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    Clinical Trial Results:
    A Phase III Clinical Trial to Study the Tolerability and Immunogenicity of V503, a Multivalent Human Papillomavirus (HPV) L1 Virus-Like Particle (VLP) Vaccine, in 16- to 26-Year-Old Men and 16- to 26-Year-Old Women

    Summary
    EudraCT number
    		 2012-002758-22
    Trial protocol
    		 DE   ES   FI   SE   DK  
    Global end of trial date
    04 Aug 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Mar 2016
    First version publication date
    24 Jan 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    V503-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01651949
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, New Jersey, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Aug 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    (1) To evaluate the tolerability of the 9vHPV (9-valent HPV L1 VLP, V503) vaccine in young men and women 16 to 26 years of age. (2) To demonstrate that administration of the 9vHPV vaccine induces non-inferior Geometric Mean Titers (GMTs) for serum anti-HPV 6, anti-HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti-HPV 52, and anti-HPV 58 in young heterosexual men 16 to 26 years of age compared to young women 16 to 26 years of age.
    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
    29 Oct 2012
    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
    Thailand: 90
    Country: Number of subjects enrolled
    Turkey: 50
    Country: Number of subjects enrolled
    United States: 627
    Country: Number of subjects enrolled
    Norway: 83
    Country: Number of subjects enrolled
    Poland: 70
    Country: Number of subjects enrolled
    Spain: 255
    Country: Number of subjects enrolled
    Sweden: 75
    Country: Number of subjects enrolled
    Denmark: 250
    Country: Number of subjects enrolled
    Germany: 155
    Country: Number of subjects enrolled
    South Africa: 50
    Country: Number of subjects enrolled
    Canada: 110
    Country: Number of subjects enrolled
    Colombia: 281
    Country: Number of subjects enrolled
    Israel: 50
    Country: Number of subjects enrolled
    Malaysia: 51
    Country: Number of subjects enrolled
    Mexico: 93
    Country: Number of subjects enrolled
    Peru: 170
    Country: Number of subjects enrolled
    Philippines: 60
    Worldwide total number of subjects
    2520
    EEA total number of subjects
    888
    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)
    309
    Adults (18-64 years)
    2211
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study enrolled healthy males and females 16 to 26 years of age who have never had Papanicolaou (Pap; cervical or anal) testing or have had only normal Pap testing results. Other inclusion and exclusion criteria applied.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Heterosexual Males
    Arm description
    		 Healthy heterosexual males 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6
    Arm type
    		 Experimental

    Investigational medicinal product name
    9vHPV Vaccine
    Investigational medicinal product code
    Other name
    V503, Multivalent Human Papillomavirus (HPV)L1 Virus-like Particle (VLP) Vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Arm title
    		 Females
    Arm description
    		 Healthy females 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6
    Arm type
    		 Experimental

    Investigational medicinal product name
    9vHPV Vaccine
    Investigational medicinal product code
    Other name
    V503, Multivalent Human Papillomavirus (HPV)L1 Virus-like Particle (VLP) Vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Arm title
    		 Men Who Have Sex With Men (MSM)
    Arm description
    		 Healthy MSM 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6
    Arm type
    		 Experimental

    Investigational medicinal product name
    9vHPV Vaccine
    Investigational medicinal product code
    Other name
    V503, Multivalent Human Papillomavirus (HPV)L1 Virus-like Particle (VLP) Vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Number of subjects in period 1
    		Heterosexual Males Females Men Who Have Sex With Men (MSM)
    Started
    1106
    1101
    313
    Vaccination 1
    1103
    1099
    313
    Vaccination 2
    1089
    1069
    298
    Vaccination 3
    1067
    1037
    291
    Completed
    1053
    1015
    282
    Not completed
    53
    86
    31
         Consent withdrawn by subject
    17
    18
    9
         Physician decision
    -
    2
    -
         Adverse event, non-fatal
    -
    2
    1
         Screen failure
    2
    2
    -
         Unknown status
    4
    4
    -
         Lost to follow-up
    30
    56
    20
         Protocol deviation
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Heterosexual Males
    Reporting group description
    		 Healthy heterosexual males 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Reporting group title
    Females
    Reporting group description
    		 Healthy females 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Reporting group title
    Men Who Have Sex With Men (MSM)
    Reporting group description
    		 Healthy MSM 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Reporting group values
    		 Heterosexual Males Females Men Who Have Sex With Men (MSM) Total
    Number of subjects
    		 1106 1101 313 2520
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 20.8 ± 3 21.3 ± 2.9 22.2 ± 2.4 -
    Gender categorical
    Units: Subjects
        Female
    		 0 1101 0 1101
        Male
    		 1106 0 313 1419

