A Phase III Placebo-controlled Clinical Trial to Study the Tolerability, Immunogenicity and Efficacy of V501 in 16- to 26-year-old Japanese Men
Phase: PHASE3
Conditions: Anogenital Human Papilloma Virus Infection, Condyloma Acuminata
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT01862874 
Document Date: 
4-Apr-2013
A Phase III Placebo-controlled Clinical Trial to Study the 
Tolerability, Immunogenicity and
Efficacy of V501 in 16- to 26-year-old Japanese men

Product:  V501 
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Protocol/Amendment No.: 122-00 
V501-122-00 Final Protocol
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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE 
STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder.
TITLE:
A Phase III Placebo-controlled Clinical Trial to Study the Tolerability, Immunogenicity and 
Efficacy of V501 in 16- to 26-year-old Japanese men
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................. 10
2.0
TRIAL DESIGN........................................................................................................ 10
2.1
Trial Design ........................................................................................................... 10
2.2
Trial Diagram........................................................................................................ 11
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 11
3.1
Primary Objective(s) & Hypothesis(es) .............................................................. 11
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 12
3.3
Exploratory Objective(s)...................................................................................... 12
4.0
BACKGROUND & RATIONALE.......................................................................... 12
4.1
Background ........................................................................................................... 12
Pharmaceutical and Therapeutic Background .................................................... 12
4.1.1
4.1.1.1
Disease Burden and Epidemiology of Human Papillomaviruses ................ 13
4.1.1.2
Biology of Human Papillomaviruses ........................................................... 14
4.1.1.3
Prophylactic HPV Vaccines......................................................................... 14
4.2
Rationale................................................................................................................ 15
Rationale for the Trial and Selected Subject Population .................................... 15
4.2.1
Rationale for Dose Selection/Regimen............................................................... 15
4.2.2
Rationale for Endpoints ...................................................................................... 16
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 16
4.2.3.2
Immunogenicity Endpoints.......................................................................... 16
4.2.3.3
Safety Endpoints.......................................................................................... 16
4.2.3.4
Future Biomedical Research........................................................................ 17
5.0
METHODOLOGY ................................................................................................... 17
5.1
Entry Criteria........................................................................................................ 17
Diagnosis/Condition for Entry into the Trial...................................................... 17
5.1.1
Subject Inclusion Criteria.................................................................................... 17
5.1.2
Subject Exclusion Criteria .................................................................................. 18
5.1.3
5.2
Trial Treatments................................................................................................... 19
Dose Selection .................................................................................................... 20
5.2.1
 
 
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5.2.1.1
Dose Selection ............................................................................................. 20
Timing of Dose Administration .......................................................................... 20
5.2.2
Trial Blinding/Masking....................................................................................... 20
5.2.3
5.3
Randomization or Treatment Allocation............................................................ 20
5.4
Stratification.......................................................................................................... 20
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 20
5.6
Rescue Medications & Supportive Care............................................................. 21
5.7
Diet/Activity/Other Considerations..................................................................... 21
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 21
5.9
Subject Replacement Strategy............................................................................. 21
5.10
Beginning and End of the Trial ........................................................................... 21
5.11
Clinical Criteria for Early Trial Termination ................................................... 22
6.0
TRIAL FLOW CHART ........................................................................................... 23
7.0
TRIAL PROCEDURES ........................................................................................... 25
7.1
Trial Procedures ................................................................................................... 25
Administrative Procedures.................................................................................. 25
7.1.1
7.1.1.1
Informed Consent......................................................................................... 25
7.1.1.1.1
General Informed Consent.................................................................... 25
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 25
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 26
7.1.1.3
Subject Identification Card .......................................................................... 26
7.1.1.4
Medical History ........................................................................................... 26
7.1.1.5
Sexual History.............................................................................................. 26
7.1.1.6
Prior and Concomitant Medications Review ............................................... 26
7.1.1.6.1
Prior Medications.................................................................................. 26
7.1.1.6.2
Concomitant Medications..................................................................... 27
7.1.1.7
Assignment of Screening Number............................................................... 27
7.1.1.8
Assignment of Randomization Number....................................................... 27
7.1.1.9
Study Vaccine Administration..................................................................... 27
7.1.1.9.1
Preparation for Administration ............................................................. 27
7.1.1.9.2
Study Vaccine Administration.............................................................. 27
 
 
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7.1.1.10 Trial Compliance ......................................................................................... 28
Clinical Procedures/Assessments........................................................................ 28
7.1.2
7.1.2.1
Anogenital Physical Examination................................................................ 28
7.1.2.2
Vital Signs.................................................................................................... 28
7.1.2.3
Vaccination Report Card (VRC).................................................................. 28
Laboratory Procedures/Assessments .................................................................. 29
7.1.3
7.1.3.1
External Genital Lesion Examination.......................................................... 29
7.1.3.1.1
Procedure for Penile and Scrotal Examination..................................... 29
7.1.3.1.2
Procedure for Perineal/Perianal Examination....................................... 30
7.1.3.2
Swab for HPV PCR ..................................................................................... 30
7.1.3.2.1
Penile/Glans Penis File and Wetted Swab for HPV PCR..................... 30
7.1.3.2.2
Scrotal File and Wetted Swab for HPV PCR ....................................... 32
7.1.3.2.3
Perineal/Perianal File and Wetted Swab for HPV PCR ....................... 32
7.1.3.2.4
Intra-anal Wetted Swab for HPV PCR ................................................. 33
7.1.3.3
External Genital Lesion Biopsy................................................................... 33
7.1.3.4
Serum for Anti-HPV Measurements............................................................ 35
7.1.3.5
STI Testing................................................................................................... 36
7.1.3.6
Future Biomedical Research........................................................................ 36
Other Procedures................................................................................................. 36
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 36
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 36
7.1.4.2
Blinding/Unblinding .................................................................................... 37
7.1.4.3
Specimens Taken Outside the Context of the Study.................................... 37
7.1.4.4
Subject Relocation ....................................................................................... 37
Visit Requirements.............................................................................................. 37
7.1.5
7.1.5.1
Prerequisites for Study Vaccination Visit.................................................... 38
7.1.5.2
Prerequisites for Study Visits with Specimen Collection............................ 38
7.2
Assessing and Recording Adverse Events .......................................................... 38
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 39
Immediate Reporting of Adverse Events to the Sponsor.................................... 39
7.2.2
7.2.2.1
Serious Adverse Events ............................................................................... 39
7.2.2.2
Events of Clinical Interest............................................................................ 40
 
 
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Evaluating Adverse Events ................................................................................. 40
7.2.3
Sponsor Responsibility for Reporting Adverse Events ...................................... 43
7.2.4
7.3
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 43
Data Monitoring Committee ............................................................................... 43
7.3.1
Clinical Adjudication Committee ....................................................................... 43
7.3.2
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 44
8.1
Statistical Analysis Plan Summary ..................................................................... 44
Efficacy Analyses ............................................................................................... 44
8.1.1
Safety Analyses................................................................................................... 44
8.1.2
Immunogenicity Analyses .................................................................................. 44
8.1.3
Power and Sample Size....................................................................................... 44
8.1.4
Interim Analysis.................................................................................................. 45
8.1.5
8.2
Statistical Analysis Plan ....................................................................................... 45
Responsibility for Analyses ................................................................................ 45
8.2.1
Trial Objectives................................................................................................... 45
8.2.2
Analysis Endpoints ............................................................................................. 45
8.2.3
8.2.3.1
Efficacy Endpoints....................................................................................... 45
8.2.3.2
Immunogenicity Endpoints.......................................................................... 46
8.2.3.3
Safety Endpoints .......................................................................................... 46
Analysis Populations........................................................................................... 47
8.2.4
8.2.4.1
Efficacy Analysis Population....................................................................... 47
8.2.4.2
Immunogenicity Analysis Populations ........................................................ 48
8.2.4.3
Safety Analysis Population.......................................................................... 49
Statistical Methods.............................................................................................. 49
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses................................................... 49
8.2.5.2
Statistical Methods for Immunogenicity Analyses ...................................... 51
8.2.5.3
Statistical Methods for Safety Analyses ...................................................... 52
8.2.5.4
Subgroup Analyses and Effect of Baseline Factors..................................... 52
Multiplicity ......................................................................................................... 53
8.2.6
Sample Size and Power Calculations.................................................................. 53
8.2.7
Interim Analysis.................................................................................................. 53
8.2.8
Compliance ......................................................................................................... 54
8.2.9
 
 
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Missing Data ....................................................................................................... 54
8.2.10
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 55
9.1
Investigational Product ........................................................................................ 55
9.2
Packaging and Labeling Information ................................................................. 55
9.3
Clinical Supplies Disclosure................................................................................. 55
9.4
Storage and Handling Requirements.................................................................. 55
9.5
Returns and Reconciliation.................................................................................. 56
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 56
10.1
Confidentiality....................................................................................................... 56
Confidentiality of Data ....................................................................................... 56
10.1.1
Confidentiality of Subject Records ..................................................................... 56
10.1.2
Confidentiality of Investigator Information........................................................ 56
10.1.3
Confidentiality of IRB/IEC Information............................................................. 57
10.1.4
10.2
Compliance with Financial Disclosure Requirements....................................... 57
10.3
Compliance with Law, Audit and Debarment ................................................... 57
10.4
Compliance with Trial Registration and Results Posting Requirements ........ 59
10.5
Quality Management System............................................................................... 59
10.6
Data Management................................................................................................. 60
10.7
Publications ........................................................................................................... 60
11.0
LIST OF REFERENCES......................................................................................... 61
12.0
APPENDICES........................................................................................................... 64
12.1
Merck Code of Conduct for Clinical Trials........................................................ 64
12.2
Collection and Management of Specimens for Future Biomedical 
Research................................................................................................................. 66
12.3
Pharmacogenetics Informational Brochure for IRBs/IECs & 
Investigational Site Staff ...................................................................................... 72
12.4
Clinical Study Conduct System ........................................................................... 81
Sponsor ............................................................................................................... 81
12.4.1
12.4.1.1 Name and Address of Sponsor..................................................................... 81
12.4.1.2 Sponsor’s Representative............................................................................. 81
12.4.1.3 Medical Expert............................................................................................. 81
 
 
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12.4.1.4 Field Monitor (CRA) Representative........................................................... 81
Clinical Research Organizations......................................................................... 82
12.4.2
Investigator ......................................................................................................... 82
12.4.3
13.0
SIGNATURES........................................................................................................... 83
13.1
Sponsor's Representative ..................................................................................... 83
13.2
Investigator............................................................................................................ 83
 
 
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LIST OF TABLES
    
Table 1 Trial Vaccination ....................................................................................................... 19
Table 2 Evaluating Adverse Events........................................................................................ 41
Table 3 Summary of Analysis Strategy for Efficacy Endpoint .............................................. 44
Table 4 Acceptable Day Ranges for Vaccination Visits......................................................... 48
Table 5 Acceptable Day Ranges for Collection of Serum Samples ....................................... 49
Table 6 Efficacy Endpoints, Statistical Methods and Analysis Populations .......................... 50
Table 7 Summary of Interim Analysis Strategy ..................................................................... 53
Table 8 Alpha Spending and Corresponding Powers at Interim Analysis and Final 
Analysis....................................................................................................................... 54
Table 9 Product Descriptions.................................................................................................. 55
 
 
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LIST OF FIGURES
Figure 1 Trial Design.............................................................................................................. 11
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Tolerability, immunogenicity and efficacy trial of V501 in Japanese 
men
Trial Phase
Phase III
Clinical Indication
Prevention of condyloma acuminata, and anal cancers and related 
precancers caused by Human Papillomavirus (HPV) 6, 11, 16 and 18
Trial Type
Interventional
Type of control
Placebo
Route of administration
Intramuscular
Trial Blinding
Double-blind
Treatment Groups 
V501 or placebo
Number of trial subjects
Approximately 1,100 subjects will be enrolled.
The enrollment of approximately 10% of Men who have sex with men 
(MSM) is targeted
Estimated duration of trial
The sponsor estimates that the trial will require approximately 50
months (Study Period for Clinical Trial Notification (CTN): From 
May 2013 to Dec 2017) from the time the first subject signs the 
informed consent until the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial for approximately 36 months, 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  Each subject will be receiving 3 doses of 
the study vaccine intramuscularly at Day 1, Month 2 and Month 6.
After the completion of vaccination each subject will be followed for
approximately 30 months.
2.0 TRIAL DESIGN
2.1
Trial Design
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial of 
V501 [quadrivalent HPV (Type 6, 11, 16 and 18) L1 Virus-like Particle (VLP) vaccine] in 
healthy male subjects to be conducted in conformance with Good Clinical Practices.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
The primary analysis is case driven and will be conducted after at least 18 primary efficacy 
cases have been observed. In addition, an interim analysis will be performed when at least 11
Randomization Ratio
Subject will be randomized in 1:1 ratio to V501 or placebo.
 
