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    Clinical Trial Results:
    A Phase II Study of the Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine in Healthy Adolescents

    Summary
    EudraCT number
    2016-001963-35
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    02 Oct 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jan 2019
    First version publication date
    05 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MET50
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02199691
    WHO universal trial number (UTN)
    U1111-1143-8537
    Other trial identifiers
    BB-IND: 14171
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur Inc.
    Sponsor organisation address
    1 Discovery Drive, Swiftwater, United States, 18370
    Public contact
    Trial Transparency Team, Sanofi Pasteur , Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur , Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001930-PIP01-16
    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
    04 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the antibody responses to the antigens present in Meningococcal Polysaccharide (Serogroups A, C, Y and W) Tetanus Toxoid (MenACYW) conjugate vaccine when MenACYW conjugate vaccine was given alone compared to those when MENVEO vaccine was given alone.
    Protection of trial subjects
    Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Jul 2014
    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: 1715
    Worldwide total number of subjects
    1715
    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)
    1356
    Adolescents (12-17 years)
    359
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study subjects were enrolled in 40 centers in the Unites States (US) from 22 July 2014 to 25 February 2015.

    Pre-assignment
    Screening details
    A total of 1715 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group 1: MenACYW Conjugate Vaccine
    Arm description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of MenACYW conjugate vaccine.
    Arm type
    Experimental

    Investigational medicinal product name
    MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose on Day 0.

    Arm title
    Group 2: MENVEO® Vaccine
    Arm description
    Healthy, meningococcal-vaccine naive subjects aged 10 to 17 years received a single dose of MENVEO® vaccine.
    Arm type
    Active comparator

    Investigational medicinal product name
    MENVEO®: Meningococcal (Groups A, C, Y and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose on Day 0.

    Arm title
    Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Arm description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of the MenACYW conjugate vaccine, Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap), and 3 doses of Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant (HPV). HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.
    Arm type
    Experimental

    Investigational medicinal product name
    MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose on Day 0.

    Investigational medicinal product name
    Tdap: Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed
    Investigational medicinal product code
    Other name
    Adacel®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose on Day 0.

    Investigational medicinal product name
    HPV: Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant
    Investigational medicinal product code
    Other name
    GARDASIL®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose each on Day 0, Day 60, and Day 180.

    Arm title
    Group 4: Tdap+HPV
    Arm description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of Tdap and 3 doses of HPV. HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.
    Arm type
    Active comparator

    Investigational medicinal product name
    Tdap: Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed
    Investigational medicinal product code
    Other name
    Adacel®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose on Day 0.

    Investigational medicinal product name
    HPV: Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant
    Investigational medicinal product code
    Other name
    GARDASIL®
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular, single dose each on Day 0, Day 60, and Day 180.

    Number of subjects in period 1
    Group 1: MenACYW Conjugate Vaccine Group 2: MENVEO® Vaccine Group 3: MenACYW conjugate vaccine+Tdap+HPV Group 4: Tdap+HPV
    Started
    505
    507
    403
    300
    Completed
    495
    500
    376
    270
    Not completed
    10
    7
    27
    30
         Protocol deviation
             3
             3
             6
             7
         Consent withdrawn by subject
             5
             3
             12
             13
         Lost to follow-up
             2
             1
             9
             10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: MenACYW Conjugate Vaccine
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 2: MENVEO® Vaccine
    Reporting group description
    Healthy, meningococcal-vaccine naive subjects aged 10 to 17 years received a single dose of MENVEO® vaccine.

    Reporting group title
    Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of the MenACYW conjugate vaccine, Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap), and 3 doses of Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant (HPV). HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.

    Reporting group title
    Group 4: Tdap+HPV
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of Tdap and 3 doses of HPV. HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.

    Reporting group values
    Group 1: MenACYW Conjugate Vaccine Group 2: MENVEO® Vaccine Group 3: MenACYW conjugate vaccine+Tdap+HPV Group 4: Tdap+HPV Total
    Number of subjects
    505 507 403 300 1715
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    405 396 320 235 1356
        Adolescents (12-17 years)
    100 111 83 65 359
        Adults (18-64 years)
    0 0 0 0 0
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.4 ± 1.39 11.4 ± 1.39 11.3 ± 1.06 11.4 ± 1.41 -
    Gender categorical
    Units: Subjects
        Female
    259 232 197 144 832
        Male
    246 275 206 156 883

    End points

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    End points reporting groups
    Reporting group title
    Group 1: MenACYW Conjugate Vaccine
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 2: MENVEO® Vaccine
    Reporting group description
    Healthy, meningococcal-vaccine naive subjects aged 10 to 17 years received a single dose of MENVEO® vaccine.

