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    Clinical Trial Results:
    A Phase 3, Single Center, Open-label, Controlled, Randomized Study to Evaluate the Safety and Immunogenicity of Novartis Men ACWY vaccine administered either alone or concomitantly with a Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine (Tdap, Boostrix®) and Quadrivalent Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine (GARDASIL®) in Healthy Adolescents

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2014-004492-23
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Sep 2008

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Jun 2016
    First version publication date
    01 Mar 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    results need to be updated due to shifting of values

    Trial information

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    Trial identification
    Sponsor protocol code
    V59P18
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00518180
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics S.r.l
    Sponsor organisation address
    Via Fiorentina, 1, Siena, Italy, 53100
    Public contact
    Posting Director, Novartis Vaccines and Diagnostics Srl, RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines and Diagnostics Srl, RegistryContactVaccinesUS@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000032-PIP01-07
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Feb 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the immune response of MenACWY, when MenACWY is (1) given concomitantly with Tdap and HPV vaccines, is not inferior to MenACWY given alone, and (2) given alone one month after Tdap, is not inferior to MenACWY given alone one month prior to Tdap. To demonstrate that the immune response to Tdap, when Tdap is given concomitantly with MenACWY and HPV, was not inferior to immune response when Tdap was administered alone.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practice (GCP), and the applicable regulatory requirement(s) for the country in which the trial was conducted according to International Conference on Harmonisation (ICH) guidelines, and applicable Standard Operating Procedures (SOPs).
    Background therapy
    		 MenACWY: one 0.5 mL injection of MenACWY was administered Intra Muscular (IM) in the deltoid area of the right arm. Tdap: one 0.5 mL injection of US-licensed Boostrix vaccine was administered IM in the deltoid area of the left arm. HPV: one 0.5 mL injection of Gardasil was administered IM in the upper anterolateral area of the thigh.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jul 2007
    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
    Costa Rica: 1620
    Worldwide total number of subjects
    1620
    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)
    247
    Adolescents (12-17 years)
    1278
    Adults (18-64 years)
    95
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at a single center in Costa Rica.

    Pre-assignment
    Screening details
    		 All enrolled subjects were randomized at a 1:1:1 ratio to receive MenACWY, Tdap, and HPV vaccines at different schedules.

    Period 1
    Period 1 title
    Overall (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 I
    Arm description
    		 The MenACWY vaccine was administered concomitantly with the Tdap vaccine and the HPV vaccine at study month 0 followed by two injections of the HPV vaccine at months 2 and 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Meningococcal (groups A, C, W, and Y) oligosaccharide diphtheria CRM-197 conjugate vaccine
    Investigational medicinal product code
    V59
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    MenACWY: one 0.5 mL injection of MenACWY was administered IM in the deltoid area of the right arm

    Arm title
    		 Group II
    Arm description
    		 The MenACWY vaccine was administered at study month 0 followed by one injection of the Tdap vaccine at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Meningococcal (groups A, C, W, and Y) oligosaccharide diphtheria CRM-197 conjugate vaccine
    Investigational medicinal product code
    V59
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    MenACWY: one 0.5 mL injection of MenACWY was administered IM in the deltoid area of the right arm

    Arm title
    		 Group III
    Arm description
    		 Tdap vaccine was administered at month 0 followed by one injection of MenACWY at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Meningococcal (groups A, C, W, and Y) oligosaccharide diphtheria CRM-197 conjugate vaccine
    Investigational medicinal product code
    V59
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    MenACWY: one 0.5 mL injection of MenACWY was administered IM in the deltoid area of the right arm

    Number of subjects in period 1
    		Group I Group II Group III
    Started
    540
    541
    539
    Completed
    475
    472
    457
    Not completed
    65
    69
    82
         Consent withdrawn by subject
    29
    30
    42
         Adverse event, non-fatal
    1
    -
    -
         Administrative reasons
    -
    2
    2
         unable to classify
    -
    2
    -
         Lost to follow-up
    30
    28
    34
         Protocol deviation
    5
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 The MenACWY vaccine was administered concomitantly with the Tdap vaccine and the HPV vaccine at study month 0 followed by two injections of the HPV vaccine at months 2 and 6.

    Reporting group title
    Group II
    Reporting group description
    		 The MenACWY vaccine was administered at study month 0 followed by one injection of the Tdap vaccine at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.

    Reporting group title
    Group III
    Reporting group description
    		 Tdap vaccine was administered at month 0 followed by one injection of MenACWY at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.