 
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primary efficacy cases have been observed. Results of the interim analysis will be reviewed 
by external Data Monitoring Committee (DMC). If the results meet the criteria (see Section 
8.2.8 for the detail of criteria), DMC will make recommendation to the Sponsor to unblind 
and conduct the primary efficacy analysis with at least 11 primary efficacy cases. If not, the 
primary analysis will be conducted when 18 primary efficacy cases have been observed.
Since the primary efficacy analysis will be conducted prior to completion of the study
irrespective of the results of interim analysis, the remainder of the study is considered as an 
extension. The purpose of the extension is to collect data on the longer-term efficacy, 
tolerability, and immunogenicity of the vaccine.
The interim analysis will be conducted by the unblinded statistician. The clinical, statistical 
and data management study personnel at the Sponsor who are involved with study conduct 
will be blinded to subject vaccination group allocations during the process of interim analysis, 
and remain blinded until either the DMC recommends to unblind or 18 cases of the primary 
efficacy endpoint have been observed and the database is unblinded for the analysis. 
Laboratory personnel, the pathology panel, and the investigators, site personnel and subjects 
will remain blinded to whether subjects received V501 or Placebo throughout the entire study 
period.
2.2
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1 Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
(1)
Objective:  To demonstrate that a 3-dose regimen of V501 will reduce the combined 
incidence of HPV 6-, 11-, 16- or 18-related persistent infection detected in samples 
from two or more consecutive visits (±1 month visit windows) 6 month or longer 
apart compared with placebo in 16- to 26-year-old Japanese men who are 
seronegative at Day 1 and polymerase chain reaction (PCR) negative Day 1 through 
Month 7 to the relevant HPV type.
 
 
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Hypothesis:  A 3-dose regimen of V501 to 16- to 26-year-old Japanese men who are 
seronegative at Day 1 and PCR negative Day 1 through Month 7 to the relevant HPV 
type reduces the combined incidence of HPV 6-, 11-, 16- or 18-related persistent 
infection detected in samples from two or more consecutive visits (±1 month visit 
windows) 6 month or longer apart compared with placebo. The statistical criterion for 
success requires that the lower bound of the two-sided 95% confidence interval for 
the vaccine efficacy excludes 0%.
(2)
Objective: To demonstrate that a 3-dose regimen of V501 to 16- to 26-year-old 
Japanese men is generally well tolerated.
3.2
Secondary Objective(s) & Hypothesis(es)
(1)
Objective: To demonstrate that a 3-dose regimen of V501 will reduce the combined 
incidence of HPV 6-, 11-, 16- or 18-related persistent infection, condyloma 
acuminata, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal or 
perineal cancer compared with placebo in 16- to 26-year-old Japanese men who are 
seronegative at Day 1 and PCR negative Day 1 through Month 7 to the relevant HPV 
type. 
Hypothesis: A 3-dose regimen of V501 to 16- to 26-year-old Japanese men who are 
seronegative at Day 1 and PCR negative Day 1 through Month 7 to the relevant HPV 
type reduces the combined incidence of HPV 6-, 11-, 16- or 18-related persistent 
infection, condyloma acuminata, penile/perianal/perineal intraepithelial neoplasia 
(PIN), penile, perianal or perineal cancer compared with placebo. The statistical 
criterion for success requires that the lower bound of the two-sided 95% confidence 
interval for the vaccine efficacy exclude 0%. 
3.3
Exploratory Objective(s) 
(1)
Objective:  To evaluate the anti-HPV 6, 11, 16 or 18 immune responses generated by 
V501 in all subjects, Heterosexual Men (HM) subjects group and Men who have Sex 
with Men (MSM) subjects group, respectively.
(2)
Objective: To evaluate that a 3-dose regimen of V501 will reduce the combined 
incidence of HPV 6-, 11-, 16- or 18-related condyloma acuminata compared with 
placebo in 16- to 26-year-old Japanese men who are seronegative at Day 1 and PCR 
negative Day 1 through Month 7 to the relevant HPV type.
4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on V501.
Pharmaceutical and Therapeutic Background
4.1.1
V501 is quadrivalent HPV (Types 6, 11, 16 and 18) vaccine having been developed based on 
VLPs, which are produced by self-assembly of recombinant HPV L1 capsid proteins
 
 
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4.1.1.1
Disease Burden and Epidemiology of Human Papillomaviruses
HPV infection causes benign and malignant dysplastic disease, localized primarily in the 
anogenital area, and also in the aerodigestive tract, in both men and women [1, 2, 3]. Disease 
burden of HPV in men includes:
Anogenital Warts. Anogenital warts are generally benign, exophytic, hyperkeratotic lesions 
on the penile shaft (most common site of lesions), scrotum, perineum, and anus in men. In
general, the lesions do not cause any physical discomfort [4]. Some patients experience
itching, burning, bleeding, moisture, irritation or soreness, especially with lesions in the
perianal region. Patients are often distressed by unsightly lesions. Treatment consists of
chemical or physical ablation and is often unsuccessful. Recurrence rates are high [5]. While 
Japan’s Infectious Disease Surveillance system [6] publishes the counts of genital warts cases 
that are reported into the surveillance system, it does not report actual incidence rates.  
However, the surveillance system does show a nominally higher number of warts cases in 
males compared to females.  This is consistent with most worldwide data, showing slightly 
higher rate of genital warts in males than in females.
Anal Cancer and Penile Cancer. Most anal cancers, and ~50% of penile cancers are caused 
by HPV. Rates of anal cancer are increasing [7, 8].  
The cumulative lifetime risk for HPV infection in sexually active women exceeds 50%. 
Available data suggest that HPV infection is also very prevalent in men [9, 10]. HPV 
infection is transmitted via contact with an infected individual or a contaminated object and 
occurs most often during sexual activity. Sixty percent (60%) of sexual partners of infected 
individuals develop lesions 4 weeks to 8 months after exposure [11]. HPV is often acquired 
immediately after sexual debut. The risk of HPV infection is strongly correlated with the 
number of lifetime sexual partners [12, 13]. Men and women 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 new sexual partners, thus increasing the risk of exposure 
to the virus. 
A few prospective studies have examined the incidence and duration of genital HPV 
infection in men. These studies indicate that HPV infection in men is self-limited and a risk 
factor for HPV genital disease. It appears that the majority of HPV infections in men clear 
within 12 months with a median time of clearance of ranging from 5.9 to 7.5 months [14, 15]. 
However, HPV 16 infections tend to last longer and clear at a median of 12.2 months [15].
HPV testing positive for HPV 6 or 11 is the strongest predictor of developing genital warts
[16]. HPV 16 infection is a recognized risk factor for penile cancer [17].
Infection with HPV has been shown to be associated with cervical, vulvar, vaginal, anal,
penile, oral and oropharyngeal cancers in women and/or men [1, 2]. Each of non-cervical
HPV-related diseases is much less frequent than cervical cancer. But taken together, they 
represent a significant human health and economic burden in both men and women [9, 18]. 
Of particular concern, the incidence of anal cancer has been increasing over the past several 
decades [19]. The risk of anal cancer is increased in men and women with a high number of 
sexual partners, current smokers, and among men who are not exclusively heterosexual or 
women who have a history of receptive anal intercourse [20]. Anal cancer is preceded by 
high-grade anal intraepithelial neoplasia (AIN) [21, 22]. Over 80% of anal cancers and over 
 
 
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90% of high-grade AIN contain high-risk HPV [23]. The high proportion of HPV-positive 
tumors suggests that HPV infection is necessary for developing anal cancer. 
4.1.1.2
Biology of Human Papillomaviruses
HPV consist of a family of small, nonenveloped icosahedral capsid viruses containing
double-stranded DNA. 2 capsid proteins are encoded in the viral genome; L1, major capsid 
protein and L2, minor capsid protein. Mature viral particles are composed of 72 pentamers of 
L1 proteins arranged in icosahedral symmetry. 
HPV types targeted by V501 belong to Species A7, A9, and A10. Species A7 and A9 contain 
most of the high-risk types. Species A10 contains low-risk HPV Types 6 and 11, which are 
responsible for over 90% of anogenital warts. The A7 Species includes HPV 18, 39, 45, 59, 
and 68. The A9 Species includes HPV 16, 31, 33, 35, 52, and 58. HPV 16 and 18 are
responsible for most cases of anal cancer [23]. 
HPV infection and replication is entirely intraepithelial. By remaining exclusively 
intraepithelial, HPV largely avoids exposure to the host immune system and evades immune 
recognition, which allows HPV infection to proceed [24, 25, 26]. Accordingly, immune 
responses to natural viral infection are poor. Nonetheless, most HPV infections are 
eventually cleared. It is thought that naturally acquired immune responses contribute to the 
clearance of infection, although the mechanisms are not well elucidated [27]. Those 
infections that are not cleared can result in dysplasia and cancer (especially the high-risk 
types).
4.1.1.3
Prophylactic HPV Vaccines
A 3-dose regimen of V501 is delivered intramuscularly and induces high levels of type-
restricted neutralizing antibodies and seroconversion in virtually 100% of the vaccinated 
subjects.
As 
of 
June 
2012, 
V501 
was 
approved 
and 
marketed 
under 
the 
names
GARDASIL™/SILGARD™in over 120 countries including Japan. In clinical trials in 16- to 
26-year-old women, prophylactic efficacy against HPV 6, 11, 16 and 18 related lesions have 
already been shown [28]. Efficacy was maintained for at least 5 years postvaccination onset 
[29]. Moreover, in an overseas Phase III study (V501 Protocol 020), V501 was found to be 
over 89% and 85% efficacious in preventing the development of HPV 6- or 11-related 
condyloma acuminata and HPV 6-, 11-, 16- or 18-related persistent infection in 16- to 26-
year-old men, respectively [30], and 77.5% efficacious in preventing HPV 6-, 11-, 16- or 18-
related AIN in 16- to 26-year-old MSM [31]. Based on these data, V501 has also been 
approved for males for prevention of vaccine type HPV-related genital warts and anal cancer 
and/or precancers in over 70 countries. In US, the Advisory Committee on Immunization 
Practices (ACIP) recommended routine use of GARDASIL™in males 11 or 12 years of age
in addition to the vaccination to females [32]. However, male indication of V501 has not 
been approved yet in Japan.
 
