outside the context of the study are strongly discouraged.  “Outside 
the context of the study” is defined as processing of samples at a local laboratory rather than 
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through the Sponsor-designated Central Laboratory. If a participant undergoes a biopsy 
outside the context of the study, all efforts will be made to obtain the operative report, local 
pathology report, diagnostic slides (for tissue biopsies), tissue block for slide preparation, 
PCR analysis and pathology panel review.  
8.2.3.3
HPV DNA PCR Assay
The HPV PCR Assay developed and published by MSD [Else, E. A., et al 2011][Roberts, 
C.C., et al 2011] is a multiplexed real-time type-specific PCR assay. The PCR assay has been 
used in previous efficacy studies that supported the licensure of GARDASIL® and 
GARDASIL®9/SILGARD®9. The PCR assay is validated for the detection of HPV DNA of 
14 HPV types, including the 12 HPV types that have been recognized as oncogenic by the 
International Agency for Research on Cancer (including HPV 16, 18, 31, 33, 35, 39, 45, 51,
52, 56, 58, and 59) [Bouvard, V., et al 2009] and the low-risk types HPV 6 and 11.
HPV vaccine types 6, 11, 16, 18, 31, 33, 45, 52, and 58 will be analyzed using this type-
specific multiplex (L1, E6, and E7 gene detection) PCR assay. HPV types 35, 39, 51, 56, and 
59 will be detected using a duplex (E6 and E7 gene detection) PCR assay using the 
preparation method described below.
Specimens are received and prepared for multiplex PCR using a DNA purification method 
(Qiagen Technology Kit). Multiplex PCR (based on real-time fluorescent PCR) allows the 
simultaneous detection of 3 gene products (L1, E6, and E7) for a given HPV type in 1 
reaction. The HPV type-specific primer pairs based on the published HPV L1, E6, and E7 
sequences, are used to specifically amplify a portion of each gene simultaneously. The 
specific amplicons are detected in real-time by fluorescently labeled oligonucleotide probes. 
The gene-specific oligonucleotide probes are each labeled with a different fluorescent label, 
and the fluorescent emission is captured during PCR cycling. After analysis of the raw 
fluorescent data by the real-time PCR instrument software, a threshold cycle (Ct), which 
represents the PCR cycle at which an increase in reporter fluorescence above a baseline 
signal can first be detected, is determined. Each gene-specific assay (ie, gene-specific dye 
layer) is considered positive if the Ct is <45 cycles. A gene-specific assay is considered 
negative if the Ct = "No Ct". A sample is called positive when 2 or 3 genes are positive or 
when the same single gene scores positive on consecutive tests. The assay has been validated 
for swab and tissue specimens.
8.3
Immunogenicity Assessments (Base Study)
8.3.1
Blood Sample Collection for Serum Anti-HPV Antibody Testing
In the base study, blood samples will be collected for analysis of antibodies specific for HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 58 titers in serum. On Day 1, blood samples will be 
collected prior to the first study vaccination to identify participants who have been exposed 
to study vaccine HPV types prior to enrollment. Serology results at Day 1 are not part of the 
inclusion/exclusion criteria; thus, no participant will be excluded from the study based on 
these results. After Day 1, serum specimens will be collected at Month 7, and Month 36 ( or 
Final Visit)  to evaluate persistence of immune responses.
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Blood sample collection, storage, and shipment instructions for serum samples will be 
provided in the Laboratory Manual. Blood samples will be collected for anti-HPV antibody 
testing per the schedule indicated in the SoA (Section 1.3). 
After completion of immunogenicity testing to evaluate the study objectives and hypotheses, 
all leftover serum samples will be stored for up to 15 years. The samples may be used to 
conduct any additional study-related testing, biomarker testing, or to support HPV assay 
development/validation activities as required by regulatory agencies or the Sponsor.
8.3.2
Competitive Luminex Immunoassay
The 9-valent HPV cLIA will be used as a primary method to evaluate antibodies specific for 
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 in serum. The purpose of the assay is to detect these 
HPV antibodies before and after vaccination with the 9vHPV vaccine in the base study. The 
testing will be performed by Q Squared Solutions (California, USA).
For the 9-valent HPV cLIA, HPV type-specific, yeast-derived VLPs are coupled to 9 distinct 
Luminex magnetic microspheres. Each VLP-coupled microsphere has its own distinct 
fluorescent dye that can be recognized by excitation with an infrared laser, allowing for the 
measurement of antibodies against multiple HPV types from a single test of an individual’s 
serum. HPV type-specific monoclonal antibodies labeled with R-Phycoerythrin (PE) compete 
with an individual’s serum antibodies for binding to the neutralizing epitopes of the VLPs. 
The fluorescent signal from the PE-labeled, type-specific monoclonal antibodies is inversely 
proportional to the anti-HPV antibody concentration of a sample. Antibody concentrations 
are derived from a standard curve, which is generated using a reference standard made from a 
pool of serum from individuals immunized against the nine HPV types. A standard curve for 
each HPV type is calculated using a weighted 4 parameter logistic curve fit. Results are 
expressed as milli-Merck Units/ml (mMU/mL). 
The assay was validated at Q Squared Solutions. Validation evaluated precision, linearity, 
LLOQ, ULOQ, and relative accuracy/dilutability for the quantitation of antibodies specific to 
HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Serostatus cutoffs for each HPV type will be 
predefined. A participant will be considered seropositive to a given HPV type at Day 1 of the 
base study if the participant’s anti-HPV titer, as assessed by cLIA, is greater than or equal to 
the corresponding serostatus cutoff for that HPV type. A participant will be considered 
seronegative to a given HPV type at Day 1 of the base study if the participant’s anti-HPV 
titer, as assessed by cLIA, is less than the corresponding serostatus cutoff for that HPV type.
8.4
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.
Planned time points for all safety assessments are provided in the SoA.
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8.4.1
Physical Examinations
A physical examination is optional and will be conducted by an investigator on Day 1 of the 
base study to determine whether the participant meets eligibility criteria for enrollment. 
Height and weight will be recorded on Day 1 of the base study before administration of the 
study vaccine.
