A Phase III, Open-Label, Clinical Trial to Study the Safety and Immunogenicity of the Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Particle (VLP) Vaccine in 9- to 15-Year-Old Japanese Boys
Phase: PHASE3
Conditions: Anogenital Human Papilloma Virus Infection, Condyloma Acuminata
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02576054 
Document Date: 
21-AUG-2015
A Phase III, Open-Label, Clinical Trial to Study the Safety and 
Immunogenicity of the Quadrivalent HPV (Types 6, 11, 16, 18) L1 
VLP Particle (VLP) Vaccine in 9- to 15-Year-Old Japanese Boys

Product:  V501
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Confidential
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., KENILWORTH, NJ, 
U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
Merck Corporate Headquarters
2000 Galloping Hill Road
Kenilworth, New Jersey, 07033, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III, Open-Label, Clinical Trial to Study the Safety and Immunogenicity of the 
Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Particle (VLP) Vaccine in 9- to 15-Year-
Old Japanese Boys
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................... 9
2.0
TRIAL DESIGN.......................................................................................................... 9
Trial Design ............................................................................................................. 9
2.1
Trial Diagram........................................................................................................ 10
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 10
Primary Objective(s) & Hypothesis(es) .............................................................. 10
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 10
3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 11
Background ........................................................................................................... 11
4.1
Pharmaceutical and Therapeutic Background .................................................... 11
4.1.1
4.1.1.1
Disease Burden and Epidemiology of Human Papillomaviruses ................ 11
4.1.1.2
Biology of Human Papillomaviruses ........................................................... 12
4.1.1.3
Prophylactic HPV Vaccines......................................................................... 13
Rationale................................................................................................................ 13
4.2
Rationale for the Trial and Selected Subject Population .................................... 13
4.2.1
Rationale for Dose Selection/Regimen............................................................... 14
4.2.2
Rationale for Endpoints ...................................................................................... 14
4.2.3
4.2.3.1
Immunogenicity Endpoints.......................................................................... 14
4.2.3.2
Safety Endpoints .......................................................................................... 14
4.2.3.3
Future Biomedical Research........................................................................ 14
Benefit/Risk ........................................................................................................... 15
4.3
5.0
METHODOLOGY ................................................................................................... 15
Entry Criteria........................................................................................................ 15
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 15
5.1.1
Subject Inclusion Criteria.................................................................................... 15
5.1.2
Subject Exclusion Criteria .................................................................................. 16
5.1.3
Trial Vaccination(s) .............................................................................................. 17
5.2
Dose Selection .................................................................................................... 18
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 18
 
 
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Timing of Dose Administration .......................................................................... 18
5.2.2
Trial Blinding/Masking....................................................................................... 18
5.2.3
Randomization or Vaccine Allocation ................................................................ 18
5.3
Stratification.......................................................................................................... 18
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 18
5.5
Rescue Medications & Supportive Care............................................................. 18
5.6
Diet/Activity/Other Considerations..................................................................... 18
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 19
5.8
Subject Replacement Strategy............................................................................. 19
5.9
Beginning and End of the Trial ........................................................................... 19
5.10
Clinical Criteria for Early Trial Termination ................................................... 19
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 20
7.0
TRIAL PROCEDURES ........................................................................................... 21
Trial Procedures ................................................................................................... 21
7.1
Administrative Procedures.................................................................................. 21
7.1.1
7.1.1.1
Informed Consent......................................................................................... 21
7.1.1.1.1
General Informed Consent.................................................................... 21
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 22
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 22
7.1.1.3
Subject Identification Card .......................................................................... 22
7.1.1.4
Medical History ........................................................................................... 22
7.1.1.5
Prior and Concomitant Medications Review ............................................... 22
7.1.1.5.1
Prior Medications.................................................................................. 22
7.1.1.5.2
Concomitant Medications..................................................................... 22
7.1.1.6
Assignment of Screening Number............................................................... 23
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 23
7.1.1.8
Trial Compliance (Vaccination) .................................................................. 23
Clinical Procedures/Assessments........................................................................ 24
7.1.2
7.1.2.1
Vital Signs.................................................................................................... 24
7.1.2.2
Vaccination Report Card (VRC).................................................................. 24
7.1.2.3
Study Vaccine Administration..................................................................... 25
 
 
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7.1.2.3.1
Preparation for Administration ............................................................. 25
7.1.2.3.2
Study Vaccine Administration.............................................................. 25
Laboratory Procedures/Assessments .................................................................. 25
7.1.3
7.1.3.1
Serum for Anti-HPV Measurements............................................................ 25
7.1.3.2
Future Biomedical Research Sample Collection ......................................... 26
Other Procedures................................................................................................. 26
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 26
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 26
7.1.4.2
Blinding/Unblinding .................................................................................... 26
7.1.4.3
Calibration of Critical Equipment................................................................ 27
Visit Requirements.............................................................................................. 27
7.1.5
7.1.5.1
Prerequisites for Study Vaccination Visit.................................................... 27
Assessing and Recording Adverse Events .......................................................... 27
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 28
Immediate Reporting of Adverse Events to the Sponsor.................................... 29
7.2.2
7.2.2.1
Serious Adverse Events ............................................................................... 29
Evaluating Adverse Events ................................................................................. 30
7.2.3
Sponsor Responsibility for Reporting Adverse Events ...................................... 33
7.2.4
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 33
Statistical Analysis Plan Summary ..................................................................... 33
8.1
RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING..................... 34
8.2
HYPOTHESES/ESTIMATION .......................................................................... 34
8.3
ANALAYSIS ENDPOINTS................................................................................. 35
8.4
Immunogenicity Endpoints................................................................................. 35
8.4.1
Safety Endpoints ................................................................................................. 35
8.4.2
ANALYSIS POPULATION................................................................................. 35
8.5
Immunogenicity Analysis Populations ............................................................... 35
8.5.1
Safety Analysis Populations ............................................................................... 37
8.5.2
STATISTICAL MEDHODS................................................................................ 37
8.6
Statistical Methods for Immunogenicity Analyses ............................................. 37
8.6.1
Statistical Methods for Safety Analyses ............................................................. 40
8.6.2
 
