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    Clinical Trial Results:
    An Investigational Vaccine in Reducing the Incidence of Anogenital Warts in Young Men

    Summary
    EudraCT number
    		 2004-002945-10
    Trial protocol
    		 FI   SE   DE   ES   Outside EU/EEA  
    Global end of trial date
    03 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2018
    First version publication date
    08 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V501-020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00090285
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was conducted to demonstrate that Gardasil™ (qHPV vaccine) 1) is well tolerated in young men, 2) reduces incidence of external genital lesions in young men, 3) reduces the incidence of anal intraepithelial neoplasia (AIN) or anal cancer in men having sex with men (MSM), and 4) reduces incidence of Human Papillomavirus (HPV) infection in young men. In the 7-month Base Study participants received randomly assigned qHPV vaccine or placebo at Day 1, Month 2, and Month 6. Base Study follow-up continued through Month 36. In Extension 1 (EXT1), participants who received placebo or an incomplete qHPV vaccine regimen in the Base Study were offered qHPV vaccine. Participants were followed in EXT1 for 7 months. In Extension 2 [LTFU (EXT2)], long-term effectiveness, immunogenicity, and safety of qHPV vaccine were followed up to 10 years following study enrollment. Participants who received ≥1 dose of qHPV vaccine in the Base Study or EXT1 were eligible to enroll in LTFU (EXT2).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2004
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 1048
    Country: Number of subjects enrolled
    Finland: 90
    Country: Number of subjects enrolled
    Netherlands: 41
    Country: Number of subjects enrolled
    Portugal: 90
    Country: Number of subjects enrolled
    Brazil: 402
    Country: Number of subjects enrolled
    Peru: 450
    Country: Number of subjects enrolled
    Mexico: 573
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    Taiwan: 221
    Country: Number of subjects enrolled
    Costa Rica: 150
    Country: Number of subjects enrolled
    Norway: 100
    Country: Number of subjects enrolled
    Philippines: 51
    Country: Number of subjects enrolled
    South Africa: 538
    Country: Number of subjects enrolled
    Sweden: 53
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Australia: 89
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    Germany: 99
    Worldwide total number of subjects
    4065
    EEA total number of subjects
    496
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    187
    Adults (18-64 years)
    3878
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 4164 participants were screened and 4065 were randomized.

    Pre-assignment
    Screening details
    		 Participants were healthy males between the ages of 16 years and 26 years + 364 days.

    Period 1
    Period 1 title
    Base Study Vaccination Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 qHPV Vaccine in Base Study
    Arm description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    qHPV vaccine, quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

    Arm title
    		 Placebo in Base Study
    Arm description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

    Number of subjects in period 1
    		qHPV Vaccine in Base Study Placebo in Base Study
    Started
    2032
    2033
    Vaccinated
    2025
    2030
    Completed
    1818
    1814
    Not completed
    214
    219
         Consent withdrawn by subject
    64
    69
         Participant incarcerated
    2
    2
         Randomized not treated
    7
    3
         HIV positive
    1
    1
         Site terminated
    1
    -
         Adverse event
    2
    4
         Uncooperative
    2
    2
         Unspecified
    2
    2
         Moved
    20
    21
         Lost to follow-up
    111
    112
         Protocol deviation
    2
    3
    Period 2
    Period 2 title
    Base Study Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 qHPV Vaccine in Base Study
    Arm description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    qHPV vaccine, quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

    Arm title
    		 Placebo in Base Study
    Arm description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

    Number of subjects in period 2
    		qHPV Vaccine in Base Study Placebo in Base Study
    Started
    1818
    1814
    Completed
    1487
    1479
    Not completed
    335
    342
         Consent withdrawn by subject
    53
    64
         Participant incarcerated
    -
    2
         Adverse event
    3
    10
         Uncooperative
    3
    4
         Unspecified
    2
    -
         Moved
    41
    36
         Lost to follow-up
    232
    226
         Protocol deviation
    1
    -
    Joined
    4
    7
         Did not complete qHPV regimen in Base Study
    4
    7
    Period 3
    Period 3 title
    Extension 1 (EXT1)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 EXT1: Placebo in Base Study
    Arm description
    		 Participants in the placebo arm in the Base Study were offered 3 doses of open-label qHPV vaccine at EXT1 Day 1, Month 2, and Month 6. Participants were followed to EXT1 Month 7.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

    Investigational medicinal product name
    qHPV vaccine, quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in EXT1.