 
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4.2
Rationale
Rationale for the Trial and Selected Subject Population
4.2.1
HPV vaccination could contribute to reducing the burden of HPV diseases in males. V501 is 
highly efficacious to prevent vaccine type HPV-related genital warts and anal cancer and
precancers in males overseas. Moreover, in contrast to cervical cancer in women, there is no 
widespread screening program for any HPV related cancers in men, making prophylactic 
vaccination the only realistic preventive measure for HPV diseases in men, in both developed 
and developing countries. An additional potential benefit of HPV vaccination in men is the 
generation of herd protection, which in turn could lead to a substantial reduction of HPV 
diseases in both males and females [9].
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. 
This trial is designed to bridge V501 efficacy finding in overseas clinical trial, V501-020, to 
Japanese young men, via the demonstration of the efficacy against HPV type 6, 11, 16 or 18 
persistent infection in Japanese young men. Considering the comparison between this trial 
data and previous trial data (V501-020), 16 to 26 years old HM and MSM are selected as this 
trial population in a manner consistent with Protocol V501-020. The enrollment of 
approximately 10% of MSM subject is targeted in this trial. Please note “10%” is a target 
number considering the challenging nature of MSM enrollment in Japan from operational 
aspect. In addition, subjects will be enrolled regardless of the history of circumcision.
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and Informed Consent documents.
Subjects in clinical trials generally cannot expect to receive direct benefit from vaccination
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational vaccine.
Rationale for Dose Selection/Regimen
4.2.2
In Japan, V501 has been approved and marketed under the name of GARDASIL™only for 
women 9 years of age or older. However, V501 has been approved for both females and 
males outside Japan and its effectiveness is well established. The formulation and regimen 
are identical between females and males. Therefore, the same regimen (3 doses at Day 1, 
Month 2 and Month 6) and formulation (HPV 6 L1 VLP 20 µg, HPV 11 L1 VLP 40 µg, 
HPV 16 L1 VLP 40 µg, HPV 18 L1 VLP 20 µg and Amorphous Aluminum Hydroxyl 
phosphate Sulfate (AAHS) 225 µg) as approved many countries including Japan will be used 
in this trial. In addition, placebo (including AAHS 225 µg) will be included in this trial to 
demonstrate the efficacy of V501.
 
 
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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The primary efficacy endpoint is the incidence of HPV 6-, 11-, 16- or 18-related persistent 
infection. This endpoint was chosen based on the finding from overseas V501 phase III trial 
in men (Protocol V501-020) that HPV related persistent infection is a predictor of HPV 
related diseases in men. In Protocol V501-020, V501 showed prophylactic efficacy against 
HPV 6-, 11-, 16- or 18-related condyloma acuminata as well as HPV 6-, 11-, 16- or 18-
related persistent infection in 16- to 26-year-old men. Additionally, the composite incidence 
of HPV 6-, 11-, 16- or 18-related persistent infection and condyloma acuminata, PIN, penile, 
perianal or perineal cancer are investigated as for the secondary endpoint. 
Subjects will undergo sampling from the penis, scrotum, and perianal region using a nail file 
followed by a wetted DACRONTM swab system for HPV PCR testing. Also, an intra-anal 
swab specimen for HPV PCR will be collected. 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 subjects who have an active HPV infection at 
enrollment and to determine persistent HPV infection endpoints.
A detailed genitourinary and perianal inspection will be performed. If a lesion observed at 
Day 1 is assessed to be possibly, probably or definitely HPV-related or of unknown etiology, 
then the subject 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. 
Tissues 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.
4.2.3.2
Immunogenicity Endpoints
Anti-HPV 6, 11, 16 or 18 will be analyzed as the indicator of immune responses to each 
vaccine components. 
Serum will be collected from all subjects for analysis of anti-HPV 6, 11, 16 and 18 by
competitive Luminex Immunoassay (cLIA). Serum sample will be collected at Day 1 for 
identification of subjects who had an HPV infection prior to enrollment.
Findings from the V501 phase III trial in men (Protocol V501-020) indicate that antibody 
responses to the vaccine are markedly reduced in MSM subjects compared to HM subjects. 
Therefore, immunogenicity of V501 will be summarized separately in these 2 populations in 
addition to all subjects group.
4.2.3.3
Safety Endpoints
Since majority of the adverse events (AEs) occurs within a few days after the vaccination, the 
subjects will be followed for 14 days following each vaccination. The Vaccination Report 
 
 
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Card (VRC) will be utilized to collect subject’s (1) oral temperature and local (i.e., injection-
site) AEs (including erythema, swelling and pain/tenderness) for 5 days starting the day of 
each vaccination, (2) systemic AEs and serious adverse events (SAEs) for 15 days (14 days 
following each vaccination), and (3) vaccine-related SAEs and deaths throughout the study.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA (blood) specimens collected 
during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs, and/or to ensure that subjects receive the 
correct dose of the correct drug at the correct time.  The details of this Future Biomedical 
Research sub-trial are presented in Section 12.2 - Collection and Management of Specimens 
for Future Biomedical Research.  Additional informational material for institutional review 
boards/ethics committees (IRBs/ERCs) and investigational site staff is provided in Section 
12.3.
5.0 METHODOLOGY
5.1
Entry Criteria
Diagnosis/Condition for Entry into the Trial
5.1.1
Healthy Male subjects between the ages of 16 and 26 years (inclusive) will be enrolled in this 
trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be a healthy, Japanese male between the ages of 16 years and 0 days and 26 years 
and 364 days.
2.
Fully understand (or, for minor subjects, parent/legal guardian and subject) study 
procedures, alternative treatments available, the risks involved with the study, and 
voluntarily agrees to participate by giving written informed consent. The subject may 
also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
 
 
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3. Agree to provide study personnel with a primary telephone number as well as an 
alternate telephone number for follow-up purposes
4. Have no clinical evidence of gross genital lesion suggesting sexually-transmitted 
disease and no clinically present external genital warts.
5. *Show no temperature ≥37.5°C (oral) within 24 hours prior to vaccinations.
6. *Agree to refrain from sexual activity (including vaginal and anal penetration and any 
genital contact) for 2 calendar days 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: Subjects 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: Subjects must identify themselves as a man who has sex with men, 
must have engaged in either insertive or receptive anal intercourse or oral sex with 
another male sexual partner within the past year, and have 0 to 5 lifetime male and/or 
female sexual partners at the enrollment. 
For protocol purposes, a female sexual partner is defined as a woman with whom the 
subject has engaged in vaginal intercourse. For protocol purposes, a male sexual 
partner is defined as a man with whom the subject engaged in insertive or receptive 
anal intercourse. 
For items with an asterisk (*), if the subject does not meet these inclusion criteria, the Day 1 
visit be rescheduled for a time when these criteria can be met.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is concurrently enrolled in clinical studies of investigational agents or studies 
involving collection of genital specimens.
2. Has history of known prior vaccination with an HPV vaccine or plans to receive the 
HPV vaccine outside of the study.
3. *Has receipt of inactivated vaccines within 14 days prior to enrollment or receipt of 
live virus vaccines within 28 days prior to enrollment.
4. Has history of external genital warts, or has clinically present external genital warts at 
Day 1.
5. Has 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]).
7. Has received any immune globulin or blood derived products within the 6 months 
prior to the first injection, or plan to receive any through Month 7 of the study.
 
 
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8. Has history of splenectomy or is currently immunocompromised or has been 
diagnosed as having a congenital or acquired immunodeficiency, HIV infection, 
lymphoma, leukemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, 
juvenile rheumatoid arthritis (JRA), inflammatory bowel disease, or other auto 
immune condition.
9. Is receiving, or has received in the year prior to enrollment the following 
immunosuppressive therapies: radiation therapy, cyclophosphamide, azathioprine, 
methotrexate, any chemotherapy, cyclosporin, leflunomide, TNF-α antagonists, 
monocolonal antibody therapies (including rituximab), intravenous gamma globulin, 
antilymphocyte sera, or other therapy known to interfere with the immune response.  
With regard to systemic corticosteroids, a subject will be excluded if he is currently 
receiving  steroid therapy, has recently (defined as within 2 weeks of enrollment) 
received such therapy, or has received 2 or more courses of  high dose corticosteroids 
(orally or parenterally) lasting at least 1 week in duration in the year prior to 
enrollment. Subjects using inhaled, nasal, or topical corticosteroids are considered 
eligible for the study.
10. Has known thrombocytopenia or any coagulation disorder that would contraindicate 
intramuscular injections.
11. Has history of recent (within the last 12 months) or ongoing alcohol or drug abuse.
Alcohol and drug abusers are defined as those who drink or use drugs despite 
recurrent social, interpersonal, and legal problems as results of alcohol or drug use.
12. 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 
subject’s participation for the full duration of the study, such that it is not in the best 
interest of the subject to participate.
13. Is unlikely to adhere to the study procedures, keep appointments, or is planning to 
relocate during the study.
For items with an asterisk (*), if the subject does not meet these exclusion criteria, the visit 
be rescheduled for a time when these criteria can be met.
5.2
Trial Treatments
The vaccine to be used in this trial is outlined below in Table 1.
Table 1 Trial Vaccination
Study 
Vaccine
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use 
V501
0.5 mL 
3
Intramuscular 
injection
Day 1, Month 2 and 
Month 6
Investigational
Placebo
(including 
AAHS 
225µg)
0.5 mL
3
Intramuscular 
injection
Day 1, Month 2 and 
Month 6
Placebo-comparator
 
 
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Trial vaccination is given on the day of randomization or as close as possible to the date on 
which the subject is allocated/assigned.
Dose Selection
5.2.1
5.2.1.1
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Timing of Dose Administration
5.2.2
V501 or placebo will be administered as a 0.5 mL intramuscular injection at Day 1, Month 2 
and Month 6. 
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used.  V501 and placebo will be packaged 
identically so that blind/masking is maintained. The subject, the investigator and Sponsor 
personnel or delegate(s) who are involved in the treatment or clinical evaluation of the 
subjects are unaware of the group assignments.
The SPONSOR personnel who are involved with study conduct will be unblinded to subject 
vaccination group assignments when the database is unblinded for the primary efficacy 
analysis. The primary efficacy analysis is case driven and may be conducted prior to the end 
of study. Therefore, the database may be unblinded during the study. However, laboratory 
personnel, the pathology panel, and the investigators, site personnel and subjects will remain 
blinded to whether subjects received V501 or Placebo throughout the entire study period. 
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
5.3
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS).  There are 2 vaccination arms.  Subjects will be 
assigned randomly in an 1:1 ratio to V501 and placebo, respectively.
5.4
Stratification
Randomization will be stratified according to the following factors:
1. HM or MSM
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited)
See the exclusion criteria for specific restrictions for prior and concomitant medications at 
Visit 1 (Day 1).
To reduce their potential interference with the evaluation of the immunologic response and 
reactogenicity of the study vaccine or placebo, non-study inactivated vaccines must not be 
administered within the 14 days before or 14 days after any dose of study vaccine. Non-study 
 
 
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live virus vaccines must not be administered within the 28 days prior to or 14 days after any 
dose of study vaccine. Non-study HPV vaccine must not be used at any time during the 
study. Immune globulin or blood-derived products must not be administered within 6 months 
prior to vaccination and should not be administered during the vaccination series or at any 
other time during the study, if at all possible. Systemic corticosteroids should not be 
administered within 2 weeks prior to vaccination through Month 7, if at all possible.
Subjects may receive allergen desensitization therapy and tuberculin skin testing while
participating in the study.
5.6
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
5.7
Diet/Activity/Other Considerations
No special restrictions will apply except for those noted under the inclusion/exclusion criteria.
5.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation is “permanent”.  Once a subject is discontinued, he/she shall not be allowed 
to enroll again.
A subject must be discontinued from the trial for any of the following reasons:
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.
5.9
Subject Replacement Strategy
A subject that discontinues from the trial will not be replaced.
5.10 Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
 
 
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5.11 Clinical Criteria for Early Trial Termination
There are no pre-specified criteria for terminating the trial early.
 