 
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Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 41
8.6.3
INTERIM ANALYSES ........................................................................................ 42
8.7
MULTIPLICITY .................................................................................................. 42
8.8
SAMPLE SIZE AND POWER CALCULATION............................................. 42
8.9
Sample Size for Estimating Immune Response .................................................. 42
8.9.1
Sample Size for comparing immune response between 9- to 15-year-old 
8.9.2
boys and 16- to 26-year-old Young men ............................................................ 43
Sample Size and Power for Safety Analyses ...................................................... 44
8.9.3
SUBGROUP ANALYSES AND EFFECT OF BASELINE FACTORS.......... 44
8.10
COMPLIANCE (MEDICATION ADHERENCE)............................................ 44
8.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 44
Investigational Product ........................................................................................ 44
9.1
Packaging and Labeling Information ................................................................. 45
9.2
Clinical Supplies Disclosure................................................................................. 45
9.3
Storage and Handling Requirements.................................................................. 45
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 45
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 45
Confidentiality....................................................................................................... 45
10.1
Confidentiality of Data ....................................................................................... 45
10.1.1
Confidentiality of Subject Records ..................................................................... 46
10.1.2
Confidentiality of Investigator Information........................................................ 46
10.1.3
Confidentiality of IRB/IEC Information............................................................. 46
10.1.4
Compliance with Financial Disclosure Requirements....................................... 47
10.2
Compliance with Law, Audit and Debarment ................................................... 47
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 49
10.4
Quality Management System............................................................................... 49
10.5
Data Management................................................................................................. 49
10.6
Publications ........................................................................................................... 50
10.7
11.0
LIST OF REFERENCES......................................................................................... 52
12.0
APPENDICES........................................................................................................... 55
Merck Code of Conduct for Clinical Trials........................................................ 55
12.1
 
 
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Collection and Management of
Specimens for Future Biomedical 
12.2
Research................................................................................................................. 57
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 61
Approximate Blood Volumes Drawn by Trial Visit and by Sample Types..... 70
12.4
Clinical Study Conduct System ........................................................................... 71
12.5
13.0
SIGNATURES........................................................................................................... 72
Sponsor's Representative ..................................................................................... 72
13.1
Investigator............................................................................................................ 72
13.2
 
 
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LIST OF TABLES
Table 1
Trial Vaccination ................................................................................................................17
Table 2
Evaluating Adverse Events.................................................................................................31
Table 3
Acceptable Day Ranges for Vaccination Visits..................................................................36
Table 4
Acceptable Day Ranges for Collection of Serum Samples.................................................36
Table 5
Analysis Strategy for Immunogenicity Variables...............................................................39
Table 6
Analysis Strategy for Safety Parameters.............................................................................41
Table 7
Probability for Primary Immunogenicity Objective ...........................................................43
Table 8
Power for Secondary Immunogenicity Objective (9- to 15-Year-Old Boys vs. 16-
to 26-Year-Old Young men).............................................................................................43
Table 9
Product Descriptions...........................................................................................................44
 
 
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LIST OF FIGURES
          
Figure 1
Trial Diagram....................................................................................................................10
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Safety and Immunogenicity trial of V501 in Japanese boys
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
No control
Route of administration
Intramuscular injection
Trial Blinding
Unblinded Open-label
Vaccination Groups
V501
Number of trial subjects
Approximately 100 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 34
months (Study Period for Clinical Trial Notification (CTN): From Sep 
2015 to Jan 2019) from the time the first subject signs the informed 
consent until the last subject completes the last study-related phone call 
or visit, discontinues from the trial or is lost to follow-up (i.e., the subject 
is unable to be contacted by the investigator).
Duration of Participation
Each subject will participate in the trial for approximately 30 months 
from the time the subject’s legally acceptable representative signs the 
Informed Consent Form (ICF) through the final contact. Each subject
will receive 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 24 months.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a nonrandomized, multi-site, open-label trial of V501 [quadrivalent HPV (Type 6, 11, 
16 and 18) L1 Virus-Like Particle (VLP) vaccine] in healthy Japanese boy subjects to be 
conducted in conformance with Good Clinical Practices. This study will consist of two 
periods. Period I of the study is to evaluate the immunogenicity and tolerability of V501 up 
to the point of Month 7. Period II of the study is to evaluate the long-term immunogenicity 
and safety from Month7 to Month30. Two analyses are planned. The first analysis will be 
conducted when all subjects have completed their Month 7 visit or have been discontinued 
before that time. The second analysis will be conducted at the end of study.
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.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
(1) Objective: To demonstrate that administration of V501 induces high seroconversion 
rates for the vaccine HPV types (6, 11, 16 and 18) at 4 weeks post dose 3 in 9- to 15-
year-old Japanese boys.
Hypothesis: Seroconversion rates for the vaccine HPV types (6, 11, 16 and 18) at 
4weeks post dose 3 will be high (The success criterion for the primary analysis 
requires that point estimates for seroconversion rates be greater than 90% for all 4 
HPV types).
(2) Objective: To demonstrate that a 3-dose regimen of V501 to 9- to 15-year-old Japanese 
boys is well tolerated.
Secondary Objective(s) & Hypothesis(es)
3.2
(1) Objective: To demonstrate that administration of V501 induces non-inferior geometric 
mean titers (GMTs) for serum anti-HPV 6, 11, 16 and 18 at 4 weeks post dose 3 in 
Japanese boys aged 9- to 15-year-old compared with those in Japanese men aged 16- to 
26-year-old in Phase III study (Protocol 122) for V501 at 4 weeks post dose 3.
 
 
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Hypothesis: V501 generates anti-HPV 6, 11, 16 and 18 GMTs 4 weeks post dose 3 in 
Japanese boys aged 9- to 15-year-old that are non-inferior to those in Japanese men 
aged 16- to 26-year-old. (The statistical criterion for success requires that the lower 
bound of two-sided 95% confidence interval of GMT ratio between boys enrolled in 
V501-200 and men enrolled in the Phase III study V501-122 be greater than 0.5 for 
each HPV type.)
(2) Objective: To describe the persistence of the serum antibody titers for the vaccine HPV 
types 24 months following the third dose of V501.
(3) Objective: To estimate the immune response for the vaccine HPV types (6, 11, 16 and
18) at 4 weeks post dose 3 using GMTs.
4.0 BACKGROUND & RATIONALE
Background
4.1
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.
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].
 