    End points

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    End points reporting groups
    Reporting group title
    Heterosexual Males
    Reporting group description
    		 Healthy heterosexual males 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Reporting group title
    Females
    Reporting group description
    		 Healthy females 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Reporting group title
    Men Who Have Sex With Men (MSM)
    Reporting group description
    		 Healthy MSM 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6

    Subject analysis set title
    Heterosexual and MSM Males - Safety Analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Healthy heterosexual males and MSMs 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6. The analysis set includes participants who received >=1 vaccination and had safety follow-up.

    Subject analysis set title
    Females - Safety Analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Healthy females 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6. The analysis set includes participants who received >=1 vaccination and had safety follow-up.

    Subject analysis set title
    Heterosexual Males - Immunogenicity Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy heterosexual males 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6. The analysis set includes participants who received the 3 vaccinations, were seronegative to the appropriate HPV type at baseline, and had Month 7 immunogenicity results for the appropriate HPV type.

    Subject analysis set title
    Females - Immunogenicity Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy females 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6. The analysis set includes participants who received the 3 vaccinations, were seronegative to the appropriate HPV type at baseline, and had Month 7 immunogenicity results for the appropriate HPV type.

    Subject analysis set title
    Men Who Have Sex With Men - Immunogenicity Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Healthy MSM 16 to 26 years of age received 9vHPV vaccine 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6. The analysis set includes participants who received the 3 vaccinations, were seronegative to the appropriate HPV type at baseline, and had Month 7 immunogenicity results for the appropriate HPV type.

    Primary: Geometric Mean Titers (GMTs) to the HPV Types Contained in the 9vHPV Vaccine

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    End point title
    		 Geometric Mean Titers (GMTs) to the HPV Types Contained in the 9vHPV Vaccine
    End point description
    Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. Statistical analysis compared GMT values between heterosexual males and females.
    End point type
    Primary
    End point timeframe
    Four weeks post vaccination 3 (Month 7)
    End point values
    		 Heterosexual Males - Immunogenicity Population Females - Immunogenicity Population
    Number of subjects analysed
    914
    884
    Units: milli Merck Units/mL
    geometric mean (confidence interval 95%)
        Anti-HPV Type 6 (n=847, 708)
    782 (738 to 828.7)
    703.9 (660.6 to 749.9)
        Anti-HPV Type 11 (n=851, 712)
    616.7 (582.4 to 653)
    564.9 (530.6 to 601.3)
        Anti-HPV Type 16 (n=899, 781)
    3346 (3158.9 to 3544.1)
    2788.3 (2621.4 to 2965.8)
        Anti-HPV Type 18 (n=906, 831)
    808.2 (754.9 to 865.4)
    679.8 (633.1 to 730.1)
        Anti-HPV Type 31 (n=908, 826)
    708.5 (662.7 to 757.6)
    570.1 (531.5 to 611.5)
        Anti-HPV Type 33 (n=901, 853)
    384.8 (362.5 to 408.4)
    322 (302.9 to 342.3)
        Anti-HPV Type 45 (n=909, 871)
    235.6 (219 to 253.6)
    185.7 (172.3 to 200.2)
        Anti-HPV Type 52 (n=907, 849)
    386.8 (363.4 to 411.6)
    335.2 (314.3 to 357.6)
        Anti-HPV Type 58 (n=897, 839)
    509.8 (479.9 to 541.6)
    409.3 (384.5 to 435.7)
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 6
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 6 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.21
    Notes
    [1] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-Inferiority Anti-HPV Type 11
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 11 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.19
    Notes
    [2] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 16
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 16 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.3
    Notes
    [3] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 18
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 18 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 1.31
    Notes
    [4] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 31
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 31 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 1.37
    Notes
    [5] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 33
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 33 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.3
    Notes
    [6] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 45
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 45 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.41
    Notes
    [7] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 52
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 52 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.26
    Notes
    [8] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 58
    Statistical analysis description
    Primary analysis evaluated non-inferiority of the GMT for anti-HPV Type 58 for heterosexual males compared with females.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 GMT Ratio
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.36
    Notes
    [9] - Criterion for non-inferiority with respect to GMT ratio (heterosexual males / females) required that the lower bound of the 95% confidence interval was >0.67, to exclude a decrease of 1.5-fold or more. An analysis of variance model with a response of log individual titers and fixed effect for group was used.