    Arm title
    		 EXT1: Incomplete qHPV Regimen in Base Study
    Arm description
    		 Participants who received who received only 1 dose of qHPV vaccine in the Base Study were offered a complete 3-dose open-label qHPV vaccine regimen (administered at EXT1 Day 1, Month 2, and Month 6). Participants who received only 2 doses of qHPV vaccine in the Base Study were offered a single additional open-label dose of qHPV vaccine (administered at EXT1 Day 1). Participants were followed to EXT1 Month 7.
    Arm type
    		 Experimental

    Investigational medicinal product name
    qHPV vaccine, quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle, a full 3-dose regimen or 2 doses at Day 1, Month 2, and Month 6 in EXT1.

    Investigational medicinal product name
    qHPV vaccine, quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle, 1 or 2 doses in the Base Study.

    Number of subjects in period 3
    		EXT1: Placebo in Base Study EXT1: Incomplete qHPV Regimen in Base Study
    Started
    1098
    16
    Completed
    1041
    15
    Not completed
    57
    1
         Consent withdrawn by subject
    13
    1
         Adverse event
    2
    -
         Unspecified
    4
    -
         Lost to follow-up
    35
    -
         Moved
    3
    -
    Period 4
    Period 4 title
    Long-term Follow-up (EXT2)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 LTFU (EXT2): Early Vaccination Group
    Arm description
    		 Participants received ≥1 dose of qHPV vaccine in Base Study and were followed up to a total of 10 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    qHPV vaccine, quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

    Arm title
    		 LTFU (EXT2): Catch-up Vaccination Group
    Arm description
    		 Participants received placebo in Base Study and qHPV vaccine in EXT1 and were followed up to a total of 7 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    qHPV vaccine, quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle in EXT1.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection in the deltoid muscle at Day 1, Month 2, and Month 6 in the Base Study

    Number of subjects in period 4
    		LTFU (EXT2): Early Vaccination Group LTFU (EXT2): Catch-up Vaccination Group
    Started
    936
    867
    Completed
    709
    664
    Not completed
    227
    203
         Physician decision
    6
    5
         Consent withdrawn by subject
    60
    53
         Adverse event
    5
    2
         Lost to follow-up
    156
    143

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    qHPV Vaccine in Base Study
    Reporting group description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.

    Reporting group title
    Placebo in Base Study
    Reporting group description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.

    Reporting group values
    		 qHPV Vaccine in Base Study Placebo in Base Study Total
    Number of subjects
    		 2032 2033 4065
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 89 98 187
        Adults (18-64 years)
    		 1943 1935 3878
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 20.6 ± 2.0 20.5 ± 2.0 -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 2032 2033 4065
    Race/Ethnicity
    Units: Subjects
        Asian
    		 201 205 406
        Black
    		 405 400 805
        Hispanic American
    		 412 423 835
        Native American
    		 1 2 3
        White
    		 719 712 1431
        Multi-racial
    		 291 283 574
        Indian (subcontinent)
    		 1 8 9
        Polynesian
    		 2 0 2
    Age
    Units: Years
        median (full range (min-max))
    		 20 (16 to 26) 20 (15 to 27) -

    End points

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    End points reporting groups
    Reporting group title
    qHPV Vaccine in Base Study
    Reporting group description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.

    Reporting group title
    Placebo in Base Study
    Reporting group description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.
    Reporting group title
    qHPV Vaccine in Base Study
    Reporting group description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.

    Reporting group title
    Placebo in Base Study
    Reporting group description
    		 The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36. No vaccinations were administered during the follow-up.
    Reporting group title
    EXT1: Placebo in Base Study
    Reporting group description
    		 Participants in the placebo arm in the Base Study were offered 3 doses of open-label qHPV vaccine at EXT1 Day 1, Month 2, and Month 6. Participants were followed to EXT1 Month 7.