    Reporting group title
    Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of the MenACYW conjugate vaccine, Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap), and 3 doses of Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant (HPV). HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.

    Reporting group title
    Group 4: Tdap+HPV
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of Tdap and 3 doses of HPV. HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.

    Primary: Percentages of Subjects Achieving Serum Bactericidal Assay Using Human Complement (hSBA) Vaccine Seroresponse for Meningococcal Serogroups A, C, Y, and W Following Vaccination With Either MenACYW Conjugate Vaccine or MENVEO® Vaccine

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    End point title
    Percentages of Subjects Achieving Serum Bactericidal Assay Using Human Complement (hSBA) Vaccine Seroresponse for Meningococcal Serogroups A, C, Y, and W Following Vaccination With Either MenACYW Conjugate Vaccine or MENVEO® Vaccine [1]
    End point description
    Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA. The hSBA vaccine seroresponse for serogroups A, C, Y, and W was defined as post-vaccination hSBA titers >= 1:8 for subjects with pre-vaccination hSBA titers < 1:8 or at least a 4-fold increase in hSBA titers from pre- to post-vaccination for subjects with pre-vaccination hSBA titers >= 1:8. Analysis was performed on Per-Protocol Analysis Set-1 (PPAS-1) defined for accessing the ACYW and the Tdap immune response data for all subjects after they had received vaccination(s) at Visit 1 (Day 0) and completed blood sampling (BL) at Visit 2 (Day 30). Here 'n' signifies number of subjects with available data for specified category, for each arm respectively.
    End point type
    Primary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical comparison was planned to be analysed for the reported arms only.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: MENVEO® Vaccine
    Number of subjects analysed
    463
    464
    Units: Percentage of subjects
    number (confidence interval 95%)
        Serogroup A (n= 463, 464)
    75.6 (71.4 to 79.4)
    66.4 (61.9 to 70.7)
        Serogroup C (n= 462, 463)
    97.2 (95.2 to 98.5)
    72.6 (68.3 to 76.6)
        Serogroup Y (n= 462, 464)
    97.0 (95.0 to 98.3)
    80.8 (76.9 to 84.3)
        Serogroup W (n= 463, 464)
    86.2 (82.7 to 89.2)
    66.6 (62.1 to 70.9)
    Statistical analysis title
    Serogroup A
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: MENVEO® Vaccine
    Number of subjects included in analysis
    927
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    9.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.4
         upper limit
    15
    Notes
    [2] - 95% confidence interval (CI) of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    Serogroup C
    Statistical analysis description
    Actual number of subjects analyzed = 925
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: MENVEO® Vaccine
    Number of subjects included in analysis
    927
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    24.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.3
         upper limit
    29
    Notes
    [3] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    Serogroup Y
    Statistical analysis description
    Actual number of subjects analyzed = 926
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: MENVEO® Vaccine
    Number of subjects included in analysis
    927
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    16.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.3
         upper limit
    20.2
    Notes
    [4] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    Serogroup W
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 2: MENVEO® Vaccine
    Number of subjects included in analysis
    927
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    19.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.2
         upper limit
    24.8
    Notes
    [5] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.

    Secondary: Percentages of Subjects Achieving hSBA Vaccine Seroresponse for Meningococcal Serogroups A, C, Y, and W Following Vaccination With Either MenACYW Conjugate Vaccine or MenACYW Conjugate Vaccine Given with Tdap and HPV Vaccines