Physical examination details will be recorded in the participant’s study chart. Any medical 
condition identified during physical examination will be documented in the data collection 
system. Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.4.2
Oral Temperature Measurements
In the base study, oral temperature will be assessed before study vaccine is administered on 
Day 1, Month 2, and Month 6 visits. If the participant has a fever (defined as an oral 
temperature of ≥37.5°C) within the 24-hour period prior to receiving a study vaccination, the 
participant should not receive the study vaccine, and the vaccination visit should be 
rescheduled until after the fever has resolved. 
Postvaccination, if an oral temperature indicates a fever (defined as an oral temperature of 
≥37.5°C), then an AE of “fever” must be documented in the eCRF.
In the extension study, oral temperature will be assessed before 9vHPV vaccine is 
administered at the visits specified in Section 1.3.2 and Section 1.3.3 of the SoA.
8.4.3
Clinical Safety Laboratory Assessments
There will be no protocol-specific clinical safety laboratory assessments for this study. If 
laboratory values from non-protocol-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 discontinuation of the 
study vaccine), then the results must be recorded in the appropriate case report form (CRF) 
(eg, SLAB).
8.4.4
Vaccination Report Card
Base Study:
The investigator or delegate will train the participant in the use of the VRC at Visit 1 (Day 
1). Temperatures, injection-site reactions, other complaints or illnesses, and concomitant 
medications or vaccinations will be recorded on the VRC by the participant. Participants 
should be informed to contact the investigator immediately in the event of a hospitalization 
or visit to another physician.
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Participants will use the VRC to document the following information:

Oral temperatures measured Day 1 (day of vaccination) through Day 5 postvaccination.

Participants will record oral temperature in the evening after each study vaccination 
and daily, at the same time of day, for 4 days after each study vaccination for the 
purpose of identifying febrile events.

Note: If an oral temperature indicates a fever (defined as an oral temperature of 
≥37.5°C), the AE of “fever” must be documented in the appropriate eCRF.

Solicited injection-site AEs (redness/erythema, swelling, and tenderness/pain) Day 1 
through Day 5 postvaccination.

Any other injection-site or systemic AEs Day 1 through Day 15 postvaccination.

Concomitant medications and non-study vaccinations Day 1 through Day 15 
postvaccination.
In order to ensure that the VRC is being filled out without delay, telephone contacts to 
remind the participant will be conducted after 15 days postvaccination.
All participants will be expected to bring the VRC to the study site at the next scheduled 
visit. The investigator or delegate will review the data captured on the VRC with the 
participant at Visit 2 (Month 2), Visit 3 (Month 6), and Visit 4 (Month 7). For the AEs 
outlined above, the investigator will use the information provided by the participant both on 
the VRC, and verbally at the time of VRC review, to apply the appropriate assessment of 
causality as described in Appendix 3. At the time of VRC review at the next scheduled visit, 
participants will be questioned regarding any new medical conditions that occurred beyond 
Day 15 postvaccination. The investigator will determine if the medical condition is to be 
reported as an SAE using the reporting guidelines provided in Section 8.4.
Extension Study:
A VRC will not be utilized for participants enrolled in the extension study and NSAEs will 
not be collected. SAEs and death will be collected from the first dose of vaccination until 1 
month after the last dose.
8.4.5
Postvaccination Observation Period (30 Minutes)
In both the base study and study extension, all participants will be observed for at least 30 
minutes after each vaccination for any immediate reactions. If any immediate AEs (including 
allergic reactions) 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.
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8.5
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.5.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity and causality.
8.5.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before randomization, must be reported by the 
investigator if they cause the participant to be excluded from the study, or are the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, placebo, or a procedure.
Base Study:
From the time of randomization through 14 days following the first vaccination(s) and from 
the time of any subsequent vaccination(s) through 14 days thereafter, all AEs must be 
reported by the investigator. All SAEs and other reportable safety events that occur from the 
time of randomization through 6 months following the last vaccination must be reported by 
the investigator, regardless of whether the events are considered to be vaccine-related by the 
investigator.
Extension Study:
SAEs and death will be collected from the first dose of vaccination until 1 month after the 
last dose.
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Base Study and Extension Study:
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is either:
•
A death that occurs before the participant completing the study, but outside the period 
specified in the previous paragraph.
OR
•
An SAE that is considered by an investigator, who is a qualified physician, to be vaccine 
related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
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 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:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine 
related.
- any death 
until participant 
completion of 
study
(Follow 
ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
NSAE=nonserious adverse event; SAE=serious adverse event.
8.5.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.5.3
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 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 
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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.
8.5.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.5.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are males and partner 
pregnancy/lactation information are not applicable.
8.5.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
None.
8.5.7
Events of Clinical Interest
None.
8.6
Treatment of Overdose
In this study, an overdose is defined as a participant receiving >1 dose of study vaccine in a 
24-hour period or more than the number of doses of study vaccine specified in the protocol 
throughout the study.
Sponsor does not recommend specific treatment for an overdose.
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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.
8.7
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.8
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.9
Biomarkers
Biomarkers are not evaluated in this study.
8.10
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
DNA for future research
8.11
Health Economics Medical Resource Utilization and Health Economics
Health Economics OR 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
Visit Requirements in Base Study
8.12.1.1
Screening Visit
The screening visit or the last screening visit (for re-screening) should be on the same day of 
randomization and the first dose of vaccination. Potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5. Screening 
procedures may be repeated after consultation with the Sponsor. 
If possible, all Day 1 visit procedures should be performed on the day of consent. If date of 
Day 1 visit (and all procedures) is later than consent date, the interval between the date of 
consent and the date of the Day 1 visit should be no more than 14 days. If the interval is 15 
days or longer, then the participant must be reconsented.
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8.12.1.2
Prerequisites for Vaccination Visit (Day 1, Month 2, and Month 6)
This section summarizes prerequisites for vaccination visits. See the inclusion/exclusion 
criteria for specific restrictions on Day 1 (see Section 5.1 and Section 5.2). At Month 2 and 
Month 6 study vaccination visits, study personnel should verify by questioning the 
participant and/or by examination that:
1. The participant has not had a fever (oral temperature ≥37.5°C) within the 24-hour period 
prior to the vaccination visit.
2. The participant has not received any systemic (oral or parenteral) corticosteroids in 14 
days prior to the Month 2 and Month 6 study vaccination visits.
3.