    Reporting group values
    		 Group I Group II Group III Total
    Number of subjects
    		 540 541 539 1620
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.9 ( 2.1 ) 13.9 ( 2.2 ) 13.8 ( 2.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 308 309 307 924
        Male
    		 232 232 232 696

    End points

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    End points reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 The MenACWY vaccine was administered concomitantly with the Tdap vaccine and the HPV vaccine at study month 0 followed by two injections of the HPV vaccine at months 2 and 6.

    Reporting group title
    Group II
    Reporting group description
    		 The MenACWY vaccine was administered at study month 0 followed by one injection of the Tdap vaccine at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.

    Reporting group title
    Group III
    Reporting group description
    		 Tdap vaccine was administered at month 0 followed by one injection of MenACWY at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.

    Subject analysis set title
    MenACWY+Tdap+HPV
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population for immunogenicity analysis included all subjects in the MITT population who provided evaluable serum samples (titer results are available) both before and after vaccination, and had no major protocol deviation. For the HPV analysis only, only subjects negative for anti-HPV at baseline were included in the PP population

    Subject analysis set title
    HPV Alone
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Three injections of the HPV vaccine were administered at study months 2, 4, and 8. This group is a combination of groups II and III

    Primary: 1. Percentage of Subjects With Human Serum Bactericidal Assay (hSBA) Seroresponse

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    End point title
    		 1. Percentage of Subjects With Human Serum Bactericidal Assay (hSBA) Seroresponse
    End point description
    Immune responses to MenACWY, as measured by the percentage of hSBA seroresponders, when given: (a) alone; (b) concomitantly with a Tetanus diphtheria acellular pertussis(Tdap) vaccine and a Human Papillomavirus Recombinant (HPV) vaccine; and (c) when given one month after a Tdap vaccine. Seroresponse to MenACWY: For a subject with baseline hSBA titer <1:4, seroresponse is defined as a postvaccination hSBA titer ≥ 1:8; for a subject with baseline hSBA titer ≥ 1:4, seroresponse is defined as a postvaccination hSBA titer of at least 4 times the baseline.
    End point type
    Primary
    End point timeframe
    1 month post MenACWY vaccination
    End point values
    		 Group I Group II Group III
    Number of subjects analysed
    494
    487
    458
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Serogroup A (N=494, 486, 458)
    80 (76 to 84)
    82 (78 to 85)
    87 (83 to 90)
        Serogroup C (N=476, 472, 457)
    83 (79 to 86)
    84 (81 to 88)
    84 (80 to 87)
        Serogroup W (N=487, 474, 458)
    77 (73 to 80)
    81 (77 to 84)
    65 (61 to 70)
        Serogroup Y (N=493, 487, 460)
    83 (79 to 86)
    82 (79 to 86)
    78 (74 to 82)
    Statistical analysis title
    		 1.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men A when MenACWY is administered concomitantly with Tdap and HPV, compared with the immune response to MenACWY when administered alone
    Comparison groups
    Group II v Group I
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 3
    Variability estimate
    Standard deviation
    Notes
    [1] - The immunogenicity of MenACWY given concomitantly with HPV and Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% confidence interaval (CI) for the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (PGroup I minus PGroupII) was greater than -10%
    Statistical analysis title
    		 2.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men C when MenACWY is administered concomitantly with Tdap and HPV, compared with the immune response to MenACWY when administered alone
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 3
    Variability estimate
    Standard deviation
    Notes
    [2] - The immunogenicity of MenACWY given concomitantly with HPV and Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% confidence interaval (CI) for the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (PGroup I minus PGroupII) was greater than -10%
    Statistical analysis title
    		 3.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men W when MenACWY is administered concomitantly with Tdap and HPV, compared with the immune response to MenACWY when administered alone
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Notes
    [3] - The immunogenicity of MenACWY given concomitantly with HPV and Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% confidence interaval (CI) for the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (PGroup I minus PGroupII) was greater than -10%
    Statistical analysis title
    		 4.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men Y when MenACWY is administered concomitantly with Tdap and HPV, compared with the immune response to MenACWY when administered alone
    Comparison groups
    Group I v Group II
    Number of subjects included in analysis
    981
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 5
    Variability estimate
    Standard deviation
    Notes
    [4] - The immunogenicity of MenACWY given concomitantly with HPV and Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% confidence interaval (CI) for the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (PGroup I minus PGroupII) was greater than -10%
    Statistical analysis title
    		 5.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men A when MenACWY is administered 1 month after Tdap, compared with immune response to MenACWY when administered alone
    Comparison groups
    Group II v Group III
    Number of subjects included in analysis
    945
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 10
    Variability estimate
    Standard deviation
    Notes
    [5] - The immunogenicity of MenACWY given after Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (P Group III minus PGroup II) was greater than -10%
    Statistical analysis title
    		 6.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men C when MenACWY is administered 1 month after Tdap, compared with immune response to MenACWY when administered alone
    Comparison groups
    Group II v Group III
    Number of subjects included in analysis
    945
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 4
    Variability estimate
    Standard deviation
    Notes
    [6] - The immunogenicity of MenACWY given after Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (P Group III minus PGroup II) was greater than -10%
    Statistical analysis title
    		 7.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men W when MenACWY is administered 1 month after Tdap, compared with immune response to MenACWY when administered alone
    Comparison groups
    Group II v Group III
    Number of subjects included in analysis
    945
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21
         upper limit
    		 -10
    Variability estimate
    Standard deviation
    Notes
    [7] - The immunogenicity of MenACWY given after Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (P Group III minus PGroup II) was greater than -10%
    Statistical analysis title
    		 8.Noninferiority of the immune response to MenACWY
    Statistical analysis description
    Immune response to Men Y when MenACWY is administered 1 month after Tdap, compared with immune response to MenACWY when administered alone
    Comparison groups
    Group II v Group III
    Number of subjects included in analysis
    945
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Notes
    [8] - The immunogenicity of MenACWY given after Tdap was considered noninferior to the immunogenicity of MenACWY administered alone if, for each serogroup, the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroresponse at one month after MenACWY vaccination (P Group III minus PGroup II) was greater than -10%

