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    Clinical Trial Results:
    A Phase III Placebo-controlled Clinical Trial to Study the Tolerability, Immunogenicity and Efficacy of V501 in 16- to 26-year-old Japanese men

    Summary
    EudraCT number
    		 2015-002931-16
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2018
    First version publication date
    15 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V501-122
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01862874
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JAPIC-CTI: 132237
    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
    30 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the efficacy and tolerability of V501 (quadrivalent Human Papilloma Virus [HPV] [Type 6, 11, 16 and 18] L1 Virus-Like Particle vaccine, GARDASIL™) in healthy, 16- to 26-year old Japanese males. The hypotheses tested are: 1) V501 reduces the combined incidence of HPV 6-, 11-, 16-, or 18-related persistent infection compared with placebo, and 2) V501 reduces the combined incidence of HPV 6-, 11-, 16-, or 18-related persistent infection, condyloma acuminata, penile/perianal/perineal intraepithelial neoplasia, or penile, perianal, or perineal cancer compared with placebo.
    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
    27 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 1124
    Worldwide total number of subjects
    1124
    EEA total number of subjects
    0
    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)
    3
    Adults (18-64 years)
    1121
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1129 participants were screened and 1124 were randomized.

    Pre-assignment
    Screening details
    		 Healthy Japanese males age 16 to 26 years were enrolled in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 V501
    Arm description
    		 Participants received V501 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quadrivalent human papillomavirus vaccine
    Investigational medicinal product code
    Other name
    (Gardasil™) human papillomavirus (types 6, 11, 16, 18) recombinant vaccine. Formulated with aluminum hydroxyphosphate sulfate (AAHS) adjuvant.
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection at Day 1, Month 2, and Month 6

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Formulated with AAHS adjuvant
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection at Day 1, Month 2, and Month 6

    Number of subjects in period 1
    		V501 Placebo
    Started
    562
    562
    Vaccination 1
    561
    562
    Vaccination 2
    539
    542
    Vaccination 3
    530
    532
    Completed
    483
    485
    Not completed
    79
    77
         Withdrawn by parent/guardian
    1
    1
         Adverse event, serious fatal
    -
    1
         Physician decision
    5
    3
         Consent withdrawn by subject
    46
    40
         Randomized not treated
    1
    -
         Adverse event, non-fatal
    -
    3
         Lost to follow-up
    26
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    V501
    Reporting group description
    		 Participants received V501 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.

    Reporting group values
    		 V501 Placebo Total
    Number of subjects
    		 562 562 1124
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 0 3 3
        Adults (18-64 years)
    		 562 559 1121
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 22.6 ± 2.1 22.6 ± 2.0 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 562 562 1124
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 562 562 1124
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 0 0 0
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    V501
    Reporting group description
    		 Participants received V501 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.

    Primary: Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection

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    End point title
    		 Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection
    End point description
    Persistent infection was defined as 1) polymerase chain reaction (PCR) positive to HPV Type 6, 11, 16, or 18 in 2 consecutive anogenital or biopsy samples collected ≥4 months apart, or 2) Pathology Panel consensus diagnosis of condyloma acuminate, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer and PCR detection of HPV Type 6, 11, 16, or 18 in an adjacent section and PCR positive for the same HPV type at a separate adjacent visit. The combined incidence of HPV Type 6, 11, 16, or 18 persistent infection detected in samples from ≥2 consecutive visits ≥6 months apart was assessed. The population was participants who were seronegative at Day 1 and PCR negative from Day 1 through Month 7 to the relevant HPV type, received all 3 vaccinations, did not deviate from the study protocol in ways that might interfere with vaccine efficacy, and had ≥1 follow-up visit after Month 7.
    End point type
    Primary
    End point timeframe
    Up to Month 36
    End point values
    		 V501 Placebo
    Number of subjects analysed
    497 [1]
    498 [2]
    Units: Cases per 100 person-years of follow-up
        number (not applicable)
    0.3
    1.9
    Notes
    [1] - 1137 person-years follow-up
    [2] - 1123 person-years follow-up
    Statistical analysis title
    		 Vaccine Efficacy
    Statistical analysis description
    Vaccine efficacy is defined as the percentage reduction in relative risk for the V501 group versus the placebo group.
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    995
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 One-sided exact test
    Parameter type
    		 Vaccine Efficacy
    Point estimate
    85.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 52.7
         upper limit
    		 97.3
    Notes
    [3] - If the lower bound of the 95% confidence interval for vaccine efficacy excludes 0%, then superiority of the V501 group is demonstrated.

    Primary: Percentage of Participants with Maximum Temperature ≥37.5°C Reported on the Vaccination Report Card

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    End point title
    		 Percentage of Participants with Maximum Temperature ≥37.5°C Reported on the Vaccination Report Card
    End point description
    Body temperature (oral or oral equivalent) was recorded on the Vaccination Report Card (VRC). The percentage of participants with a maximum temperature ≥37.5°C was summarized. The population was participants who received ≥1 study vaccination and had follow-up data available.
    End point type
    Primary
    End point timeframe
    Up to 5 days after any vaccination
    End point values
    		 V501 Placebo
    Number of subjects analysed
    551
    557
    Units: Percentage of participants
        number (not applicable)
    2.7
    3.9
    Statistical analysis title
    		 Incidence of elevated temperature
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    1108
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.256
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 0.9
    Notes
    [4] - Risk difference (V501 - placebo) was estimated using the Miettinen & Nurminen method.