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    End point title
    Percentages of Subjects Achieving hSBA Vaccine Seroresponse for Meningococcal Serogroups A, C, Y, and W Following Vaccination With Either MenACYW Conjugate Vaccine or MenACYW Conjugate Vaccine Given with Tdap and HPV Vaccines [6]
    End point description
    Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA. The hSBA vaccine seroresponse for serogroups A, C, Y, and W was defined as post-vaccination hSBA titers >= 1:8 for subjects with pre-vaccination hSBA titers < 1:8 or at least a 4-fold increase in hSBA titers from pre- to post-vaccination for subjects with pre-vaccination hSBA titers >= 1:8. Analysis was performed on PPAS-1. Here 'n' signifies number of subjects with available data for specified category, for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical comparison was planned to be analysed for the reported arms only.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Number of subjects analysed
    463
    360
    Units: Percentage of subjects
    number (not applicable)
        Serogroup A (n= 463, 360)
    75.6
    80.6
        Serogroup C (n= 462, 360)
    97.2
    97.2
        Serogroup Y (n= 462, 360)
    97.0
    95.6
        Serogroup W (n= 463, 360)
    86.2
    83.9
    Statistical analysis title
    Serogroup A
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Number of subjects included in analysis
    823
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    10.5
    Notes
    [7] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    Serogroup C
    Statistical analysis description
    Actual number of subjects analyzed = 822.
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Number of subjects included in analysis
    823
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [8]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    2.4
    Notes
    [8] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    Serogroup Y
    Statistical analysis description
    Actual number of subjects analyzed = 822.
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Number of subjects included in analysis
    823
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [9]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    1.2
    Notes
    [9] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.
    Statistical analysis title
    Serogroup W
    Comparison groups
    Group 1: MenACYW Conjugate Vaccine v Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Number of subjects included in analysis
    823
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [10]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    -2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.3
         upper limit
    2.6
    Notes
    [10] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was > -10%.

    Secondary: Geometric Mean Concentrations (GMCs) of PT, FHA, PRN, and FIM Antibodies Following Vaccination with Either MenACYW Conjugate Vaccine Given With Tdap and HPV Vaccines or Tdap and HPV Vaccines

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    End point title
    Geometric Mean Concentrations (GMCs) of PT, FHA, PRN, and FIM Antibodies Following Vaccination with Either MenACYW Conjugate Vaccine Given With Tdap and HPV Vaccines or Tdap and HPV Vaccines [11]
    End point description
    Anti-Pertussis toxoid (PT), Filamentous hemagglutinin (FHA), Pertactin (PRN), and Fimbriae types 2 and 3 (FIM) antibodies were measured by enzyme-linked immunosorbent assay (ELISA). Analysis was performed on PPAS-1. Here 'n' signifies number of subjects with available data for specified category, for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical comparison was planned to be analysed for the reported arms only.
    End point values
    Group 3: MenACYW conjugate vaccine+Tdap+HPV Group 4: Tdap+HPV
    Number of subjects analysed
    360
    263
    Units: ELISA units (EU)/mL
    geometric mean (confidence interval 95%)
        PT (n= 339, 258)
    37.5 (33.8 to 41.7)
    44.4 (39.5 to 49.9)
        FHA (n= 358, 263)
    180 (168 to 194)
    242 (218 to 268)
        PRN (n= 360, 263)
    200 (177 to 225)
    265 (231 to 304)
        FIM (n= 350, 262)
    339 (285 to 403)
    499 (414 to 601)
    Statistical analysis title
    PT: Geometric Mean Ratio
    Statistical analysis description
    Actual number of subjects analyzed = 597
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    623
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [12]
    Method
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.845
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.722
         upper limit
    0.99
    Notes
    [12] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio was >2/3.
    Statistical analysis title
    FHA: Geometric Mean Ratio
    Statistical analysis description
    Actual number of subjects analyzed = 621
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    623
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [13]
    Method
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.746
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.661
         upper limit
    0.842
    Notes
    [13] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio was >2/3.
    Statistical analysis title
    PRN: Geometric Mean Ratio
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    623
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [14]
    Method
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.753
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.627
         upper limit
    0.903
    Notes
    [14] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio was >2/3.
    Statistical analysis title
    FIM: Geometric Mean Ratio
    Statistical analysis description
    Actual number of subjects analyzed = 612
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    623
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [15]
    Method
    Parameter type
    Geometric Mean Ratio
    Point estimate
    0.679
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.525
         upper limit
    0.878
    Notes
    [15] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the ratio was >2/3.

    Secondary: Percentage of Subjects Achieving Anti-Tetanus and Anti-Diphtheria Concentrations >= 1.0 International Unit (IU)/mL Following Vaccination With Either MenACYW Conjugate Vaccine Given With Tdap and HPV Vaccines or Tdap and HPV Vaccines