    Primary: Percentage of Participants with one or more Injection-site Adverse Experiences Prompted on the Vaccine Report Card

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    End point title
    		 Percentage of Participants with one or more Injection-site Adverse Experiences Prompted on the Vaccine Report Card
    End point description
    An adverse experience (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, 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 study vaccine is also an AE. Injection-site AEs prompted on the Vaccine Report Card were erythema, pain, and swelling. Participants were instructed to use the Vaccine Report Card to record adverse events daily after each study vaccination.
    End point type
    Primary
    End point timeframe
    Up to 5 days after any vaccination
    End point values
    		 Heterosexual and MSM Males - Safety Analysis Females - Safety Analysis
    Number of subjects analysed
    1394
    1075
    Units: Percentage of participants
    number (not applicable)
        Overall VRC-prompted Injection-site AEs
    66.7
    84
        Injection-site Erythema
    20.7
    32.2
        Injection-site Pain
    63.4
    82.5
        Injection-site Swelling
    20.2
    37.5
    Statistical analysis title
    		 Injection-site Erythema
    Statistical analysis description
    The incidence of AEs of injection-site erythema reported on the Vaccine Report Card was compared between heterosexual / MSM male participants and female participants.
    Comparison groups
    Heterosexual and MSM Males - Safety Analysis v Females - Safety Analysis
    Number of subjects included in analysis
    2469
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -11.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 -8
    Statistical analysis title
    		 Injection-site Pain
    Statistical analysis description
    The incidence of AEs of injection-site pain reported on the Vaccine Report Card was compared between heterosexual / MSM male participants and female participants.
    Comparison groups
    Heterosexual and MSM Males - Safety Analysis v Females - Safety Analysis
    Number of subjects included in analysis
    2469
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -19.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.5
         upper limit
    		 -15.7
    Statistical analysis title
    		 Injection-site Swelling
    Statistical analysis description
    The incidence of AEs of injection-site swelling reported on the Vaccine Report Card was compared between heterosexual / MSM male participants and female participants.
    Comparison groups
    Heterosexual and MSM Males - Safety Analysis v Females - Safety Analysis
    Number of subjects included in analysis
    2469
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -17.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.8
         upper limit
    		 -13.7

    Primary: Percentage of Participants with Elevated Oral Body Temperature (>=37.8° C, >=100° F)

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    End point title
    		 Percentage of Participants with Elevated Oral Body Temperature (>=37.8° C, >=100° F)
    End point description
    Participants were instructed by the investigator to use the Vaccination Report Card to document evening oral temperature daily after each study vaccination
    End point type
    Primary
    End point timeframe
    Up to 5 days after any vaccination
    End point values
    		 Heterosexual and MSM Males - Safety Analysis Females - Safety Analysis
    Number of subjects analysed
    1386 [10]
    1066 [11]
    Units: Percentage of participants
        number (not applicable)
    4.4
    5.9
    Notes
    [10] - Participants who received >=1 vaccination and had oral or oral equivalent temperature results
    [11] - Participants who received >=1 vaccination and had oral or oral equivalent temperature results
    Statistical analysis title
    		 Elevated Body Temperature
    Statistical analysis description
    The incidence of maximum body temperature >37.8° C reported on the Vaccine Report Card was compared between heterosexual / MSM male participants and female participants.
    Comparison groups
    Heterosexual and MSM Males - Safety Analysis v Females - Safety Analysis
    Number of subjects included in analysis
    2452
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.091
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 0.2