    Reporting group title
    EXT1: Incomplete qHPV Regimen in Base Study
    Reporting group description
    		 Participants who received who received only 1 dose of qHPV vaccine in the Base Study were offered a complete 3-dose open-label qHPV vaccine regimen (administered at EXT1 Day 1, Month 2, and Month 6). Participants who received only 2 doses of qHPV vaccine in the Base Study were offered a single additional open-label dose of qHPV vaccine (administered at EXT1 Day 1). Participants were followed to EXT1 Month 7.
    Reporting group title
    LTFU (EXT2): Early Vaccination Group
    Reporting group description
    		 Participants received ≥1 dose of qHPV vaccine in Base Study and were followed up to a total of 10 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).

    Reporting group title
    LTFU (EXT2): Catch-up Vaccination Group
    Reporting group description
    		 Participants received placebo in Base Study and qHPV vaccine in EXT1 and were followed up to a total of 7 years after their first dose of qHPV vaccine. No vaccinations were administered during LTFU (EXT2).

    Subject analysis set title
    MSM qHPV Vaccine in Base Study
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Vaccination Period for the Base study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6. This per protocol population includes MSM participants who received ≥1 dose of qHPV in Base Study.

    Primary: Base Study: Incidence of Human Papillomavirus (HPV) Type 6/11/16/18-related External Genital Warts, Penile/Perianal/Perineal Intraepithelial Neoplasia (PIN), Penile, Perianal or Perineal Cancer

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    End point title
    		 Base Study: Incidence of Human Papillomavirus (HPV) Type 6/11/16/18-related External Genital Warts, Penile/Perianal/Perineal Intraepithelial Neoplasia (PIN), Penile, Perianal or Perineal Cancer
    End point description
    Participants with HPV 6/11/16/18-related external genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal or perineal cancer per 100 person-years of follow-up was assessed. Per-protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by Competitive Luminex Immunoassay, cLIA) at Day 1 and polymerase chain reaction (PCR) negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.
    End point type
    Primary
    End point timeframe
    Base study: through Month 36
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    1394
    1404
    Units: Incidence per 100 person-years
        number (not applicable)
    0.1
    1.0
    Statistical analysis title
    		 Percent Relative Risk Reduction
    Comparison groups
    Placebo in Base Study v qHPV Vaccine in Base Study
    Number of subjects included in analysis
    2798
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    90.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 70.1
         upper limit
    		 98.2
    Notes
    [1] - Confidence Interval (CI) based on binomial tail probabilities and not from a dispersion parameter.

    Primary: Base Study: Number of Participants with Severe Injection Site Adverse Experiences (AEs)

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    End point title
    		 Base Study: Number of Participants with Severe Injection Site Adverse Experiences (AEs) [2]
    End point description
    An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR'S product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the SPONSOR'S product, is also an adverse experience. A severe AE is incapacitating with inability to work or do usual activities. The analysis population included all vaccinated participants excluding 6 participants who received non-compliant mixed regimens of qHPV vaccine and placebo.
    End point type
    Primary
    End point timeframe
    Base study: through Day 5 after any vaccination
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analyses were planned or conducted for this endpoint.
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    2020
    2029
    Units: Participants
    25
    20
    No statistical analyses for this end point

    Primary: Base Study: Number of Participants with Vaccine-Related Serious Adverse Events (SAEs)

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    End point title
    		 Base Study: Number of Participants with Vaccine-Related Serious Adverse Events (SAEs) [3]
    End point description
    A serious adverse event is an AE that 1) results in death, 2) is life threatening, 3) results in persistent or significant disability or incapacity, 4) results in or prolongs an existing hospitalization, 5) is a congenital anomaly or birth defect, 6) is a cancer, 7) is an overdose, or 8) based on appropriate medical judgment may jeopardize the participant and may require medical or surgical intervention. A vaccine-related AE is one deemed to be possibly, probably or definitely related to study vaccine by the investigator. The analysis population included all vaccinated participants excluding 6 participants who received non-compliant mixed regimens of qHPV vaccine and placebo.
    End point type
    Primary
    End point timeframe
    Base study: through Month 36
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analyses were planned or conducted for this endpoint.
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    2020
    2029
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Primary: Overall Study: Incidence of HPV Type 6/11-related Genital Warts