 
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Visit Number:
1 
2
3
4
5
6
7
8
9
Scheduled Day/Month.:
Day 1
Month 2
Month 6
Month 7
Month 12
Month 18
Month 24
Month 30
Month 36
Visit Window1:
2 months
after Day 1, 
±3 weeks
6 months 
after Day 1,
±4 weeks
3 to 7 weeks after 
Month 6
12, 18, 24, 30 or 36 months after Day 1, ±4 weeks
PCR4
Intra-anal wetted swab for HPV PCR  4
X
X
X
X
X
X
X
External genital lesion biopsy (if indicated) 5
X
X
X
X
X
X
X
X
Serum for Anti-HPV 6
X
X
X
STI Testing (local laboratory testing, if clinically 
indicated) 7
X
X
X
X
X
X
X
X
X
Blood (DNA) for Future Biomedical Research 8
X
1 To calculate visit windows, assume 1 month equals 30 days and 1 week equals 7 days. With regard to protocol study visit windows, the following situations require consultation 
between the investigator and the SPONSOR and written documentation of the collaborative decision: a subject needs to be scheduled earlier than the start of a visit window, the 
study site is considering skipping a visit, or a study site needs significant guidance on scheduling visit windows.  
2 See Section 5.5 for prerequisites for medications and non-study vaccines.
3 If the subject has a fever (defined as an oral temperature of ≥37.5°C) within the 24-hour period prior to receiving a study vaccination, the subject should not receive study 
vaccine, and the vaccination visit should be rescheduled until after the fever has resolved. Vital sign should be measured prior to each vaccination. Height and weight are 
measured at Visit 1 only.
4 Type-specific HPV Polymerase Chain Reaction (PCR) testing to be performed at the SPONSOR-designated Central Laboratory. Swabs must be shipped as specified by the 
SPONSOR/Central Laboratory.
5 Processed and analyzed at Central Laboratory.
6 Serum for anti-HPV measurements may be collected after the genitourinary/perianal examination, but must be collected before vaccination. Serum (including Reference Serum) 
must be shipped as specified by the SPONSOR/Central Laboratory.
7 Sexually transmitted infection (STI) tests, including HSV, syphilis, and HIV, may be performed at any visit as needed.
8 Informed consent for future biomedical research samples must be obtained before the DNA sample is collected. DNA sample for analysis (8.5-mL blood sample) should be 
collected before vaccine administration, on Day 1 (or with the next scheduled blood draw, as soon as consent is obtained) and on randomized subjects only.
 
 
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
 
 
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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
In addition, demographics and substance use will be collected in the data collection system, 
as discussed in the Electronic Case Report Form (eCRF) Entry Guideline.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. At Visit 1 (Day 
1), the subject’s lifetime genitourinary history and medical history for the year prior to Visit 
1 will be collected. After Visit 1, any new medical history that has not been previously 
documented (either as adverse experiences or as medical history conditions) will be collected. 
7.1.1.5
Sexual History
A sexual history will be obtained by the investigator or qualified designee. At Visit 1 (Day 1), 
the subject’s lifetime number of female and/or male sexual partners and age of first sexual 
intercourse will be collected. After Visit 1, the subject’s sexual activity including the number 
of new females and/or males with which the subject engaged in sexual intercourse (for 
females, insertive vaginal intercourse; for males insertive or receptive anal intercourse) will 
be collected.
7.1.1.6
Prior and Concomitant Medications Review
7.1.1.6.1 Prior Medications
The investigator or qualified designee will review prior medication use, and record prior 
medication taken by the subject before starting the trial.
Use of medicines and non-study vaccines should be documented in the data collection system 
in the following manner:
−
Medications (corticosteroids, immunosuppressives, immune globulins, and blood 
products) from 3 days prior to Day 1 through Month 7;
−
Medications from 3 days prior to each study vaccination through 14 days after each 
study vaccination;
−
Non-Replicating (Inactive) Vaccines for 14 days prior to each study vaccination through 
14 days after each study vaccination; and
 
 
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−
Replicating (Live) Vaccines for 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 subject 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.  
Please refer to the eCRF Entry Guidelines for further details.
7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial as described in Section 7.1.1.6.1.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.  Any subject who is screened multiple times will retain the original 
screening number assigned at the initial screening visit.
7.1.1.8
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
7.1.1.9
Study Vaccine Administration
7.1.1.9.1 Preparation for Administration
The study vaccine must be used as supplied (no dilution before administration).  Prior to 
administration, mix the contents of the vial thoroughly by rolling the vial between the palms 
of both hands for 30 seconds.  Withdraw a 0.5-mL dose from the vial, which contains 
approximately 0.75 mL of study vaccine. The study vaccine should be a whitish, semi-
translucent suspension when thoroughly mixed.  If the appearance is otherwise, do not 
administer, and contact the SPONSOR immediately
7.1.1.9.2 Study Vaccine Administration
At each vaccination visit, subjects will receive V501 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 into the buttocks area. Injections should not 
be given within 2 cm of a tattoo, scar, or skin deformity.
 
 
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Study vaccine should be administered using a 1.0-mL syringe.  Injections should be 
administered at a 90° angle into the muscle tissue using a needle long enough to ensure 
intramuscular deposition of vaccine.
All subjects will be observed for at least 30 minutes after each study vaccination for any 
untoward effects, including allergic reactions. This observation period will be documented in 
the subject’s chart.
7.1.1.10 Trial Compliance
Administration of trial vaccine will be witnessed by the investigator and documented in the 
subject’s chart.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Anogenital Physical Examination
A physical examination will be performed prior to the external genital lesion examination. A 
physical examination details will be documented in the subject’s chart and any medical 
conditions including will be documented in the data collection system.
7.1.2.2
Vital Signs
Vital signs (oral temperature, sitting pulse, blood pressure and respirations) will be taken 
before each study vaccination. Height and weight are measured at Visit 1 only.
Height and weight at Visit 1, and pre-vaccination oral temperature will be documented in the 
data collection system and the other vital signs will be documented in the subject’s chart. If 
the subject has fever (defined as an oral temperature of ≥37.5˚C) within the 24-hour period 
prior to receiving a study vaccination, the subject should not receive study vaccine, and the 
vaccination visit should be rescheduled.
7.1.2.3
Vaccination Report Card (VRC)
Each subject will receive a VRC at the study vaccination visit. On the VRC, the subject will 
be asked to record his oral temperature in the evening after each study vaccination and daily 
for 4 days after each study vaccination for the purpose of identifying febrile events. Also, 
beginning after each study vaccination and for a total of 15 days including the day of 
vaccination, the subject will be asked to record injection-site and systemic adverse 
experiences, concomitant medications, and concomitant vaccinations on the VRC. The 
information on VRC should be generated only by the subject and must be signed and dated 
by the subject to confirm the accuracy of the recorded information. The subject will be asked 
to bring the VRC to the study site at the next scheduled visit.
When the VRC is returned, the VRC should be reviewed for completeness by study site 
personnel.  If clarification is needed, the study site personnel will discuss the VRC with the 
subject.  Original information on the VRC should never be altered by study personnel, 
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of the VRC. Only the subject can make corrections to his information on the VRC.  Any 
corrections to the VRC should be made by using an ink pen to add the omitted data and/or to 
draw a single line through the error and add the correct information.  The subject should 
initial/date all VRC corrections.  
All VRC information will be recorded in the Electronic Data Capture (EDC) system.  The 
physician investigator/sub-investigator will determine causality of systemic and injection-site 
adverse experiences recorded on the VRC using the reporting guidelines given in the 
protocol and will classify each event as a serious adverse experience (SAE) or non-serious 
adverse experience (NSAE).  If an oral temperature indicates a fever (defined as an oral 
temperature of ≥37.5°C), the adverse experience of “fever” must be documented in the 
eCRFs.  At the time of VRC review at the next scheduled visit, subjects will be questioned 
regarding any new medical conditions that occurred beyond Postdose Day 15.  The physician 
investigator/sub-investigator will determine if the medical condition is to be reported as an 
SAE using the reporting guidelines provided in Section 7.2.2.1.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
7.1.3.1
External Genital Lesion Examination
The external genital lesion examination should be completed prior to any specimen collection.
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)
7.1.3.1.1 Procedure for Penile and Scrotal Examination
1)
The examiner should inquire as to whether the subject has shaved their genital region 
and/or applied any post-shave lotion or lubricants within 24 hours prior to the visit.
2)
The examiner should inquire as to whether the subject has noticed any bumps or lesions 
or unusual symptoms (e.g., etching, dyspareunia, or dysuria). Begin with the inspection 
of the penile shaft, glans penis and urethral meatus, noting and recording evidence of 
abnormalities, including any abnormalities of the skin, rashes, minor lacerations, or 
bruises, etc.
 
 
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3)
The entire penis is to be palpated, region by region, for apparent cutaneous and 
subcutaneous lesions or wart-like growths.
4)
After completing the inspection of the penis, continue with a careful 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.
5)
At the investigator’s discretion, low power magnification with the colposcope may be 
used for better visualization of an identified lesion.
6)
Acetic acid is not be used routinely. It may be used for confirmation of a suspected 
lesion.
7.1.3.1.2 Procedure for Perineal/Perianal Examination
1)
The examiner should inquire as to whether the subject has noticed any bumps or lesions 
or unusual symptoms (e.g., etching, dyspareunia)
2)
Inspect the anus, perianal and perineal areas for the presence of anogenital warts.
3)
The perianal and perineal regions are to be palpated, for apparent cutaneous and 
subcutaneous lesions or wart-like growths.
4)
The examiner should spread the contiguous skin by the use of his/her thumbs, and note 
the condition of the anus.
5)
The examiner is to be performed using the hand-held magnifying glass and/or 
colposcope and should include the perianal and anal region.
6)
At the investigator’s discretion, low power magnification with the colposcope may be 
used for better visualization of an identified lesion.
7)
Acetic acid is not be used routinely. It may be used for confirmation of a suspected 
lesion.
7.1.3.2
Swab for HPV PCR
After the completion of external genital lesion examination, swab specimens from the penile 
shaft, scrotum, perineal, perianal and intra-anal region will be collected. Swabs will be tested 
for detection of HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. In addition 
to this testing, swabs may be tested for other HPV types. HPV type 6, 11, 16 and 18 will be 
analyzed by type-specific multiplex (L1, E6 and E7 gene detection) PCR assay.
7.1.3.2.1 Penile/Glans Penis File and Wetted Swab for HPV PCR
1)
In order to prepare the subject 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 subject to rub it on his hands.
 
 
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2)
Remove the nail file from the packaging; remove the DACRON™swab from the 
packaging, then twist the top off of the sterile saline ampule, and wet the entire head of 
the DACRON™ 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 
DACRON™ 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.
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 DACRON™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.
 
 
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7.1.3.2.2 Scrotal File and Wetted Swab for HPV PCR
1)
Remove the nail file from the packaging; remove the DACRON™swab from the 
packaging, then twist the top off of the sterile saline ampule, and wet the entire head of 
the DACRON™ 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 
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 subject 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 subject 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 DACRON™ swab to blanch the 
skin while also be twisted or rotated in order to increase surface area exposure for
collection of debris. Only one file and one swab are to be used in the scrotal sampling.
4)
Discard the file in a Biohazard Sharps container.
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.
7.1.3.2.3 Perineal/Perianal File and Wetted Swab for HPV PCR
1)
Remove the nail file from the packaging. Remove the DACRON™swab from the 
packaging, then twist the top off of the sterile saline ampule, and wet the entire head of 
the DACRON™ swab, 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 perineal/perianal sampling.
2)
If the subject is in the left lateral position, the subject 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
 
 
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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 DACRON™ 
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 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 label for the Perianal Sample on the STM vial.
7.1.3.2.4 Intra-anal Wetted Swab for HPV PCR
1)
Remove the DACRON™ swab from the packaging, then twist the top off of the sterile 
saline ampule, and wet the entire head of the DACRON™ swab with the sterile saline.
2)
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.
3)
Once at the 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.
4)
Place the swab in an STM vial and break the pre-scored handle. Do not add saline to 
STM vial either before or after swabbing.
5)
Securely cap the collection/transport tube containing the specimens.
6)
Place the appropriate label for the Intra-Anal sample on the STM vial.
7.1.3.3
External Genital Lesion Biopsy
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 
 
 
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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 subject.
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 
EDC system).

