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    Clinical Trial Results:
    An Open-Label Phase III Clinical Trial to Study the Immunogenicity and Tolerability of GARDASIL®9 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Adult Women (27 to 45 Year-Olds) compared to Young Adult Women (16 to 26 Year-Olds)

    Summary
    EudraCT number
    		 2015-005093-38
    Trial protocol
    		 DE   FI   AT   ES   IT   BE  
    Global end of trial date
    19 Nov 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 May 2020
    First version publication date
    03 Aug 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    V503-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03158220
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, 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
    19 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of study is to demonstrate that the administration of the 9-valent human papillomavirus (9vHPV) vaccine in 27- to 45-year-old women induces non-inferior geometric mean titers (GMTs) for serum anti-HPV 16, 18, 31, 33, 45, 52, and 58 compared with 16 to 26 year-old women. The primary hypothesis of the study states that anti-HPV 16, 18, 31, 33, 45, 52, and 58 geometric mean titers (GMTs) at 4 weeks postdose 3 are non-inferior in 27- to 45-year-old women as compared with GMTs in 16- to 26-year-old women..
    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
    14 Sep 2017
    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
    Austria: 162
    Country: Number of subjects enrolled
    Belgium: 192
    Country: Number of subjects enrolled
    Finland: 263
    Country: Number of subjects enrolled
    Germany: 165
    Country: Number of subjects enrolled
    Italy: 154
    Country: Number of subjects enrolled
    Spain: 276
    Worldwide total number of subjects
    1212
    EEA total number of subjects
    1212
    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)
    42
    Adults (18-64 years)
    1170
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Healthy women aged 16-45 years of age were enrolled in the study. Other inclusion/exclusion criteria applied.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Women 16-26 years of age
    Arm description
    		 Young adult women 16 to 26-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gardasil ®9
    Investigational medicinal product code
    Other name
    V503
    Pharmaceutical forms
    Solution for injection, Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6

    Arm title
    		 Women 27-45 years of age
    Arm description
    		 Adult women 27 to 45-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gardasil ®9
    Investigational medicinal product code
    Other name
    V503
    Pharmaceutical forms
    Solution for injection, Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6

    Number of subjects in period 1
    		Women 16-26 years of age Women 27-45 years of age
    Started
    570
    642
    Vaccination 1
    570
    640
    Vaccination 2
    563
    635
    Vaccination 3
    556
    629
    Completed
    553
    626
    Not completed
    17
    16
         Consent withdrawn by subject
    8
    9
         Physician decision
    1
    -
         Screen Failure
    -
    1
         Status unknown
    -
    1
         Lost to follow-up
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Women 16-26 years of age
    Reporting group description
    		 Young adult women 16 to 26-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.

    Reporting group title
    Women 27-45 years of age
    Reporting group description
    		 Adult women 27 to 45-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.

    Reporting group values
    		 Women 16-26 years of age Women 27-45 years of age Total
    Number of subjects
    		 570 642 1212
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 21.6 ± 2.8 35.8 ± 5.5 -
    Gender Categorical
    Units: Subjects
        Female
    		 570 642 1212
        Male
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 1 3
        Asian
    		 17 10 27
        Black or African American
    		 5 3 8
        American Indian or Alaska Native, White
    		 1 1 2
        Black or African American, White
    		 5 0 5
        White, Asian
    		 1 0 1
        White
    		 539 627 1166
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 21 7 28
        Not Hispanic or Latino
    		 548 634 1182
        Unknown
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Women 16-26 years of age
    Reporting group description
    		 Young adult women 16 to 26-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.

    Reporting group title
    Women 27-45 years of age
    Reporting group description
    		 Adult women 27 to 45-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.

    Subject analysis set title
    Women 16-26 years of age - Immunogenicity
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Each HPV type had its own immunogenicity analysis population. Criteria for inclusion were: received all 3 vaccinations of the correct dose of the 9vHPV vaccine within acceptable day ranges as specified in the protocol, had evaluable serology results at Day 1 and Month 7 based on serum samples collected within acceptable day ranges as specified in the protocol, must have been seronegative to the appropriate HPV type at Day 1 and had no protocol deviations that could interfere with the evaluation of participant's immune response to the 9vHPV vaccine.