The participant has not received a non-study inactivated or recombinant vaccine within 
14 days prior to any study vaccination visit or a non-study live vaccine within 28 days 
prior to any study vaccination visit.
If the participant does not meet the requirements listed above, the study visit (including 
specimen collection and study vaccination) should be re-scheduled.
8.12.1.3
Prerequisites for Anogenital Sample Collection Visits
See the inclusion/exclusion criteria for specific restrictions on Day 1 (see Section 5.1 and 
Section 5.2). For visits that include collection of study specimens, the site study personnel 
should verify by questioning the participant that he had not engaged in sexual activity within 
48 hours nor shaved their genital region and/or applied any post-shave lotion or lubricants 
within 24 hours prior to any visit that includes collection of swabs, and/or biopsies 
specimens. See section 8.1.14 for details regarding documentation of sexual activity. If the 
participant does not meet the requirements listed above, the study visit should be re-
scheduled.
8.12.1.4
Early Termination Procedures
Once at least 17 primary efficacy endpoint cases and at least 17 secondary efficacy endpoint 
cases have been observed, initial database lock and unblinding will be performed and notified 
to the study sites. Following notification, participants remaining in the study (ie, who have 
not yet completed a Final Visit) will proceed to a Final Visit in the base study promptly. 
Under that scenario, participants who have not yet completed a Final Visit will complete the 
specified procedures in Final Visit in this Schedule of Activities. 
Participants who have not yet completed Month 36 should schedule a Final Visit with 
collection of serum sample within the specific day ranges from Day 913 to Day 1277 (within 
the acceptable ranges for collection of serum sample, see Section 9.5.2), if possible. At the 
Final Visit, serum sample should not be collected from the participants who have already 
completed Month 36 or outside of the day ranges from Day 913 to Day 1277.
If the Sponsor elects to terminate earlier under this scenario, the limited procedures shown in 
the SoA (Section 1.3) will be conducted at the final visit as follows; update medical history, 
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review prior/concomitant medication and non-study vaccination review, monitor AEs, and 
blood sample collection for serum for anti-HPV (only for the participants who have not yet 
completed Month 36). Refer to Section 8.1.4, 8.1.6, 8.3.1 and 8.5, respectively, for the details 
of each procedure.
8.12.2
Visit Requirements in Extension Study
8.12.2.1
Prerequisites for Vaccination Visit (Extension Visit 1, Extension Visit 2a/2b, 
and Extension Visit 3)
This section summarizes prerequisites for vaccination visits in the extension study. See the 
inclusion/exclusion criteria for specific restrictions on Extension Visit 1 (see Section 5.1.2 
and Section 5.2.2). At Extension Visit 2a/2b, and Extension Visit 3, study personnel should 
verify by questioning the participant and/or by examination that:
1. The participant has not had a fever (oral temperature ≥37.5°C) within the 24-hour period 
prior to the vaccination visit.
If the participant does not meet the requirements listed above, the study visit should be re-
scheduled.
8.12.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study vaccinations but continue in the study will attend study 
visits per the SoA including sampling of swabs, and/or biopsies specimens (Section 1.3) in 
the base study. However, serum will not be collected at the Month 7 study visit or subsequent 
visits from participants who did not complete the 3-dose study vaccination regimen.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or secondary hypotheses, or the statistical methods related to those hypotheses, 
then the protocol will be amended (consistent with ICH Guideline E-9). Changes to 
exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in a supplemental statistical 
analysis plan (sSAP) and referenced in the CSR for the study. Post-hoc exploratory analyses 
will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary 
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12. The same analysis plan for analysis populations and 
methods without hypothesis testing will be applied to evaluate decreasing of selected efficacy 
and immunogenicity endpoints from the first database lock for primary analysis, by using 
data up to the end-of-base-study (the database lock after the completion of the final efficacy 
sample assessment for the final efficacy analysis and after the last participant’s Final Visit in 
the base study for the final immunogenicity and safety analysis). Descriptive analysis of 
selected safety endpoints will be reported in an end-of-base-study report and an extension 
study report.
Study Design Overview
A Phase 3, randomized, placebo-controlled clinical study to 
evaluate the efficacy, immunogenicity and safety of the 
9vHPV vaccine in Japanese males, 16 to 26 years of age.
Treatment Assignment
All enrolled participants will be randomized in a 1:1 ratio to 
the 9vHPV vaccine group or placebo group.
Analysis Populations
Efficacy: Pre-Protocol Efficacy (PPE) population
Immunogenicity: Per-Protocol Immunogenicity (PPI) 
population
Safety: All Participants as Treated (APaT) population
Primary Endpoint
Efficacy: HPV 6/11/16/18-related anogenital persistent 
infection
Key Secondary 
Endpoints
Efficacy: HPV 31/33/45/52/58-related anogenital persistent 
infection
Immunogenicity: 
•
GMTs to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 
58 at 1 month post last dose (Month 7).
•
Seroconversion to each of HPV 6, 11, 16, 18, 31, 33, 
45, 52, and 58 at 1 month post last dose (Month 7). 
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Statistical Methods for 
Efficacy Analyses
The primary efficacy hypothesis will be evaluated by 
comparing the 9vHPV vaccine with placebo with respect to 
the primary efficacy endpoint. The p-value for testing the 
hypothesis that vaccine efficacy (VE) is greater than 0% as 
well as 95% confidence interval (CI) for VE will be 
provided using the exact binomial method proposed by 
Chan and Bohidar (1998) [Chan, I. S. F. and Bohidar, N. R. 
1998]. The statistical criterion for success requires that the 
lower bound of the 2-sided 95% CI for VE against the 
primary efficacy endpoint is greater than 0%.
The secondary efficacy hypothesis will be evaluated by 
comparing the 9vHPV vaccine with placebo with respect to
the secondary efficacy endpoint based on the same method 
to be used in testing the primary efficacy hypothesis. The 
statistical criterion for success requires that the lower bound 
of the 2-sided 95% CI for VE against the secondary efficacy 
is greater than 0%.