    Primary: Percentage of Participants with an Adverse Event

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    End point title
    		 Percentage of Participants with an Adverse Event [12]
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, 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 study vaccine is also an AE. Injection-site AEs include both those prompted on the Vaccine Report Card and those not prompted. Systemic AEs include all that are not classified as injection-site AEs.
    End point type
    Primary
    End point timeframe
    Up to Day 15 after any vaccination
    Notes
    [12] - 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 statistical analysis was conducted for Percentage of Participants with an Adverse Event
    End point values
    		 Heterosexual and MSM Males - Safety Analysis Females - Safety Analysis
    Number of subjects analysed
    1394
    1075
    Units: Percentage of participants
        number (not applicable)
    75.4
    88.7
    No statistical analyses for this end point

    Primary: Percentage of Participants who had Study Vaccine Discontinued Due to an Adverse Event

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    End point title
    		 Percentage of Participants who had Study Vaccine Discontinued Due to an Adverse Event [13]
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, 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 study vaccine is also an AE.
    End point type
    Primary
    End point timeframe
    Up to Month 6
    Notes
    [13] - 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 statistical analysis was conducted for Percentage of Participants who had Study Vaccine Discontinued Due to an Adverse Event
    End point values
    		 Heterosexual and MSM Males - Safety Analysis Females - Safety Analysis
    Number of subjects analysed
    1394
    1075
    Units: Percentage of participants
        number (not applicable)
    0.1
    0.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Seroconversion to the HPV Types Contained in the 9vHPV Vaccine