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    End point title
    		 Overall Study: Incidence of HPV Type 6/11-related Genital Warts [4] [5]
    End point description
    Incidence of HPV Type 6/11-related genital warts is expressed as events per 10,000 person-years of follow-up. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7. This endpoint applied only to participants in the Base Study qHPV vaccine group.
    End point type
    Primary
    End point timeframe
    Up to 10 years after the first dose of qHPV vaccine
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analyses were planned or conducted for this endpoint.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applied only to participants in the Base Study qHPV vaccine group.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    1243
    Units: Incidence per 10,000 person-years
        number (confidence interval 95%)
    4.3 (0.9 to 12.5)
    No statistical analyses for this end point

    Primary: Overall Study: Incidence of HPV Type 6/11/16/18-related External Genital Warts, PIN, Penile, Perianal or Perineal Cancer

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    End point title
    		 Overall Study: Incidence of HPV Type 6/11/16/18-related External Genital Warts, PIN, Penile, Perianal or Perineal Cancer [6] [7]
    End point description
    Incidence of HPV Type 6/11/16/18-related external genital warts, PIN, penile, perianal or perineal cancer is expressed as events per 10,000 person-years of follow-up. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7. This endpoint applied only to participants in the Base Study qHPV vaccine group.
    End point type
    Primary
    End point timeframe
    Up to 10 years after the first dose of qHPV vaccine
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analyses were planned or conducted for this endpoint.
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applied only to participants in the Base Study qHPV vaccine group.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    1395
    Units: Incidence per 10,000 person-years
        number (confidence interval 95%)
    3.8 (0.8 to 11.1)
    No statistical analyses for this end point

    Primary: Overall Study: Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer

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    End point title
    		 Overall Study: Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer [8]
    End point description
    Incidence of HPV Type 6/11/16/18-related AIN and anal cancer is expressed as events per 10,000 person-years of follow-up. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7. This endpoint applied only to MSM participants in the Base Study qHPV vaccine group.
    End point type
    Primary
    End point timeframe
    Up to 10 years after the first dose of qHPV vaccine
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint applied only to MSM participants in the Base Study qHPV vaccine group.
    End point values
    		 MSM qHPV Vaccine in Base Study
    Number of subjects analysed
    194
    Units: Incidence per 10,000 person-years
        number (confidence interval 95%)
    69.3 (25.4 to 150.8)
    No statistical analyses for this end point

    Primary: LTFU (EXT2): Number of Participants with Vaccine-Related SAEs

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    End point title
    		 LTFU (EXT2): Number of Participants with Vaccine-Related SAEs [9]
    End point description
    An SAE is an AE that 1) results in death, 2) is life threatening, 3) results in persistent or significant disability or incapacity, 4) results in or prolongs an existing hospitalization, 5) is a congenital anomaly or birth defect, 6) is a cancer, 7) is an overdose, or 8) based on appropriate medical judgment may jeopardize the participant and may require medical or surgical intervention. A vaccine-related AE is one deemed to be possibly, probably or definitely related to study vaccine by the investigator. The population analyzed was all randomized participants receiving at least 1 dose of qHPV vaccine in the Base Study or EXT1 and enrolled in LTFU (EXT2).
    End point type
    Primary
    End point timeframe
    qHPV Vaccine in Base Study: up to 12 years after last dose of qHPV vaccine; Placebo in Base Study: up to 7 years after last dose of qHPV vaccine
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The population analyzed included only participants who enrolled in LTFU (EXT2).
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    936
    867
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Primary: LTFU (EXT2): Number of Participants who Died

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    End point title
    		 LTFU (EXT2): Number of Participants who Died [10]
    End point description
    The number of participants who died was assessed. The population analyzed was all randomized participants receiving at least 1 dose of qHPV vaccine in the Base Study or EXT1 and enrolled in LTFU (EXT2).
    End point type
    Primary
    End point timeframe
    qHPV Vaccine in Base Study: up to 12 years after last dose of qHPV vaccine; Placebo in Base Study: up to 7 years after last dose of qHPV vaccine
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The population analyzed included only participants who enrolled in LTFU (EXT2).
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    936
    867
    Units: Participants
    5
    2
    No statistical analyses for this end point

    Secondary: Base Study: Incidence of HPV Type 6/11/16/18-related Persistent Infection