 
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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
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
 
 
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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 February
2015, V501 was approved and marketed under the names
GARDASIL™/SILGARD™ in over 130 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 6 years after the first 
vaccination [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]. In Japan, the clinical trial in Japanese male 
aged 16 to 26 years old to evaluate efficacy and tolerability, V501-122, is on-going. Male 
indication of V501 has not been approved yet in Japan.
Rationale
4.2
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.
 
 
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This trial is designed to bridge V501 efficacy findings in young adult men in overseas 
clinical trial, V501-020 and on-going Japanese clinical trial, V501-122, to Japanese boys, via 
the comparison of the immunogenicity against HPV type 6, 11, 16 and 18 between 9- to 15-
year-old Japanese boys and 16- to 26-year-old Japanese men enrolled in V501-122. 
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 the same 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 in many countries including Japan will be 
used in this trial. 
Rationale for Endpoints
4.2.3
4.2.3.1
Immunogenicity Endpoints
Anti-HPV 6, 11, 16 or 18 will be analyzed as the indicator of immune responses to each
vaccine components. Assessment of efficacy of V501 in 16- to 26-year-old men is ongoing 
under a different study (Protocol 122). Direct efficacy evaluation of prophylactic HPV 
vaccine in 9- to 15-year-old subjects is not feasible due to social and cultural constraints 
surrounding the notion of sexual activity among younger adolescents and the limited ability 
to perform anogenital examination in this age group.
Serum will be collected from all subjects for analysis of anti-HPV 6, 11, 16 and 18 by
competitive Luminex Immunoassay (cLIA) at Day 1, Month 7, Month 18 and Month 30. 
Serum sample will be collected at Day 1 for identification of subjects who had an HPV 
infection prior to enrollment.
4.2.3.2
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
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.
4.2.3.3
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA specimens collected for 
future biomedical research during this clinical trial.
 
 
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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. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine 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.
Benefit/Risk
4.3
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 immunogenicity of an investigational vaccine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Healthy Male subjects between the ages of 9 and 15 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 age of 9 years and 0 days and 15 years and 
364 days on the day of the first study vaccination.
2. Have a legal representative who provides written informed consent for the trial on the 
subject’s behalf. The legal representative may also provide consent for Future 
Biomedical Research on the subject’s behalf. However, the subject may participate in 
the main trial without participating in Future Biomedical Research.
3. Have a legal representative who is able to read, understand, and complete the vaccine
report card.
 
 
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4. Agree to provide study personnel with a primary telephone number as well as an 
alternate telephone number/email address for follow-up purpose.
5. Show no temperature ≥37.5˚C (oral) within 24 hours prior to vaccinations. If the 
subject does not meet this criterion, the Day 1 visit will be rescheduled for a time 
when this criterion can be met.
6. Must not yet have had coitarche and does not plan on becoming sexually active 
during the Day 1 through Month 7.
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
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. If the subject meets this 
criterion, the Day 1 visit will be rescheduled for a time when this criterion is not met.
4. Has history of severe allergic reaction (e.g., swelling of the mouth and throat,
difficulty breathing, hypotension or shock) that required medical intervention.
5. Is allergic to any vaccine component, including aluminum, yeast, or BENZONASE™
(nuclease, Nycomed [used to remove residual nucleic acids from this and other
vaccines]).
6. 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.
7. 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.
8. 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
 
 
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(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.
9. Has known thrombocytopenia or any coagulation disorder that would contraindicate
intramuscular injections.
10. 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.
11. 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.
12. Is unlikely to adhere to the study procedures, keep appointments, or is planning to
relocate during the study.
13. Has a history of genital warts or a positive test for HPV.
14. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Vaccination(s)
5.2
The vaccine to be used in this trial is outlined below in Table 1.
Table 1
Trial Vaccination
Vaccine.
Dose/Potency
Dose 
Frequency
Route of 
Administration
Vaccination 
Regimen
Use
V501
0.5 mL
3
Intramuscular 
injection
Day 1, Month 2 
and Month 6
Investigational
Trial vaccination is given on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
 
 
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Dose Selection
5.2.1
5.2.1.1
Dose Selection (Preparation)
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 will be administered as a 0.5 mL intramuscular injection at Day 1, Month 2 and
Month 6.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
vaccine administered.
Randomization or Vaccine Allocation
5.3
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
See the exclusion criteria for specific restrictions for prior and concomitant medications at 
Day 1.
To reduce their potential interference with the evaluation of the immunologic response and 
reactogenicity of the study vaccine, non-study inactivated vaccines must not be administered 
within the 14 days before or 14 days after any dose of study vaccine. Non-study 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 through Month 7. 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.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
No special restrictions will apply except for those noted under the inclusion/exclusion criteria.
 