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    End point title
    		 Percentage of Participants with Seroconversion to the HPV Types Contained in the 9vHPV Vaccine
    End point description
    Serum antibodies to HPV types were measured with a Competitive Luminex Immunoassay. The serostatus cutoffs (milli Merck U/mL) for HPV types were as follows: HPV Type 6: ≥30; HPV Type 11: ≥16; HPV Type 16: ≥20; HPV Type 18: ≥24; HPV Type 31: ≥10; HPV Types 33, 45, 52, and 58: ≥8. Statistical analysis compared seroconversion rates between heterosexual males and females.
    End point type
    Secondary
    End point timeframe
    Four weeks post vaccination 3 (Month 7)
    End point values
    		 Heterosexual Males - Immunogenicity Population Females - Immunogenicity Population Men Who Have Sex With Men - Immunogenicity Population
    Number of subjects analysed
    914
    884
    239
    Units: Percentage of Participants
    number (confidence interval 95%)
        Anti-HPV Type 6 (n=847, 708, 164)
    99.6 (99 to 99.9)
    99.6 (98.8 to 99.9)
    99.4 (96.6 to 100)
        Anti-HPV Type 11 (n=851, 712, 165)
    100 (99.6 to 100)
    99.9 (99.2 to 100)
    100 (97.8 to 100)
        Anti-HPV Type 16 (n=899, 781, 212)
    100 (99.6 to 100)
    99.9 (99.3 to 100)
    100 (98.3 to 100)
        Anti-HPV Type 18 (n=906, 831, 220)
    99.9 (99.4 to 100)
    99.8 (99.1 to 100)
    99.5 (97.5 to 100)
        Anti-HPV Type 31 (n=908, 826, 227)
    100 (99.6 to 100)
    100 (99.6 to 100)
    100 (98.4 to 100)
        Anti-HPV Type 33 (n=901, 853, 230)
    100 (99.6 to 100)
    99.9 (99.3 to 100)
    100 (98.4 to 100)
        Anti-HPV Type 45 (n=909, 871, 232)
    99.8 (99.2 to 100)
    99.5 (98.8 to 99.9)
    100 (98.4 to 100)
        Anti-HPV Type 52 (n=907, 849, 232)
    100 (99.6 to 100)
    99.8 (99.2 to 100)
    100 (98.4 to 100)
        Anti-HPV Type 58 (n=897, 839, 223)
    100 (99.6 to 100)
    99.8 (99.1 to 100)
    100 (98.4 to 100)
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 6
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 6 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [14]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.9
    Notes
    [14] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 11
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 11 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [15]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.8
    Notes
    [15] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 16
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 16 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [16]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.7
    Notes
    [16] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 18
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 18 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [17]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.8
    Notes
    [17] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 31
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 31 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [18]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.5
    Notes
    [18] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 33
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 33 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [19]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.7
    Notes
    [19] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 45
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 45 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [20]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 1
    Notes
    [20] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 52
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 52 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [21]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.9
    Notes
    [21] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.
    Statistical analysis title
    		 Non-inferiority Anti-HPV Type 58
    Statistical analysis description
    Analysis evaluated non-inferiority of the difference in percentage of participants who seroconverted for Anti-HPV Type 58 for heterosexual males compared with females. Point and interval estimates for the difference of proportions were obtained using the methods developed by Miettinen and Nurminen.
    Comparison groups
    Heterosexual Males - Immunogenicity Population v Females - Immunogenicity Population
    Number of subjects included in analysis
    1798
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [22]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.9
    Notes
    [22] - Criterion for non-inferiority with respect to seroconversion percentage (heterosexual males minus females) required that the lower bound of the 95% confidence interval was greater than -5.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Month 12
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Females - Safety Analysis
    Reporting group description
    		 Healthy females 16 to 26 years of age received V503 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6. The analysis set includes participants who received >-1 vaccination and had safety follow-up.

    Reporting group title
    Heterosexual and MSM Males - Safety Analysis
    Reporting group description
    		 Healthy heterosexual males and MSMs 16 to 26 years of age received V503 0.5 mL intramuscular injection on Day 1, Month 1, and Month 6. The analysis set includes participants who received >=1 vaccination and had safety follow-up.

    Serious adverse events
    		 Females - Safety Analysis Heterosexual and MSM Males - Safety Analysis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 1075 (2.42%)
    23 / 1394 (1.65%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    4 / 1075 (0.37%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion incomplete
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    4 / 1075 (0.37%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    2 / 1075 (0.19%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal malpresentation
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst rupture
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophreniform disorder
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 1075 (0.00%)
    2 / 1394 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exposure to communicable disease
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Familial periodic paralysis
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 1075 (0.09%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 1075 (0.19%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ligament disorder
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1075 (0.09%)
    2 / 1394 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    External ear cellulitis
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 1075 (0.09%)
    0 / 1394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 1075 (0.00%)
    1 / 1394 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Females - Safety Analysis Heterosexual and MSM Males - Safety Analysis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    924 / 1075 (85.95%)
    976 / 1394 (70.01%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    246 / 1075 (22.88%)
    200 / 1394 (14.35%)
         occurrences all number
    378
    271
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    348 / 1075 (32.37%)
    291 / 1394 (20.88%)
         occurrences all number
    539
    422
    Injection site pain
         subjects affected / exposed
    893 / 1075 (83.07%)
    886 / 1394 (63.56%)
         occurrences all number
    2101
    1877
    Injection site swelling
         subjects affected / exposed
    408 / 1075 (37.95%)
    285 / 1394 (20.44%)
         occurrences all number
    661
    431

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2013
    The primary purpose of the Protocol V503-003-03 amendment was to revise the inclusion criterion regarding the definition of sexual partners to make it consistent with that used in prior HPV vaccine studies, and to revise the maximum number of lifetime male or female sexual partners allowable for MSM subjects in the study.

    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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