    Primary: 2. Percentage of Subjects With Antidiphtheria and Antitetanus Toxin ≥1.0 IU/mL

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    End point title
    		 2. Percentage of Subjects With Antidiphtheria and Antitetanus Toxin ≥1.0 IU/mL [9]
    End point description
    To compare the immune response to Tdap given concomitantly with MenACWY and HPV vaccine with the immune response to Tdap when administered alone
    End point type
    Primary
    End point timeframe
    1 month post Tdap vaccination
    Notes
    [9] - 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: No statistical analysis is associated to this endpoint.
    End point values
    		 Group I Group III
    Number of subjects analysed
    492
    487
    Units: Percentages of subjects
    number (confidence interval 95%)
        Diphtheria
    100 (99 to 100)
    98 (96 to 99)
        Tetanus
    100 (99 to 100)
    100 (99 to 100)
    Statistical analysis title
    		 1.Noninferiority of the immune response to Tdap
    Statistical analysis description
    Noninferiority of the immune response to diphtheria antigen, when Tdap is administered concomitantly with MenACWY and HPV, compared with the immune response to Tdap when administered alone
    Comparison groups
    Group I v Group III
    Number of subjects included in analysis
    979
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 4
    Variability estimate
    Standard deviation
    Notes
    [10] - Noninferiority of the immune response to Tdap when administered concomitantly with MenACWY and HPV, compared with the immune response to Tdap when administered alone, was demonstrated for the diphtheria and tetanus antigens if the lower limits of the twosided 95% CIs around the difference in the percentages of subjects with ELISA anti-D toxin and anti-T toxin ≥ 1.0 IU/mL [Group I minus Group III] were greater than -10%
    Statistical analysis title
    		 2. Noninferiority of the immune response Tdap
    Statistical analysis description
    Noninferiority of the immune response to tetanus antigen, when Tdap is administered concomitantly with MenACWY and HPV, compared with the immune response to Tdap when administered alone
    Comparison groups
    Group I v Group III
    Number of subjects included in analysis
    979
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Variability estimate
    Standard deviation
    Notes
    [11] - Noninferiority of the immune response to Tdap when administered concomitantly with MenACWY and HPV, compared with the immune response to Tdap when administered alone, was demonstrated for the diphtheria and tetanus antigens if the lower limits of the twosided 95% CIs around the difference in the percentages of subjects with ELISA anti-D toxin and anti-T toxin ≥ 1.0 IU/mL [Group I minus Group III] were greater than -10%

    Primary: 3. Geometric Mean Concentrations (GMC) of Antipertussis Toxin [Anti-PT], Antifilamentous Hemagglutinin [Anti-FHA], and Antipertactin [Anti-PRN]

