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    Clinical Trial Results:
    A Phase IV, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of 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 when Administered with MenACWY Conjugate Vaccine

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2011-000476-34
    Trial protocol
    		 IT  
    Global end of trial date
    20 Dec 2012

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Jun 2016
    First version publication date
    12 Apr 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    re-QC if the study needed because of EudraCT system glitch and updates are required.

    Trial information

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    Trial identification
    Sponsor protocol code
    V59_40
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01424644
    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
    CR&D Southern Europe, Novartis Vaccines and Diagnostic, +39 0577 249226, noemi.giglioli@novartis.com
    Scientific contact
    CR&D Southern Europe, Novartis Vaccines and Diagnostic, +39 0577 249226, noemi.giglioli@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Immunogenicity Objectives: Co-primary 1. To demonstrate that the immune response of Tdap given concomitantly with MenACWY-CRM and HPV vaccine is non inferior to the response of Tdap vaccine when given with placebo and HPV when measured at 1 month after 1 dose of Tdap. 2. To demonstrate that the immune response of HPV vaccine given concomitantly with MenACWY and Tdap is non-inferior to the response when HPV is given with placebo and Tdap when measured at 1 month after the third dose of HPV vaccination. Safety objectives: - To describe the safety profile of Tdap + HPV + MenACWY versus Tdap + HPV + placebo
    Protection of trial subjects
    This clinical study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US Code of Federal Regulations Title 21, Novartis codes on the protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2011
    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: 554
    Country: Number of subjects enrolled
    Italy: 247
    Worldwide total number of subjects
    801
    EEA total number of subjects
    247
    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)
    498
    Adolescents (12-17 years)
    284
    Adults (18-64 years)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled from 20 centers located in Italy and USA.

    Pre-assignment
    Screening details
    		 All subjects enrolled were included in the trial.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MenACWY-CRM+Tdap+HPV
    Arm description
    		 Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Meningococcal (groups A, C, W, and Y) oligosaccharide diphtheria CRM-197 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
    After reconstitution, one dose (0.5 ml) of MenACWY injectable solution was administered by IM.

    Investigational medicinal product name
    Tdap vaccine
    Investigational medicinal product code
    Other name
    (GSK Boostrix vaccine)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 ml) of Tdap was administered by IM.

    Investigational medicinal product name
    HPV vaccine
    Investigational medicinal product code
    Other name
    (Merck & Co. Gardasil vaccine)
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 ml) of HPV was administered by IM on day 1, month 2 and 6 months after the first dose.

    Arm title
    		 Placebo+Tdap+HPV
    Arm description
    		 Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.
    Arm type
    		 Placebo Comparator

    Investigational medicinal product name
    Tdap vaccine
    Investigational medicinal product code
    Other name
    (GSK Boostrix vaccine)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 ml) of Tdap was administered by IM.

    Investigational medicinal product name
    HPV vaccine
    Investigational medicinal product code
    Other name
    (Merck & Co. Gardasil vaccine)
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 ml) of HPV was administered by IM on day 1, month 2 and 6 months after the first dose.

    Investigational medicinal product name
    Placebo (NaCl 0.9%)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One 0.5 ml dose of saline placebo was administered by IM injection.

    Number of subjects in period 1
    		MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Started
    402
    399
    Completed
    369
    372
    Not completed
    33
    27
         Consent withdrawn by subject
    9
    12
         Adverse Event
    2
    -
         Administrative Reason
    1
    -
         Lost to follow-up
    16
    12
         Unable to Classify
    1
    -
         Protocol deviation
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MenACWY-CRM+Tdap+HPV
    Reporting group description
    		 Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.

    Reporting group title
    Placebo+Tdap+HPV
    Reporting group description
    		 Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.

    Reporting group values
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV Total
    Number of subjects
    		 402 399 801
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.9 ( 1.7 ) 11.8 ( 1.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 169 155 324
        Male
    		 233 244 477

    End points

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    End points reporting groups
    Reporting group title
    MenACWY-CRM+Tdap+HPV
    Reporting group description
    		 Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.

    Reporting group title
    Placebo+Tdap+HPV
    Reporting group description
    		 Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.

    Subject analysis set title
    All Enrolled Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The enrolled population contained all subjects enrolled and randomized in the study, ie, all subjects who had data in panel DEMOG. These were subjects who signed informed consent, were enrolled into the study and were randomized. This population was used for the analysis of demographics and all subject listings.

