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    Clinical Trial Results:
    A Phase III, Stratified, Randomized, Double-Blind, Multicenter, Non-Inferiority Study to Evaluate Safety and Immunogenicity of Cell-Based Quadrivalent Subunit Influenza Virus Vaccine and Cell-Based Trivalent Subunit Influenza Virus Vaccines in Subjects Ages >=4 Years to <18 Years.

    Summary
    EudraCT number
    		 2015-000133-70
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    19 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jul 2016
    First version publication date
    01 Mar 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V130_03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01992107
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics, Inc
    Sponsor organisation address
    350 Massachusetts Ave, Cambridge, MA, United States, 02139
    Public contact
    Posting Director, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@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
    19 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Immunogenicity Objective • To demonstrate noninferiority of antibody responses of Quadrivalent Subunit Influenza Virus Vaccine (QIVc) to comparator Trivalent Subunit Influenza Virus Vaccine (TIVc ) in subjects >=4 to <18 years of age , as assessed by the ratio of geometric mean titer (GMT) for each of the 4 vaccine strains separately after vaccination. • To demonstrate noninferiority of antibody responses of QIVc to comparator TIVc after vaccination in subjects >=4 to <18 years of age, as assessed by differences in seroconversion rates for each of the 4 vaccine strains separately after vaccination. The study was considered a success -as both co-primary immunogenicity objectives were achieved.
    Protection of trial subjects
    This trial was performed with the ethical principles that have their origin in the Declaration of Helsinki, that are consistent with Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines, the applicable regulatory requirements(s) for the country in which the study is conducted, and applicable standard operating procedures (SOPs
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Regulatory reason
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 2333
    Worldwide total number of subjects
    2333
    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)
    1588
    Adolescents (12-17 years)
    745
    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
    		 Subjects were recruited from 90 centers in the United States (US)

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QIVc (≥4 to <18 years)
    Arm description
    		 Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Influenza Virus Vaccine (cell-derived seasonal quadrivalent) [2013/2014] thimerosal free)
    Investigational medicinal product code
    V130
    Other name
    QIVc (quadrivalent influenza vaccine)
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL

    Arm title
    		 TIV1c (≥4 to <18 years)
    Arm description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Influenza Virus Vaccine (cell-derived seasonal Trivalent) [2013/2014] thimerosal free)
    Investigational medicinal product code
    TIV1c
    Other name
    TIV1c (trivalent influenza vaccine)
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL

    Arm title
    		 TIV2c (≥4 to <18 years)
    Arm description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Influenza Virus Vaccine (cell-derived seasonal trivalent) [2013/2014] thimerosal free)
    Investigational medicinal product code
    TIV2c
    Other name
    TIV2c (trivalent influenza vaccine)
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL

    Number of subjects in period 1
    		QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Started
    1159
    593
    581
    Completed
    1091
    560
    545
    Not completed
    68
    33
    36
         Consent withdrawn by subject
    13
    7
    8
         Adverse event, non-fatal
    -
    1
    -
         Other
    7
    3
    2
         Administrative reasons
    2
    -
    -
         Lost to follow-up
    46
    22
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QIVc (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Reporting group title
    TIV1c (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season

    Reporting group title
    TIV2c (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Reporting group values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years) Total
    Number of subjects
    		 1159 593 581 2333
    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)
    		 9.5 ( 3.8 ) 9.5 ( 3.8 ) 9.3 ( 3.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 556 284 284 1124
        Male
    		 603 309 297 1209

    End points

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    End points reporting groups
    Reporting group title
    QIVc (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Reporting group title
    TIV1c (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season

    Reporting group title
    TIV2c (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Subject analysis set title
    TIV1c_First Vaccine (≥4 to <6 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season

    Subject analysis set title
    QIVc _First Vaccine (≥4 to <6 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Subject analysis set title
    TIV2c _First Vaccine (≥4 to <6 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Subject analysis set title
    QIVc _Second Vaccine (≥4 to <6 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Subject analysis set title
    TIV1c_Second Vaccine (≥4 to <6 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season

    Subject analysis set title
    TIV2c _Second Vaccine (≥4 to <6 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Subject analysis set title
    QIVc _First Vaccine (≥6 to <9 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Subject analysis set title
    TIV1c_First Vaccine (≥6 to <9 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2,B1) recommended for 2013-2014 season