Statistical Methods for 
Immunogenicity 
Analyses
The secondary immunogenicity objective will be addressed 
by summarizing antibody titer responses measured using 
cLIA at Month 7. The GMTs and the corresponding 95% 
CIs will be estimated based on the t-distribution for HPV 
types of 6, 11, 16, 18, 31, 33, 45, 52, and 58. Point 
estimates and the corresponding 95% CIs of percent 
seroconversion will be provided using the exact binomial 
method of Clopper and Pearson [Clopper, C. J. and Pearson, 
E. S. 1934] for HPV types of 6, 11, 16, 18, 31, 33, 45, 52, 
and 58, for all participants, HM group and MSM group, 
respectively.
Statistical Methods for 
Key Safety Analyses
There are no Tier 1 AEs identified in this study. For Tier-2
AEs, 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events
using the methods proposed by Miettinen and Nurminen 
[Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
No interim analyses are planned in this study.
Multiplicity
The overall type 1 error rate associated with testing the 
primary and secondary efficacy hypotheses will be 
controlled to not exceed 0.025 (1-sided) by a fixed sequence 
procedure. The secondary efficacy hypothesis will be tested 
only if the primary efficacy hypothesis is successfully 
demonstrated.
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Sample Size and Power 
Testing the primary efficacy hypothesis with 17 total cases 
has 94% power to demonstrate that the efficacy of the 
9vHPV vaccine compared to placebo is greater than 0% at 
1-sided type 1 error rate ≤ 0.025 if the underlying true VE 
against the primary efficacy endpoint is at least 85%.
Testing the secondary efficacy hypothesis with 17 total 
cases has also 94% power to demonstrate that the efficacy 
of the 9vHPV vaccine compared to placebo is greater than 
0% at an overall 1-sided type 1 error rate ≤ 0.025 if the 
underlying true VE against the secondary endpoint is at 
least 85%.
A total of approximately 1050 participants are needed to be 
enrolled in order to accumulate approximately 17 total 
primary endpoint cases and at least 17 total secondary 
efficacy endpoint cases within 56 months from the time the 
first study participant signs the ICF.
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. 
The base study will be conducted as a double-blind study under in-house blinding procedures.  
The official 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 
first database lock will be executed, and a study report will be written reporting of the test of 
the primary and secondary efficacy hypotheses when at least 17 confirmed cases for each 
primary endpoint and secondary endpoint have been accumulated. After the first database lock
for primary analysis, data for immunogenicity and safety endpoints will continue to be 
collected, and additional database locks will be executed, including a second database lock for 
the final efficacy analysis after the completion of the final sample assessment for efficacy in 
the base study and a final database lock of the base study for the final immunogenicity and 
safety analysis after the last participant’s Final Visit in the base study. A report will be written
after each database lock. Participants will be unblinded after the initial database lock to 
determine eligibility for participation in the extension study.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IRT system.
9.3
Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3. Data in the first database lock 
will be used for hypothesis testing.
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9.4
Analysis Endpoints 
9.4.1
Efficacy Endpoints 
Primary efficacy endpoint 
HPV 6/11/16/18-related anogenital persistent infection is defined to have occurred if any of 
the following occurs:
•
The participant is positive by an HPV PCR assay (type 6, 11, 16, or 18) to at least 1 
common gene for the given vaccine HPV type in anogenital or biopsy samples collected 
in two or more consecutive visits 6 months (± 1-month window) apart (The minimum 
length of time between samples for a participant to be counted as a case of persistent 
infection is 4 months); OR
•
The participant has Pathology Panel consensus diagnosis of genital warts, PIN, penile, 
perianal or perineal cancer AND detection of HPV 6, 11, 16 or 18 by Thinsection PCR in 
an adjacent section of the same biopsy block AND is PCR positive for the same HPV 
type to at least 1 common gene in the sample obtained at a separate adjacent visit with 
regardless of visit interval, prior to or following the biopsy showing HPV disease.
Secondary efficacy endpoint 
HPV 31/33/45/52/58-related anogenital persistent infection is defined to have occurred if any 
of the following occurs:
•
The participant is positive by an HPV PCR assay (type 31, 33, 45, 52 or 58) to at least 1 
common gene for the given vaccine HPV type in anogenital or biopsy samples collected 
in two or more consecutive visits 6 months (± 1-month window) apart (The minimum 
length of time between samples for a participant to be counted as a case of persistent 
infection is 4 months); OR
•
The participant has Pathology Panel consensus diagnosis of genital warts, PIN, penile, 
perianal or perineal cancer AND detection of HPV 31, 33, 45, 52 or 58 by Thinsection 
PCR in an adjacent section of the same biopsy block AND is PCR positive for the same 
HPV type to at least 1 common gene in the sample obtained at a separate adjacent visit 
with regardless of visit interval, prior to or following the biopsy showing HPV disease.
Exploratory efficacy endpoints 
•
HPV 6/11/16/18/31/33/45/52/58-related anogenital persistent infection detected in 
samples from two or more consecutive visits 6 months (± 1-month window) or longer 
apart.
•
HPV 6/11/16/18/31/33/45/52/58-related genital warts, PIN, penile, perianal or perineal 
cancer
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•
HPV 6/11/16/18/31/33/45/52/58-related intra-anal persistent infection detected in 
samples from two or more consecutive visits 6 months (± 1-month window) or longer 
apart.
•
HPV 6/11/16/18/31/33/45/52/58-related anogenital persistent infection detected in 
samples from three or more consecutive visits 6 months (± 1-month window) or longer 
apart (i.e., at least 12 months persistent infection)
These endpoints will be also evaluated for each HPV types.
9.4.2
Immunogenicity Endpoints 
GMT to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 at 1 month post last dose (Month 
7) based on cLIA using serum samples.
Seroconversion to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 at 1 month post last dose 
(Month 7) based on cLIA using serum samples. Seroconversion is defined as changing a 
participant’s serostatus from seronegative at Day 1 to seropositive at 1 month post last dose 
(Month 7). A participant with anti-HPV cLIA titer at or above the serostatus cutoff of the 
cLIA for a given HPV type is considered seropositive for that HPV type.
9.4.3
Safety Endpoints
•
Solicited injection-site AEs and elevated temperatures during Days 1 through 5 
postvaccination 
•
Systemic AEs and SAEs during Days 1 through 15 postvaccination 
•
Serious vaccine-related AEs observed any time during the study
9.5
Analysis Populations 
In efficacy and immunogenicity analysis populations, participants are analyzed in the 
vaccination group to which they were randomized (i.e., as-randomized). In safety analysis 
population, participants are analyzed according to the vaccination regimen actually received 
(i.e., as-treated).
