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    Clinical Trial Results:
    A Randomized, International, Double-Blinded (With In-House Blinding), Controlled With GARDASIL™, Dose-Ranging Study of Octavalent Human Papillomavirus (HPV) (Types 6, 11, 16, 18, 31, 45, 52, and 58) L1 Virus-Like Particle (VLP) Vaccine Administered to 16-23-Year-Old Women

    Summary
    EudraCT number
    2017-000109-19
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    22 Aug 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Mar 2017
    First version publication date
    10 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V502-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00260039
    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
    22 Aug 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Aug 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This dose-ranging study evaluated an investigational vaccine with the following objectives: (1) To demonstrate that the vaccine is well-tolerated in women (2) To evaluate immune responses in women who are between 16 and 23 years of age at enrollment. The primary hypothesis for the study are as follows: 1) the geometric mean titers (GMTs) at 4 weeks Postdose 3 for each of the Human Papillomavirus (HPV) Types 6, 11, 16, 18 for participants receiving V502 vaccination are non-inferior to those induced by qHPV vaccine (Gardasil), and 2) V502 administered to 16 to 23-year old women is generally well-tolerated.
    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
    06 Dec 2005
    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: 225
    Country: Number of subjects enrolled
    Peru: 150
    Country: Number of subjects enrolled
    Colombia: 305
    Worldwide total number of subjects
    680
    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)
    16
    Adults (18-64 years)
    664
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Healthy female participants between 16 and 23 years of age were enrolled into the study.

    Pre-assignment
    Screening details
    A total of 738 participants were screened and 680 were randomized into 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
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    qHPV Vaccine
    Arm description
    Participants received qHPV vaccine (Gardasil) 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.
    Arm type
    Active comparator

    Investigational medicinal product name
    qHPV Vaccine
    Investigational medicinal product code
    Other name
    Gardasil™ quadrivalent HPV (Types 6, 11, 16, 18) L1 Virus-like Particle (VLP) vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits

    Arm title
    Low-dose Octavalent HPV Vaccine
    Arm description
    Participants received Low-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.
    Arm type
    Experimental

    Investigational medicinal product name
    Low-dose Octavalent HPV Vaccine
    Investigational medicinal product code
    Other name
    Low-dose Octavalent HPV (Types 6, 11, 16, 18, 31, 45, 52, 58) L1 Virus-like Particle (VLP) vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits

    Arm title
    Mid-dose Octavalent HPV Vaccine
    Arm description
    Participants received Mid-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.
    Arm type
    Experimental

    Investigational medicinal product name
    Mid-dose Octavalent HPV Vaccine
    Investigational medicinal product code
    Other name
    Mid-dose Octavalent HPV (Types 6, 11, 16, 18, 31, 45, 52, 58) L1 Virus-like Particle (VLP) vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits

    Arm title
    High-dose Octavalent HPV Vaccine
    Arm description
    Participants received High-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.
    Arm type
    Experimental

    Investigational medicinal product name
    High-dose Octavalent HPV Vaccine
    Investigational medicinal product code
    Other name
    High-dose Octavalent HPV (Types 6, 11, 16, 18, 31, 45, 52, 58) L1 Virus-like Particle (VLP) vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits

    Number of subjects in period 1
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Started
    168
    172
    168
    172
    Completed
    157
    162
    162
    165
    Not completed
    11
    10
    6
    7
         Moved
             2
             1
             1
             1
         Adverse event, non-fatal
             -
             1
             -
             -
         Other reasons
             -
             -
             1
             -
         Consent withdrawn by subject
             4
             2
             1
             -
         Lost to follow-up
             5
             6
             3
             6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    qHPV Vaccine
    Reporting group description
    Participants received qHPV vaccine (Gardasil) 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    Low-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received Low-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    Mid-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received Mid-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    High-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received High-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine Total
    Number of subjects
    168 172 168 172 680
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    5 2 3 6 16
        Adults (18-64 years)
    163 170 165 166 664
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    20.4 ± 1.6 20.7 ± 1.7 20.3 ± 1.6 20.4 ± 1.7 -
    Gender Categorical
    Units: Subjects
        Female
    168 172 168 172 680
        Male
    0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    qHPV Vaccine
    Reporting group description
    Participants received qHPV vaccine (Gardasil) 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    Low-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received Low-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    Mid-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received Mid-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    High-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received High-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Primary: Geometric Mean Titer (GMT) of Anti-HPV 6 Antibody

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    End point title
    Geometric Mean Titer (GMT) of Anti-HPV 6 Antibody
    End point description
    Anti-HPV Type 6 antibodies were measured by a Competitive Luminex Immunoassay (cLIA). The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and polymerase chain reaction (PCR) negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 6 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    109
    104
    107
    106
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    1612.5 (1400 to 1857.3)
    1349.4 (1139.9 to 1597.5)
    1464.3 (1247.9 to 1718.3)
    1472.8 (1239.9 to 1749.5)
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [1]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    1
    Notes
    [1] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [2]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.12
    Notes
    [2] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [3]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.15
    Notes
    [3] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.