    Subject analysis set title
    TIV1c_Second Vaccine (≥6 to <9 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season

    Subject analysis set title
    QIVc _Second Vaccine (≥6 to <9 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Subject analysis set title
    TIV2c _First Vaccine (≥6 to <9 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Subject analysis set title
    TIV1c (≥9 to <18 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season

    Subject analysis set title
    QIVc (≥9 to <18 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Subject analysis set title
    TIV2c _Second Vaccine (≥6 to <9 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Subject analysis set title
    TIV2c (≥9 to <18 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Primary: 1.Geometric Mean Titre (GMT) in subjects after receiving one or two doses of either QIVc, TIV1c or TIV2c

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    End point title
    		 1.Geometric Mean Titre (GMT) in subjects after receiving one or two doses of either QIVc, TIV1c or TIV2c
    End point description
    Immunogenicity of QIVc to comparator TIVc (For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c) was assessed in terms of ratios of GMT in subjects (Previously vaccinated and Not previously vaccinated) measured by hemagglutination inhibition (HI) assay, three weeks after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c
    End point type
    Primary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Titers
    geometric mean (confidence interval 95%)
        H1N1: Day 1 (N=1014, 510)
    96 (86 to 107)
    100 (86 to 116)
    0 (0 to 0)
        H1N1: Day 22/Day 50 (N=1014, 510)
    1090 (1027 to 1157)
    1125 (1034 to 1224)
    0 (0 to 0)
        H3N2: Day 1 (N=1013, 510)
    206 (188 to 225)
    196 (172 to 222)
    0 (0 to 0)
        H3N2: Day 22/Day 50 (N=1013, 510)
    738 (703 to 774)
    776 (725 to 831)
    0 (0 to 0)
        B1: Day 1 (N=1013, 510)
    26 (24 to 28)
    23 (21 to 26)
    0 (0 to 0)
        B1: Day 22/Day 50 (N=1013, 510)
    155 (146 to 165)
    154 (141 to 168)
    0 (0 to 0)
        B2: Day 1(N=1009, 501)
    23 (21 to 25)
    0 (0 to 0)
    23 (21 to 26)
        B2: Day 22/Day 50 (N=1013, 501)
    185 (171 to 200)
    0 (0 to 0)
    185 (166 to 207)
    Statistical analysis title
    		 1.Non-inferiority testing geometric mean titer
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c, assessed in terms of ratios of GMT against influenza strain H1N1
    Comparison groups
    QIVc (≥4 to <18 years) v TIV1c (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 ANCOVA
    Parameter type
    		 Ratios of GMT (Day 22/Day 50)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.14
    Variability estimate
    Standard deviation
    Notes
    [1] - Non-inferiority was established if the upper bound of the two-sided 95% confidence interval (CI) for the ratio of GMTs (GMT TIV1c/GMT QIVc) for HI antibody does not exceed the non-inferiority margin of 1.5
    Statistical analysis title
    		 2. Non-inferiority testing geometric mean titer
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c, assessed in terms of ratios of GMT against influenza strain H3N2
    Comparison groups
    QIVc (≥4 to <18 years) v TIV1c (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 ANCOVA
    Parameter type
    		 Ratios of GMT (Day 22/Day 50)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.14
    Variability estimate
    Standard deviation
    Notes
    [2] - Non-inferiority was established if the upper bound of the two-sided 95% confidence interval (CI) for the ratio of GMTs (GMT TIV1c/GMT QIVc) for HI antibody does not exceed the non-inferiority margin of 1.5
    Statistical analysis title
    		 3.Non-inferiority testing geometric mean Titer
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c, assessed in terms of ratios of GMT against influenza strain B1
    Comparison groups
    QIVc (≥4 to <18 years) v TIV1c (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    		 ANCOVA
    Parameter type
    		 Ratios of GMT (Day 22/Day 50)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.1
    Variability estimate
    Standard deviation
    Notes
    [3] - Non-inferiority was established if the upper bound of the two-sided 95% confidence interval (CI) for the ratio of GMTs (GMT TIV1c/GMT QIVc) for HI antibody does not exceed the non-inferiority margin of 1.5
    Statistical analysis title
    		 4. Non-inferiority testing geometric mean Titer
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c, assessed in terms of ratios of GMT against influenza strain B2
    Comparison groups
    QIVc (≥4 to <18 years) v TIV2c (≥4 to <18 years)
    Number of subjects included in analysis
    1740
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    		 ANCOVA
    Parameter type
    		 Ratios of GMT (Day 22/Day 50)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.14
    Variability estimate
    Standard deviation
    Notes
    [4] - Non-inferiority was established if the upper bound of the two-sided 95% confidence interval (CI) for the ratio of GMTs (GMT TIV1c/GMT QIVc) for HI antibody does not exceed the non-inferiority margin of 1.5