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    End point title
    Percentage of Subjects Achieving Anti-Tetanus and Anti-Diphtheria Concentrations >= 1.0 International Unit (IU)/mL Following Vaccination With Either MenACYW Conjugate Vaccine Given With Tdap and HPV Vaccines or Tdap and HPV Vaccines [16]
    End point description
    Anti-Diphtheria antibodies were measured by a toxin neutralization test. Anti-Tetanus antibodies were measured by ELISA. Analysis was performed on PPAS-1. Here 'n' signifies number of subjects with available data for specified category, for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Day 30 (post-vaccination)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical comparison was planned to be analysed for the reported arms only.
    End point values
    Group 3: MenACYW conjugate vaccine+Tdap+HPV Group 4: Tdap+HPV
    Number of subjects analysed
    360
    263
    Units: percentage of subjects
    number (confidence interval 95%)
        Diphtheria (n =360, 263)
    97.8 (95.7 to 99.0)
    98.9 (96.7 to 99.8)
        Tetanus (n=360, 262)
    99.7 (98.5 to 100.0)
    99.6 (97.9 to 100.0)
    Statistical analysis title
    Serogroup Diphtheria
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    623
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [17]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    1.3
    Notes
    [17] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was >-10%.
    Statistical analysis title
    Serogroup Tetanus
    Statistical analysis description
    Actual number of subjects analyzed = 622
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    623
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [18]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    1.9
    Notes
    [18] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was >-10%.

    Secondary: Percentage of Subjects Achieving Seroconversion for Anti-HPV6, HPV11, HPV16, and HPV18 Antibodies Following Vaccination With Either MenACYW Conjugate Vaccine Given With Tdap and HPV Vaccines or Tdap and HPV Vaccines

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    End point title
    Percentage of Subjects Achieving Seroconversion for Anti-HPV6, HPV11, HPV16, and HPV18 Antibodies Following Vaccination With Either MenACYW Conjugate Vaccine Given With Tdap and HPV Vaccines or Tdap and HPV Vaccines [19]
    End point description
    Anti-HPV 6, 11, 16, and 18 antibodies were measured using a competitive Luminex immunoassay. Seroconversion was defined as changing serostatus from seronegative to seropositive. Cutoff values for HPV seropositivity were >= 20 milli-Merck units per milliliter (mMU/mL) for types 6 and 16, >= 16 mMU/mL for type 11, and >= 24mMU/mL for type 18. Analysis was performed on Per-Protocol Analysis Set-2 (PPAS-2) defined for accessing the HPV immune response data for subjects in Group 3 and in Group 4 after they had received the third HPV vaccination at Visit 4 and complete blood sample at Visit 5 (BL3 [Day 210]).
    End point type
    Secondary
    End point timeframe
    Day 210 (post-vaccination)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical comparison was planned to be analysed for the reported arms only.
    End point values
    Group 3: MenACYW conjugate vaccine+Tdap+HPV Group 4: Tdap+HPV
    Number of subjects analysed
    242
    164
    Units: Percentage of subjects
    number (confidence interval 95%)
        HPV Type 6
    97.5 (94.7 to 99.1)
    95.7 (91.4 to 98.3)
        HPV Type 11
    99.6 (97.7 to 100.0)
    98.8 (95.7 to 99.9)
        HPV Type 16
    99.2 (97.0 to 99.9)
    98.8 (95.7 to 99.9)
        HPV Type 18
    99.2 (97.0 to 99.9)
    98.8 (95.7 to 99.9)
    Statistical analysis title
    HPV Type 6
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [20]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    6.3
    Notes
    [20] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was >-10%.
    Statistical analysis title
    HPV Type 11
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [21]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    3.9
    Notes
    [21] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was >-10%.
    Statistical analysis title
    HPV Type 16
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [22]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    3.6
    Notes
    [22] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was >-10%.
    Statistical analysis title
    HPV Type 18
    Comparison groups
    Group 3: MenACYW conjugate vaccine+Tdap+HPV v Group 4: Tdap+HPV
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [23]
    Method
    Parameter type
    Percentage Difference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    3.6
    Notes
    [23] - 95% CI of the difference was calculated from the Wilson Score Method without continuity correction. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI of the difference between the 2 percentages was >-10%.