    Subject analysis set title
    Exposed Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the enrolled population who received a study vaccination.

    Subject analysis set title
    MITT Population -Tdap
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The MITT population included all subjects in the enrolled population who received all the relevant doses of vaccine, and provided at least 1 evaluable serum sample after baseline. For purposes of analysis of this population, subjects were to be included in the group they were assigned to during randomization.

    Subject analysis set title
    MITT Population- MenACWY
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The MITT population included all subjects in the enrolled population who received all the relevant doses of vaccine, and provided at least 1 evaluable serum sample after baseline. For purposes of analysis of this population, subjects were to be included in the group they were assigned to during randomization.

    Subject analysis set title
    Per Protocol (PP) Population - Tdap
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included all subjects in the MITT immunogenicity population who: ▫ correctly received all the relevant doses of vaccine; ▫ provided evaluable serum samples at the relevant time points; and ▫ had no major protocol deviation as defined prior to study unblinding.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who had received at least 1 study vaccine and had postbaseline safety data were included in the safety analysis.

    Subject analysis set title
    Per Protocol (PP) Population- MenACWY
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population included all subjects in the MITT immunogenicity population who: ▫ correctly received all the relevant doses of vaccine; ▫ provided evaluable serum samples at the relevant time points; and ▫ had no major protocol deviation as defined prior to study unblinding.

    Primary: 1. Percentages of Subjects With Anti-diphtheria and Anti-tetanus Antibody Concentrations ≥ 1.0 IU/mL When Tdap is Administered Concomitantly With HPV and MenACWY-CRM Vaccine Compared to Tdap Given Concomitantly With HPV and Placebo

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    End point title
    		 1. Percentages of Subjects With Anti-diphtheria and Anti-tetanus Antibody Concentrations ≥ 1.0 IU/mL When Tdap is Administered Concomitantly With HPV and MenACWY-CRM Vaccine Compared to Tdap Given Concomitantly With HPV and Placebo
    End point description
    The percentages of subjects with anti-diphtheria and anti-tetanus antibody concentrations ≥ 1.0 IU/mL (as measured by ELISA) following concomitant administration of Tdap with HPV and MenACWY-CRM vaccine as compared to concomitant administration of Tdap with HPV and placebo. Analysis was done on the Tdap per protocol population, i.e., all subjects who received all the relevant doses of vaccine correctly, and provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to unblinding.
    End point type
    Primary
    End point timeframe
    1 month post Tdap vaccination
    End point values
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Number of subjects analysed
    376
    382
    Units: percentages of subjects
    number (confidence interval 95%)
        Day 1 (diphtheria) (N=375, 380)
    5 (3 to 8)
    3 (2 to 5)
        One month post dose (diphtheria)
    95 (93 to 97)
    82 (78 to 86)
        Day 1 (tetanus ) (N=375, 380)
    28 (24 to 33)
    28 (23 to 32)
        One month post dose (tetanus)
    99 (97 to 100)
    98 (97 to 99)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Non-inferiority of anti-diphtheria immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo
    Comparison groups
    MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Vaccine group difference
    Point estimate
    13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9
         upper limit
    		 17
    Notes
    [1] - The immune response to diphtheria toxin for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of the Placebo+Tdap+HPV group if the lower limit of the two-sided 95% CI of the difference in seroprotection rates [(MenACWYCRM+ Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than -10%, at 1 month after Tdap vaccination
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Non-inferiority of anti-tetanus immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
    Comparison groups
    MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Vaccine group difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 2
    Notes
    [2] - The immune response to tetanus toxin for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of Placebo+Tdap+HPV group if the lower limit of the two-sided 95% CI of the difference in seroprotection rates [(MenACWY-CRM+ Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than -10%, at 1 month after Tdap vaccination.