 
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Subject Withdrawal/Discontinuation Criteria
5.8
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 from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
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.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form. The subject 
participation portion of the overall trial ends when the last subject completes the last study-
related phone call or visit, discontinues from the trial or is lost to follow-up (i.e., the subject 
is unable to be contacted by the investigator). For purposes of analysis and reporting, the 
overall trial ends when the Sponsor receives the last serology assay result or subject data 
from the last study-related phone call or visit.
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Period I
Period II
Visit Number:
1
2
3
4
5
6
Scheduled Day/Month :
Day 1
Month 2
Month 6
Month 7
Month 18
Month 30
Visit Window 1:
2 months 
after Day 1 
± 3 weeks
6 months 
after Day 1 
± 4 weeks
3 to 7 
weeks after 
Month 6
18 months 
after Day 1 
± 4 weeks
30 months 
after Day 1 ±
4 weeks
Administrative Procedures
Informed Consent/Assent 2
X
Informed Consent for Future Biomedical Research
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Medical History
X
Update Medical History (New condition not already 
recorded as medical history or adverse experiences)
X
X
X
X
X
Concomitant Medication and Non Study Vaccination 
Review 3
X
X
X
X
X
X
Assign Screening and Randomization/Treatment
number
X
Clinical Procedures/Assessments
Vital Signs (oral temperature, height, weight, sitting 
pulse, blood pressure, and respirations) 4
X
X
X
Provide Vaccination Report Card (VRC)
X
X
X
Review and collect VRC data
X
X
X
V501 Administration 5
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
Laboratory Procedures/Assessments
Serum for Anti-HPV antibody testing (including 
retention serum) 6
X
X
X
X
Blood (DNA) for Future Biomedical Research 7
X
1.
To calculate visit windows, assume 1 month equals 30 days and 1 week equals 7 days.
2.
Written assent of the subject himself is to be obtained as far as possible.
3.
See section 7.1.1.5 of the protocol for details for prerequisites for medications and non-study vaccines
4.
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.
5.
Observe subjects for 30 minutes after each vaccination for immediate untoward effects.
6.
Serum for anti-HPV measurements must be collected before vaccination. 
7.
Informed consent for future biomedical research samples must be obtained to collect the DNA sample.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
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 or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative 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.
 
 
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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.
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.
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 immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. At Visit 1 (Day
1), 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
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, and record prior 
medication taken by the subject before first dose of trial vaccination. Refer to the exclusion 
criteria for specific restrictions for prior medications and vaccines at Day 1.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Use of medicines and non-study vaccines should be documented in the data collection system
in the following manner:
 
 
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・
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
・
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 nonstudy 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
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.
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.   Once a
treatment/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 treatment/randomization number.
7.1.1.8
Trial Compliance (Vaccination)
Administration of trial vaccination will be witnessed by the investigator and/or trial staff.
 
 
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Clinical Procedures/Assessments
7.1.2
7.1.2.1
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.
7.1.2.2
Vaccination Report Card (VRC)
Each subject will receive a VRC at the study vaccination visit. On the VRC, the 
parent/guardian of 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 parent/guardian of 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 parent/guardian of the subject and must be signed and dated by the subject's parent or
guardian to confirm the accuracy of the recorded information. The subject's parent or
guardian 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’s parent/guardian. Original information on the VRC should never be altered by study 
personnel, although comments can be written in the designated area for study site personnel 
on the front of the VRC. Corrections to the VRC can only be made by the subject’s 
parent/guardian. 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’s parent/guardian 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.
 
 
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7.1.2.3
Study Vaccine Administration 
7.1.2.3.1 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,
semitranslucent suspension when thoroughly mixed. If the appearance is otherwise, do not 
administer, and contact the SPONSOR immediately.
7.1.2.3.2 Study Vaccine Administration 
At each vaccination visit, subjects will receive V501 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.
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.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn over the course of the trial, including 
approximate blood volumes drawn by visit by sample type per subject can be found in 
Section 12.4.
7.1.3.1
Serum for Anti-HPV Measurements
The 4-valent HPV cLIA is the primary assay used for the primary and secondary objectives
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
(nonheprinized, non-serum separator, red-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
 
 
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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 Retention 
serum should be shipped separately from the Serum sample.
7.1.3.2
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
・
Blood (DNA) for future research.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the next trial 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 .
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 
contacting 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 
(clinical.specimen.management@merck.com), 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.
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
This is an open label trial; there is no blinding for this trial.
 
 
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7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
・
Refrigerator
・
Centrifuge
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.
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:
・
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.
・
The subject has not received any systemic (oral or parenteral) corticosteroids in the 2
weeks prior to any study vaccination visit.
・
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.
Assessing and Recording Adverse Events
7.2
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.
 
 
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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 clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed 
but before 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of allocation/randomization 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, all adverse 
events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets. The reporting timeframe 
for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher 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 non-serious adverse event, unless other serious 
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 adverse event, using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
 
 
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reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
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 an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. 
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 2 for additional details regarding each of the above criteria.  
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization 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,   
any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause, whether or not related to the Sponsor's product, must be reported within 24 hours to 
the Sponsor either by electronic media or paper. Electronic reporting procedures can be 
found in the EDC data entry guidelines. Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
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:
 
 
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1. A death that occurs prior to the subject completing the trial, but outside the time period 
specified in the previous paragraph.
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.
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 5 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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements; or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is 
reportable to the Sponsor within 24 hours to meet certain local requirements.
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 SPONSOR
CLINICAL DIRECTOR 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 the AE is more likely explained by another cause than the Sponsor’s product.  (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, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  
Changes to analyses made after the protocol has been finalized, but prior to final database 
lock, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly 
identified in the CSR.
The immunogenicity and safety analysis of Day 1 through Month 7 will be performed 
after the data through Month 7 have been declared final and complete. The analysis of 
Month 18 through Month 30 immunogenicity and safety data will take place at the end of 
the study. The results of this study will be summarized in 2 separate reports. The first 
report is the CSR including the immunogenicity and safety results based on the data 
through Month 7. The second one is an update to the CSR, including persistence of 
immune response and safety results through the end of the study.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive 
plan is provided in Sections 8.2-8.12.  
Study Design Overview
A phase III, open-label, clinical trial to study the safety and 
immunogenicity of the quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP 
Particle (VLP) vaccine in 9- to 15-year-old boy
Treatment Assignment
Subjects meeting inclusion/exclusion criteria will be allocated to V501.
Analysis Populations
Immunogenicity: Per-Protocol Immunogenicity (PPI)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Primary immunogenicity endpoint will be seroconversion rate for the 
vaccine HPV types (6, 11, 16 and 18) at 4 weeks post dose 3.
Key Secondary Endpoints
Key secondary endpoint includes cLIA geometric mean titers (GMTs) 
for the vaccine HPV type (6, 11, 16 and 18) at 4 weeks post dose 3.
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypothesis with respect to anti-HPV 6, 11, 16 and 18 
seroconversion percentages by 4 weeks post dose 3 will be evaluated by 
computing point estimates and constructing 95% confidence interval. 
(The success criterion for the primary analysis requires that point 
estimates for seroconversion rate be greater than 90% for all 4 vaccine 
HPV types.)
The secondary hypothesis will be evaluated by comparing anti-HPV 6, 
11, 16 and 18 GMTs at 4 weeks post dose 3 in 9- to 15-year-old boys
from this study with those in 16- to 26-year old young men (all young
men who were vaccinated by V501 and met the per-protocol 
immunogenicity criteria of PN122 will be included) by constructing a 
95% confidence interval for the ratio of GMTs.
 