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    End point title
    		 Base Study: Incidence of HPV Type 6/11/16/18-related Persistent Infection
    End point description
    Participants with HPV Type 6/11/16/18-related persistent infection per 100 person-years of follow-up was assessed. Per-protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.
    End point type
    Secondary
    End point timeframe
    Base study: through Month 36
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    1390
    1402
    Units: Infection per 100 person-years
        number (not applicable)
    0.7
    4.8
    Statistical analysis title
    		 Percent Relative Risk Reduction
    Comparison groups
    qHPV Vaccine in Base Study v Placebo in Base Study
    Number of subjects included in analysis
    2792
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    85.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 77
         upper limit
    		 91.3
    Notes
    [11] - Confidence interval based on binomial tail probabilities and not from a dispersion parameter. Hochberg multiplicity adjustment applied to the CI.

    Secondary: Base Study: Incidence of HPV 6/11/16/18-related Deoxyribonucleic Acid (DNA) Detection

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    End point title
    		 Base Study: Incidence of HPV 6/11/16/18-related Deoxyribonucleic Acid (DNA) Detection
    End point description
    Participants with HPV 6/11/16/18-related DNA detection per 100 person-years of follow-up was assessed. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with the evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.
    End point type
    Secondary
    End point timeframe
    Base study: through Month 36
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    1390
    1402
    Units: Detection per 100 person-years
        number (not applicable)
    5.3
    10.7
    Statistical analysis title
    		 Percent Relative Risk Reduction
    Comparison groups
    qHPV Vaccine in Base Study v Placebo in Base Study
    Number of subjects included in analysis
    2792
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 40.3
         upper limit
    		 59.9
    Notes
    [12] - Confidence interval based on binomial tail probabilities and not from a dispersion parameter. Hochberg multiplicity adjustment applied to the CI.

    Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 7 Assessed by cLIA

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    End point title
    		 Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 7 Assessed by cLIA [13]
    End point description
    Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 7
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: cLIA mMU/mL
    number (confidence interval 95%)
        HPV Type 6 (n=1090)
    447.7 (415.9 to 481.9)
        HPV Type 11 (n=1090)
    624.4 (588.4 to 662.6)
        HPV Type 16 (n=1133)
    2406.1 (2245.0 to 2578.8)
        HPV Type 18 (n=1173)
    402.8 (373.9 to 433.9)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 36 Assessed by cLIA

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    End point title
    		 Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 36 Assessed by cLIA [14]
    End point description
    Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 36
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: cLIA mMU/mL
    number (confidence interval 95%)
        HPV Type 6 (n=845)
    71.5 (66.7 to 76.7)
        HPV Type 11 (n=845)
    82.5 (77.0 to 88.5)
        HPV Type 16 (n=875)
    293.6 (271.6 to 317.4)
        HPV Type 18 (n=904)
    33.2 (30.2 to 36.4)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 72 Assessed by cLIA

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    End point title
    		 Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 72 Assessed by cLIA [15]
    End point description
    Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 72 [first sample in LTFU (EXT2) ranged from Month 48 to 84 with a median of Month 72]
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: cLIA mMU/mL
    number (confidence interval 95%)
        HPV Type 6 (n=575)
    57.2 (52.3 to 62.5)
        HPV Type 11 (n=575)
    62.1 (56.7 to 68.1)
        HPV Type 16 (n=609)
    249.4 (225.6 to 275.8)
        HPV Type 18 (n=633)
    25.9 (23.2 to 28.9)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by cLIA

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    End point title
    		 Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by cLIA [16]
    End point description
    Antibodies to HPV types were measured using cLIA. Antibody titers were expressed as cLIA milli Merck units/mL (cLIA mMU/mL). The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 120
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: cLIA mMU/mL
    geometric mean (confidence interval 95%)
        HPV Type 6 (n=374)
    49.4 (44.1 to 55.4)
        HPV Type 11 (n=374)
    38.7 (34.5 to 43.5)
        HPV Type 16 (n=393)
    182.9 (161.4 to 207.3)
        HPV Type 18 (n=408)
    17.6 (15.5 to 19.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Seropositive for HPV Type 6, 11, 16, and 18 at Month 7 Assessed by cLIA