9.5.1
Efficacy Analysis Populations
Per-Protocol Efficacy (PPE) Population
The PPE population will serve as the primary population for the analysis of efficacy in this 
study. To be included in the per-protocol population, participants must:
1. Have received all 3 vaccinations with the correct dose of the correct clinical material 
within 1 year.
2. Have Month 7 swab samples collected within 14 to 72 days post dose 3 with non-missing 
PCR result.
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3. Be seronegative to the appropriate HPV type(s) at baseline and PCR-negative to the 
appropriate HPV type(s) on all swabs and biopsies (if collected) from baseline through 
Month 7.
4. Have no other protocol violations that could interfere with the evaluation of efficacy.
The final determination on protocol violations, which will be used for determining the PPE 
population, will be made prior to the database lock and will be documented in a separate 
memo or the sSAP.
HPV Type-Specific Naïve (HN-TS) Population 
The HN-TS population will serve as a supportive population for the analysis of efficacy in 
this study. To be included in the HN-TS population, participants must:
1. Have received at least 1 vaccination,
2. Be seronegative and PCR-negative to appropriate HPV type(s) at Day 1. 
Participants who receive incorrect clinical material or an incorrect dose of vaccine will be 
included in the vaccination group to which they were randomized. Protocol violations that 
could interfere with the evaluation of efficacy will not cause participants to be excluded from 
the HN-TS population.
For each of the PPE and HN-TS analysis populations, to be included in the analysis 
population with respect to either HPV type 6 or 11, participants must be HPV-negative at the 
relevant time point(s) for both HPV 6 and 11.  To be included in the analysis populations 
with respect to any other vaccine HPV type, participants need to be HPV-negative at the 
relevant time point(s) only for the HPV type under evaluation.
In the PPE population, efficacy endpoints are counted starting after Month 7 (after 1 month 
post dose 3). In the HN-TS population, efficacy endpoints are counted starting after Day 1.
9.5.2
Immunogenicity Analysis Populations
Per-Protocol Immunogenicity (PPI) Population
The PPI population will serve as the primary population for the analysis of immunogenicity 
in this study. To be included in this population, participants must satisfy all the criteria for 
the PPE population, and additionally must:
1. Have received all vaccinations within acceptable day ranges (see Table 4)
2. Have provided blood samples for serology testing within the acceptable day range (see 
Table 5)
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All Naïve Participants with Serology (ANPS) 
A supportive analysis of immunogenicity will be conducted on the ANPS population. To be 
included in this population, participants must:
1. Have received at least 1 vaccination 
2. Have provided serum samples with evaluable results
3. Be seronegative at Day 1 and PCR-negative from Day 1 through Month 7 to the 
appropriate HPV type(s).
Participants who receive incorrect clinical material or an incorrect dose of vaccine will be 
included in the analysis in the group to which they were randomized.
Table 4
Acceptable Day Ranges for Vaccination Visits
Dose of the 9vHPV Vaccine 
Scheduled for Injection
Protocol Specified
Visit Window
Day Range for Inclusion in
Statistical Analysis (Relative
to Day 1†)
Dose 1
Dose 2
Dose 3
Day 1†
Month 2 ± 3 weeks
Month 6 ± 4 weeks
0
36 to 84
148 to 218
† Day 1 refers to the date when dose 1 of the 9vHPV vaccine is injected.
Table 5
Acceptable Day Ranges for Collection of Serum Samples
Study Visit
Sample
Type
Target Collection Day
(Relative to Day 1†)
Day Range for Inclusion in 
Statistical Analysis (Relative
to Day 1†)
Day 1
Month 7
Month 36
Serum
Serum
Serum
0
30 days post dose 3
1095
–14 to 0
21 to 49 post dose 3
913 to 1277
†  Day 1 refers to the date when dose 1 of the 9vHPV vaccine is injected. For Month 7, indicated target
collection/day range is relative to date of injection of dose 3 of the 9vHPV vaccine.
9.5.3
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of the 9vHPV vaccine or placebo and have provided 
safety data at any time during the study. Participants will be included in the treatment group 
corresponding to the study treatment they actually received (i.e., 3 doses of vaccine or 3 
doses of placebo). For participants who received injections of vaccine and placebo (i.e., 
cross-treated participants) corresponding to a regimen that does not correspond to any of the 
protocol-defined vaccination groups (i.e., not 3 doses of vaccine nor 3 doses of placebo), a 
safety profile listing will be created separate from the safety reports that will be provided for 
the protocol-defined vaccination groups.
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9.6
Statistical Methods 
Statistical methods for efficacy and immunogenicity analyses are described in Section 9.6.1 
and Section 9.6.2, respectively. The same analysis plan for analysis populations and methods 
without hypothesis testing will be applied to evaluate decreasing of selected efficacy and 
immunogenicity endpoints from the first database lock for primary analysis, by using data up 
to the end-of-base-study (the database lock after the completion of the final efficacy sample 
assessment for the final efficacy analysis and after the last participant’s Final Visit in the 
base study for the final immunogenicity and safety analysis). Safety analysis approaches are 
described in Section 9.6.3. Selected safety endpoints will be summarized separately using 
descriptive methods for Tier 3 events in an end-of-base-study report. Only SAE/death will be 
summarized separately using descriptive methods in an extension study report. Methods 
related to exploratory objectives will be further described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analyses
For each of the primary and secondary efficacy objectives, the hypothesis that VE is greater 
than 0% will be tested. 
The null and alternative hypotheses to be tested are:
H0: VE ≤ 0%
H1: VE >0%;
where VE is defined as: 
and Rv and Rp are the incidence rates of the relevant efficacy endpoint in the 9vHPV vaccine 
and placebo groups, respectively. VE is equivalent to the percent reduction in the risk of 
becoming a case of an efficacy endpoint in the 9vHPV vaccine group relative to the risk in
the placebo group. The incidence rate Rv is defined as Rv = Cv/Tv, where Cv = the count of 
the relevant efficacy endpoint cases in the vaccine group and Tv = total person-years of 
follow-up for efficacy in the vaccine group. The incidence rate Rp is defined similarly.