    Secondary: Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Vaccination at Day 0: Group 1 and Group 2

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    End point title
    Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Vaccination at Day 0: Group 1 and Group 2 [24]
    End point description
    A solicited reaction was an Adverse Event (AE) that was prelisted in the electronic Case Report Form (eCRF) and considered to be related to vaccination. Solicited injection site reactions: Pain, Erythema, Swelling. Percentages of subjects with at least one solicited injection site reactions were reported. Analysis was performed on safety analysis set defined as those subjects who had received at least one dose of the trial vaccine(s) and had any safety data available. All subjects had their safety data analysed according to the vaccine(s) they actually received. Here 'n' signifies number of subjects with available data for specified category, for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Within 7 days after vaccines injections at Day 0
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms applicable for this endpoint are reported.
    End point values
    Group 1: MenACYW Conjugate Vaccine Group 2: MENVEO® Vaccine
    Number of subjects analysed
    503
    501
    Units: percentage of subjects
    number (not applicable)
        MenACYW/MENVEO: Pain (n=496, 492)
    45.2
    42.5
        MenACYW/MENVEO: Erythema (n=496, 491)
    5.0
    7.5
        MenACYW/MENVEO: Swelling (n=496, 491)
    5.4
    6.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Vaccination at Day 0: Group 3

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    End point title
    Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Vaccination at Day 0: Group 3 [25]
    End point description
    A solicited reaction was an AE that was prelisted in the eCRF and considered to be related to vaccination. Solicited injection site reactions: Pain, Erythema, Swelling. Percentages of subjects with at least one solicited injection site reactions were reported. Analysis was performed on safety analysis set. Here, subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Within 7 days after vaccines injections at Day 0
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arm applicable for this endpoint is reported.
    End point values
    Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Number of subjects analysed
    388
    Units: percentage of subjects
    number (not applicable)
        MenACYW/MENVEO: Pain
    47.2
        MenACYW/MENVEO: Erythema
    3.9
        MenACYW/MENVEO: Swelling
    4.4
        Tdap: Pain
    73.7
        Tdap: Erythema
    7.2
        Tdap: Swelling
    6.2
        HPV: Pain
    74.2
        HPV: Erythema
    8.0
        HPV: Swelling
    6.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Vaccination at Day 0: Group 4

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    End point title
    Percentage of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Vaccination at Day 0: Group 4 [26]
    End point description
    A solicited reaction was an AE that was prelisted in the eCRF and considered to be related to vaccination. Solicited injection site reactions: Pain, Erythema, Swelling. Percentages of subjects with at least one solicited injection site reactions were reported. Analysis was performed on safety analysis set. Here, subjects analysed = subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Within 7 days after vaccines injections at Day 0
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arm applicable for this endpoint is reported.
    End point values
    Group 4: Tdap+HPV
    Number of subjects analysed
    289
    Units: percentage of subjects
    number (not applicable)
        Tdap: Pain
    73.0
        Tdap: Erythema
    4.8
        Tdap: Swelling
    6.9
        HPV: Pain
    69.6
        HPV: Erythema
    5.5
        HPV: Swelling
    8.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE data were collected from Day 0 up to Day 30 post-vaccination. Solicited Reaction (SR) data were collected from Day 0 up to Day 7 post-vaccination.
    Adverse event reporting additional description
    A SR was an AE that was prelisted (i.e.,solicited) in the eCRF and considered to be related to vaccination (adverse drug reaction). An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the eCRF (i.e.,solicited) in terms of symptom and/or onset post-vaccination. Safety Analysis Set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Group 1 MenACYW
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of MenACYW conjugate vaccine.

    Reporting group title
    Group 2: MENVEO® Vaccine
    Reporting group description
    Healthy, meningococcal-vaccine naive subjects aged 10 to 17 years received a single dose of MENVEO® vaccine.

    Reporting group title
    Group 3: MenACYW conjugate vaccine+Tdap+HPV
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of the MenACYW conjugate vaccine, Tdap, and 3 doses of HPV. HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.

    Reporting group title
    Group 4: Tdap+HPV
    Reporting group description
    Healthy, meningococcal-vaccine naïve subjects aged 10 to 17 years received a single dose of Tdap and 3 doses of HPV. HPV Dose 2 and Dose 3 were given 2 and 6 months, respectively, after Dose 1 given on Day 0.