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    End point title
    		 Percentage of Participants Seropositive for HPV Type 6, 11, 16, and 18 at Month 7 Assessed by cLIA [17]
    End point description
    Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 7
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: Percentage of participants
    number (confidence interval 95%)
        HPV Type 6 (n=1090)
    98.9 (98.1 to 99.4)
        HPV Type 11 (n=1090)
    99.2 (98.4 to 99.6)
        HPV Type 16 (n=1133)
    98.8 (97.9 to 99.3)
        HPV Type 18 (n=1173)
    97.4 (96.3 to 98.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 36 Assessed by cLIA

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    End point title
    		 Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 36 Assessed by cLIA [18]
    End point description
    Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 36
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: Percentage of participants
    number (confidence interval 95%)
        HPV Type 6 (n=845)
    88.9 (86.6 to 90.9)
        HPV Type 11 (n=845)
    94.0 (92.1 to 95.5)
        HPV Type 16 (n=875)
    97.9 (96.8 to 98.8)
        HPV Type 18 (n=904)
    57.1 (53.8 to 60.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 72 Assessed by cLIA

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    End point title
    		 Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 72 Assessed by cLIA [19]
    End point description
    Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 72 [first sample in LTFU (EXT2) ranged from Month 48 to 84 with a median of Month 72]
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: Percentage of participants
    number (confidence interval 95%)
        HPV Type 6 (n=575)
    84.3 (81.1 to 87.2)
        HPV Type 11 (n=575)
    88.0 (85.1 to 90.5)
        HPV Type 16 (n=609)
    97.0 (95.4 to 98.2)
        HPV Type 18 (n=633)
    49.6 (45.6 to 53.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by cLIA

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    End point title
    		 Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by cLIA [20]
    End point description
    Antibodies to HPV types were measured using cLIA. Thresholds for seropositive were ≥20, 16, 20, and 24 cLIA mMU/mL for HPV Types 6, 11, 16, and 18, respectively. The per-protocol population included all participants who 1) were seronegative (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 120
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: Percentage of participants
    number (confidence interval 95%)
        HPV Type 6 (n=374)
    79.1 (74.7 to 83.2)
        HPV Type 11 (n=374)
    79.9 (75.5 to 83.9)
        HPV Type 16 (n=393)
    94.9 (92.2 to 96.9)
        HPV Type 18 (n=408)
    40.2 (35.4 to 45.1)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by Immunoglobulin G Luminex Immunoassay (IgG LIA)

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    End point title
    		 Geometric Mean Titers to HPV Types 6, 11, 16, and 18 at Month 120 Assessed by Immunoglobulin G Luminex Immunoassay (IgG LIA) [21]
    End point description
    Antibodies to HPV types were measured using Luminex immunoassay (IgG-LIA). The unit of measure for this assay is IgG LIA mMU/mL; this unit cannot be directly compared with the cLIA mMU/mL unit reported for the cLIA results. The per-protocol population included all participants who 1) were seronegative at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 120
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: IgG LIA mMU/mL
    geometric mean (confidence interval 95%)
        HPV Type 6 (n=278)
    38.8 (34.0 to 44.2)
        HPV Type 11 (n=274)
    31.0 (27.2 to 35.3)
        HPV Type 16 (n=291)
    162.0 (141.2 to 185.7)
        HPV Type 18 (n=305)
    19.7 (17.0 to 22.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by IgG LIA

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    End point title
    		 Percentage of Participants Seropositive to HPV Type 6, 11, 16, and 18 at Month 120 Assessed by IgG LIA [22]
    End point description
    Antibodies to HPV types were measured using IgG LIA. Thresholds for seropositive were ≥9, 6, 5, and 5 IgG LIA mMU/mL for HPV Types 6, 11, 16,and 18, respectively. The per-protocol population included all participants who 1) were seronegative at Day 1 and PCR negative to the relevant HPV type(s) at Day 1 through Month 7, 2) received all 3 vaccinations within pre-specified day ranges, and 3) did not deviate from the study protocol in ways that could interfere with the effects of the vaccine. Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point type
    Secondary
    End point timeframe
    Month 120
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of immunogenicity was planned and conducted only for participants who received qHPV vaccine in the Base Study.
    End point values
    		 qHPV Vaccine in Base Study
    Number of subjects analysed
    2025
    Units: Percentage of participants
    number (confidence interval 95%)
        HPV Type 6 (n=278)
    91.7 (87.8 to 94.7)
        HPV Type 11 (n=274)
    92.0 (88.1 to 94.9)
        HPV Type 16 (n=291)
    99.7 (98.1 to 100)
        HPV Type 18 (n=305)
    92.1 (88.5 to 94.9)
    No statistical analyses for this end point