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    End point title
    		 3. Geometric Mean Concentrations (GMC) of Antipertussis Toxin [Anti-PT], Antifilamentous Hemagglutinin [Anti-FHA], and Antipertactin [Anti-PRN] [12]
    End point description
    To compare the immune response of Tdap given concomitantly with MenACWY and HPV vaccine with the immune response of Tdap when administered alone
    End point type
    Primary
    End point timeframe
    1 month post Tdap vaccination (Group I and Group III at Visit 2 - Day 31).
    Notes
    [12] - 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: No statistical analysis is associated to this endpoint.
    End point values
    		 Group I Group III
    Number of subjects analysed
    492
    487
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-PT (N=479,477)
    51 (47 to 55)
    63 (58 to 69)
        Anti-FHA (N=489,485)
    342 (310 to 376)
    511 (464 to 563)
        Anti-PRN (N=492,487)
    819 (727 to 923)
    1197 (1061 to 1350)
    Statistical analysis title
    		 1.Noninferiority of the immune response to Tdap
    Statistical analysis description
    Noninferiority of the immune response to Tdap when administered concomitantly with MenACWY and HPV, compared with the immune response to Tdap when administered alone, for PT antigen
    Comparison groups
    Group I v Group III
    Number of subjects included in analysis
    979
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Ratio
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.9
    Variability estimate
    Standard deviation
    Notes
    [13] - Tdap concomitant with MenACWY was considered noninferior to Tdap alone if, for PT, FHA, and pertactin, the lower limit of the twosided 95% CI for the ratio of the GMCs (GMC Group I / GMC Group III) at one month after vaccination was > 0.67
    Statistical analysis title
    		 3.Noninferiority of the immune response to Tdap
    Statistical analysis description
    Noninferiority of the immune response to Tdap when administered concomitantly with MenACWY and HPV, compared with the immune response to Tdap when administered alone, for PRN antigen
    Comparison groups
    Group I v Group III
    Number of subjects included in analysis
    979
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [14]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Ratio
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.81
    Variability estimate
    Standard deviation
    Notes
    [14] - Tdap concomitant with MenACWY was considered noninferior to Tdap alone if, for PT, FHA, and pertactin, the lower limit of the twosided 95% CI for the ratio of the GMCs (GMC Group I / GMC Group III) at one month after vaccination was > 0.67
    Statistical analysis title
    		 2.Noninferiority of the immune response to Tdap
    Statistical analysis description
    Noninferiority of the immune response to Tdap when administered concomitantly with MenACWY and HPV, compared with the immune response to Tdap when administered alone, for FHA antigen
    Comparison groups
    Group I v Group III
    Number of subjects included in analysis
    979
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [15]
    Method
    		 ANCOVA
    Parameter type
    		 Vaccine Group Ratio
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.76
    Variability estimate
    Standard deviation
    Notes
    [15] - Tdap concomitant with MenACWY was considered noninferior to Tdap alone if, for PT, FHA, and pertactin, the lower limit of the twosided 95% CI for the ratio of the GMCs (GMC Group I / GMC Group III) at one month after vaccination was > 0.67

    Secondary: 4. Effect of Concomitant and Sequential Vaccination on hSBA Geometric Mean Titers (GMTs) for A, C, W, and Y Serogroups

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    End point title
    		 4. Effect of Concomitant and Sequential Vaccination on hSBA Geometric Mean Titers (GMTs) for A, C, W, and Y Serogroups
    End point description
    The immune responses to the MenACWY conjugate vaccine, as measured by the hSBA Geometric Mean Titers (GMTs) when given: (a) alone, (b) concomitantly with the Tdap vaccine and the HPV vaccine, and (c) when given one month after the Tdap vaccine.
    End point type
    Secondary
    End point timeframe
    1 month post MenACWY vaccination
    End point values
    		 Group I Group II Group III
    Number of subjects analysed
    494
    487
    460
    Units: Titers
    geometric mean (confidence interval 95%)
        Serogroup A (N=494, 486,458)
    62 (52 to 74)
    67 (56 to 80)
    95 (79 to 113)
        Serogroup C (N=476, 472,457)
    66 (56 to 77)
    70 (60 to 83)
    68 (58 to 79)
        Serogroup W (N=487,474, 458)
    146 (129 to 165)
    159 (140 to 181)
    104 (91 to 119)
        Serogroup Y (N=493, 487,460)
    72 (62 to 84)
    81 (70 to 95)
    57 (49 to 67)
    No statistical analyses for this end point