    Primary: Percentage of Participants with an Injection-site Adverse Event Prompted on the Vaccination Report Card

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    End point title
    		 Percentage of Participants with an Injection-site Adverse Event Prompted on the Vaccination Report Card
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. The percentage of participants with an injection-site AE prompted on the VRC (erythema, pain, and swelling) was summarized. The population was participants who received ≥1 study vaccination and had follow-up data available.
    End point type
    Primary
    End point timeframe
    Up to 5 days after any vaccination
    End point values
    		 V501 Placebo
    Number of subjects analysed
    554
    559
    Units: Percentage of participants
    number (not applicable)
        Injection-site erythema
    24.5
    21.6
        Injection-site pain
    54.9
    48.5
        Injection-site swelling
    21.3
    14.5
    Statistical analysis title
    		 Incidence of injection-site erythema
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.251
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 7.9
    Notes
    [5] - Risk difference (V501 - placebo) was estimated using the Miettinen & Nurminen method.
    Statistical analysis title
    		 Incidence of injection-site pain
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.033
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 12.2
    Notes
    [6] - Risk difference (V501 - placebo) was estimated using the Miettinen & Nurminen method.
    Statistical analysis title
    		 Incidence of injection-site swelling
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.003
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 11.3
    Notes
    [7] - Risk difference (V501 - placebo) was estimated using the Miettinen & Nurminen method.

    Primary: Percentage of Participants with a Systemic Adverse Event

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    End point title
    		 Percentage of Participants with a Systemic Adverse Event
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. The percentage of participants with a systemic AE was summarized. The population was participants who received ≥1 study vaccination and had follow-up data available.
    End point type
    Primary
    End point timeframe
    Up to 15 days after any vaccination
    End point values
    		 V501 Placebo
    Number of subjects analysed
    554
    559
    Units: Percentage of participants
        number (not applicable)
    14.4
    15.4
    Statistical analysis title
    		 Incidence of systemic AEs
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 3.3
    Notes
    [8] - Risk difference (V501 - placebo) was estimated using the Miettinen & Nurminen method.

    Primary: Percentage of Participants with a Vaccine-related Systemic Adverse Event

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    End point title
    		 Percentage of Participants with a Vaccine-related Systemic Adverse Event
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study drug. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug or a protocol-specified procedure, whether or not considered related to the study drug or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study drug or protocol-specified procedure is also an AE. Vaccine-related AEs are those that were deemed possibly, probably, or definitely related to vaccine administration by the investigator. The percentage of participants with a vaccine-related systemic AE was summarized. The population was participants who received ≥1 study vaccination and had follow-up data available
    End point type
    Primary
    End point timeframe
    Up to 15 days after any vaccination
    End point values
    		 V501 Placebo
    Number of subjects analysed
    554
    559
    Units: Percentage of participants
        number (not applicable)
    3.4
    5.0
    Statistical analysis title
    		 Incidence of vaccine-related systemic AEs
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    1113
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 0.8
    Notes
    [9] - Risk difference (V501 - placebo) was estimated using the Miettinen & Nurminen method.

    Secondary: Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection or Disease

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    End point title
    		 Combined Incidence of HPV Type 6, 11, 16, or 18-related Persistent Infection or Disease
    End point description
    Persistent infection was defined as in the first primary endpoint above. Disease was defined as HPV Type 6, 11, 16, or 18-related condyloma acuminate, PIN, penile, perianal, or perineal cancer. The combined incidence of HPV Type 6, 11, 16, or 18 persistent infection or disease was assessed. The population was participants who were seronegative at Day 1 and PCR negative from Day 1 through Month 7 to the relevant HPV type, received all 3 vaccinations, did not deviate from the study protocol in ways that might interfere with vaccine efficacy, and had ≥1 follow-up visit after Month 7.
    End point type
    Secondary
    End point timeframe
    Up to Month 36
    End point values
    		 V501 Placebo
    Number of subjects analysed
    498 [10]
    498 [11]
    Units: Cases per 100 person-years at risk
        number (not applicable)
    0.3
    1.9
    Notes
    [10] - 1148 person-years follow-up
    [11] - 1132 person-years follow-up
    Statistical analysis title
    		 Vaccine Efficacy
    Statistical analysis description
    Vaccine efficacy is defined as the percentage reduction in relative risk for the V501 versus the placebo group.
    Comparison groups
    V501 v Placebo
    Number of subjects included in analysis
    996
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.001
    Method
    		 One-sided exact test
    Parameter type
    		 Vaccine Efficacy
    Point estimate
    86.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 55.2
         upper limit
    		 97.4
    Notes
    [12] - If the lower bound of the 95% confidence interval for vaccine efficacy excludes 0%, superiority of the V501 group is demonstrated.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 36 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.

    Reporting group title
    V501
    Reporting group description
    		 Participants received V501 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Follow-up was up to Month 36.

    Serious adverse events
    		 Placebo V501
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 559 (0.18%)
    0 / 554 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 559 (0.18%)
    0 / 554 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo V501
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    303 / 559 (54.20%)
    329 / 554 (59.39%)
    General disorders and administration site conditions
    Injection-site erythema
         subjects affected / exposed
    122 / 559 (21.82%)
    137 / 554 (24.73%)
         occurrences all number
    179
    217
    Injection-site swelling
         subjects affected / exposed
    82 / 559 (14.67%)
    118 / 554 (21.30%)
         occurrences all number
    121
    181
    Injection-site pain
         subjects affected / exposed
    271 / 559 (48.48%)
    304 / 554 (54.87%)
         occurrences all number
    480
    563

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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