    Primary: 2.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc, TIV1c or TIV2c

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    End point title
    		 2.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc, TIV1c or TIV2c
    End point description
    Immunogenicity of QIVc to comparator TIVc (For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c) was assessed in terms of number (%) of subjects (Previously vaccinated and Not previously vaccinated) showing seroconversion or significant increase in HI antibody titers, three weeks after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c Seroconversion is defined in subjects seronegative at baseline (i.e., HI titer <1:10 at Day 1) as postvaccination HI titer ≥1:40, and defined in subjects seropositive at baseline (i.e., HI titer ≥1:10 at Day 1) as a minimum of a 4-fold increase in post-vaccination HI titer.
    End point type
    Primary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Percentages of Subjects
    number (confidence interval 95%)
        H1N1: Day 22/Day 50 (N=1014,510)
    72 (69 to 75)
    75 (70 to 78)
    0 (0 to 0)
        H3N2: Day 22/Day 50 (N=1013, 510)
    47 (44 to 50)
    51 (46 to 55)
    0 (0 to 0)
        B1: Day 22/Day 50 (N=1013,510)
    66 (63 to 69)
    66 (62 to 70)
    0 (0 to 0)
        B2: Day 22/Day 50 (N=1009,501)
    73 (70 to 76)
    0 (0 to 0)
    71 (67 to 75)
    Statistical analysis title
    		 1.Non-inferiority testing SC rates of QIVc to TIVc
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c in terms of differences in seroconversion rates against influenza strain H1N1
    Comparison groups
    TIV1c (≥4 to <18 years) v QIVc (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    		 ANCOVA
    Parameter type
    		 Difference b/w SC rates (Day 22/Day 50)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 6.9
    Variability estimate
    Standard deviation
    Notes
    [5] - Non-inferiority was established if the upper bound of the two-sided 95% CI for the difference between seroconversion rates (% seroconversion TIV1c – % seroconversion QIVc) for HI antibody does not exceed the margin of 10%
    Statistical analysis title
    		 2.Non-inferiority testing SC rates of QIVc to TIVc
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c in terms of differences in seroconversion rates against influenza strain H3N2
    Comparison groups
    QIVc (≥4 to <18 years) v TIV1c (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    		 ANCOVA
    Parameter type
    		 Difference b/w SC rates (Day 22/Day 50)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 9.2
    Variability estimate
    Standard deviation
    Notes
    [6] - Non-inferiority was established if the upper bound of the two-sided 95% CI for the difference between seroconversion rates (% seroconversion TIV1c – % seroconversion QIVc) for HI antibody does not exceed the margin of 10%
    Statistical analysis title
    		 3.Non-inferiority testing SC rates of QIVc to TIVc
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c in terms of differences in seroconversion rates against influenza strain B1
    Comparison groups
    QIVc (≥4 to <18 years) v TIV1c (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    		 ANCOVA
    Parameter type
    		 Difference b/w SC rates (Day 22/Day 50)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 4.5
    Variability estimate
    Standard deviation
    Notes
    [7] - Non-inferiority was established if the upper bound of the two-sided 95% CI for the difference between seroconversion rates (% seroconversion TIV1c – % seroconversion QIVc) for HI antibody does not exceed the margin of 10%
    Statistical analysis title
    		 4.Non-inferiority testing SC rates of QIVc to TIVc
    Statistical analysis description
    Non-inferiority of immune responses of QIVc to TIV1c in terms of differences in seroconversion rates against influenza strain B2
    Comparison groups
    QIVc (≥4 to <18 years) v TIV2c (≥4 to <18 years)
    Number of subjects included in analysis
    1740
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    		 ANCOVA
    Parameter type
    		 Difference b/w SC rates (Day 22/Day 50)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 3.2
    Variability estimate
    Standard deviation
    Notes
    [8] - Non-inferiority was established if the upper bound of the two-sided 95% CI for the difference between seroconversion rates (% seroconversion TIV1c – % seroconversion QIVc) for HI antibody does not exceed the margin of 10%