To perform the biopsy, cleanse the biopsy area first with an antiseptic solution.

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 subject.

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.
 
 
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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 subjects. 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, 35, 39, 45, 51, 52, 
56, 58 and 59. In addition to this testing, specimens may be tested for other HPV types. HPV 
type 6, 11, 16 and 18 will be analyzed by type-specific multiplex (L1, E6 and E7 gene 
detection) PCR assay.
If a subject has an external genital lesion biopsy taken, that subject may remain in the study.
7.1.3.4
Serum for Anti-HPV Measurements
The 4-valent HPV cLIA is the primary assay used for the secondary objective of the trial. 
Additional testing may be conducted using other HPV immunological assays (Total IgG 
Luminex 
Immunoassay, 
Pseudovirion-based 
Neutralization Assay) 
for 
supportive 
exploratory analyses.
For each visit that requires a serum specimen for anti-HPV measurements, a 10-mL (non-
heprinized, non-serum separator, redo-top tube provide by the SOPONSOR-designated 
Central Laboratory) blood specimen will be collected and should be separated to avoid 
hemolysis. A minimum of 3.0 mL of serum should be aliquoted to a vial provided by the 
SPONSOR-designated Central Laboratory. An additional 1.5 mL of serum (“Retention 
Serum”) should be aliquoted to a vial provided by the SPONSOR-designated Central 
Laboratory and labeled with the “Retention Serum” label provided by the SPONSOR-
designated Central Laboratory.
“Serum” vials will be stored at -20˚C (or lower) until shipped on dry ice. The site should ship 
Retention serum separately from the Serum sample.
 
 
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7.1.3.5
STI Testing
Local laboratory testing for Sexually Transmitted Infection (STIs) including chlamydia, 
gonorrhea, herpes simplex virus (HSV), syphilis, hepatitis B and HIV may be performed at 
any visit 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 trial, known HIV-Positive subjects should not be enrolled in the trial.
7.1.3.6
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:
Blood for genomics use
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the next scheduled visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. If a subject must discontinue/withdraw after the Month 7 study 
visit, the subject should be asked to return for a final visit if it has been at least 4 months 
since the last trial visit. This visit would consist of the same specimen collections and tests 
conducted at the next scheduled visit and the subject would be formally discontinued from 
the study at the end of this visit. The discontinuation visit should not be done if it is 
medically contraindicated or if the subject refuses. If no discontinuation visit is performed, 
the subject should be formally discontinued from the study on the day the decision to 
discontinue is made. All attempts must be made to contact a subject who is lost to follow-up
(a certified letter must be sent at the final attempt). Subjects who are lost to follow-up should 
be formally discontinued from the study on the day of the last unsuccessful attempt at 
contact.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
writing to the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
, and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.  No new analyses would be generated after the request is received.
 
 
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In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
Disclosure envelopes containing vaccine/placebo disclosure information are stored and 
managed strictly and securely by the “MSD Emergency Center.” The envelope should be 
opened only in the case of an emergency.
Envelopes are unsealed according to the following procedures.
When the investigator or sub-investigator needs to identify the clinical material received by a 
subject in case of emergency, e.g., the occurrence of serious adverse experiences, he/she will 
contact “MSD Emergency Center” by telephone and make a request for emergency key 
unblinding. As requested by the investigator or sub-investigator, “MSD Emergency Center” 
will provide the information to him/her promptly and report the Disclosure envelopes 
unblinding to the Sponsor. “MSD Emergency Center” will make a record promptly. 
However, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed, their relation to study drug, the reason thereof, etc. in the medical 
chart, etc. before unblinding the emergency key in principle. After the unblinding of the 
study, disclosure envelopes are to be returned to the Sponsor.
7.1.4.3
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 
through the SPONSOR-designated Central Laboratory. If a subject 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.  
7.1.4.4
Subject Relocation
Given the duration of the study and the age of the study population, it can be expected that 
subjects may relocate during the study. The SPONSOR must be contacted for each temporary 
and permanent relocation as soon as the situation is known. Every effort should be made to 
adjust study visits around a subject’s temporary absence (e.g., college breaks, summer 
vacation) so that the visits will be within the visit windows.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
 
 
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7.1.5.1
Prerequisites for Study Vaccination Visit
See the inclusion/exclusion criteria for specific restrictions at Visit 1 (Day 1). For visits with 
study vaccination (Visit 1, 2 and 3), study personnel should verify by questioning the subject 
and/or by examination that:
1)
The subject has not had a fever (define as an oral temperature of ≥37.5˚C) within 24-
hour period prior to any study vaccination visit.
2)
The subject has not received any systemic (oral or parenteral) corticosteroids in the 2 
weeks prior to any study vaccination visit.
3)
The subject has not received a non-study inactive 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.
7.1.5.2
Prerequisites for Study Visits with Specimen Collection
See the inclusion/exclusion criteria for specific restrictions at Visit 1 (Day 1). For visits that
include collection of study specimens, study personnel should verify by questioning the
subject that the subject has refrained from sexual activity (vaginal and anal penetration and 
any genital contact) for 2 calendar days prior to any visit that includes collection of swabs, 
and/or biopsies specimens.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during the course of the use of the Sponsor's product in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in clinical 
practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.
 
 
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Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
All adverse events will be collected from the time the consent form is signed through 14 days 
(42 days for live attenuated vaccines) following the first vaccination(s) and from the time of 
any subsequent vaccination(s) through 14 days (42 days for live attenuated vaccines) 
thereafter, and such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
Administration of more than 1 dose (> 0.75 mL) of any individual study vaccine in any 24 
hour period will be considered an overdose for this protocol.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder.
Immediate Reporting of Adverse Events to the Sponsor
7.2.2
7.2.2.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is a cancer;
●
Is associated with an overdose;
●
Is an other important medical event 
Refer to Table 2 for additional details regarding each of the above criteria.  
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause, that occurs to any subject from the time the consent is signed through 14 days (42 
days for live attenuated vaccines) following the first vaccination(s) and from the time of any 
subsequent vaccination(s) through 14 days (42 days for live attenuated vaccines) thereafter, 
whether or not related to the Sponsor's product, must be reported within 24 hours to the 
 
 
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Sponsor either by electronic media or paper.  Sponsor Contact information can be found in 
the Investigator Trial File Binder.
Additionally, any serious adverse event brought to the attention of an investigator who is a 
qualified physician at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor if the event is either:
1. A death that resulted in the subject discontinuing the trial 
or
2. A serious adverse event that is considered by an investigator who is a qualified physician 
to be vaccine related.
All subjects with serious adverse events must be followed up for outcome.
7.2.2.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor either by electronic media or paper.  Sponsor Contact 
information can be found in the Investigator Trial File Binder.
Events of clinical interest for this trial include:

an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
Evaluating Adverse Events
7.2.3
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 2. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 2 for instructions in evaluating adverse events.
 
 
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Table 2 Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities) 
Injection site redness or swelling from the day of vaccination through Day 4 post-vaccination will be evaluated by maximum size.
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer; or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose 
that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the test vaccine to be discontinued?
Relationship 
to test vaccine 
Did the test vaccine cause the adverse event?   The determination of the likelihood that the test vaccine caused the adverse event 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 vaccine and the adverse event based upon the 
available information.  
The following components are to be used to assess the relationship between the test vaccine and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the test vaccine caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the test vaccine such as:  reliable history, acceptable compliance assessment 
(e.g., diary), seroconversion or identification of vaccine virus in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the test vaccine? 
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
 
 
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Relationship
The following components are to be used to assess the relationship between the test vaccine and the AE:  (continued)
to test vaccine 
Dechallenge
(not applicable for vaccines)
(continued) 
Rechallenge
Was the subject reexposed to the test vaccine in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose 
vaccine trial.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE 
BEEN CAUSED BY THE TEST VACCINE, OR IF REEXPOSURE TO THE TEST VACCINE POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. 
CLINICAL MONITOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency with Trial 
Vaccine Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test vaccine or vaccine class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.  
Record one of the following:
Use the following criteria as guidance (not all criteria must be present to be indicative of a vaccine relationship).
Yes, there is a reasonable possibility of 
vaccine relationship.
There is evidence of exposure to the test vaccine.  The temporal sequence of the AE onset relative to the administration of the test vaccine 
is reasonable.  The AE is more likely explained by the test vaccine than by another cause.
No, there is not a reasonable possibility of 
vaccine relationship
Subject did not receive the test vaccine OR temporal sequence of the AE onset relative to administration of the test vaccine is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.4
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
7.3
TRIAL GOVERNANCE AND OVERSIGHT
Data Monitoring Committee
7.3.1
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. The DMC 
will include 2 clinicians experienced in urology/dermatology and 1 external statistician; this 
is in addition to the unblinded trial statistician who will be a non-voting member of the 
committee. 
The DMC will make recommendations to the Sponsor regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  The DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.1.5 - Interim 
Analyses) and recommend to the Sponsor if the trial should continue in accordance with the 
protocol.
Specific details regarding responsibilities and governance, including the roles and 
responsibilities of the various members and the Sponsor protocol team; meeting facilitation; 
the trial governance structure; and requirements for and proper documentation of DMC 
reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
A DMC recommendation will be communicated to the Sponsor as agreed to in the 
Collaboration agreement based on reviewing the interim analysis results.
Clinical Adjudication Committee
7.3.2
The HPV Vaccine Program Pathology Panel will be responsible for providing the definitive 
pathologic diagnoses of external genital lesion biopsies for study purpose (not for medical 
management). Slides from external genital lesion biopsies will be evaluated by HPV Vaccine 
Program Pathology Panel. The HPV Vaccine Pathology Panel will prepare reports on each 
tissue specimen without knowing the vaccination groups of subjects. A separate guideline 
that details the HPV Vaccine Program Pathology Panel process has been approved by the 
HPV Program Pathology Panel.
 