    Primary: GMT of Anti-HPV 11 Antibody

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    End point title
    GMT of Anti-HPV 11 Antibody
    End point description
    Anti-HPV Type 11 antibodies were measured by a cLIA. The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. A value of 9999 indicates that the GMT was <10 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 11 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    109
    104
    107
    106
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    2354.6 (2074.1 to 2673.1)
    2085 (1808.1 to 2404.2)
    2242.6 (1956.8 to 2570.2)
    2078.8 (1759.9 to 2455.6)
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [4]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.05
    Notes
    [4] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [5]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.18
    Notes
    [5] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [6]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.08
    Notes
    [6] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.

    Primary: GMT of Anti-HPV 16 Antibody

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    End point title
    GMT of Anti-HPV 16 Antibody
    End point description
    Anti-HPV Type 16 antibodies were measured by a cLIA. The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 16 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    108
    104
    111
    104
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    3310.3 (2905.8 to 3771.2)
    2700.5 (2328.1 to 3132.5)
    3057.9 (2624.3 to 3563)
    2987.9 (2544.2 to 3509.1)
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [7]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    0.99
    Notes
    [7] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [8]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.12
    Notes
    [8] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [9]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.09
    Notes
    [9] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.

    Primary: GMT of Anti-HPV 18 Antibody

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    End point title
    GMT of Anti-HPV 18 Antibody
    End point description
    Anti-HPV Type 18 antibodies were measured by a cLIA. The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 18 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    120
    118
    126
    122
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    846.8 (708.9 to 1011.4)
    704.4 (584.6 to 848.6)
    709.9 (596.1 to 845.4)
    795.4 (654.3 to 967)
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [10]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.05
    Notes
    [10] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [11]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.08
    Notes
    [11] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.
    Statistical analysis title
    Non-inferiority Analysis
    Statistical analysis description
    The criterion for non-inferiority is that the lower bound of the 95% confidence interval for the fold-difference in GMT (experimental / control) is >0.5.
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [12]
    Method
    ANOVA
    Parameter type
    Fold difference in GMT
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    1.16
    Notes
    [12] - The estimated GMT, fold difference, confidence intervals, and p-value is based on a statistical analysis model adjusting for country.

    Primary: GMT of Anti-HPV 31 Antibody

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    End point title
    GMT of Anti-HPV 31 Antibody [13]
    End point description
    Anti-HPV Type 31 antibodies were measured by a cLIA. The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 16 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 31 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    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: There was no protocol pre-planned statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    116
    120
    119
    116
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    28.4 (22.1 to 36.4)
    829.5 (700 to 982.9)
    1429.9 (1189.8 to 1718.4)
    2318.7 (1972.1 to 2726.3)
    No statistical analyses for this end point

    Primary: GMT of Anti-HPV 45 Antibody

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    End point title
    GMT of Anti-HPV 45 Antibody [14]
    End point description
    Anti-HPV Type 45 antibodies were measured by a cLIA. The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 16 milli Merck U/mL. A value of 9999 indicates that the GMT was <16 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 45 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [14] - 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: There was no protocol pre-planned statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    123
    128
    128
    118
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    9999 (9999 to 9999)
    321.1 (262.3 to 393)
    618.1 (487.8 to 783.2)
    1030.5 (837.6 to 1267.9)
    No statistical analyses for this end point

    Primary: GMT of Anti-HPV 52 Antibody

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    End point title
    GMT of Anti-HPV 52 Antibody [15]
    End point description
    Anti-HPV Type 52 antibodies were measured by a cLIA. The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 20 milli Merck U/mL. A value of 9999 indicates that the GMT was <20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 52 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [15] - 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: There was no protocol pre-planned statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    115
    119
    112
    113
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    9999 (9999 to 9999)
    776.9 (654.6 to 922)
    1622.1 (1348.8 to 1950.7)
    2801.1 (2289.1 to 3427.5)
    No statistical analyses for this end point