 
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Statistical Methods for Key 
Safety Analyses
The adverse experiences of interest in this study include injection site 
adverse experiences/vaccine-related adverse experiences prompted for 
on the VRC occurring Day 1 through Day 5 following any vaccination, 
systemic adverse experiences/vaccine-related adverse experiences
reported Day 1 through Day 15, elevated temperatures from Day 1 to 
Day 5 following any vaccination.  Summary tables will be provided.
Interim Analyses
The immunogenicity and safety analysis of Day 1 through Month 7 will be
performed after the data through Month 7 have been declared final and
complete. The analysis of  Month 18 through Month 30 immunogenicity
and safety data will take place at the end of the study.
Multiplicity
For the primary hypothesis, no multiplicity adjustment is required since 
success requires the observed seroconversion rates for all 4 vaccine HPV 
types to be greater than 90%.  Similarly, for the secondary hypothesis for 
comparing GMTs between 9- to 15-year-old boys and 16- to 26-year old 
young men, success is required on all 4 vaccine HPV types. Therefore, 
no multiplicity adjustment will be made to account for the multiple HPV 
types. The secondary hypothesis will only be tested if the primary 
hypothesis is demonstrated successfully.
Sample Size and Power 
This study will enroll 100 subjects to receive V501, and will allow 
estimation of seroconversion percentage with a 95% confidence interval 
with a half-width of approximately 5 percentage points to assess the 
primary objective. Given the true seroconversion percentage of 95%, 
there is 92% probability that the point estimates are greater than 90% for 
all 4 vaccine HPV types. This is based on the assumption of an 
approximately 5% dropout and/or protocol violation rate. For the 
secondary hypothesis, a sample size of 95 boys from this study and 400 
young men from PN122 has more than 99% probability that the lower 
bounds of 95%CI exceed 0.5 for all 4 HPV types given the underlying 
true GMT ratio is 1.0. This is based on the following assumptions for 
young men from PN122 in addition to that for boys described above: no 
general protocol violation of 95%; exclusion rate due to Day 1 
seropositive or PCR positive between Day 1 and Month 7 to HPV 6, 11, 
16, and 18 is approximately 15%; 90% of randomized subjects 
completed vaccination phase.
RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING
8.2
The statistical analysis of the data obtained from this study will be the responsibility of 
the designee/Clinical Biostatistics department of the SPONSOR. This trial is being 
conducted as a non-randomized, open-label study, i.e., subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
HYPOTHESES/ESTIMATION
8.3
Objectives and hypotheses of the study are stated in Section 3.1.
 
 
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ANALAYSIS ENDPOINTS
8.4
Immunogenicity and safety endpoints that will be evaluated for within- and/or between-
age group differences are listed below, followed by the descriptions of the derivations of 
selected endpoints.
Immunogenicity Endpoints
8.4.1
The primary immunogenicity endpoints are seroconversion percentages to HPV 6, 11, 16 
and 18 by 4 weeks post dose 3. Seroconversion is defined as changing serostatus from 
seronegative to seropositive. A subject with a competitive Luminex Immunoassay (cLIA)
titer at or above the serostatus cutoff for a given HPV type is considered seropositive for 
that HPV type. The key secondary immunogenicity endpoints include cLIA geometric 
mean titers (GMTs) to HPV 6, 11, 16 and 18 at 4 weeks post dose 3. Other secondary 
endpoints include both cLIA GMTs and seroconversion percentages for each vaccine 
HPV type at Months 18 and 30 to assess persistence of immune responses.
Safety Endpoints
8.4.2
Safety assessment will focus on the injection site adverse experiences/vaccine-related 
adverse experiences and elevated temperatures on Days 1 to 5 post-vaccination, and 
systemic adverse experiences/vaccine-related systemic adverse experiences on Days 1 to 
15 post-vaccination, reported on the Vaccination Report Card (VRC). Serious adverse 
experiences reported Days 1 to 15 post-vaccination, vaccine-related serious adverse 
experiences reported any time during the study and new medical condition occurring any 
time during the study will also be summarized.
ANALYSIS POPULATION
8.5
Immunogenicity Analysis Populations
8.5.1
Per Protocol Immunogenicity (PPI) Population
The Per Protocol Immunogenicity (PPI) population will serve as the primary population 
for the analysis of immune response to each of the 4 HPV types (6, 11, 16 and 18). To be 
included in this population, subjects must:
(1) Have received all 3 vaccinations with the correct dose of the correct clinical material, 
and each vaccination visit must occur within acceptable day ranges (See Table 3 for 
acceptable day ranges for vaccination visits).
(2) Have provided Month 7 serology result within 21 to 49 days post dose 3.
(3) Be seronegative to the appropriate HPV type at Day 1 (See Table 4 for acceptable day 
ranges for serum samples at Day 1).
(4) Have no other protocol violations that could interfere with the evaluation of subject’s 
immune response to the study vaccine.
 