 
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8.0 STATISTICAL ANALYSIS PLAN
8.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Efficacy Analyses
8.1.1
The efficacy endpoints, analysis population, and statistical methods to be employed for the 
efficacy analyses are presented in Table 3. The Per-Protocol Efficacy population will consist 
of subjects who receive the full vaccination series within 1 year, and have 1 or more follow-
up visits following Month 7, do not have any general protocol violations, and are 
seronegative at baseline and PCR-negative from baseline through Month 7 for the relevant 
HPV type.
Table 3 Summary of Analysis Strategy for Efficacy Endpoint
Endpoint/Variable
(Description)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Objective
HPV6/11/16/18 related 
persistent infection
Exact 95% CI for vaccine 
efficacy 
PPE
Not imputed
PPE=Per-Protocol Efficacy. HPV=human papilliomavins. CI=Confidence Interval
The study is case-driven and the final analysis will be conducted at the time of 18 persistent 
infection cases collected, if no early stop for efficacy in interim analysis which is planned to 
be conducted at the time of 11 cases collected. 
Safety Analyses
8.1.2
All subjects who received at least 1 study vaccination and have follow-up data will be 
included in the analysis of safety. The primary interest for safety will be the incidence of 
vaccine-related serious adverse experiences, which will be summarized and tabulated.
Immunogenicity Analyses
8.1.3
Anti-HPV6, 11, 16, 18 seroconversion percentages and Geometric Mean Titer (GMT) by 
Month 7 will be evaluated by computing point estimates and constructing 95% Confidence 
Intervals (CI) for all subjects, and for HM and MSM subjects, respectively.
Power and Sample Size
8.1.4
This study will enroll approximately 1100 subjects. For Asian males in Protocol V501-020, 
the observed incidence rate for HPV6/11/16/18-related Persistent Infection among placebo 
recipients was 2.3 per 100 person-years with the vaccine efficacy of 100%. If the true 
incidence rate on HPV6/11/16/18-related Persistent Infection is 2.3 per 100 person-years in 
Japanese males, with the assumption of vaccine efficacy of 85%, about 59% of enrolled 
subjects with evaluable data and one interim analysis at time of 11 persistent infection cases 
collected, the study will have at least 90% power to achieve success for the primary 
hypothesis. With the assumption of vaccine efficacy of 90%, the study will have more than 
98% power to achieve success for the primary hypothesis. The total number of persistent 
 
 
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infection cases needed to keep the power is 18. The statistical criterion for success requires 
that the lower bound of the two-sided 95% confidence interval for vaccine efficacy be greater 
than 0. The rate of drop-out is estimated as 0.41 based on Protocol V501-020. The details are
as follows: no general protocol violation: 95%; exclusion rate due to Day1 seropositive or 
PCR positive between Day 1 and Month 7 to HPV 6, 11, 16, and 18 is not greater than 15%; 
90% of randomized subjects completed vaccination phase and 80% of Month 7 subjects 
complete 30-month follow-up period. 
Interim Analysis
8.1.5
There is one planned interim analysis in this trial. The interim analysis will occur after 11 
persistent infection cases are collected. The trial has >56% power to detect significant 
vaccine efficacy at alpha=0.006 one-sided in interim analysis if the true vaccine efficacy is 
85%. A p-value of 0.6% for vaccine efficacy approximately corresponds to equal or less than 
1 of 11 persistent infection cases occurring in the vaccine group. 
8.2
Statistical Analysis Plan
There are no plans to issue a separate Statistical Analysis Plan (SAP) for this trial. If, after
the trial has begun, important changes are made that affect principal features of the primary 
or key secondary analyses, then the protocol will be amended, as appropriate (consistent with 
ICH Guideline E-9). Any other changes made to the planned analyses after the protocol has 
been finalized, along with an explanation as to when and why they occurred, will be listed in 
the Clinical Study Report (CSR) for the trial. Post hoc exploratory analyses will be clearly 
identified in the CSR.
Responsibility for Analyses
8.2.1
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
Trial Objectives
8.2.2
See Section 3.0 for primary objectives.
Analysis Endpoints
8.2.3
8.2.3.1
Efficacy Endpoints
(1) Primary Endpoint: the incidence of HPV 6-, 11-, 16- or 18-related persistent infection.
Persistent infection is defined to have occurred if any of the following occurs:
 
 
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
The subject 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 2 consecutive anogenital or biopsy
samples collected at least 4 months apart; OR

The subject has Pathology Panel consensus diagnosis of condyloma acuminata, 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, prior to or following the biopsy showing HPV disease.
(2) Secondary Endpoint: combined incidence of HPV 6-, 11-, 16- or 18-related persistent 
infection, condyloma acuminata, PIN, penile, perianal or perineal cancer.
Disease is defined to have occurred if on a single biopsy or excised tissue, there is

Pathology 
Panel 
consensus 
diagnosis 
of 
condyloma 
acuminata,
penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal or perineal 
cancer; AND

At least one of HPV types 6, 11, 16, or 18 is detected by Thinsection PCR in an
adjacent section from the same tissue block.
(3) Exploratory Endpoint: combined incidence of HPV 6-, 11-, 16- or 18-related condyloma 
acuminata
8.2.3.2
Immunogenicity Endpoints
The immunogenicity endpoints are seroconversion percentages by Month 7 to each of HPV 
6, 11, 16, and 18. Seroconversion is defined as changing serostatus from seronegative to 
seropositive. A subject with a cLIA titer at or above the serostatus cutoff for a given HPV 
type is considered seropositive for that type. The immunogenicity endpoint includes cLIA
GMTs at each time point. On total IgG, same exploratory analysis will be conduct.
8.2.3.3
Safety Endpoints
Safety assessment will focus on the injection site adverse experiences/vaccine-related
adverse experiences prompted for on the VRC occurring Day 1 through Day 5 following any 
vaccination, elevated temperature from Day 1 to 5 following any vaccination and systemic 
adverse experiences/vaccine-related adverse experiences occurring Day 1 through Day 15 
following any vaccination. Serious adverse experiences occurring Day 1 through Day 15 
following any vaccination, serious vaccine-related adverse experiences and new medical 
condition occurring any time during the study will be summarized.
 
 
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Analysis Populations
8.2.4
8.2.4.1 Efficacy Analysis Population
Three subject populations will be considered for the efficacy analyses: 1 per-protocol
population and 2 modified intention-to-treat (MITT) populations.  The efficacy analysis 
using the per-protocol population will be the primary analysis for the primary and the 
secondary endpoints related to HPV types 6, 11, 16 and 18. Supplemental analyses for those 
endpoints will be provided using the 2 MITT populations.  The per-protocol and MITT 
populations differ with regard to the inclusion/exclusion of protocol violators who are 
described below.
Per-Protocol Efficacy (PPE) Populations
To be included in the per-protocol analyses, subjects must:
(1) Have received all 3 vaccinations with the correct dose of the correct clinical material 
within 1 year, and have 1 or more follow-up visits following Month 7,
(2) Be seronegative to the appropriate HPV type(s) at baseline and PCR-negative to the 
appropriate HPV type(s) on all swabs and biopsies from baseline through Month 7,
(3) Have a Month 7 visit within a day range considered acceptable (14 to 72 days following 
the Month 6 vaccination) for defining the subject’s Month 7 PCR status,
(4) Have no other protocol violations that could interfere with the evaluation of subject’s 
effectiveness response to the study vaccine.
(5) Subjects must have refrained from sexual intercourse for 2 days prior to the visit at 
which infection or detection is determined.
(6) Not receive any nonstudy inactivated vaccine within 14 days before or after a study
vaccination, or any nonstudy live virus vaccine within 28 days before or 14 days after a 
study vaccination;
(7) Not receive any immune globulin or blood-derived products at any time through Month 
7 of the study;
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.
To be included in the effectiveness analysis with respect to either HPV type 6 or 11, subjects 
must be negative at the aforementioned time points for both HPV 6 and 11.  For evaluations 
of efficacy with respect to any other vaccine HPV type, subjects need only be negative at the 
aforementioned time points for the HPV type under evaluation.
 
 
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Full analysis set (FAS)
The populations will be restricted to subjects who received at least 1 vaccination and have 
any follow-up visit. General protocol violators will be included. All efficacy cases occurring 
after Day 1 will be counted. The population will not be restricted to subjects who are 
seronegative and PCR-negative at Day 1 to the appropriate HPV types. Subjects 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.
Modified Intention-to-Treat (MITT) Population
The populations will be restricted to subjects who received at least 1 vaccination and have 
any follow-up visit. General protocol violators will be included. All efficacy cases occurring 
after Day 1 will be counted. The MITT population (also labeled as HNRT [Naïve to the Relevant 
HPV type]) will include only subjects who are seronegative and PCR-negative at Day 1 to the 
appropriate HPV types. In the MITT population, subjects 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.
8.2.4.2
Immunogenicity Analysis Populations
The primary analysis population will be the Per-Protocol Immunogenicity (PPI) population. 
To be included in this population, subjects 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)
A supportive analysis of immunogenicity will be conducted on the All Naïve Subjects With 
Serology (ANSS) population. To be included in this population, subjects must have received 
at least one dose of study vaccine, must have provided serology data, and must have been 
seronegative at Day 1 and PCR-negative from Day 1 through Month 7 to the appropriate 
HPV types. Subjects 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. Immune 
responses at 4 weeks postdose 3 will also be summarized in subjects who are (1) seropositive
and PCR negative at Day 1; (2) seronegative and PCR positive at Day 1; and (3) seropositive 
and PCR positive at Day 1, for the given HPV type.
Table 4 Acceptable Day Ranges for Vaccination Visits
Dose of 4-Valent HPV L1 VLP
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 4-valent HPV L1 VLP vaccine is injected.
 
 
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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 4-valent HPV L1 VLP vaccine is injected. For Month 7, 
indicated target collection/day range is relative to date of injection of dose 3 of 4-valent HPV L1 VLP 
vaccine.
8.2.4.3 Safety Analysis Population
All subjects who received at least 1 study vaccination and have follow-up data will be
included in the analysis of safety.
Statistical Methods
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses
There are two efficacy analyses planned in this study. At the time when 11 cases of persistent
HPV 6-, 11-, 16- or 18-related infection have been observed in the PPE population, an 
interim analysis will be conducted. If non-significant results are reached in the interim 
analysis, the final analysis will occur at the time of 18 cases of persistent HPV 6-, 11-, 16- or 
18-related infection observed. The study conclusions regarding the vaccine efficacy will be 
made based on these analyses. 
The primary efficacy hypothesis for vaccine efficacy >0% against persistent infection will be 
tested based on the number of cases among vaccine recipients relative to the total number of 
cases. A one-sided exact test based on a binomial distribution which conditions on the total 
number of cases will be used. The vaccine efficacy is defined (1 – RV501 /  Rplacebo ) * 100 
[%], where RV501 and Rplacebo are persistent infection incidence for V501 and placebo. The 
95% confidence interval for the vaccine efficacy is calculated based on a proportion ( p ) of 
V501 recipients among all cases. The exact 95% confidence interval for p is calculated based 
on F distribution, and the exact 95% confidence interval for vaccine efficacy can be 
computed from the confidence bounds for p. The estimate of vaccine efficacy is adjusted by 
the “ratio of the amount of follow-up” (k), where k = (total amount of follow-up in the 
placebo group / total amount of follow-up in the V501 group).  The relationship between p
and the vaccine efficacy is as follows.
The point estimate of the vaccine efficacy ( ˆ ) = [ 1- p (1 + k )] / ( 1- p )
The 95% lower confidence limit for the vaccine efficacy = [ 1- pu (1 + k )] / ( 1- pu )
The 95% upper confidence limit for the vaccine efficacy = [ 1- pl (1 + k )] / ( 1- pl )
Where pu and pl are the upper and lower bounds of the exact confidence interval for p 
respectively. 
Secondary efficacy endpoint and exploratory endpoint will be analyzed via the same manner 
used for the primary efficacy analysis.
 