    Primary: GMT of Anti-HPV 58 Antibody

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    End point title
    GMT of Anti-HPV 58 Antibody [16]
    End point description
    Anti-HPV Type 58 antibodies were measured by a cLIA. The unit of measure was milli Merck Units/mL (mMU/mL). The seropositive cut-off threshold for this assay is defined as 16 milli Merck U/mL. A value of 9999 indicates that the GMT was <16 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 58 antibody .
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [16] - 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: There was no protocol pre-planned statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    118
    117
    123
    115
    Units: mMU/mL
        geometric mean (confidence interval 95%)
    9999 (9999 to 9999)
    354.8 (301.3 to 417.8)
    640.8 (533 to 770.3)
    957.8 (817.8 to 1121.8)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 6

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 6 [17]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 6 cLIA level of >=20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 6 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [17] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    109
    104
    107
    106
    Units: Percentage of participants
        number (confidence interval 95%)
    100 (96.7 to 100)
    100 (96.5 to 100)
    100 (96.6 to 100)
    100 (96.6 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 11

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 11 [18]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 11 cLIA level of >=20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 11 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [18] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    109
    104
    107
    106
    Units: Percentage of participants
        number (confidence interval 95%)
    100 (96.7 to 100)
    100 (96.5 to 100)
    100 (96.6 to 100)
    100 (96.6 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 16

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 16 [19]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 16 cLIA level of >=20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 16 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [19] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    108
    104
    111
    104
    Units: Percentage of participants
        number (confidence interval 95%)
    100 (96.6 to 100)
    100 (96.5 to 100)
    100 (96.7 to 100)
    100 (96.5 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 18

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 18 [20]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 18 cLIA level of >=20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 18 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [20] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    120
    118
    126
    122
    Units: Percentage of participants
        number (confidence interval 95%)
    100 (97 to 100)
    100 (96.9 to 100)
    100 (97.1 to 100)
    100 (97 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 31

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 31 [21]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 31 cLIA level of >=16 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 31 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [21] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    116
    120
    119
    116
    Units: Percentage of participants
        number (confidence interval 95%)
    64.7 (55.2 to 73.3)
    100 (97 to 100)
    99.2 (95.4 to 100)
    100 (96.9 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 45

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 45 [22]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 45 cLIA level of >=16 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 45 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [22] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    123
    128
    128
    118
    Units: Percentage of participants
        number (confidence interval 95%)
    17.9 (11.6 to 25.8)
    99.2 (95.7 to 100)
    97.7 (93.3 to 99.5)
    100 (96.9 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 52

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 52 [23]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 52 cLIA level of >=20 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 52 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [23] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    115
    119
    112
    113
    Units: Percentage of participants
        number (confidence interval 95%)
    6.1 (2.5 to 12.1)
    100 (96.9 to 100)
    99.1 (95.1 to 100)
    99.1 (95.2 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Seroconverted to HPV Type 58

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    End point title
    Percentage of Participants Who Seroconverted to HPV Type 58 [24]
    End point description
    Seroconversion was defined as achieving an anti-HPV Type 58 cLIA level of >=16 milli Merck U/mL. Participants analyzed included those who were not protocol violators, received all 3 vaccinations, were seronegative at Day 1 and PCR negative from Day 1 through Month 7 for the relevant HPV Type, and had a Month 7 serum sample collected and tested for anti-HPV 58 antibody.
    End point type
    Primary
    End point timeframe
    Month 7 (1 month postdose 3)
    Notes
    [24] - 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: There was no protocol pre-planned between-group statistical analysis for this endpoint.
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    118
    117
    123
    115
    Units: Percentage of participants
        number (confidence interval 95%)
    22 (14.9 to 30.6)
    100 (96.9 to 100)
    99.2 (95.6 to 100)
    100 (96.8 to 100)
    No statistical analyses for this end point

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

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    End point title
    Percentage of Participants with Maximum Oral Temperature >=37.8 °C (>=100 °F)
    End point description
    Participants used the Vaccination Report Card to record oral temperature. The participants analyzed included those who received at least one vaccination and had follow-up.
    End point type
    Primary
    End point timeframe
    Up to Day 5 after any vaccination
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    168
    169
    167
    172
    Units: Percentage of participants
        number (not applicable)
    8.9
    11.8
    7.8
    9.3
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method for 95% confidence intervals and a test-based normal approximation for p-values.
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.383
    Method
    Test-based normal approximation
    Parameter type
    Risk difference (RD)
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.7
         upper limit
    3.7
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method for 95% confidence intervals and a test-based normal approximation for p-values.
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.706
    Method
    Test-based normal approximation
    Parameter type
    Risk difference (RD)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    7.4
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method for 95% confidence intervals and a test-based normal approximation for p-values.
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.905
    Method
    Test-based normal approximation
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.7
         upper limit
    6