 
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To be included in the PPI population for HPV 6 or 11, subjects must be seronegative to 
both HPV 6 and 11 at Day 1. To be included in the PPI population for any other vaccine 
HPV type, subjects need to be seronegative at Day 1 only for the HPV type being 
analyzed. The final determination on protocol violations, which will be used for 
determining the Per-Protocol Immunogenicity population, will be made prior to the 
database lock and will be documented in a separate memo.
Table 3
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
Day 1†
0
Dose 2
Month 2 ± 3 weeks
36 to 84
Dose 3
Month 6 ± 4 weeks
148 to 218
† Day 1 refers to the date when dose 1 of 4-valent HPV L1 VLP vaccine is injected. 
Table 4
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
Serum
0
–14 to 0
Month 7
Serum
30 days post dose 3
21 to 49 post dose 3
Month 18
Serum
548
366 to 730
Month 30
Serum
913
731 to 1004
†
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.
All Type-Specific Naïve Subjects with Serology (ANSS) Population
A supportive immunogenicity analysis will be carried out on the all type-specific naïve 
subjects with serology population. To be included in this population, subjects must:
(1) Have received all 3 vaccinations
(2) Have provided post dose 3 serology data
(3) Be seronegative to the appropriate HPV type at Day 1
To be included in the ANSS population for HPV 6 or 11, subjects must be seronegative 
to both HPV 6 and 11 at Day 1. To be included in the ANSS population for any other 
vaccine HPV type, subjects need to be seronegative at Day 1 only for the HPV type being 
analyzed. Unlike the PPI population, this population will include general protocol 
 
 
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violators. In addition, no ranges on the timing of the vaccination will be applied. 
Acceptable day ranges for serum samples at Day 1 will be the same as in the PPI 
population. Acceptable day range for serum samples at Month 7 will be broader than in 
the PPI population, extending from Day 1 post dose 3 to Day 105 post dose 3.
Safety Analysis Populations
8.5.2
All subjects who received at least 1 study vaccination and have follow-up data will be 
included in the analysis of safety.
STATISTICAL MEDHODS
8.6
Statistical testing and inference for safety analyses are described in 8.6.2. 
Immunogenicity results that will be deemed to be statistically significant after 
consideration of the Type I error control strategy are described in Section 8.8, 
Multiplicity. Nominal p-values may be computed for other immunogenicity analyses, but 
should be interpreted with caution due to potential issues of multiplicity, sample size, etc. 
Unless otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) 
level.
Statistical Methods for Immunogenicity Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives. 
Estimation of seroconversion percentage
The primary immunogenicity hypothesis with respect to anti-HPV 6, 11, 16 and 18 
seroconversion percentages by 4 weeks post dose 3 will be evaluated by computing point 
estimates and constructing 95% confidence interval. Calculation of the confidence 
interval is based on the exact binomial method proposed by Clopper and Pearson (1934). 
Success of this study requires that the point estimates of seroconversion percentage on all 
the 4 HPV types exceed 90%.
Estimation of GMTs
Anti-HPV 6, 11, 16 and 18 GMT at 4 weeks post dose 3 will be evaluated by computing 
point estimates and constructing 95% confidence interval. The values will be log-
transformed before analysis. As such, the confidence intervals 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 confidence intervals will yield estimates 
for the population geometric means titer and confidence intervals about the geometric 
means titer on the original scale.
Comparison of immune response (9-15 years old boys vs. 16-26 years old young men)
 
 
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The secondary hypothesis that the immune response in 9- to 15-year-old boys is non-
inferior to that in 16- to 26-year-old young men (all men who were vaccinated by V501 
and met the per-protocol immunogenicity criteria of PN122) will be addressed by 95%
confidence intervals based on one-sided tests (one corresponding to each HPV type) 
conducted at the α=0.025 level (1-sided). For each HPV type, the hypotheses to be tested 
are:
H0: GMT1/GMT2 ≤0.5
H1: GMT1/GMT2 >0.5
where GMT1 represents the GMTs at Month 7 in the 9- to 15-year-old boys and GMT2
represents the GMTs at Month 7 in the 16- to 26-year old young men. The test above will 
be performed using an analysis of variance model with a response of log-transformed
individual titers and a fixed effect for age group. The statistical criterion requires that the 
lower bound of two-sided 95% confidence interval of GMT ratio (9- to 15-year-old boys
divided by 16- to 26-year-old  young men) be greater than 0.5 for all 4 HPV types. For 
exploratory purposes, 95% confidence interval for the difference (9- to 15-year-old boys
minus 16- to 26-year-old young men) in seroconversion percentages by 4 weeks post 
dose 3 for each of the vaccine HPV types will be constructed. The calculation will be
based on the method proposed by Miettinen and Nurminen (1985).
Persistence of immune responses
Anti-HPV 6, 11, 16 and 18 GMTs and seroconversion percentages at Months 18 and 30 
will be summarized in the PPI population to assess the persistence of immune responses.
Longitudinal plots of the GMTs from Day 1 through Month 30 will also be provided for 
graphical display.
Table 5 summarizes the immunogenicity analyses.
 
 
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Table 5
Analysis Strategy for Immunogenicity Variables
Endpoints
Variable
Primary
/secondary
/supportive
Margin
PPI
ANSS
Point estimate 
and 95% CI
Immune Response at 4 weeks post dose 3
Seroconversion percentage to HPV 6, 11, 16 and 18 by 4 
weeks post dose 3 (each type will be analyzed separately)
Seroconversion percentage by 4 weeks post dose 3
Primary
N/A
●
●
●
Anti-HPV 6, 11, 16 and 18 Titer at 4 weeks post dose 3
(each type will be analyzed separately)
GMT at 4 weeks post dose 3
Secondary
N/A
●
●
●
Comparison of immune response between 9- to 15- year-old boys and 16- to 26-year-old young men
Anti-HPV 6, 11, 16 and 18 Titer at 4 weeks post dose 3
(each type will be compared separately)
Ratio of GMT at 4 weeks post dose 3
(9- to 15- year-old boys divided by
16- to 26- year-old men)
Secondary
2- fold
(0.5)
●
●
Seroconversion percentage to HPV 6, 11, 16 and 18 by 4 
weeks post dose 3 (each type will be summarized 
separately)
Difference in seroconversion percentage by 4 weeks 
post dose 3
(9- to 15- year-old boys minus 16- to 26-year-old men)
Supportive
Not 
determined
●
●
Persistent Immune response
Anti-HPV 6, 11, 16 and 18 Titer
at each time point (each type will be compared separately)
GMT at each time point
Secondary
N/A
●
●
Seroconversion percentage to HPV 6, 11, 16 and 18 by each 
time point (each type will be summarized separately)
Seroconversion percentage by each time point
Supportive
N/A
●
●
PPI=Per protocol immunogenicity; ANSS= all type-specific naïve subjects with serology.
 