 
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Table 6 summarizes the efficacy analyses to be performed, and they are described in detail in 
the following sections.
Table 6 Efficacy Endpoints, Statistical Methods and Analysis Populations
Endpoint
Statistical Method
Analysis 
Population
Primary Endpoint: HPV6/11/16/18 related persistent infection
Tests of Efficacy Hypotheses
HPV 6/11/16/18 related persistent infection 
Supplementary Efficacy Analyses 
Overall and by HPV Type
Impact of Baseline Characteristics
Age, Sexual Orientation, Circumcision, Smoking, Lifetime Sexual Partners, 
Presence of Other HPV Types
Robustness of Persistent Infection Definition
Persistent infection relaxing the 6 month (+/- 1 month) interval requirement 
(i.e., 0 months duration) 
Persistent infection requiring 2, 3, or 4consecutive positive results over 12 
months duration
Robustness of DNA Detection Definition
Incident DNA Detection at 1 or More Visits
Analysis of VE†
Analysis of VE
Analysis of VE
Analysis of VE 
Analysis of VE 
Analysis of VE
PPE
PPE, HNRT, FAS
PPE
PPE
PPE
PPE
Secondary Endpoint: HPV6/11/16/18 related persistent infection, condyloma acuminata, PIN, and penile/ perianal/ perineal cancer
Tests of Efficacy Hypotheses
HPV 6/11/16/18 related persistent infection and disease
Supplementary Efficacy Analyses 
Overall, by HPV Type, by Persistent Infection or Disease, by Lesion type
Impact of Baseline Characteristics
Age, Sexual Orientation, Circumcision, Smoking, Lifetime Sexual Partners, 
Presence of Other HPV Types
Analysis of VE
Analysis of VE
Analysis of VE
PPE
PPE, HNRT, FAS
PPE
Other Endpoint
Intra-anal persistent infection
HPV 6/11/16/18-Related Intra-anal Persistent Infection – Overall, by HPV Type
HPV 6/11/16/18-Related Intra-anal Persistent Infection – Overall, by Baseline 
Characteristics (Age, Sexual Orientation, Circumcision, Smoking, Lifetime 
Sexual Partners, Presence of Other HPV Types)
Persistent infection excluding intra-anal persistent infection
HPV 6/11/16/18-Related Persistent Infection excluding Intra-anal Persistent 
Infection – Overall, by HPV Type
HPV 6/11/16/18-Related Persistent Infection excluding Intra-anal Persistent 
Infection – Overall, by Baseline Characteristics (Age, Sexual Orientation, 
Circumcision, Smoking, Lifetime Sexual Partners, Presence of Other HPV 
Types)
Time to Event Analysis
Time to Occurrence of HPV 6/11/16/18-Related persistent infection
Time to Occurrence of HPV 6/11/16/18-Related persistent infection and 
diseases
Time to Occurrence of HPV 6/11/16/18-Related intra-anal persistent infection
Time to Occurrence of HPV 6/11/16/18-Related persistent infection excluding 
intra-anal persistent infection
Therapeutic Efficacy
HPV 6/11/16/18-Related Persistent Infection – Overall, by HPV Type
HPV 6/11/16/18-Related Intra-anal Persistent Infection – Overall, by HPV Type
HPV 6/11/16/18-Related Persistent Infection excluding intra-anal persistent 
infection – Overall, by HPV Type
Incidence of clearance of HPV 6/11/16/18 Infection
Analysis of VE
Analysis of VE
Analysis of VE
Analysis of VE
Kaplan-Meier Estimate
Kaplan-Meier Estimate
Kaplan-Meier Estimate
Kaplan-Meier Estimate
Analysis of VE
Analysis of VE
Analysis of VE
Estimation of Incidence‡
PPE, HNRT, FAS
PPE
PPE, HNRT, FAS
PPE
PPE, HNRT, FAS
PPE, HNRT, FAS
PPE, HNRT, FAS
PPE, HNRT, FAS
Day 1 PCR- and Sero+
Day 1 PCR- and Sero+
Day 1 PCR- and Sero+
Day 1 PCR+ and Sero-,
Day 1 PCR+ and Sero+
† refers to point and confidence interval estimation of vaccine efficacy (1-relative risk)
‡ refers to point and confidence interval estimation of incidence, expressed as rate per 100 person-years
HPV = Human Papillomavirus; VE = Vaccine Efficacy; PIN = Penile/Perianal/perineal intraepithelial neoplasia;
PPE = Per-protocol efficacy; FAS = Full analysis set; HNRT = Naïve to the Relevant HPV type; 
PCR = Polymerase chain reaction; PCR+ = PCR positive; PCR- = PCR negative; Sero+ = Seropositive; Sero- = Seronegative
 
 
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Computation of Follow-Up Time
Follow-up for the primary analysis begins following the Month 7 visit. Therefore the follow-
up time for a subject will be the interval in days between his Month 7 visit and his last day of 
follow-up. For cases, this will be the visit at which the biopsy detecting the endpoint was 
taken. If a subject develops more than one case of disease that fits into a given endpoint 
classification, the final visit date will be the date at which the first of these endpoints was 
detected. For non-cases, the last day of follow-up will be defined as the cutoff date when the 
database is locked for analysis. Follow-up time will be similarly calculated for secondary and 
exploratory endpoints.
For the MITT analyses, follow-up begins following Day 1 instead of Month 7, so the follow-
up time for a subject will be the interval in days between the Day 1 visit and the last day of 
follow-up, as described above.
The date of occurrence of each endpoint is defined as follows. For disease cases, it is the date 
of the sample from which the diagnosis of disease was made. For persistent infection it is the 
date of the first consecutive sample which was positive for HPV by PCR.
Kaplan-Meier estimates of the time-to-event curves will be generated for certain efficacy
endpoints. Subjects without the endpoint will be censored at the end of their follow-up time, 
as defined in this section.
8.2.5.2
Statistical Methods for Immunogenicity Analyses
There are no formal immunogenicity hypotheses comparing the vaccination groups since it is 
anticipated that placebo recipients will have anti-HPV titers below the limit of detection of 
the cLIA and total IgG assay. 
Estimation of seroconversion percentage
The seroconversion percentages with respect to anti-HPV 6, 11, 16, 18, by Month 7 will be 
evaluated by computing point estimates and constructing 95% CI. Calculation of the CI is 
based on the exact binomial method proposed by Clopper and Pearson (1934).
Estimation of GMTs
Anti-HPV 6, 11, 16, 18 GMT at Month 7 will be evaluated by computing point estimates and 
constructing 95% CI. The values will be log transformed before analysis. As such, the CI for 
the means will be constructed on the natural log scale and will reference the t-distribution.
Exponentiating the means and lower and upper limits of these CI will yield estimates for the 
population GMT and CI about the GMT on the original scale.
Persistence of immune responses
Anti-HPV 6, 11, 16, 18 GMTs and seroconversion percentages at Months 7 and 36 will be 
summarized in the PPI population to assess the persistence of immune responses.
Longitudinal plots of the GMTs from Day 1 through Month 36 will also be provided for 
graphical display.
 
 
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8.2.5.3
Statistical Methods for Safety Analyses
All subjects who received at least one injection and have follow-up data will be included in 
the analysis of safety, including protocol violators and subjects discontinuing from the study.
The following approach will be used for the analysis of safety parameters across all 
injections.
To provide an overall assessment, summary measures such as the incidence of (a) any
adverse experiences; (b) any injection-site experiences; (c) any systemic adverse experiences; 
and (d) any vaccine-related adverse experiences will be summarized in both groups. Adverse 
experiences will be summarized as frequencies and percentages by vaccination group, by 
vaccination visit and across all vaccination visits. To address specific adverse experiences, 
the incidences of injection-site adverse experiences Days 1 to 5 and specific systemic adverse 
experiences within 14 days postvaccination occurring in at least 1% of the subjects will be 
tabulated. Risk differences between the vaccination groups will be estimated and their 95% 
two-sided confidence intervals calculated, by the method of Miettinen and Nurminen [33].
Statistical testing of no difference in safety parameters between the vaccine and placebo
group will be restricted to injection site adverse experiences prompted for on the VRC
(namely, injection site pain, redness and swelling), and for temperature elevations (maximum 
oral equivalent temperature ≥37.5°C), across all vaccination visits. The testing will use the 
method of Miettinen and Nurminen [33] for a difference in proportions.
Tables of specific adverse experiences will be restricted to those events occurring in at least 
1% of either vaccination group. Tables will also be generated for the subsets of subjects who 
were seropositive to at least one of the vaccine HPV types at Day 1, and who were 
seronegative to all vaccine HPV types at Day 1.
The incidence of greatest adverse experience intensity (mild, moderate, severe) reported by a 
subject will be tabulated for: all injection site adverse experiences (Day 1 to Day 5 following 
any vaccination visit); all systemic adverse experiences (Day 1 to Day 14 following any 
vaccination visit); any adverse experience (Day 1 to Day 14 following any vaccination visit). 
For those injection site events which are measured (redness and swelling), 0 to 1 inch would 
be categorized as mild, >1 inch to 2 inches will be categorized as moderate and >2 inches 
will be categorized as severe. Similar tables will be produced summarizing the greatest 
intensity per subject for each of the prompted adverse experiences individually.
The distribution of maximum temperatures recorded from Day 1 to Day 5 following each
injection on VRCs will be summarized. The proportions of subjects who experience a 
maximum temperature of at least 37.5°C (oral equivalent) across all vaccination visits and by 
visit, will be provided.
8.2.5.4
Subgroup Analyses and Effect of Baseline Factors
The impact of baseline characteristics on efficacy outcomes will be explored by presenting 
vaccine efficacy estimates within subsets defined by the characteristics listed in Section 
8.2.5.1.
Data permitting, all the planned analysis will be provided both for HM and MSM subgroups.
 
 
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Multiplicity
8.2.6
This study tests one primary endpoint which is performed at up to 2 analysis times (1 interim 
analysis and a final analysis).
The overall probability of making a false claim of superiority, across the two analysis times, 
is controlled at level 0.025. The nominal alpha levels for positive vaccine efficacy findings 
were 0.006 at interim analysis and 0.02273 at final analysis. One formal interim analysis for 
the primary endpoint will be conducted during the study. The gamma spending function, 
used for alpha on endpoints as outlined by Hwang, Shih, and DeCani [34] was used in 
calculation. The information time for the interim analyses will be based on the proportion of 
events observed during the study.
Sample Size and Power Calculations
8.2.7
This study will enroll approximately 1100 subjects. For Asian males in Protocol V501-020, 
the observed incidence rate for HPV6/11/16/18-related Persistent Infection among placebo 
recipients was 2.3 per 100 person-years with the vaccine efficacy of 100%. If the true 
incidence rate on HPV6/11/16/18-related Persistent Infection is 2.3 per 100 person-years in 
Japanese males, with the assumption of vaccine efficacy of 85%, about 59% of enrolled 
subjects with evaluable data and one interim analysis at time of 11 persistent infection cases 
observed, the study will have at least 90% power to achieve success for the primary 
hypothesis. The total persistent infection cases needed to keep the power is 18. With the 
assumption of vaccine efficacy of 90%, the study will have more than 98% power to achieve 
success for the primary hypothesis. The power for a given number of observed primary
endpoints was computed using the method of Chan and Bohidar [35]. The statistical criterion 
for success requires that the lower bound of the two-sided 95% confidence interval for 
vaccine efficacy be greater than 0. The rate of drop-out is estimated as 0.41 based on V501 
PN020 study. The details are as follows: no general protocol violation 95%; exclusion rate 
due to Day1 seropositive or PCR positive between Day 1 and Month 7 to HPV 6, 11, 16, and 
18 is not greater than 15%; 90% of randomized subjects completed vaccination phase and 
80% of Month 7 subjects completed 30-months' follow-up period. 
Interim Analysis
8.2.8
One interim analysis will be performed in this study. Results will be reviewed by a DMC. 
The endpoint, timing, and purpose of the interim analysis are summarized in Table 7 below.
Table 7 Summary of Interim Analysis Strategy
Endpoint for interim Analysis
Timing of Interim Analysis
Purpose of Interim Analysis
HPV6/11/16/18 related persistent 
infection
11 persistent infection cases are 
documented across the 2 arms
Getting significant VE results 
earlier
The main purpose of the interim analysis s is to make a superiority claim earlier. The primary
endpoint at interim analysis is to be tested with overall one-sided alpha = 0.006. The 
spending function preserves much of the alpha for the final analysis (alpha=0.02273). The 
exact method was used to calculate the actual alpha spending in interim analysis [35] and 
HSD method was used to decide the alpha for the final analysis [34]. If one or less persistent 
 
 
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infection case is observed in vaccine group among total 11 persistent infection cases, 
significant results can be reached. If the true vaccine efficacy is 85% we have 57% 
probability to make a superiority claim. With vaccine efficacy of 90%, the probability will 
increase to 73.6%
The decision rules are driven by the one-sided p-values and vaccine efficacy, Table 8
summaries the alpha spending and corresponding powers at interim analysis and final 
analysis. Interim analysis will be conducted by an unblinded statistician.
Table 8 Alpha Spending and Corresponding Powers at Interim Analysis and Final Analysis
Vaccine 
Efficacy
Interim analysis
Final Analysis
Overall 
Significant 
Probability
Boundary p-
values
Significant 
Probability
Boundary p-
values
Significant 
Probability
85%
0.006
57.0%
0.0227
83.1%
92.7%
90%
0.006
73.6%
0.0227
93.0%
98.1%
At Interim Analysis, the frequency of adverse experiences among vaccinated patients will
also be evaluated in each vaccination group.
An independent DMC will carefully monitor the formal safety and efficacy interim results of 
this trial. In terms of efficacy, the DMC will use the guidelines proposed below for 
recommendation of either continuation or early termination of the study at the interim 
analysis. Additionally, the DMC will review safety data of the ongoing study at close, regular 
intervals as specified in the DMC charter. Such safety data will be summarized by blinded 
vaccination groups. A detailed description of the structure, function, and guidelines for 
decision-making by the DMC are also outlined in the DMC charter.
Compliance
8.2.9
Compliance is defined in this study as receipt of all scheduled study vaccinations. The 
numbers of subjects who receive each vaccination will be tabulated by vaccination group
The numbers of subjects who complete each follow-up visit will be tabulated by vaccination 
group. The numbers of subjects with biopsies or excision procedures performed outside of 
the study and the numbers of these subjects for whom the tissue samples were not available, 
will be tabulated by vaccination group. Differences in these numbers will be assessed 
observationally and the potential impact on the efficacy analyses noted.
Exposure to vaccine will be summarized by tabulating the number of subjects receiving each 
of the three study vaccinations.
Missing Data
8.2.10
There will be no imputation of results where data are missing. Biopsy samples with missing 
PCR results cannot be counted as a case for the primary analysis.
 