The hypothesis that VE is greater than 0% will be tested by constructing a 100*(1α) % CI 
for VE with respect to the relevant efficacy endpoint, denoted as (VEL, VEU). The test of 
hypothesis will be declared successful if VEL >0%. 
Generally, the 100*(1α) % CI for VE, (VEL, VEU), will be computed as follows. Under the 
assumption that Rv and Rp are the means of independent Poisson processes, and given that 
there is a total of n = Cv + Cp efficacy endpoint cases observed across 2 vaccination groups, 
then the number of efficacy cases Cv in the 9vHPV vaccine group is distributed as 
Binomial(n,), where the binomial probability is defined as:
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The probability is a person-years-adjusted estimate of the probability that a particular 
participant who became a case of the relevant efficacy endpoint belongs to the 9vHPV 
vaccine group. The lower bound of the 100*(1α) % exact CI for the probability is 
obtained by searching for the proportion L such that the probability of observing Cv or more 
efficacy endpoint cases out of n total efficacy cases is ≤α/2. Similarly, the upper bound of the 
100*(1α)% exact CI for the probability is obtained by searching for the proportion U
such that the probability of observing Cv or fewer efficacy endpoint cases out of n total 
efficacy cases is ≤α/2 [Chan, I. S. F. and Bohidar, N. R. 1998]. VEL and VEU are then 
calculated from L and U as follows:
where = Tp/Tv is the ratio of the total person-years of follow-up for efficacy in the placebo 
group over the 9vHPV vaccine group. 
The efficacy analyses strategy are summarized in Table 6.
Table 6
Analysis Strategy for Efficacy Variable
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Efficacy Hypothesis
HPV 6/11/16/18-related anogenital 
persistent infection 
P
Point 
estimate, 95% 
CI and p-
value by 
exact method
PPE
Observed 
data only
S
Point estimate
and 95% CI
by exact 
method
HN-TS
Observed 
data only
Secondary Efficacy Hypothesis
HPV 31/33/45/52/58-related 
anogenital persistent infection
P
Point 
estimate, 95% 
CI and p-
value by exact 
method
PPE
Observed 
data only
S
Point estimate
and 95% CI
by exact 
method
HN-TS
Observed 
data only
Abbreviations: HN-TS=HPV Type-Specific Naïve, P=Primary, PPE=Per-Protocol Efficacy, S=Supportive
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9.6.2
Statistical Methods for Immunogenicity Analyses
9.6.2.1
Estimation of GMTs
Anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 antibody GMT and the corresponding 2-sided 
95% CI will be evaluated at 1 month post last dose (Month 7) by vaccine group. For this 
purpose, the mean and corresponding 95% CI of the natural logarithm of the anti-HPV titers 
will be calculated and exponentiated to generate the GMT and the corresponding 95% CI. 
The 95% CI of the mean of the natural logarithm of anti-HPV titers will be constructed based 
on the t-distribution. Reverse cumulative distribution (RCD) plots will be provided for 
graphical representation of distributions of HPV titers at Month 7.
Anti-HPV titers reported as less than the LLOQ of the relevant anti-HPV type will be 
replaced by the half of the LLOQ in the numerical computation of GMT.
9.6.2.2
Estimation of Percent Seroconversion
The percent seroconversion with respect to anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58, at 
Month 7 will be evaluated by computing point estimates and corresponding 2-sided 95% CIs 
by vaccine group. Calculation of the 95% CI of percent seroconversion will be based on the 
exact binomial method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 
1934].
9.6.3
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements. The analysis of safety results will 
follow a tiered approach (Table 7). The tiers differ with respect to the analyses that will be 
performed. AEs (specific terms as well as system organ class terms) are either pre-specified 
as “Tier 1” endpoints or will be classified as belonging to “Tier 2” or “Tier 3” based on the 
observed proportions of participants with an event. The safety analysis strategy is 
summarized in Table 7. 
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. There are 
no Tier 1 events for this protocol based on the global safety data on the 9vHPV vaccine.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with corresponding 95% CIs provided 
for the differences in the proportion of participants with events (using the Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985]). Membership in Tier 2 requires 
that at least 1% of participants in any treatment group exhibit the event. 
In addition to individual events that occur in at least 1% of participants in any treatment 
group, the broad AE categories consisting of the proportion of participants with SAEs during 
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Days 1 through 15 postvaccination, vaccine-related SAEs observed any time during the 
study, and elevated temperatures (≥37.5°C) will be considered Tier 2 endpoints. The 
proportion of participants with solicited injection-site AEs (pain/tenderness, swelling, and 
redness) and severe injection-site AEs during Days 1 through 5 postvaccination will also be 
included in Tier 2 endpoints. Detailed endpoints and day ranges are summarized in Table 7. 
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates (counts and percentages) by vaccination group are provided for Tier 3 safety 
parameters. Safety analyses will be based on the observed data (i.e., with no imputation of 
missing data).
Table 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint (a)
95% CI for 
Comparison of 
9vHPV to 
Placebo
Descriptive 
Statistics
Tier 2
Injection-site pain/tenderness, swelling, and redness 
during Days 1 through 5 postvaccination
X
X
Other injection-site AEs (incidence ≥1% of participants 
in either group) during Days 1 through 5 postvaccination
X
X
Severe injection-site AEs (b) during Days 1 through 5 
postvaccination
X
X
Systemic AEs (incidence ≥1% of participants in either 
group) during Days 1 through 15 postvaccination
X
X
Elevated temperatures (c) during Days 1 through 5 
postvaccination
X
X
SAEs during Days 1 through 15 postvaccination
X
X
Serious vaccine-related AEs observed any time during 
the study
X
X
Tier 3
AEs by SOC
X
Maximum intensity rating for each category of injection-
site AEs
X
Maximum intensity rating, over all systemic AEs
X
Maximum temperatures
X
New medical conditions
X
Abbreviations: AE=adverse event, SAE=serious adverse event, SOC=System Organ Class
(a) The day of vaccination is counted as Day 1. Day ranges for endpoints are as follows: injection-site AEs 
and maximum temperatures Days 1 through 5 postvaccination; systemic AEs Days 1 through 15 
postvaccination.
(b) For the injection-site redness and swelling 0 to 2.5 cm (0 to 1 inch) will be categorized as mild, >2.5 to 
5 cm (>1 inch to 2 inches) will be categorized as moderate, and >5 cm (>2 inches) will be categorized as 
severe.