    Other pre-specified: Base Study: Sub-study to Evaluate the Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer in Men Having Sex with Men (MSM)

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    End point title
    		 Base Study: Sub-study to Evaluate the Incidence of HPV Type 6/11/16/18-related Anal Intraepithelial Neoplasia (AIN) and Anal Cancer in Men Having Sex with Men (MSM)
    End point description
    Participants with HPV 6/11/16/18-related AIN or anal cancer per 100 person-years of follow-up was assessed. Only a subset of the enrolled population was used for the analysis of this sub-study. Per protocol population: participants must have received 3 doses of qHPV vaccine or placebo within 1 year, must have no protocol violations that could interfere with evaluation of vaccine efficacy, must be seronegative to the relevant HPV type (as measured by cLIA) at Day 1 and PCR negative to the relevant HPV type Day 1 through Month 7, and must provide follow-up data after Month 7.
    End point type
    Other pre-specified
    End point timeframe
    Base study: through Month 36
    End point values
    		 qHPV Vaccine in Base Study Placebo in Base Study
    Number of subjects analysed
    194
    208
    Units: Incidence per 100 person-years
        number (not applicable)
    1.3
    5.8
    Statistical analysis title
    		 Percent Relative Risk Reduction
    Comparison groups
    qHPV Vaccine in Base Study v Placebo in Base Study
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    77.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 39.6
         upper limit
    		 93.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Base study: all AEs through Month 36 of Base Study. EXT1: SAEs through Month 7 of EXT1. LTFU (EXT2): SAEs and deaths through 7 years of LTFU (EXT2). Non-serious AEs were not solicited during EXT1 or LTFU (EXT2).
    Adverse event reporting additional description
    Analysis population: Base Study: all participants vaccinated in Base Study excluding 6 participants who received non-compliant mixed regimens of qHPV vaccine and placebo; EXT1: all participants who received qHPV vaccine in EXT1 and had follow-up data; LTFU (EXT2): all participants enrolled in LTFU (EXT2).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    qHPV Vaccine in Base Study
    Reporting group description
    		 The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time participants received qHPV vaccine at Day 1, Month 2 and Month 6.

    Reporting group title
    Placebo in Base Study
    Reporting group description
    		 The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time participants received placebo at Day 1, Month 2 and Month 6.

    Reporting group title
    qHPV Vaccine in EXT1
    Reporting group description
    		 Participants who received placebo and participants who received only 1 dose of qHPV vaccine in the Base Study were offered a complete 3-dose qHPV vaccine regimen (administered at EXT1 Day 1, Month 2 and Month 6). Participants who received only 2 doses of qHPV vaccine in the base Study were offered a single additional dose of qHPV vaccine (administered at EXT1 Day 1).

    Reporting group title
    LTFU (EXT2)
    Reporting group description
    		 Participants received ≥1 dose of qHPV vaccine in Base Study, or received placebo in Base Study and qHPV vaccine in EXT1.