    Primary: 2. Geometric Mean Concentrations of Antibodies Against Pertussis Antigens After Concomitant Administration of Tdap With HPV and MenACWY-CRM Compared to Concomitant Administration of Tdap With HPV and Placebo

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    End point title
    		 2. Geometric Mean Concentrations of Antibodies Against Pertussis Antigens After Concomitant Administration of Tdap With HPV and MenACWY-CRM Compared to Concomitant Administration of Tdap With HPV and Placebo
    End point description
    The geometric mean concentrations (GMCs) of antibodies against pertussis antigens (Pertussis Toxin (PT), Filamentous Hemagglutinin (FHA) and Pertactin (PRN), as measured by ELISA, following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo. Analysis was done on the Tdap per protocol population, i.e., all subjects who received all the relevant doses of vaccine correctly, and provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to unblinding.
    End point type
    Primary
    End point timeframe
    1 month post Tdap vaccination
    End point values
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Number of subjects analysed
    376
    382
    Units: Concentration of antibodies
    geometric mean (confidence interval 95%)
        PT (Day 1) (N= 375, 380)
    4.77 (4.11 to 5.53)
    4.16 (3.59 to 4.82)
        PT (One month post dose)
    44 (40 to 48)
    44 (40 to 48)
        FHA (Day 1) (N= 375, 380)
    24 (21 to 27)
    21 (18 to 23)
        FHA (One month post dose)
    202 (187 to 218)
    240 (222 to 259)
        PRN (Day 1) (N= 375, 380)
    20 (18 to 23)
    21 (18 to 24)
        PRN (One month post dose)
    330 (300 to 363)
    403 (367 to 443)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Non-inferiority of anti-PT immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
    Comparison groups
    MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Vaccine group ratio of GMCs
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.14
    Notes
    [3] - The immune response to PT antigen for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of the Placebo+Tdap+HPV group if the lower limit of the two-sided 95% CI of the ratio of the GMCs of the MenACWY-CRM +Tdap+HPV group to the Placebo+Tdap + HPV group was greater than 0.5, at 1 month after Tdap vaccination.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Non-inferiority of anti-FHA immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
    Comparison groups
    MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Vaccine group ratio of GMCs
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 0.93
    Notes
    [4] - The immune response to FHA antigen for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of Placebo+Tdap+HPV group if the lower limit of the 95% CI of the difference [(MenACWY-CRM +Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than 0.5, at 1 month after Tdap vaccination.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Non-inferiority of anti-PRN immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
    Comparison groups
    MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Vaccine group ratio of GMCs
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.93
    Notes
    [5] - The immune response to PRN antigen for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of Placebo+Tdap+HPV group if the lower limit of the 95% CI of the difference [(MenACWY-CRM+Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than 0.5, at 1 month after vaccination.

    Secondary: 3. Geometric Mean of Human Serum Bactericidal Assay (hSBA) Titers Against N. meningitidis when MenACWY-CRM is Concomitantly Administered With Tdap and HPV

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    End point title
    		 3. Geometric Mean of Human Serum Bactericidal Assay (hSBA) Titers Against N. meningitidis when MenACWY-CRM is Concomitantly Administered With Tdap and HPV
    End point description
    The Geometric Mean of hSBA Titers Against N meningitidis Serogroups A, C, W, and Y were determined at 1 Month After MenACWY or Placebo Vaccination.
    End point type
    Secondary
    End point timeframe
    1 month post MenACWY-CRM vaccination or Placebo Vaccination
    End point values
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Number of subjects analysed
    371
    99
    Units: Geometric mean of hSBA titers
    geometric mean (confidence interval 95%)
        Men A
    35 (29 to 42)
    2.13 (1.97 to 2.31)
        Men C (N=370, 97)
    59 (48 to 73)
    3.92 (3.3 to 4.66)
        Men W (N=369, 96)
    61 (53 to 69)
    12 (9.26 to 17)
        Men Y (N=369, 97)
    48 (40 to 58)
    3.54 (2.9 to 4.31)
    No statistical analyses for this end point

    Secondary: 4. Number of Subjects With Solicited Local and Systemic Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo

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    End point title
    		 4. Number of Subjects With Solicited Local and Systemic Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo
    End point description
    The number of subjects reporting solicited local and systemic reactions following concomitant administration of MenACWY-CRM vaccine, Tdap and HPV vaccine as compared to concomitant administration of placebo with Tdap and HPV. Analysis was done on the safety population.
    End point type
    Secondary
    End point timeframe
    Day 1-7 after any vaccination
    End point values
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Number of subjects analysed
    389
    385
    Units: Subjects
        Local
    209
    164
        Injection site pain
    158
    134
        Injection site erythema
    65
    25
        Injection site induration
    61
    37
        Systemic
    205
    179
        Chills
    60
    50
        Nausea
    54
    39
        Malaise
    57
    44
        Myalgia
    115
    101
        Arthralgia
    35
    43
        Headache
    113
    95
        Rash
    4
    7
        Fever ≥ 38°C
    9
    8
        Other
    88
    80
        Stayed home due to reaction
    25
    33
        Analgesic / Antipyretic medication used
    74
    65
    No statistical analyses for this end point