    Subject analysis set title
    Women 27-45 years of age - Immunogenicity
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Each HPV type had its own immunogenicity analysis population. Criteria for inclusion were: received all 3 vaccinations of the correct dose of the 9vHPV vaccine within acceptable day ranges as specified in the protocol, had evaluable serology results at Day 1 and Month 7 based on serum samples collected within acceptable day ranges as specified in the protocol, must have been seronegative to the appropriate HPV type at Day 1 and had no protocol deviations that could interfere with the evaluation of participant's immune response to the 9vHPV vaccine.

    Subject analysis set title
    Women 16-26 years of age - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants that received at least 1 vaccination and had available data for endpoint.

    Subject analysis set title
    Women 27-45 years of age- Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants that received at least 1 vaccination and had available data for endpoint.

    Primary: Anti-HPV Geometric Mean Titers for Each Anti-HPV Type

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    End point title
    		 Anti-HPV Geometric Mean Titers for Each Anti-HPV Type
    End point description
    Antibodies to the HPV types contained in V503 were measured using a competitive luminex immunoassay. Antibody titers were expressed as milli Merck units/mL (mMU/mL). Statistical comparisons between arms was performed for the HPV types considered oncogenic (HPV Types 16/18/31/33/45/52/58).
    End point type
    Primary
    End point timeframe
    4 weeks post vaccination 3 (Month 7)
    End point values
    		 Women 16-26 years of age - Immunogenicity Women 27-45 years of age - Immunogenicity
    Number of subjects analysed
    485
    533
    Units: mMU/mL
    geometric mean (confidence interval 95%)
        Anti-HPV 6 (n=421; 448)
    787.8 (732.5 to 847.2)
    638.4 (594.9 to 685.0)
        Anti-HPV 11 (n-421; 448)
    598.7 (558.7 to 641.6)
    453.5 (424.1 to 485.0)
        Anti-HPV 16 (n=436; 448)
    3075.8 (2863.4 to 3303.9)
    2147.5 (2001.1 to 2304.5)
        Anti-HPV 18 (n=421; 471)
    744.5 (685.0 to 809.1)
    532.1 (491.8 to 575.7)
        Anti-HPV 31 (n=447; 488)
    596.1 (551.1 to 644.9)
    395.7 (367.0 to 426.6)
        Anti-HPV 33 (n=457; 493)
    354.5 (331.7 to 378.9)
    259.0 (242.9 to 276.1)
        Anti-HPV 45 (n=470; 515)
    214.9 (197.7 to 233.7)
    145.6 (134.4 to 157.7)
        Anti-HPV 52 (n=456; 496)
    346.5 (324.0 to 370.5)
    244.7 (229.4 to 261.0)
        Anti-HPV 58 (n=451; 478)
    428.0 (399.4 to 458.6)
    296.4 (277.1 to 317.0)
    Statistical analysis title
    		 Fold Difference Anti-HPV 16
    Statistical analysis description
    Fold difference calculated as GMT 27-45 year-olds/GMT 16-26 year-olds
    Comparison groups
    Women 16-26 years of age - Immunogenicity v Women 27-45 years of age - Immunogenicity
    Number of subjects included in analysis
    1018
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Fold Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.77
    Notes
    [1] - Non-inferiority of GMT in 27-45 year-olds relative to 16-26 year-olds was demonstrated if the lower limit of the 95% confidence interval (CI) for the fold difference was greater than 0.5.
    Statistical analysis title
    		 Fold Difference Anti-HPV 18
    Statistical analysis description
    Fold difference calculated as GMT 27-45 year-olds/GMT 16-26 year-olds
    Comparison groups
    Women 16-26 years of age - Immunogenicity v Women 27-45 years of age - Immunogenicity
    Number of subjects included in analysis
    1018
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.001 [3]
    Method
    		 ANOVA
    Parameter type
    		 Fold Difference
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 0.8
    Notes
    [2] - Non-inferiority of GMT in 27-45 year-olds relative to 16-26 year-olds was demonstrated if the lower limit of the 95% confidence interval (CI) for the fold difference was greater than 0.5.
    [3] - Analysis of variance (ANOVA) model with response of log individual titers and a fixed effect for age groups.
    Statistical analysis title
    		 Anti-HPV Type 31
    Statistical analysis description
    Fold difference calculated as GMT 27-45 year-olds/GMT 16-26 year-olds
    Comparison groups
    Women 16-26 years of age - Immunogenicity v Women 27-45 years of age - Immunogenicity