    Secondary: 3.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc, TIV1c or TIV2 c in ≥4 to <18 years

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    End point title
    		 3.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc, TIV1c or TIV2 c in ≥4 to <18 years
    End point description
    Immunogenicity was assessed in terms of number (%) of subjects (Previously vaccinated and Not previously vaccinated) showing seroconversion or significant increase in HI antibody titers, three weeks after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c Seroconversion is defined in subjects seronegative at baseline (i.e., HI titer <1:10 at Day 1) as post-vaccination HI titer ≥1:40, and defined in subjects seropositive at baseline (i.e., HI titer ≥1:10 at Day 1) as a minimum of a 4-fold increase in post-vaccination HI titer. The Center for Biologics Evaluation, Research, and Review (CBER) criterion for an adult population is that the lower bound of the two-sided 95% CI for the percentage of subjects achieving seroconversion for HI antibody should meet or exceed 40%
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Percentages of Subjects
    number (confidence interval 95%)
        H1N1: Day 22 or Day 50 (N=1113,566)
    73 (70 to 76)
    74 (70 to 77)
    0 (0 to 0)
        H3N2: Day 22 or Day 50 (N=1112,566)
    47 (44 to 50)
    51 (47 to 55)
    0 (0 to 0)
        B1: Day 22 or Day 50 (N=1112,566)
    67 (64 to 70)
    66 (61 to 69)
    0 (0 to 0)
        B2: Day 22 or Day 50 (N=1108,566)
    73 (70 to 76)
    0 (0 to 0)
    72 (68 to 76)
    No statistical analyses for this end point

    Secondary: 4.Number (%) of subjects achieving HI titer ≥1:40 after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years

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    End point title
    		 4.Number (%) of subjects achieving HI titer ≥1:40 after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years
    End point description
    Immunogenicity was assessed in terms of number (%) of subjects (Previously vaccinated and Not previously vaccinated) showing HI titer ≥1:40, three weeks after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c The CBER criterion for adult population is that the lower bound of the two-sided 95% CI for the percentage of subjects achieving an HI antibody titer ≥1:40 should meet or exceed 70%
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Percentages of Subjects
    number (confidence interval 95%)
        H1N1: Day 1(N=1113,566)
    76 (73 to 78)
    79 (75 to 82)
    0 (0 to 0)
        H1N1: Day 22 or Day 50(N=1113,566)
    99 (98 to 100)
    99 (98 to 100)
    0 (0 to 0)
        H3N2: Day 1(N=1112,566)
    90 (88 to 91)
    89 (86 to 92)
    0 (0 to 0)
        H3N2: Day 22 or Day 50(N=1112,566)
    100 (99 to 100)
    99 (98 to 100)
    0 (0 to 0)
        B1: Day 1(N=1112,566)
    49 (46 to 52)
    45 (41 to 49)
    0 (0 to 0)
        B1: Day 22 or Day 50(N=1112,566)
    92 (91 to 94)
    93 (90 to 95)
    0 (0 to 0)
        B2: Day 1(N=1108,556)
    46 (43 to 49)
    0 (0 to 0)
    47 (43 to 51)
        B2: Day 22 or Day 50(N=1108,556)
    91 (89 to 93)
    0 (0 to 0)
    91 (88 to 93)
    No statistical analyses for this end point

    Secondary: 5.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years

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    End point title
    		 5.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years
    End point description
    Immunogenicity was assessed in terms of number (%) of subjects (Previously vaccinated and Not previously vaccinated) showing seroconversion or significant increase in HI antibody titers, three weeks after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c Seroconversion is defined in subjects seronegative at baseline (i.e., HI titer <1:10 at Day 1) as post-vaccination HI titer ≥1:40, and defined in subjects seropositive at baseline (i.e., HI titer ≥1:10 at Day 1) as a minimum of a 4-fold increase in post-vaccination HI titer. The Committee for Medicinal Products for Human Use (CHMP) criterion for adult population is that the percentage of subjects with seroconversion or significant increase in HI antibody is >40%
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Percentages of Subjects
    number (confidence interval 95%)
        H1N1: Day 22/Day 50(N=1113,566)
    73 (70 to 76)
    74 (70 to 77)
    0 (0 to 0)
        H3N2: Day 22/Day 50(N=1112,566)
    47 (44 to 50)
    51 (47 to 55)
    0 (0 to 0)
        B1: Day 22/Day 50(N=1112,566)
    67 (64 to 70)
    66 (61 to 69)
    0 (0 to 0)
        B2: Day 22/Day 50(N=1108,556)
    73 (70 to 76)
    0 (0 to 0)
    72 (68 to 76)
    No statistical analyses for this end point