 
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The strategy to address multiplicity issues with regard to multiple immunogenicity endpoints, 
and/or multiple time points is described in Section 8.8, Multiplicity.
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs).
The analysis of safety results usually follow a tiered approach in the studies conducted by the 
SPONSOR. However, this study has only 1 treatment group. Thus, the following summaries 
will be provided as described in Table 6.
–
Incidence is defined as (number of subjects with the indicated endpoint divided by the 
total number of subjects with follow-up over the relevant period)*100%.
–
For the measured adverse experiences of redness and swelling, 0 to 1 inch will be 
categorized as mild intensity, >1 inch to 2 inches will be categorized as moderate intensity, 
and >2 inches will be categorized as severe intensity
The specific events of interest in this study will be injection-site adverse experiences 
prompted for on the VRC, such as pain/tenderness, swelling and redness occurring Day 1 
through Day 5 following any vaccination, and elevated temperature (≥37.5°C), from Day 1 to 
Day 5 following any vaccination.
 
 
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Table 6
Analysis Strategy for Safety Parameters
Follow-Up Period
After Any Vaccination Visit
Any Time 
During Study
Adverse Experience Endpoint
Day 1
to Day 5†
Day 1
To Day 15†
Clinical AEs/vaccine-related AEs
Any AE/vaccine-related AE
●
Deaths
●
Injection site AEs/vaccine-related AEs
AEs/vaccine-related AEs of pain/tenderness, swelling, and redness 
Other injection site AEs/vaccine-related AEs
●
●
Severe injection site AEs§/vaccine-related AEs
●
Number (%) of subjects by maximum intensity rating, 
over all injection site AEs§/vaccine-related AEs
●
Number (%) of subjects by maximum intensity rating, 
within each of the categories of injection site AEs§/vaccine-related AEs
●
Systemic AEs/vaccine-related AEs
Systemic AEs/vaccine-related AEs
●
Number (%) of subjects by maximum intensity rating, 
over all systemic AEs/vaccine-related AEs
●
Temperatures
Elevated temperatures#
●
Maximum temperatures††
●
AEs of Special Interest
Serious AEs
Serious vaccine-related AEs
●
●
New medical conditions‡‡
●
†
The day of vaccination is counted as Day 1.  Day 1 to Day 5 refers to the period within 4 days of a vaccination.  Day 1 
to Day 15 refers to the period within 14 days of a vaccination.
§
For the measured adverse experiences of redness and swelling 0 to 1 inch will be categorized as mild, >1 inch to 2 
inches will be categorized as moderate and >2 inches will be categorized as severe.
#
Defined as maximum (over the follow-up period) temperature ≥37.5°C.
†† Distribution of maximum temperatures over the relevant follow-up period. 
‡‡ Including new medical conditions considered potentially of an autoimmune nature.
AEs = Adverse experiences; 
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
Baseline characteristics and demographic variables
Baseline characteristics and demographic variables will be summarized by the use of tables 
and/or graphs. The number and percentage of patients screened, enrolled, vaccinated and the 
primary reason for discontinuation will be displayed. Demographic variables, baseline 
characteristics and prior and concomitant therapies (relevant pre-injection day ranges for 
summarization will be 3 days for medications, 14 days for non-live virus vaccines and 28
days for live virus vaccines) will be summarized either by descriptive statistics or categorical 
tables.
 
 
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Baseline HPV Status
A serum sample will be collected from all subjects at the Day 1 visit for the purpose of 
assessing baseline HPV serostatus to the 4-valent HPV L1 VLP vaccine HPV types (HPV 6, 
11, 16 and 18).  A subject will be considered seropositive to a given HPV type at Day 1 if the 
subject’s anti-HPV titer is ≥ the corresponding serostatus cutoff for that HPV type or
seronegative to a given HPV type at Day 1 if the subject’s anti-HPV titer is < the 
corresponding serostatus cutoff for that HPV type. For each HPV type, the proportions of 
subjects who are seronegative or seropositive will be summarized.
INTERIM ANALYSES
8.7
The immunogenicity and safety analysis of Day 1 through Month 7 will be performed after 
the data through Month 7 have been declared final and complete. The analysis of  Month 18 
through Month 30 immunogenicity and safety data will take place at the end of the study.
MULTIPLICITY
8.8
For the primary hypothesis, no multiplicity adjustment is necessary since success requires the 
observed seroconversion rates for all 4 vaccine HPV types to be greater than 90%. Similarly, 
for the secondary hypothesis for comparing GMTs in 9- to 15-year-old boys with those in 16-
to 26-year old Japanese men, success is required on all 4 vaccine HPV types. Therefore, no 
multiplicity adjustment will be necessary to account for the multiple HPV types. The 
secondary hypothesis will only be tested if the primary hypothesis is demonstrated 
successfully.
SAMPLE SIZE AND POWER CALCULATION
8.9
Sample Size for Estimating Immune Response
8.9.1
Seroconversion percentage by Month 7
This study will enroll 100 subjects to receive V501, and will allow estimation of 
seroconversion percentage among subjects receiving V501 with a 95% confidence interval 
with a half-width of approximately 5 percentage points. This is based on the following 
assumptions: 1) an approximately 5% dropout and/or protocol violation rate, 2) an 
underlying response rate of 95% in the study population. Previously conducted studies of
V501 indicate the seroconversion percentage is approximately 100%. For reference, 
seroconversion percentages (95% confidence intervals) were 97.5% (91.3, 99.7), 98.8%
(93.2, 100), 98.8% (93.4, 100) and 98.8% (93.4, 100) for HPV 6, 11, 16 and 18, respectively,
in Japanese girls (PN028).  The calculation is based on the exact binomial method proposed 
by Clopper and Pearson (1934) with 95 subjects in the population expected to be included in 
the analysis, and is carried out using SAS ver. 9.2. Table 7 summarizes estimates of 
probability that the point estimates of seroconversion percentage on 4 HPV types exceed 
90%.
 