    Number of subjects included in analysis
    1018
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 < 0.001 [5]
    Method
    		 ANOVA
    Parameter type
    		 Fold Difference
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.74
    Notes
    [4] - Non-inferiority of GMT in 27-45 year-olds relative to 16-26 year-olds was demonstrated if the lower limit of the 95% confidence interval (CI) for the fold difference was greater than 0.5.
    [5] - ANOVA model with response of log individual titers and a fixed effect for age groups.
    Statistical analysis title
    		 Anti-HPV 33
    Statistical analysis description
    Fold difference calculated as GMT 27-45 year-olds/GMT 16-26 year-olds
    Comparison groups
    Women 16-26 years of age - Immunogenicity v Women 27-45 years of age - Immunogenicity
    Number of subjects included in analysis
    1018
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 < 0.001 [7]
    Method
    		 ANOVA
    Parameter type
    		 Fold Difference
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 0.8
    Notes
    [6] - Non-inferiority of GMT in 27-45 year-olds relative to 16-26 year-olds was demonstrated if the lower limit of the 95% confidence interval (CI) for the fold difference was greater than 0.5.
    [7] - ANOVA model with response of log individual titers and a fixed effect for age groups.
    Statistical analysis title
    		 Anti-HPV 45
    Statistical analysis description
    Fold difference calculated as GMT 27-45 year-olds/GMT 16-26 year-olds
    Comparison groups
    Women 16-26 years of age - Immunogenicity v Women 27-45 years of age - Immunogenicity
    Number of subjects included in analysis
    1018
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    P-value
    		 < 0.001 [9]
    Method
    		 ANOVA
    Parameter type
    		 Fold Difference
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.76
    Notes
    [8] - Non-inferiority of GMT in 27-45 year-olds relative to 16-26 year-olds was demonstrated if the lower limit of the 95% confidence interval (CI) for the fold difference was greater than 0.5.
    [9] - ANOVA model with response of log individual titers and a fixed effect for age groups.
    Statistical analysis title
    		 Anti-HPV 52
    Statistical analysis description
    Fold difference calculated as GMT 27-45 year-olds/GMT 16-26 year-olds
    Comparison groups
    Women 16-26 years of age - Immunogenicity v Women 27-45 years of age - Immunogenicity
    Number of subjects included in analysis
    1018
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    P-value
    		 < 0.001 [11]
    Method
    		 ANOVA
    Parameter type
    		 Fold Difference
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 0.78
    Notes
    [10] - Non-inferiority of GMT in 27-45 year-olds relative to 16-26 year-olds was demonstrated if the lower limit of the 95% confidence interval (CI) for the fold difference was greater than 0.5.
    [11] - ANOVA model with response of log individual titers and a fixed effect for age groups.
    Statistical analysis title
    		 Fold Difference Anti-HPV 58
    Statistical analysis description
    Fold difference calculated as GMT 27-45 year-olds/GMT 16-26 year-olds
    Comparison groups
    Women 16-26 years of age - Immunogenicity v Women 27-45 years of age - Immunogenicity
    Number of subjects included in analysis
    1018
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Fold Difference
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.76
    Notes
    [12] - Non-inferiority of GMT in 27-45 year-olds relative to 16-26 year-olds was demonstrated if the lower limit of the 95% confidence interval (CI) for the fold difference was greater than 0.5.

    Secondary: Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)

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    End point title
    		 Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)
    End point description
    An AE is any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an AE. The percentage of participants with 1 or more AEs was assessed.
    End point type
    Secondary
    End point timeframe
    Up to 1 month post vaccination 3 (up to 7 months)
    End point values
    		 Women 16-26 years of age - Safety Women 27-45 years of age- Safety
    Number of subjects analysed
    570
    640
    Units: Percentage of Participants
        number (not applicable)
    92.8
    92.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Had Study Vaccine Discontinued Due to Adverse Event.