    Primary: Percentage of Participants with One or More Injection-site Adverse Experiences

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    End point title
    Percentage of Participants with One or More Injection-site Adverse Experiences
    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 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 AE. Participants used the Vaccination Report Card to record injection-site AEs. The participants analyzed included those who received at least one vaccination and had follow-up.
    End point type
    Primary
    End point timeframe
    Up to Day 5 after any vaccination
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    168
    169
    167
    172
    Units: Percentage of participants
        number (not applicable)
    84.5
    89.3
    87.4
    86
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method for 95% confidence intervals and a test-based normal approximation for p-values.
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.189
    Method
    Test-based normal approximation
    Parameter type
    Risk difference (RD)
    Point estimate
    -4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.2
         upper limit
    2.4
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method for 95% confidence intervals and a test-based normal approximation for p-values.
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.445
    Method
    Test-based normal approximation
    Parameter type
    Risk difference (RD)
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.5
         upper limit
    4.7
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method for 95% confidence intervals and a test-based normal approximation for p-values.
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.692
    Method
    Test-based normal approximation
    Parameter type
    Risk difference (RD)
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    6.1

    Primary: Percentage of Participants with One or More Systemic Adverse Experiences

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    End point title
    Percentage of Participants with One or More Systemic Adverse Experiences
    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 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 AE. Percentage of participants with a systemic AE was recorded. The participants analyzed included those who received at least one vaccination and had follow-up.
    End point type
    Primary
    End point timeframe
    Up to Day 15 after any vaccination
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    168
    169
    167
    172
    Units: Percentage of participants
        number (not applicable)
    67.3
    76.3
    70.1
    72.1
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method.
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -9.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.6
         upper limit
    0.6
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.7
         upper limit
    7.2
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.6
         upper limit
    5

    Primary: Percentage of Participants with One or More Serious Vaccine-related Adverse Experiences

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    End point title
    Percentage of Participants with One or More Serious Vaccine-related Adverse Experiences
    End point description
    A serious AE is an AE that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs a hospitalization, is a congenital anomaly or birth defect, is a cancer, or is an overdose. A vaccine-related AE was deemed by the investigator to be possibly, probably, or definitely related to a study procedure. The participants analyzed included those who received at least one vaccination and had follow-up.
    End point type
    Primary
    End point timeframe
    Up to Month 7
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    168
    169
    167
    172
    Units: Percentage of participants
        number (not applicable)
    0
    0
    0
    0
    Statistical analysis title
    Risk Difference Analysis
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 1
    Method
    Miettinen and Nurminen
    Parameter type
    Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    2.2
    Statistical analysis title
    Risk Difference Analysis
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 1
    Method
    Miettinen and Nurminen
    Parameter type
    Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    2.2
    Statistical analysis title
    Risk Difference Analysis
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 1
    Method
    Miettinen and Nurminen
    Parameter type
    Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    2.2

    Primary: Percentage of Participants with One or More Severe Injection-site Adverse Experiences

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    End point title
    Percentage of Participants with One or More Severe Injection-site Adverse Experiences
    End point description
    A severe AE is an AE that is deemed by the investigator to be incapacitating with inability to work or do usual activity. For injection-site erythema and injection-site swelling, severe is defined as a maximum size of >2 inches, or 5 centimeters. The participants analyzed included those who received at least one vaccination and had follow-up.
    End point type
    Primary
    End point timeframe
    Up to Day 5 after any vaccination
    End point values
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Number of subjects analysed
    168
    169
    167
    172
    Units: Percentage of participants
        number (not applicable)
    6
    5.3
    4.8
    4.7
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method
    Comparison groups
    qHPV Vaccine v Low-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.6
         upper limit
    6
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method
    Comparison groups
    qHPV Vaccine v Mid-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    6.4
    Statistical analysis title
    Risk Difference Analysis
    Statistical analysis description
    The analysis used the Miettinen and Nurminen method
    Comparison groups
    qHPV Vaccine v High-dose Octavalent HPV Vaccine
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    6.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Month 7
    Adverse event reporting additional description
    Adverse events are reported for all participants who received at least one vaccination.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    qHPV Vaccine
    Reporting group description
    Participants received qHPV vaccine (Gardasil) 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    Low-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received Low-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    Mid-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received Mid-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Reporting group title
    High-dose Octavalent HPV Vaccine
    Reporting group description
    Participants received High-dose Octavalent HPV Vaccine 0.5 mL intramuscular injection at the Day 1, Month 2, and Month 6 visits.