    Secondary: 5. Percentage of Subjects With Anti-HPV Seroconversion

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    End point title
    		 5. Percentage of Subjects With Anti-HPV Seroconversion
    End point description
    To compare the immune response of HPV vaccine given concomitantly with MenACWY and Tdap to the response when HPV vaccine is given alone. (Immune response against HPV types 6, 11, 16, and 18 was measured at one month after the third HPV vaccination.) Anti-HPV Seroconversion (SC): SC was defined as negative (baseline HPV titer < type-specific cut-off) for anti-HPV and anti-HPV ≥ an HPV type-specific cut-off at one month after the third HPV injection
    End point type
    Secondary
    End point timeframe
    1 month after third HPV vaccination
    End point values
    		 MenACWY+Tdap+HPV HPV Alone
    Number of subjects analysed
    364
    744
    Units: Percentages of subjects
    number (confidence interval 95%)
        HPV 6 (N=361, 737)
    99 (98 to 100)
    100 (99 to 100)
        HPV 11 (N=362, 744)
    100 (99 to 100)
    100 (99 to 100)
        HPV 16 (N=360, 744)
    100 (99 to 100)
    100 (99 to 100)
        HPV 18 (N=364, 743)
    100 (98 to 100)
    99 (99 to 100)
    No statistical analyses for this end point

    Secondary: 6. Anti-HPV Geometric Mean Titers (GMTs)

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    End point title
    		 6. Anti-HPV Geometric Mean Titers (GMTs)
    End point description
    To compare the immune response of HPV vaccine given concomitantly with MenACWY and Tdap to the response when HPV vaccine is given alone. (Immune response against HPV types 6, 11, 16, and 18 was measured at one month after the third HPV vaccine vaccination.)
    End point type
    Secondary
    End point timeframe
    1 month after third HPV vaccination
    End point values
    		 MenACWY+Tdap+HPV HPV Alone
    Number of subjects analysed
    364
    745
    Units: Titers
    geometric mean (confidence interval 95%)
        HPV 6 (N=361, 737)
    1059 (926 to 1212)
    1461 (1327 to 1608)
        HPV 11 (N=362, 744)
    1264 (1134 to 1408)
    1701 (1575 to 1837)
        HPV 16 (N=360, 744)
    5286 (4705 to 5939)
    6590 (6068 to 7158)
        HPV 18 (N=364, 743)
    908 (798 to 1032)
    1117 (1019 to 1224)
    No statistical analyses for this end point

    Secondary: 7. Percentage of Subjects With hSBA ≥ 1:8 , hSBA titer ≥ 1:4 for A, C, W, and Y Serogroups

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    End point title
    		 7. Percentage of Subjects With hSBA ≥ 1:8 , hSBA titer ≥ 1:4 for A, C, W, and Y Serogroups
    End point description
    The immune responses to MenACWY, as measured by the number of subjects with hSBA titer ≥ 1:8, hSBA titer ≥ 1:4 when given: (a) alone, (b) concomitantly with Tdap and HPV vaccine; and (c) when given one month after Tdap.
    End point type
    Secondary
    End point timeframe
    1 month post MenACWY vaccination
    End point values
    		 Group I Group II Group III
    Number of subjects analysed
    475
    472
    457
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Serogroup A¬ hSBA ≥ 1:8 (N=494,486,458)
    81 (78 to 85)
    82 (79 to 86)
    89 (85 to 91)
        Serogroup C- hSBA ≥ 1:8 (N=494,487,457)
    92 (89 to 94)
    90 (87 to 93)
    93 (90 to 95)
        Serogroup W- hSBA ≥ 1:8 (N=487,474,458)
    98 (96 to 99)
    99 (98 to 100)
    95 (93 to 97)
        Serogroup Y- hSBA ≥ 1:8 (N=493,487,460)
    93 (90 to 95)
    93 (90 to 95)
    92 (90 to 95)
        Serogroup A¬ hSBA ≥ 1:4(N=408,404,412)
    83 (79 to 86)
    83 (79 to 86)
    90 (87 to 93)
        Serogroup C- hSBA ≥ 1:4 (N=456,447,430)
    92 (90 to 94)
    92 (89 to 94)
    94 (92 to 96)
        Serogroup W- hSBA ≥ 1:4(N=478,471,443)
    98 (97 to 99)
    99 (98 to 100)
    97 (95 to 98)
        Serogroup Y - hSBA ≥ 1:4 (N=465,456,438)
    94 (92 to 96)
    94 (91 to 96)
    95 (93 to 97)
    No statistical analyses for this end point

    Secondary: 8. The Effect of Sequential Vaccination on Immunogenicity for Diphtheria and Tetanus

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    End point title
    		 8. The Effect of Sequential Vaccination on Immunogenicity for Diphtheria and Tetanus [16]
    End point description
    To demonstrate that immune response to the Tdap vaccine, as measured by the percentages of subjects with antidiphtheria and antitetanus toxin ≥1.0 IU/mL.
    End point type
    Secondary
    End point timeframe
    1 month post Tdap 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: No statistical analysis is associated to this endpoint.
    End point values
    		 Group II Group III
    Number of subjects analysed
    458
    487
    Units: Percentages of subjects
    number (confidence interval 95%)
        Diphtheria
    100 (99 to 100)
    98 (96 to 99)
        Tetanus
    100 (99 to 100)
    100 (99 to 100)
    No statistical analyses for this end point