    Serious adverse events
    		 qHPV Vaccine in Base Study Placebo in Base Study qHPV Vaccine in EXT1 LTFU (EXT2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 2020 (0.40%)
    11 / 2029 (0.54%)
    3 / 1084 (0.28%)
    7 / 1803 (0.39%)
         number of deaths (all causes)
    3
    10
    2
    7
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neuroma
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 2020 (0.00%)
    1 / 2029 (0.05%)
    1 / 1084 (0.09%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Chemical poisoning
         subjects affected / exposed
    0 / 2020 (0.00%)
    1 / 2029 (0.05%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 2020 (0.00%)
    1 / 2029 (0.05%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 2020 (0.05%)
    3 / 2029 (0.15%)
    1 / 1084 (0.09%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 1
    Head injury
         subjects affected / exposed
    0 / 2020 (0.00%)
    1 / 2029 (0.05%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Multiple drug overdose
         subjects affected / exposed
    0 / 2020 (0.00%)
    1 / 2029 (0.05%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 2020 (0.05%)
    1 / 2029 (0.05%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    Traumatic brain injury
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Blast injury
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Burns second degree
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Craniocerebral injury
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 2020 (0.00%)
    1 / 2029 (0.05%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 2020 (0.00%)
    1 / 2029 (0.05%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 2020 (0.00%)
    2 / 2029 (0.10%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 2020 (0.05%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    1 / 1084 (0.09%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    HIV infection
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    0 / 2020 (0.00%)
    0 / 2029 (0.00%)
    0 / 1084 (0.00%)
    1 / 1803 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 qHPV Vaccine in Base Study Placebo in Base Study qHPV Vaccine in EXT1 LTFU (EXT2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1277 / 2020 (63.22%)
    1183 / 2029 (58.30%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    179 / 2020 (8.86%)
    207 / 2029 (10.20%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    222
    275
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    118 / 2020 (5.84%)
    125 / 2029 (6.16%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    131
    149
    0
    0
    Injection-site erythema
         subjects affected / exposed
    304 / 2020 (15.05%)
    275 / 2029 (13.55%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    446
    384
    0
    0
    Injection-site pain
         subjects affected / exposed
    1116 / 2020 (55.25%)
    992 / 2029 (48.89%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    2087
    1767
    0
    0
    Injection-site pruritus
         subjects affected / exposed
    23 / 2020 (1.14%)
    24 / 2029 (1.18%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    27
    29
    0
    0
    Injection-site swelling
         subjects affected / exposed
    219 / 2020 (10.84%)
    187 / 2029 (9.22%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    318
    270
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    19 / 2020 (0.94%)
    23 / 2029 (1.13%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    21
    23
    0
    0
    Diarrhoea
         subjects affected / exposed
    40 / 2020 (1.98%)
    36 / 2029 (1.77%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    44
    38
    0
    0
    Nausea
         subjects affected / exposed
    27 / 2020 (1.34%)
    16 / 2029 (0.79%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    30
    16
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    38 / 2020 (1.88%)
    37 / 2029 (1.82%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    38
    37
    0
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    42 / 2020 (2.08%)
    44 / 2029 (2.17%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    43
    47
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    44 / 2020 (2.18%)
    50 / 2029 (2.46%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    46
    59
    0
    0
    Pharyngitis
         subjects affected / exposed
    22 / 2020 (1.09%)
    20 / 2029 (0.99%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    23
    21
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 2020 (1.34%)
    20 / 2029 (0.99%)
    0 / 1084 (0.00%)
    0 / 1803 (0.00%)
         occurrences all number
    28
    22
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jun 2005
    Amendment 2: clarified terms for external genital endpoints, changed enrollment to 3700, added wording that participants who do not complete the 3-dose series will be allowed to continue in the study, clarified timing of retention contact visits, revised criteria for the clinical impression of external genital lesions, revised procedures for high-resolution anoscopy
    13 Mar 2006
    Amendment 3: changed enrollment to 3870, clarified that participants who test positive for HIV will not be discontinued, clarified wording as to management of lesions observed on Day 1 as to etiology, assumed vaccine efficacy for MSM endpoint changed to 85%.
    21 May 2007
    Amendment 4: adopted registered trademark name, GARDASIL™, updated planned enrollment numbers, clarified sexual history information, updated competitive Luminex immunoassay information, clarified or corrected details for sample handling, notifications, and other technical matters.
    21 May 2009
    Amendment 10: provided for the vaccination of placebo recipients, clarified the MSM sub-study endpoint, described the Type 1 Error adjustment for testing the MSM sub-study hypothesis, clarified the visit schedule to finalize efficacy phase, added and clarified criteria to unblind participants, added information on eligibility of participants to receive the vaccination series in the Study Vaccination Extension.
    29 Mar 2010
    Amendment 20: provided for long term evaluation of vaccine effectiveness in males, through active follow-up of study participants for up to 10 years from the day of enrollment into the Base Study.
    01 Dec 2010
    Amendment 21: clarified definitions of AE relationship to study vaccine, added or clarified details for sample collection and study visits.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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