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    End point title
    		 Percentage of Participants Who Had Study Vaccine Discontinued Due to Adverse Event.
    End point description
    An adverse event is any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an adverse event. The percentage of participants who discontinued the study vaccine due to an adverse event regardless of study completion status was assessed.
    End point type
    Secondary
    End point timeframe
    Up to 1 month post vaccination 3 (up to 7 months)
    End point values
    		 Women 16-26 years of age - Safety Women 27-45 years of age- Safety
    Number of subjects analysed
    570
    640
    Units: Percentage of Participants
        number (not applicable)
    0.0
    0.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least 1 Solicited Injection-site Adverse Event

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    End point title
    		 Percentage of Participants With at Least 1 Solicited Injection-site Adverse Event
    End point description
    Participants were asked to record any injection-site reactions prompted in the Vaccination Report Card, i.e., injection-site tenderness, swelling, or redness, occurring after each study vaccination (solicited injection-site reactions). The percentage of participants with 1 or more solicited injection-site AE was assessed.
    End point type
    Secondary
    End point timeframe
    Up to 5 days post any vaccination
    End point values
    		 Women 16-26 years of age - Safety Women 27-45 years of age- Safety
    Number of subjects analysed
    570
    640
    Units: Percentage of Participants
        number (not applicable)
    87.2
    84.7
    Statistical analysis title
    		 Difference in Percentages
    Statistical analysis description
    Difference in percentages calculated as % Women 27-45 Years of Age minus % Women 16-26 Years of Age.
    Comparison groups
    Women 16-26 years of age - Safety v Women 27-45 years of age- Safety
    Number of subjects included in analysis
    1210
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.212
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentages
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 1.4

    Secondary: Percentage of Participants Who Reported at Least 1 Systemic Adverse Event

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    End point title
    		 Percentage of Participants Who Reported at Least 1 Systemic Adverse Event
    End point description
    An AE is defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with study vaccine. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study vaccine or a protocol-specified procedure, whether or not considered related to the study vaccine or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study vaccine or protocol-specified procedure is also an AE. Systemic AEs are those not categorized as injection-site AEs. The percentage of participants that reported at least 1 systemic AE was assessed
    End point type
    Secondary
    End point timeframe
    Up to 15 days post any vaccination
    End point values
    		 Women 16-26 years of age - Safety Women 27-45 years of age- Safety
    Number of subjects analysed
    570
    640
    Units: Percentage of Participants
        number (not applicable)
    66.3
    64.4
    Statistical analysis title
    		 Difference in Percentages
    Statistical analysis description
    Difference in percentages calculated as % Women 27-45 Years of Age minus % Women 16-26 Years of Age.
    Comparison groups
    Women 16-26 years of age - Safety v Women 27-45 years of age- Safety
    Number of subjects included in analysis
    1210
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentages
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 3.4

    Secondary: Percentage of Participants With Elevated Temperature (Fever)

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    End point title
    		 Percentage of Participants With Elevated Temperature (Fever)
    End point description
    Participants were asked to record oral body temperature in the Vaccination Report Card. The percentage of participants with elevated temperature (≥37.8°C or 100.0°F) was assessed.
    End point type
    Secondary
    End point timeframe
    Up to 5 days post any vaccination
    End point values
    		 Women 16-26 years of age - Safety Women 27-45 years of age- Safety
    Number of subjects analysed
    569
    640
    Units: Percentage of Participants
        number (not applicable)
    3.5
    2.5
    Statistical analysis title
    		 Difference in Percentages
    Statistical analysis description
    Difference in percentages calculated as % Women 27-45 Years of Age minus % Women 16-26 Years of Age.
    Comparison groups
    Women 16-26 years of age - Safety v Women 27-45 years of age- Safety
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentages
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 0.9

    Secondary: Percentage of Participants Who Seroconverted to Each of the Anti-HPV Types