    Secondary: 9. Geometric Mean Concentrations (GMC) for Diphtheria and Tetanus

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    End point title
    		 9. Geometric Mean Concentrations (GMC) for Diphtheria and Tetanus [17]
    End point description
    To compare the immune response of Tdap, as measured by the antidiphtheria and antitetanus GMCs, when administered one month after the MenACWY vaccine with the immune response of the Tdap vaccine when administered alone.
    End point type
    Secondary
    End point timeframe
    1 month post Tdap vaccination (Group II at Visit 3 -Day 61 -and Group III at Visit 2 - Day 31)
    Notes
    [17] - 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: No statistical analysis is associated to this endpoint.
    End point values
    		 Group II Group III
    Number of subjects analysed
    458
    487
    Units: Titers
    geometric mean (confidence interval 95%)
        Diphteria
    10 (9.12 to 12)
    10 (9.38 to 11)
        Tetanus
    12 (11 to 13)
    10 (9.46 to 11)
    No statistical analyses for this end point

    Secondary: 11. Percentages of Subjects With at Least a 4-fold Rise for PT, FHA, and PRN

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    End point title
    		 11. Percentages of Subjects With at Least a 4-fold Rise for PT, FHA, and PRN [18]
    End point description
    To compare the immune response of Tdap, defined by the percentage of subjects with a 4-fold rise in antibody titer over baseline against PT, FHA, PRN, when administered one month after the MenACWY with the immune response of Tdap when administered alone.
    End point type
    Secondary
    End point timeframe
    1 month post Tdap vaccination
    Notes
    [18] - 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: No statistical analysis is associated to this endpoint.
    End point values
    		 Group II Group III
    Number of subjects analysed
    458
    487
    Units: Percentage Subjects
    number (confidence interval 95%)
        Anti-PT (N=479, 451,477)
    89 (86 to 92)
    86 (83 to 89)
        Anti-FHA (N=489, 457,485)
    90 (87 to 93)
    78 (74 to 82)
        Anti-PRN (N=492, 458,487)
    95 (92 to 97)
    89 (85 to 91)
    No statistical analyses for this end point

    Secondary: 12. Number of Subjects With at Least One Reactogenicity Sign After MenACWY and Tdap Vaccination

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    End point title
    		 12. Number of Subjects With at Least One Reactogenicity Sign After MenACWY and Tdap Vaccination
    End point description
    Number of subjects with specified local and systemic reactions were assessed after MenACWY and Tdap vaccinations
    End point type
    Secondary
    End point timeframe
    Days 1 to 7 after MenACWY or Tdap vaccination
    End point values
    		 Group I Group II Group III
    Number of subjects analysed
    540
    541
    539
    Units: Subjects
        Injection site pain MenACWY
    263
    246
    239
        Injection site pain Tdap
    367
    310
    383
        Injection site erythema MenACWY
    68
    66
    64
        Injection site erythema Tdap
    78
    38
    70
        Injection site induration MenACWY
    68
    70
    63
        Injection site induration Tdap
    90
    64
    110
        Chills postvaccination 1
    77
    66
    70
        Chills postvaccination 2
    0
    42
    45
        Nausea postvaccination 1
    88
    72
    82
        Nausea postvaccination 2
    0
    42
    64
        Malaise postvaccination 1
    133
    110
    115
        Malaise postvaccination 2
    0
    91
    88
        Myalgia postvaccination 1
    146
    104
    142
        Myalgia postvaccination 2
    0
    81
    82
        Arthralgia postvaccination 1
    94
    62
    76
        Arthralgia postvaccination 2
    0
    52
    52
        Headache postvaccination 1
    217
    194
    200
        Headache postvaccination 2
    0
    125
    138
        Rash postvaccination 1
    21
    17
    20
        Rash postvaccination 2
    0
    15
    13
        Fever ≥ 38°Celsius postvaccination 1
    27
    19
    17
        Fever ≥ 38°Celsius postvaccination 2
    0
    25
    30
        Analgesic/Antipyretic Med. Used postvac 1
    110
    83
    96
        Analgesic/Antipyretic Med. Used postvac 2
    0
    58
    49
    No statistical analyses for this end point

    Secondary: 13. Number of Subjects With at Least One Reactogenicity Sign After Each HPV Vaccination