 
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 9.
Table 9 Product Descriptions
Product Name & Potency
Dosage Form
V501 (Quadrivalent HPV Vaccine) 20/40/40/20 μg/0.5 
mL HPV types 6/11/16/18 or matching Placebo
Sterile suspension for IM injection
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive one (1) blinded vial of V501 or matching placebo at Day 1 (Visit 1), 
Month 2 (Visit 2) and Month 6 (Visit 3). No kitting is required.
9.3
Clinical Supplies Disclosure
Supplies will be provided with random code/disclosure envelopes or lists containing drug 
disclosure information. The Sponsor will provide one sealed envelope to the central 
emergency unblinding center for each randomization number.
Drug identification information is to be unmasked ONLY if necessary for the welfare of the 
subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date
and reason) must be documented promptly, and the Sponsor Clinical Monitor notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
 
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9.5
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
Confidentiality of Data
10.1.1
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 institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1)
name, address, telephone number and e-mail address;
2)
hospital or clinic address and telephone number;
3)
curriculum vitae or other summary of qualifications and credentials; and
4)
other professional documentation.
 
 
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Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.2 Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
 
 
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The sponsor also recognizes that documents may need 
to be retained for a longer period if required by local regulatory requirements. All trial 
documents shall be made available if required by relevant regulatory authorities. The 
investigator must consult with and obtain written approval by the Sponsor prior to discarding 
trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
 
 
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
10.5 Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
 
 
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standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
10.6 Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided by the Sponsor.
10.7 Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
 
 
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paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1.
Paavonen J. Human papillomavirus infection and the development of cervical cancer
and related genital neoplasias. Int J Infect Dis 2007;11(Suppl 2):S3-S9.
2.
Madkan VK, Cook-Norris RH, Steadman MC, Arora A, Mendoza N, Tyring SK. The
oncogenic potential of human papillomaviruses: a review on the role of host genetics
and environmental cofactors. Br J Dermatol 2007;157:228-41.
3.
Stamataki S, Nikolopoulos TP, Korres S, Felekis D, Tzangaroulakis A, Ferekidis E.
Juvenile recurrent respiratory papillomatosis: still a mystery disease with difficult
management. Head Neck 2007;29:155-62.
4.
Chuang T-Y, Perry HO, Kurland LT, Ilstrup DM. Condyloma acuminatum in
Rochester, Minn, 1950-1978:II anaplasias and unfavorable outcomes. Arch Dermatol
1984;120:476-83.
5.
Stone KM. Human papillomavirus infection and genital warts: update on
epidemiology and treatment. Clin Infec Dis 1995;20(Suppl 1):S91-S97.
6.
Infectious Disease Surveillance Center. Annual Surveillance Data (Sentinel-
Reporting 
Diseases):
Sexually-transmitted 
diseases. 
URL: 
http://idsc.nih.go.jp/idwr/ydata/report-Jb.html. .
7.
Bosch FX, Munoz N. The viral etiology of cervical cancer. Virus Research
2002;89(2):183-90.
8.
Christensen ND. Emerging human papillomavirus vaccines. Expert Opin Emerg
Drugs 2005;10(1):5-19.
9.
Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J
Clin Virol 2005;32S:S16-S24.
 
 
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10.
Palefsky JM. Human papillomavirus-related disease in men: not just a women’s issue.
J Adolesc Health 2010 Apr;46(4 Suppl):S12-9.
11.
Oriel JD. Natural history of genital warts. Brit J Vener Dis 1971;47:1-13.
12.
Xi LF, Koutsky LA. Epidemiology of genital human papillomavirus infections. Bull
Inst Pasteur 1997;95:161-78.
13.
Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med
1997;102(5A):3-8.
14.
Lu B, Wu Y, Nielson CM, et al. Factors associated with acquisition and clearance of
human papillomavirus infection in a cohort of US men: a prospective study. J. Infect.
Dis. 2009 ;199:362–71.
15.
Giuliano AR, Lee JH, Fulp W, et al. Incidence and clearance of genital human
papillomavirus infection in men (HIM): a cohort study. Lancet 2011;377:932–40.
16.
Garland SM, Steben M, Sings HL, et al. Natural history of genital warts: analysis of
the placebo arm of 2 randomized phase III trials of a quadrivalent human
papillomavirus (types 6, 11, 16, and 18) vaccine. J. Infect. Dis. 2009;199:805–14.
17.
Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical
conditions, and sexual activity and risk of penile cancer. J. Natl. Cancer Inst.
1993;85:19–24.
18.
Hu D, Goldie S. The economic burden of noncervical human papillomavirus disease
in the United States. Am J Obstet Gynecol 2008;198:500.e1-500.e7.
19.
Uronis HE, Bendell JC. Anal cancer: an overview. Oncologist 2007;12:524-34.
20.
Daling JR, Madeleine MM, Johnson LG et al. Human papillomavirus, smoking and
sexual practices in the etiology of anal cancer. Cancer 2004;101:270-80.
21.
Scholefield JH, Castle MT, Watson NF. Malignant transformation of high-grade anal
intraepithelial neoplasia. Br J Surg 2005;92:1133-6.
22.
Watson AJ, Smith BB, Whitehead MR, Sykes PH, Frizelle FA. Malignant
progression of anal intraepithelial neoplasia. ANZ J Surg 2006;76:715-7.
23.
de Vuyst H, Clifford GM, Nascimento MC et al. Prevalence and type distribution of
human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina
and anus: a meta-analysis. Int J Cancer 2008;124:1626-36.
24.
Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, et al. American 
Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent 
cervical cancer and its precursors. CA Cancer J Clin 2007;57(1):7-28.
25.
Stern PL. Immune control of human papillomavirus (HPV) associated anogenital
disease and potential for vaccination. J Clin Virol 2005;Suppl 32:S72-S81.
26.
Stanley M.
Immunobiology of HPV and HPV vaccines. Gynecol Oncol
2008;109:S15-S21.
27.
Frazer IH. Interaction of human papillomaviruses with the host immune system: A
well evolved relationship. Virology 2009;384(2):410-4.
 
 
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28.
Shi L, Sings HL, Bryan JT, Wang B, Wang Y, Mach H, et al. GARDASIL®:
prophylactic human papillomavirus vaccine development - from bench top to bedside.
Clin Pharmacol Ther 2008;81(2):259-64.
29.
Olsson S-E, Villa LL, Costa RLR, Petta CA, Andrade RP, Malm C, et al. Induction of
immune memory following administration of a prophylactic quadrivalent human
papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine
2007;25:4931-9.
30.
Giuliano AR, Palefsky JM, Goldstone S, Moreira ED, Penny ME, Aranda C, et al.
Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N
Engl J Med 2011;364(5):401-11.
31.
Palefsky JM, Giuliano AR, Goldstone S, Moreira Jr. ED, Aranda C, Jessen H, et al.
HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J
Med 2011;365:1576-85.
32.
Recommendations on the use of quadrivalent human papillomavirus vaccine in 
males--Advisory Committee on Immunization Practices (ACIP), 2011. Centers for 
Disease Control and Prevention (CDC) et al. MMWR Morb Mortal Wkly Rep. (2011)
33.
Miettinen, O. and Nurminen, M. Comparative analysis of two rates. Stat Med
1985;4:213-26.
34.
Hwang  I  K   Shih  W  J   & deCani   J   S   1990)    Group  sequential  designs using 
a family of type I error probability  spending functions    Statistics in  Medicine  9  
1439-1445.
35.
Chan, I.S.F. and Bohidar, N.R. Exact power and sample size for vaccine efficacy
studies. Comm Stat – Theory Meth 1998:27;1305-22
 
 
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12.0 APPENDICES
12.1 Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
i.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
ii.
Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
iii.
Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
1.
IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
2.
Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
3.
Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
4.
Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
1.
Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
2.
Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
3.
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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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12.2 Collection and Management of Specimens for Future Biomedical Research
1)
Definitions
1)
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
2)
Pharmacogenomics:  The investigation of variations of DNA and RNA 
characteristics as related to drug response.2
3)
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug response.2
4)
DNA:  Deoxyribonucleic acid.
5)
RNA:  Ribonucleic acid.
2)
Scope of Future Biomedical Research
The DNA specimen(s) collected in the current trial will be used to study various causes 
for how subjects may respond to a drug.  The DNA specimen(s) will be stored to provide 
a resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug enters and is removed by the body, how a drug works, other 
pathways a drug may interact with, or other aspects 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, 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 Merck or designees and research will be 
monitored and reviewed by a committee of our scientists and clinicians.
3)
Summary of Procedures for Future Biomedical Research

Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.

Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
 
 
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Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial.  Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.

eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.

Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4)
Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
 
 
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now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5)
Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6)
Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
writing to the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
 
 
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 and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7)
Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  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 trial site will be shipped to a central laboratory and then shipped to 
the Merck 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 Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8)
Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9)
Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
 
 
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maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10) Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11) Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. [insert: Risks 
include those associated with venipuncture to obtain the whole blood specimen.  This 
specimen will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12) Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13) Questions
 
 
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Any questions related to the future biomedical research should be e-mailed directly to 
14) References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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12.3 Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
 
 
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12.4 Clinical Study Conduct System 
Sponsor
12.4.1
12.4.1.1 Name and Address of Sponsor
KITANOMARU SQURE 1-13-12, Kudankita, Chiyoda-ku, Tokyo 102-8667
12.4.1.2 Sponsor’s Representative
Japan Development, MSD K.K.
KITANOMARU SQURE 1-13-12, Kudankita, Chiyoda-ku, Tokyo 102-8667
TEL:  
   FAX:  
Role of Sponsor’s Representative
Sponsor's Responsible Medical Officer will sign the protocol as the representative of the 
Sponsor.
12.4.1.3 Medical Expert
Japan Development, MSD K.K.
KITANOMARU SQURE 1-13-12, Kudankita, Chiyoda-ku, Tokyo 102-8667
TEL:  
   FAX:  
12.4.1.4 Field Monitor (CRA) Representative
Site Monitoring, Japan Development, MSD K.K.
TEL:  
   FAX:  
 
 
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Clinical Research Organizations
12.4.2
See Japanese version
Investigator
12.4.3
A list of the primary investigators and participating institutions is given in Attachment 1.
 
 
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13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
13.2 Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
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