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    End point title
    		 Percentage of Participants Who Seroconverted to Each of the Anti-HPV Types
    End point description
    Antibodies to the HPV types contained in V503 were measured using a competitive luminex immunoassay. The percentage of participants who were seronegative on Day 1 and have anti-HPV titer greater or equal to the type-specific serostatus cutoff at 4 weeks postdose 3 was assessed.
    End point type
    Secondary
    End point timeframe
    4 weeks post vaccination 3 (Month 7)
    End point values
    		 Women 16-26 years of age - Immunogenicity Women 27-45 years of age - Immunogenicity
    Number of subjects analysed
    485
    533
    Units: Percentage of Participants
    number (confidence interval 95%)
        Anti HPV 6 (n=421; 448)
    99.8 (98.7 to 100.0)
    100.0 (99.2 to 100.0)
        Anti HPV 11 (n=421; 448)
    100.0 (99.1 to 100.0)
    99.8 (98.8 to 100.0)
        Anti HPV 16 (n=436; 448)
    100.0 (99.2 to 100.0)
    100.0 (99.2 to 100.0)
        Anti HPV 18 (n=421; 471)
    100.0 (99.1 to 100.0)
    99.6 (98.5 to 99.9)
        Anti HPV 31 (n=447; 488)
    100.0 (99.2 to 100.0)
    99.8 (98.9 to 100.0)
        Anti HPV 33 (n=457; 493)
    100.0 (99.2 to 100.0)
    99.8 (98.9 to 100.0)
        Anti HPV 45 (n=470; 515)
    99.6 (98.5 to 99.9)
    99.2 (98.0 to 99.8)
        Anti HPV 52 (n=456; 496)
    100.0 (99.2 to 100.0)
    100.0 (99.3 to 100.0)
        Anti HPV 58 (n=451; 478)
    100.0 (99.2 to 100.0)
    99.8 (98.8 to 100.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 1 month post vaccination 3 (up to 7 months)
    Adverse event reporting additional description
    Population included all participants that received at least 1 vaccination.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Women 27-45 years of age
    Reporting group description
    		 Adult women 27 to 45-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.

    Reporting group title
    Women 16-26 years of age
    Reporting group description
    		 Young adult women 16 to 26-years old received V503 vaccination, 0.5 mL in a 3-dose regimen administered on Day 1, Month 2, and Month 6.

    Serious adverse events
    		 Women 27-45 years of age Women 16-26 years of age
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 640 (1.25%)
    6 / 570 (1.05%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 570 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 570 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 570 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 570 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 640 (0.16%)
    2 / 570 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Basilar migraine
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 570 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal death
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 570 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 570 (0.18%)
         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
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 570 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 640 (0.16%)
    0 / 570 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 640 (0.00%)
    1 / 570 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 640 (0.16%)
    1 / 570 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Women 27-45 years of age Women 16-26 years of age
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    574 / 640 (89.69%)
    518 / 570 (90.88%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    200 / 640 (31.25%)
    185 / 570 (32.46%)
         occurrences all number
    320
    297
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    33 / 640 (5.16%)
    28 / 570 (4.91%)
         occurrences all number
    42
    36
    Injection site erythema
         subjects affected / exposed
    111 / 640 (17.34%)
    112 / 570 (19.65%)
         occurrences all number
    163
    166
    Injection site pain
         subjects affected / exposed
    532 / 640 (83.13%)
    492 / 570 (86.32%)
         occurrences all number
    1244
    1246
    Injection site swelling
         subjects affected / exposed
    152 / 640 (23.75%)
    137 / 570 (24.04%)
         occurrences all number
    224
    206
    Pyrexia
         subjects affected / exposed
    28 / 640 (4.38%)
    36 / 570 (6.32%)
         occurrences all number
    31
    40
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    27 / 640 (4.22%)
    31 / 570 (5.44%)
         occurrences all number
    32
    35
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    22 / 640 (3.44%)
    51 / 570 (8.95%)
         occurrences all number
    27
    65
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    46 / 640 (7.19%)
    40 / 570 (7.02%)
         occurrences all number
    53
    44
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    56 / 640 (8.75%)
    53 / 570 (9.30%)
         occurrences all number
    69
    57

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2017
    Amendement 2: The primary reason for the amendment was change in sponsor of the study from MSD Vaccins, a French société par actions simplifiée to Merck Sharp & Dohme Corp.

    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
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