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    End point title
    		 13. Number of Subjects With at Least One Reactogenicity Sign After Each HPV Vaccination
    End point description
    Number of subjects with specified local and systemic reactions was solicited for 7 days after the HPV vaccination.
    End point type
    Secondary
    End point timeframe
    Days 1 to 7
    End point values
    		 Group I Group II Group III
    Number of subjects analysed
    540
    494
    486
    Units: Subjects
        Injection site pain postvaccination 1
    265
    180
    204
        Injection site erythema postvaccination 1
    74
    36
    42
        Injection site induration postvaccination 1
    54
    27
    26
        Injection site pain postvac 2 (N=498, 483, 468)
    208
    208
    189
        Injection site erythema postvaccination 2
    62
    48
    57
        Injection site induration postvaccination 2
    46
    37
    50
        Injection site pain postvaccination 3
    229
    227
    208
        Injection site erythema postvaccination 3
    60
    56
    55
        Injection site induration postvaccination 3
    60
    47
    48
        Chills postvaccination 1
    77
    27
    30
        Nausea postvaccination 1
    88
    39
    32
        Malaise postvaccination 1
    133
    49
    55
        Myalgia postvaccination 1
    146
    32
    56
        Arthralgia postvaccination 1
    94
    33
    28
        Headache postvaccination 1
    217
    93
    97
        Rash postvaccination 1
    21
    7
    6
        Fever (≥ 38°C) postvaccination 1
    27
    17
    20
        Stayed home postvaccination 1
    110
    26
    34
        Chills postvaccination 2
    23
    22
    26
        Nausea postvaccination 2
    38
    30
    29
        Malaise postvaccination 2
    53
    45
    34
        Myalgia postvaccination 2
    42
    38
    51
        Arthralgia postvaccination 2
    30
    28
    21
        Headache postvaccination 2
    88
    78
    71
        Rash postvaccination 2
    4
    11
    9
        Fever (≥ 38°C) postvaccination 2
    21
    22
    16
        Chills postvaccination 3
    22
    24
    25
        Nausea postvaccination 3
    32
    35
    34
        Malaise postvaccination 3
    49
    50
    41
        Myalgia postvaccination 3
    53
    49
    37
        Arthralgia postvaccination 3
    37
    26
    30
        Headache postvaccination 3
    79
    85
    79
        Rash postvaccination 3
    9
    7
    10
        Fever (≥ 38°C) postvaccination 3
    23
    22
    25
    No statistical analyses for this end point

    Secondary: 10. Geometric Mean Titers (GMTs) of Pertussis Antigens

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    End point title
    		 10. Geometric Mean Titers (GMTs) of Pertussis Antigens [19]
    End point description
    To compare the immune response to Tdap administered one month after MenACWY vaccine with the immune response of the Tdap administered alone.
    End point type
    Secondary
    End point timeframe
    1 month post Tdap vaccination (Group II at Visit 3 - Day 61 - and Group III at Visit 2 - Day 31).
    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: No statistical analysis is associated to this endpoint.
    End point values
    		 Group II Group III
    Number of subjects analysed
    458
    487
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-PT (N=451,477)
    79 (72 to 87)
    63 (58 to 69)
        Anti-FHA (N=457,485)
    1106 (989 to 1238)
    498 (446 to 556)
        Anti-PRN (N=458,487)
    1563 (1390 to 1758)
    1180 (1052 to 1323)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period
    Adverse event reporting additional description
    Data provided in Other Adverse Events (>5%) were collected throughout the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Group I
    Reporting group description
    		 The MenACWY vaccine was administered concomitantly with the Tdap vaccine and the HPV vaccine at study month 0 followed by two injections of the HPV vaccine at months 2 and 6.

    Reporting group title
    Group II
    Reporting group description
    		 The MenACWY vaccine was administered at study month 0 followed by one injection of the Tdap vaccine at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.

    Reporting group title
    Group III
    Reporting group description
    		 Tdap vaccine was administered at month 0 followed by one injection of MenACWY at month 1, followed by three injections of the HPV vaccine at months 2, 4, and 8.