    Serious adverse events
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 168 (0.60%)
    3 / 169 (1.78%)
    1 / 167 (0.60%)
    0 / 172 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 169 (0.59%)
    0 / 167 (0.00%)
    0 / 172 (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
    Nervous system disorder
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 169 (0.59%)
    0 / 167 (0.00%)
    0 / 172 (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
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 169 (0.59%)
    0 / 167 (0.00%)
    0 / 172 (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
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 169 (0.59%)
    0 / 167 (0.00%)
    0 / 172 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 169 (0.00%)
    1 / 167 (0.60%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    qHPV Vaccine Low-dose Octavalent HPV Vaccine Mid-dose Octavalent HPV Vaccine High-dose Octavalent HPV Vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    148 / 168 (88.10%)
    165 / 169 (97.63%)
    159 / 167 (95.21%)
    161 / 172 (93.60%)
    Investigations
    Body temperature decreased
         subjects affected / exposed
    9 / 168 (5.36%)
    14 / 169 (8.28%)
    10 / 167 (5.99%)
    2 / 172 (1.16%)
         occurrences all number
    10
    19
    10
    2
    Respiratory, thoracic and mediastinal disorders
    Pharyngolaryngeal pain
         subjects affected / exposed
    8 / 168 (4.76%)
    12 / 169 (7.10%)
    6 / 167 (3.59%)
    5 / 172 (2.91%)
         occurrences all number
    9
    12
    6
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    61 / 168 (36.31%)
    63 / 169 (37.28%)
    55 / 167 (32.93%)
    64 / 172 (37.21%)
         occurrences all number
    117
    113
    103
    101
    Dizziness
         subjects affected / exposed
    15 / 168 (8.93%)
    11 / 169 (6.51%)
    10 / 167 (5.99%)
    13 / 172 (7.56%)
         occurrences all number
    20
    14
    13
    17
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    26 / 168 (15.48%)
    33 / 169 (19.53%)
    35 / 167 (20.96%)
    37 / 172 (21.51%)
         occurrences all number
    37
    48
    50
    54
    Injection site pain
         subjects affected / exposed
    137 / 168 (81.55%)
    151 / 169 (89.35%)
    147 / 167 (88.02%)
    148 / 172 (86.05%)
         occurrences all number
    319
    336
    354
    375
    Injection site swelling
         subjects affected / exposed
    32 / 168 (19.05%)
    35 / 169 (20.71%)
    44 / 167 (26.35%)
    45 / 172 (26.16%)
         occurrences all number
    42
    54
    73
    72
    Pyrexia
         subjects affected / exposed
    18 / 168 (10.71%)
    22 / 169 (13.02%)
    16 / 167 (9.58%)
    19 / 172 (11.05%)
         occurrences all number
    25
    29
    17
    20
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 168 (3.57%)
    10 / 169 (5.92%)
    9 / 167 (5.39%)
    6 / 172 (3.49%)
         occurrences all number
    6
    16
    10
    6
    Nausea
         subjects affected / exposed
    17 / 168 (10.12%)
    9 / 169 (5.33%)
    17 / 167 (10.18%)
    4 / 172 (2.33%)
         occurrences all number
    18
    10
    18
    4
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 168 (1.19%)
    7 / 169 (4.14%)
    1 / 167 (0.60%)
    11 / 172 (6.40%)
         occurrences all number
    2
    10
    1
    11
    Infections and infestations
    Influenza
         subjects affected / exposed
    12 / 168 (7.14%)
    24 / 169 (14.20%)
    17 / 167 (10.18%)
    19 / 172 (11.05%)
         occurrences all number
    16
    26
    19
    21
    Nasopharyngitis
         subjects affected / exposed
    9 / 168 (5.36%)
    6 / 169 (3.55%)
    8 / 167 (4.79%)
    10 / 172 (5.81%)
         occurrences all number
    9
    6
    9
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Aug 2006
    Protocol Amendment 1 changes included the following: added the U.S. IND number, revised language regarding participants who become pregnant after Day 1, clarified the definition of out-of-context study visits, clarified triage for abnormal Pap and biopsy tests obtained at Month 7, corrected the seropositivity cutoffs for HPV types, and replaced with the most recent version of the Subject Pregnancy Reporting and Follow-up Standard Operating Procedure.

    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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