(c) Defined as maximum (over the follow-up period) temperature ≥37.5°C.
Note: X = indicated summary statistic will be provided.
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9.6.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Baseline characteristics and demographic variables
Baseline and demographic characteristics; prior and concomitant therapies; counts and 
percent of participants screened, enrolled, vaccinated and the primary reason for 
discontinuation; will be summarized in tabular format by vaccine group. No statistical 
hypothesis tests will be performed on these characteristics.
9.7
Interim Analyses 
No interim analyses are planned in this study.
9.8
Multiplicity 
The overall type 1 error rate associated with testing the primary and secondary efficacy 
hypotheses will be controlled by a fixed sequence procedure. When at least 17 cases of the 
primary endpoint and at least 17 cases of the secondary endpoint have been observed, the 
primary efficacy hypothesis will be tested at a 1-sided type 1 error rate ≤ 0.025, as discussed 
in Section 9.9.1. The secondary efficacy hypothesis will be tested at a 1-sided type 1 error 
rate ≤ 0.025 only if the primary efficacy hypothesis is successfully demonstrated.
9.9
Sample Size and Power Calculations 
This is an event-driven study and the planned sample size is approximately 1050 participants.
9.9.1
Sample Size and Power for Testing the Primary Efficacy Hypothesis
With a 1:1 randomization between the 2 arms, the decision rule displayed in Table 8 for 
testing the primary efficacy hypothesis of VE >0% at a total of 17 cases will have 1-sided 
type 1 error rate ≤ 0.025 and power has 94% if the true VE is at least 85% (see Table 8). 
Type 1 error rate and power calculations were done based on the method proposed by Chan 
and Bohidar (1998) [Chan, I. S. F. and Bohidar, N. R. 1998]. Table 8 also displays the 
decision rule that will be used if the primary efficacy hypothesis is tested with total cases
greater than 17.
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Table 8
Decision Rule and Corresponding Type 1 Error rate and Power for Testing the 
Primary Efficacy Hypothesis
Analysis 
Time 
Point
Total 
Cases
Critical Case Split
Type 1 
Error
rate
True Vaccine Efficacy (VE)
Vaccine
Placebo
75%
80%
85%
90%
95%
Power (%)
Final
17
4
13
0.0245
76
86
94
98
>99
18
4
14
0.0154
72
83
92
98
>99
19
4
15
0.0096
67
80
91
98
>99
20
5
15
0.0207
80
90
96
99
>99
21
5
16
0.0133
77
88
95
99
>99
22
5
17
0.0085
73
85
94
99
>99
23
6
17
0.0173
84
93
98
>99
>99
24
6
18
0.0113
81
91
97
>99
>99
25
7
18
0.0216
89
96
99
>99
>99
A total of approximately 1050 participants are needed to be enrolled in order to accumulate 
approximately 17 total primary endpoint cases within 56 months from the time the first study 
participant signs the ICF based on the following assumptions. Assumption is based on V501-
122:
•
14 months enrollment;
•
Exclusion rate from PPE analysis is approximately 15%;
•
Attrition rate is approximately 5% per year; 
•
Annual incidence rate for the primary efficacy endpoint is 1.9% per year;
•
True VE is 85%.
9.9.2
Sample Size and Power for Testing the Secondary Efficacy Hypothesis
Table 8 also displays the decision rule that will be used for testing the secondary efficacy 
hypothesis with 17 or more total cases. The testing of the secondary efficacy hypothesis of 
VE >0% at 17 total cases will have 1-sided type 1 error rate ≤ 0.025 and power has 94% if 
the true VE is at least 85% (see Table 8).
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A total of approximately 1050 participants are needed to be enrolled in order to accumulate  
at least 17 total secondary endpoint cases at the time of accumulation of at least 17 primary 
efficacy cases, i.e., within 56 months from the time the first study participant signs the ICF, 
when the annual incidence rate of the secondary efficacy endpoint is 2.0% per year and true 
VE is equal to 85% (based on the same enrollment duration, attrition, and exclusions from 
the PPE population assumed in Section 9.9.1.
9.9.3
Sample Size and Power for Safety Analysis
The probability of observing at least one SAE in this study depends on the number of 
participants vaccinated and the underlying percentage of participants with SAE in the study 
population. If the underlying incidence of SAE is 0.5%, there is a 93% chance of observing 
at least one SAE among 525 participants in the 9vHPV vaccine group.  If no adverse 
experiences are observed among the 525 participants in the 9vHPV vaccine group, this study 
will provide 95% confidence that the underlying percentage of participants with an SAE is 
<0.6%.
9.10
Subgroup Analyses 
To determine whether the treatment effect is consistent across various subgroups, the point 
and 95% CI estimates of VE for the primary, the secondary efficacy and the exploratory 
endpoint will be provided by Age, Sexual Orientation, Smoking, Lifetime Sexual Partners, 
Presence of Other HPV Types.
Both for HM and MSM subgroups analyses will be performed for following endpoints.
Efficacy:
•
HPV 6/11/16/18-related anogenital persistent infection detected in samples from two or 
more consecutive visits 6 months (± 1-month window) or longer apart
•
HPV 31/33/45/52/58-related anogenital persistent infection detected in samples from two 
or more consecutive visits 6 months (± 1-month window) or longer apart
•
HPV 6/11/16/18/31/33/45/52/58-related anogenital persistent infection detected in 
samples from two or more consecutive visits 6 months (± 1-month window) or longer 
apart
•
HPV 6/11/16/18/31/33/45/52/58-related genital warts, PIN, penile, perianal or perineal 
cancer
•
HPV 6/11/16/18/31/33/45/52/58-related intra-anal persistent infection detected in 
samples from two or more consecutive visits 6 months (± 1-month window) or longer 
apart
•
HPV 6/11/16/18/31/33/45/52/58-related anogenital persistent infection detected in 
samples from three or more consecutive visits 6 months (± 1-month window) or longer 
apart (i.e., at least 12 months persistent infection)
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Immunogenicity:
•
GMT to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 at Month 7
•
Seroconversion to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 at Month 7
9.11
Compliance (Medication Adherence) 
Compliance in this study is defined as receipt of all 3 doses of the 9vHPV vaccine. To 
summarize compliance, the numbers of participants who receive each vaccination will be 
tabulated. For each of doses 2 and 3, histograms of the time (in weeks) of administration of the 
vaccine relative to the target vaccination visit will be provided. 