    Serious adverse events
    		 Group I Group II Group III
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 540 (0.19%)
    7 / 541 (1.29%)
    3 / 539 (0.56%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour benign
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 541 (0.00%)
    0 / 539 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 540 (0.00%)
    0 / 541 (0.00%)
    1 / 539 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Behcet's Syndrome
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 541 (0.18%)
    0 / 539 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 541 (0.18%)
    1 / 539 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Bezoar
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 541 (0.18%)
    0 / 539 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Haemorrhagic Ovarian Cyst
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 541 (0.18%)
    0 / 539 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Testicular Torsion
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 541 (0.18%)
    0 / 539 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 540 (0.00%)
    0 / 541 (0.00%)
    1 / 539 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Cushing's Syndrome
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 541 (0.00%)
    0 / 539 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 540 (0.00%)
    2 / 541 (0.37%)
    0 / 539 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group I Group II Group III
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    481 / 540 (89.07%)
    449 / 541 (82.99%)
    467 / 539 (86.64%)
    Nervous system disorders
    headache
         subjects affected / exposed
    260 / 540 (48.15%)
    284 / 541 (52.50%)
    278 / 539 (51.58%)
         occurrences all number
    519
    749
    804
    General disorders and administration site conditions
    injection site pain (MenACWY)
         subjects affected / exposed
    264 / 540 (48.89%)
    246 / 541 (45.47%)
    239 / 539 (44.34%)
         occurrences all number
    307
    289
    266
    injection site erythema (MenACWY)
         subjects affected / exposed
    69 / 540 (12.78%)
    66 / 541 (12.20%)
    65 / 539 (12.06%)
         occurrences all number
    80
    68
    71
    injection site induration(MenACWY)
         subjects affected / exposed
    68 / 540 (12.59%)
    70 / 541 (12.94%)
    65 / 539 (12.06%)
         occurrences all number
    76
    72
    68
    injection site erythema (Tdap)
         subjects affected / exposed
    78 / 540 (14.44%)
    38 / 541 (7.02%)
    72 / 539 (13.36%)
         occurrences all number
    93
    40
    82
    injection site induration (Tdap)
         subjects affected / exposed
    90 / 540 (16.67%)
    64 / 541 (11.83%)
    110 / 539 (20.41%)
         occurrences all number
    101
    67
    125
    injection site pain (HPV)
         subjects affected / exposed
    387 / 540 (71.67%)
    320 / 541 (59.15%)
    313 / 539 (58.07%)
         occurrences all number
    778
    666
    648
    injection site induration (HPV)
         subjects affected / exposed
    119 / 540 (22.04%)
    81 / 541 (14.97%)
    84 / 539 (15.58%)
         occurrences all number
    178
    115
    134
    injection site erythema (HPV)
         subjects affected / exposed
    134 / 540 (24.81%)
    105 / 541 (19.41%)
    101 / 539 (18.74%)
         occurrences all number
    212
    147
    166
    injection site pain (Tdap)
         subjects affected / exposed
    367 / 540 (67.96%)
    310 / 541 (57.30%)
    383 / 539 (71.06%)
         occurrences all number
    410
    351
    428
    malaise
         subjects affected / exposed
    171 / 540 (31.67%)
    209 / 541 (38.63%)
    194 / 539 (35.99%)
         occurrences all number
    284
    402
    428
    Pyrexia
         subjects affected / exposed
    62 / 540 (11.48%)
    87 / 541 (16.08%)
    83 / 539 (15.40%)
         occurrences all number
    77
    129
    123
    chills
         subjects affected / exposed
    100 / 540 (18.52%)
    117 / 541 (21.63%)
    130 / 539 (24.12%)
         occurrences all number
    131
    201
    238
    Gastrointestinal disorders
    nausea
         subjects affected / exposed
    124 / 540 (22.96%)
    133 / 541 (24.58%)
    142 / 539 (26.35%)
         occurrences all number
    191
    255
    289
    Skin and subcutaneous tissue disorders
    rash
         subjects affected / exposed
    31 / 540 (5.74%)
    47 / 541 (8.69%)
    42 / 539 (7.79%)
         occurrences all number
    36
    64
    66
    Musculoskeletal and connective tissue disorders
    myalgia
         subjects affected / exposed
    178 / 540 (32.96%)
    187 / 541 (34.57%)
    200 / 539 (37.11%)
         occurrences all number
    276
    339
    440
    arthralgia
         subjects affected / exposed
    119 / 540 (22.04%)
    131 / 541 (24.21%)
    131 / 539 (24.30%)
         occurrences all number
    188
    225
    248

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Oct 2007
    Amendment 1, dated 15 Oct 2007,changed the number of subjects to be enrolled from 1500 to 1620.
    11 Mar 2008
    Amendment 2, dated 11 Mar 2008 (prior to interim database lock), included a change in the study objectives (i.e., to demonstrate that the immune response to MenACWY administered alone one month after Tdap is not inferior to the immune response of MenACWY administered alone one month prior to Tdap was elevated from a secondary to become the third co-primary objective) and the adding of a new laboratory for Tdap testing.

    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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