    Serious adverse events
    Group 1 MenACYW Group 2: MENVEO® Vaccine Group 3: MenACYW conjugate vaccine+Tdap+HPV Group 4: Tdap+HPV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 503 (0.80%)
    4 / 501 (0.80%)
    4 / 392 (1.02%)
    4 / 296 (1.35%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 503 (0.00%)
    0 / 501 (0.00%)
    1 / 392 (0.26%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 501 (0.00%)
    1 / 392 (0.26%)
    0 / 296 (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
    General disorders and administration site conditions
    Mucosal Inflammation
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 501 (0.00%)
    0 / 392 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal Behaviour
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 501 (0.20%)
    0 / 392 (0.00%)
    0 / 296 (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
    Major Depression
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 501 (0.20%)
    0 / 392 (0.00%)
    0 / 296 (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
    Suicidal Ideation
         subjects affected / exposed
    0 / 503 (0.00%)
    0 / 501 (0.00%)
    1 / 392 (0.26%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 501 (0.00%)
    0 / 392 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema Multiforme
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 501 (0.20%)
    0 / 392 (0.00%)
    0 / 296 (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
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 503 (0.00%)
    0 / 501 (0.00%)
    1 / 392 (0.26%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 Diabetes Mellitus
         subjects affected / exposed
    1 / 503 (0.20%)
    0 / 501 (0.00%)
    0 / 392 (0.00%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 503 (0.00%)
    1 / 501 (0.20%)
    0 / 392 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Scalded Skin Syndrome
         subjects affected / exposed
    0 / 503 (0.00%)
    0 / 501 (0.00%)
    0 / 392 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Group 1 MenACYW Group 2: MENVEO® Vaccine Group 3: MenACYW conjugate vaccine+Tdap+HPV Group 4: Tdap+HPV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    331 / 503 (65.81%)
    338 / 501 (67.47%)
    348 / 392 (88.78%)
    263 / 296 (88.85%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    155 / 503 (30.82%)
    159 / 501 (31.74%)
    137 / 392 (34.95%)
    87 / 296 (29.39%)
         occurrences all number
    166
    169
    145
    90
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    25 / 503 (4.97%)
    37 / 501 (7.39%)
    44 / 392 (11.22%)
    24 / 296 (8.11%)
         occurrences all number
    25
    37
    74
    30
    Injection Site Pain
         subjects affected / exposed
    224 / 503 (44.53%)
    209 / 501 (41.72%)
    327 / 392 (83.42%)
    234 / 296 (79.05%)
         occurrences all number
    224
    209
    759
    412
    Injection Site Swelling
         subjects affected / exposed
    27 / 503 (5.37%)
    32 / 501 (6.39%)
    42 / 392 (10.71%)
    32 / 296 (10.81%)
         occurrences all number
    27
    32
    67
    43
    Malaise
         subjects affected / exposed
    130 / 503 (25.84%)
    131 / 501 (26.15%)
    113 / 392 (28.83%)
    81 / 296 (27.36%)
         occurrences all number
    130
    131
    113
    81
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    175 / 503 (34.79%)
    174 / 501 (34.73%)
    239 / 392 (60.97%)
    161 / 296 (54.39%)
         occurrences all number
    175
    174
    239
    161
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    15 / 503 (2.98%)
    32 / 501 (6.39%)
    22 / 392 (5.61%)
    14 / 296 (4.73%)
         occurrences all number
    15
    34
    22
    16
    Upper Respiratory Tract Infection
         subjects affected / exposed
    24 / 503 (4.77%)
    30 / 501 (5.99%)
    27 / 392 (6.89%)
    12 / 296 (4.05%)
         occurrences all number
    27
    33
    31
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2014
    Following amendments were made: Clarified the collection dates of safety data, the timing of the third dose of HPV and additional vaccinations during the study period, and that parents (not subjects) would be interviewed concerning safety data; updated batch numbers for the vaccines and clarified how each vaccine would be supplied; clarified the presentation of the antibody concentrations or titers, the procedure to follow if the site staff were unable to obtain the first blood draw, and the timelines for Visits 3, 4, and 5; added the collection of concomitant medications during the review of the memory aid, clarified the follow-up of early terminated subjects, clarified that site staff will verify the subject's number on the label prior to drawing blood, improved the clarity of the text regarding serious adverse events (SAE), clarified the definition (and timing of collection) of the medically-attended adverse events of special interest (MAAESIs) and the definition of the second per-protocol analysis set; and also clarified that an interim analyses will be conducted on data collected up to Visit 2 and that subjects and/or the parent may receive a stipend for participation in the study.
    17 Feb 2015
    Added a preliminary analysis to the study plan; clarified follow-up and visit timing for 6 month follow-up and Visit 5, the reporting and collection of MAAESIs and SAEs, and the definition of any unplanned contact of a physician's office; corrected the window (and days) for Visit 3 and Visit 4 to comply with Advisory Committee on Immunization Practices recommendations for the HPV vaccination schedule; updated the trial calendar; updated the description of the HPV assay; prioritized HPV testing; added Celsius scale temperature ranges; and amended the interim analysis section.

    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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