 
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Table 7
Probability for Primary Immunogenicity Objective
True seroconversion 
percentage
Probability that the point estimate 
exceeds 90% for a specific HPV type
Probability that the point estimates 
exceed 90% for all 4 HPV types
95%
0.98
0.92
99%
> 0.99
> 0.99
The criterion requires that the point estimates of seroconversion percentage exceed 90%.
GMT at Month 7
This study will allow estimation of GMT among subjects receiving V501 with a 95% 
confidence interval with a half-width of 0.24 (ln mMU/mL) on the natural log scale
(equivalently 1.27 fold on the original scale). The precision is based on the following 
assumptions: 1) an approximately 5% dropout and/or protocol violation rate, and 2) a SD of 
the natural-log-transformed titers of 1.2.
Sample Size for comparing immune response between 9- to 15-year-old boys and 
8.9.2
16- to 26-year-old Young men
Table 8 summarizes the probability calculations for various true GMT ratios. The probability 
shown in the table is for meeting the secondary immunogenicity hypothesis in all 4 HPV 
types for 9- to 15-year-old boys vs. 16- to 26- year-old young men (all young men who were 
vaccinated by V501 and met the per-protocol immunogenicity criteria of PN122). The 
probability is based on the following assumptions: 1) an approximately 5% dropout and/or 
protocol violation rate in 9- to 15-year-old boys, 2) an approximately 40% of subjects are 
excluded from 550 young men vaccinated by V501 from PN122, 3) a margin of 2-fold, and 
4) a standard deviation of 1.2 on the log scale (ln(mMU/mL)). The calculation is based on the 
t-test at alpha=0.025 (one-sided) with 95 boys and 400 young men expected to be included in 
the analysis and is carried out using SAS ver. 9.2. As shown in Table 8, this study will have 
more than 99% probability that the lower bounds of 95% confidence interval exceed 0.5 for 
all 4 HPV types given the underlying true GMT ratio is 1.0.
Table 8
Power for Secondary Immunogenicity Objective (9- to 15-Year-Old Boys vs. 16-
to 26-Year-Old Young men)
True GMT Ratio
Probability that 95%CI lies above 0.5
for a specific HPV type
Probability that 95%CI lies above 0.5
For all 4 HPV types
1.0
>0.99
>0.99
1.5
> 0.99
> 0.99
The statistical criterion requires that the lower bound of two-sided 95% confidence interval of GMT ratio (boys vs. 
young men) being greater than 0.5.
 
 
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Sample Size and Power for Safety Analyses
8.9.3
The probability of observing at least one specific adverse experience in this study depends on 
the number of subjects vaccinated and the underlying percentage of subjects with a specific 
adverse experience in the study population. If the underlying incidence of a specific adverse 
experience is 1%, there is a 63% chance of observing at least one specific adverse experience
among 100 subjects.  If no adverse experiences are observed among the 100 subjects, this 
study will provide 80% confidence that the underlying percentage of subjects with an adverse 
experience is <1.6%.
SUBGROUP ANALYSES AND EFFECT OF BASELINE FACTORS
8.10
Point estimates along with 95% confidence intervals for Month 7 anti- HPV Types 6, 11, 16
and 18 GMTs will be provided for 9-12 and 13-15 year old age strata.
COMPLIANCE (MEDICATION ADHERENCE)
8.11
Compliance is defined in this study as receipt of all scheduled study vaccinations. To 
summarize compliance, the numbers of subjects who receive each vaccination will be 
tabulated.  Compliance with the planned vaccination schedule (Day 1, Month 2, Month 6) 
will be described by histograms of actual intervals between vaccinations relative to the 
expected interval.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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
1 dose (0.5 mL)
Sterile suspension for intramuscular 
injection
 
 
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Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label single-dose vials at Day 1 (Visit 1), Month 2 (Visit 2) and 
Month 6 (Visit 3). No kitting is required.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Vaccine (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
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.
Discard/Destruction/Returns and Reconciliation
9.5
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, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
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.
 
 
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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.
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.
 
 
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Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
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.
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.
 
 
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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 will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  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 destroying 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.
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 
 
 
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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.
Compliance with Trial Registration and Results Posting Requirements
10.4
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.
Quality Management System
10.5
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 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
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.
 
 
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
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 
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 
 
 
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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.
 
 
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oncogenic potential of human papillomaviruses: a review on the role of host genetics and 
environmental cofactors. Br J Dermatol 2007;157:228-41.
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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.
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Chuang T-Y, Perry HO, Kurland LT, Ilstrup DM. Condyloma acuminatum in Rochester, 
Minn, 
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anaplasias 
and 
unfavorable 
outcomes. 
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Stone KM. Human papillomavirus infection and genital warts: update on epidemiology 
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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.
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.
 
 
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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.
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. Japanese Package Insert for GARDASIL®: June 2013
 
 
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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)
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
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
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of 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. 
2. 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.
3. 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
A. 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. 
B. 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.
C. 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.  
D. 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
A. 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.
B. 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.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices 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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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.2 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine 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/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. 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.  
 
 
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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.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
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, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines 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.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
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 
contacting the principal investigator for the main trial. If medical records for the main 
 
 
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trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent 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 the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
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. 
After the clinical trial has completed, if any exploratory results are definitively associated 
 
 
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with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. 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.
The Sponsor 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.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. 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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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood Volumes Drawn by Trial Visit and by Sample Types
12.4
Trial Visit/Cycle/etc:
Visits 1
Day 1
Visit 4-6
Month 7-30
Blood Parameter 
Approximate Blood Volume (mL)
Serum for Anti-HPV antibody
10 mL
10 mL
Blood (DNA) for Future 
Biomedical Research 
8.5 mL
NA
Expected Total (mL)
18.5 mL
10 mL
 
 
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Clinical Study Conduct System
12.5
Clinical study conduct system is shown in Attachment 1 and 2.
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
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
TITLE
SIGNATURE
DATE SIGNED
 
 
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