    Secondary: 5. Number of Subjects With Unsolicited Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo

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    End point title
    		 5. Number of Subjects With Unsolicited Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo
    End point description
    The number of subjects reporting any unsolicited adverse reactions (AEs) when Tdap and HPV are concomitantly administered with MenACWY-CRM as compared to when Tdap and HPV vaccine are concomitantly administered with placebo. Note: A total of 2 MenACWY-CRM+Tdap+HPV subjects reported AEs leading to premature withdrawal - one subject due to treatment emergent AEs and another subject prior to study vaccination on day 1. Analysis was done on the safety population.
    End point type
    Secondary
    End point timeframe
    Throughout the study (Day 1 to Day 211)
    End point values
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Number of subjects analysed
    396
    397
    Units: Subjects
        Any AEs
    201
    197
        At least possibly related AEs
    17
    14
        Serious AEs
    4
    3
        AEs leading to Premature Withdrawal
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From day 1 through day 211
    Adverse event reporting additional description
    Serious adverse events (SAEs) were collected from Day 1 through Day 211.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    MenACWY-CRM+Tdap+HPV
    Reporting group description
    		 Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.

    Reporting group title
    Placebo+Tdap+HPV
    Reporting group description
    		 Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose.

    Serious adverse events
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 396 (1.01%)
    3 / 397 (0.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Peritonsillar abscess
         subjects affected / exposed
    0 / 396 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 396 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    289 / 396 (72.98%)
    251 / 397 (63.22%)
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    128 / 396 (32.32%)
    106 / 397 (26.70%)
         occurrences all number
    165
    146
    General disorders and administration site conditions
    Chills
    alternative assessment type: Systematic
         subjects affected / exposed
    66 / 396 (16.67%)
    51 / 397 (12.85%)
         occurrences all number
    78
    62
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    80 / 396 (20.20%)
    30 / 397 (7.56%)
         occurrences all number
    93
    34
    Injection site induration
    alternative assessment type: Systematic
         subjects affected / exposed
    70 / 396 (17.68%)
    43 / 397 (10.83%)
         occurrences all number
    75
    47
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed
    196 / 396 (49.49%)
    167 / 397 (42.07%)
         occurrences all number
    236
    207
    Malaise
    alternative assessment type: Systematic
         subjects affected / exposed
    59 / 396 (14.90%)
    46 / 397 (11.59%)
         occurrences all number
    72
    55
    Gastrointestinal disorders
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    59 / 396 (14.90%)
    43 / 397 (10.83%)
         occurrences all number
    73
    57
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    40 / 396 (10.10%)
    49 / 397 (12.34%)
         occurrences all number
    49
    56
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    118 / 396 (29.80%)
    112 / 397 (28.21%)
         occurrences all number
    136
    125
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    22 / 396 (5.56%)
    21 / 397 (5.29%)
         occurrences all number
    23
    25

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2011
    Amendment No. 1. The amendment included clarifications and revisions primarily related to operational aspects of the protocol.
    19 Jul 2011
    Amendment No. 2. The rationale for the amendment was the requirement to switch from MenACWY prefilled syringe and vial presentation to a vial-vial presentation, as well as to require that all female subjects have a negative urine pregnancy test before enrollment, instead of only female subjects of child bearing potential.
    20 Dec 2012
    Amendment No. 3. The third amendment dated 20 JUN 2013, was due to delays associated with testing of immune response to HPV types at an external laboratory. The protocol was revised to include a stepwise analysis for the 2 coprimary objectives as follows. A final analysis including all safety data and immunogenicity data for the first primary and secondary objectives would be conducted on cleaned data. The results of this analysis would be presented in the clinical study report, including individual listings and unblinded data. The immunogenicity analysis for the second primary objective (assessment of immune response against HPV antigens) would be performed as soon as serological results become available. The HPV results would be presented in an addendum to the clinical study report. This change was communicated to and accepted by regulatory authorities in the US and Italy.

    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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