9.12
Extent of Exposure 
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered the 9vHPV or placebo.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study.  MSD will 
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support clinical trial investigators to enroll underrepresented groups and expand access to those who will 
ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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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 review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide their financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their 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 their 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.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
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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
Clinical Adjudication Committee (CAC)
A CAC, the HPV Vaccine Program Pathology Panel in this study, will evaluate the potential 
genital warts, PIN, penile, perianal or perineal cancer for the purposes of confirming them. 
The HPV Vaccine Program Pathology Panel will be responsible for providing the definitive 
pathologic diagnoses of external genital lesion biopsies for study purposes (not for medical 
management).  Slides from external genital lesion biopsies will be evaluated by HPV 
Vaccine Program Pathology Panel.  The HPV Vaccine Program Pathology Panel will prepare 
reports on each tissue specimen without knowing the vaccination groups of the participants.  
A separate guideline that details the HPV Vaccine Program Pathology Panel process has 
been approved by the HPV Vaccine Program Pathology Panel.
All personnel involved in the adjudication process will remain blinded to study intervention 
allocation throughout the study.
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 ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical 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, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
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 
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or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period 
(eg, EU CTR: 25 years after the end of the study). 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 
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investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
There are no protocol-specific requirements for safety laboratory testing.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.5.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will assess the intensity of 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 with a legally 
acceptable representative: awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies with a legally acceptable representative: 
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 used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies with a legally acceptable representative: extremely distressed or unable to do 
usual activities).
•
Injection-site erythema/redness or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
Assessment of causality
•
Did the study intervention cause the AE?
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•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a
relationship between the test product and the AE based on the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (diary, etc.), 
seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant reexposed to the study intervention in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose vaccine study; or (3) study 
intervention(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
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-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.5.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Combination Medicinal Products: Complaints, Product Quality 
Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in the protocol apply to combination 
medicinal products as described below. For purposes of this section, combination medicinal 
products in scope for device information collection include combination medicinal products 
as listed in Section 6.1.1. Product Quality Complaints/Malfunctions must be reported to the 
Sponsor.
10.4.1
Definitions
Medical Device – Devices, etc, (other than regenerative medicine products) intended for use 
in the diagnosis, treatment, or prevention of disease in humans or animals, or intended to 
affect the structure or functions of the body of humans or animals.
Combination Medicinal Product – The products to be manufactured and marketed as a 
single drug, medical device, or regenerative medical product by combining two or more 
different type of drugs, medical devices or processed cells that are presumed to fall under the 
category of drugs, medical devices, or regenerative medical products if it is distributed alone.
Malfunction – When the device constituent part of a combination medicinal product, as 
described in the protocol, has quality, safety, or performance issue, such as damage or failure 
in operation, regardless of the stage of design, delivery, storage, or use.
Serious Adverse Event Due to Malfunction – A SAE occurring in a participant and/or the 
associated person in a clinical trial caused by, or suspected to be caused by, the use of the 
device constituent part of the combination medicinal product, as described in the protocol.
Malfunction That May Lead to Serious Adverse Events – Any malfunction of a device 
constituent part of a combination medicinal product, as described in the protocol, which 
might have led to the death of a participant and/or the associated person or to a serious 
deterioration in their state of health. “Which might have led to” means there is the possibility 
that death or a serious deterioration might have occurred in a participant and/or the associated 
person, although no event has occurred.
10.4.2
Recording, Assessing Causality, and Follow-up of Complaints, 
PQCs/Malfunctions
Recording
•
When a Complaint, PQC/malfunction occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.
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•
AEs occurring during the study will be recorded in the participant’s medical records (or 
equivalent), in accordance with the investigator’s normal clinical practice, and on the 
appropriate CRF (paper or electronic) as per instructions in the data entry guidelines (or 
equivalent). Device constituent part of drug-device combination product/combination 
medicinal product information (regardless of participants or associated persons) will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 
8.5.1 via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
•
It is important that the investigator provides an assessment of causality (relationship to 
the medical device) at the time of the initial report.
•
Malfunction, which may lead to SAEs, will be reported to the Sponsor within 5 calendar 
days of learning of the information via a paper reporting form.
Assessing Causality
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes should also be considered and investigated, such as underlying 
disease(s), concomitant therapy, and other risk factors as well as the temporal relationship 
of the event to study intervention administration.
Follow-up
•
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
Not applicable.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.10 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
9vHPV
9-valent human papillomavirus
AE
adverse event 
AIN
Anal intraepithelial neoplasia
ANPS
All Naïve Participants with Serology
APaT
All Participants as Treated
CI
confidence interval
cLIA
competitive Luminex Immunoassay
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
Clinical Study Report
DNA
deoxyribonucleic acid 
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice 
GMT
Geometric mean titer
H&E
hematoxylin & eosin
HIV
human immunodeficiency virus
HM
heterosexual males
HN-TS
HPV Type-Specific Naïve 
HPV
human papillomavirus
HSV
herpes simplex virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
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Abbreviation
Expanded Term
IEC
Independent Ethics Committee
IRB
Institutional Review Board 
IRT
interactive response technology
IVIG
intravenous gamma globulin
LLOQ
lower limit of quantitation
mMU/mL
milli-Merck Units per milliliter
MSM
males who have sex with males
PCR
polymerase chain reaction
PIN
penile/perianal/perineal intraepithelial neoplasia
PK
pharmacokinetic
PPE
Per-Protocol Efficacy
PPI
Per-Protocol Immunogenicity
PQC
product quality complaint
qHPV
quadrivalent HPV
RCD
reverse cumulative distribution
RNA
ribonucleic acid
SAE
serious adverse event 
SoA
schedule of activities
sSAP
supplemental statistical analysis plan
STI
Sexually Transmitted Infection
SUSAR
suspected unexpected serious adverse reaction
TNF-α
tumor necrosis factor-alpha
ULOQ
upper limit of quantitation
VE
vaccine efficacy
VLP
virus-like particle
VRC
vaccination report card
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