    Secondary: 6.Number (%) of subjects achieving HI titer ≥1:40 after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years

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    End point title
    		 6.Number (%) of subjects achieving HI titer ≥1:40 after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years
    End point description
    Immunogenicity was assessed in terms of number (%) of subjects (Previously vaccinated and Not previously vaccinated) showing HI titer ≥1:40, three weeks after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c The CHMP criterion for an adult population is that the percentage of subjects achieving an HI titer ≥1:40 is >70%
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Percentages Of subjects
    number (confidence interval 95%)
        H1N1: Day 1(N=1113,566)
    76 (73 to 78)
    79 (75 to 82)
    0 (0 to 0)
        H1N1: Day 22/Day 50(N=1113,566)
    99 (98 to 100)
    99 (98 to 100)
    0 (0 to 0)
        H3N2: Day 1(N=1112,566)
    90 (88 to 91)
    89 (86 to 92)
    0 (0 to 0)
        H3N2: Day 22/Day 50(N=1112,566)
    100 (99 to 100)
    99 (98 to 100)
    0 (0 to 0)
        B1: Day 1(N=1112,566)
    49 (46 to 52)
    45 (41 to 49)
    0 (0 to 0)
        B1: Day 22/Day 50(N=1112,566)
    92 (91 to 94)
    93 (90 to 95)
    0 (0 to 0)
        B2: Day 1(N=1108,556)
    46 (43 to 49)
    0 (0 to 0)
    47 (43 to 51)
        B2: Day 22/Day 50(N=1108,556)
    91 (89 to 93)
    0 (0 to 0)
    91 (88 to 93)
    No statistical analyses for this end point

    Secondary: 7.Geometric mean ratios (GMR) in subjects after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years age

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    End point title
    		 7.Geometric mean ratios (GMR) in subjects after one or two doses of either QIVc, TIV1c or TIV2c in ≥4 to <18 years age
    End point description
    Immunogenicity was measured in subjects (Previously vaccinated and Not previously vaccinated) as the geometric mean ratio (GMR). The ratio of postvaccination to prevaccination HI GMTs, three weeks after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c The CHMP criterion for GMR in adult population is >2.5
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Ratio
    geometric mean (confidence interval 95%)
        A/H1N1: TIV1c/QIVc [Day 22 (Day 50)/Day1]
    11 (10 to 13)
    12 (10 to 13)
    0 (0 to 0)
        A/H3N2: TIV1c/QIVc [Day 22 (Day 50)/Day1]
    3.65 (3.4 to 3.91)
    3.97 (3.59 to 4.38)
    0 (0 to 0)
        B1: TIV1c/QIVc [Day 22 (Day 50)/Day1]
    6.15 (5.72 to 6.61)
    6.24 (5.64 to 6.91)
    0 (0 to 0)
        B2: TIV2c/QIVc [Day 22 (Day 50)/Day1]
    8.17 (7.5 to 8.89)
    0 (0 to 0)
    8.45 (7.5 to 9.53)
    No statistical analyses for this end point

    Secondary: 8.GMT in subjects after receiving one or two doses of either QIVc, TIV1c against B2 strain

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    End point title
    		 8.GMT in subjects after receiving one or two doses of either QIVc, TIV1c against B2 strain [9]
    End point description
    Immunogenicity of QIVc to comparator TIV1c was assessed in terms of ratios of GMT in subjects (Previously vaccinated and Not previously vaccinated) measured by HI assay, three weeks after last vaccination with one or two doses of either QIVc or TIV1c Superiority was established if the upper bound of the two-sided 95% CI for the ratio of GMTs (GMT TIV1c /GMT QIVc) for HI antibody does not exceed the superiority margin of 1
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    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: Statistics only for applicable arms
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    Units: Titers
    geometric mean (confidence interval 95%)
        Day1(N=1108,563)
    22 (20 to 24)
    21 (18 to 23)
        Day 22/Day 50(N=1108,563)
    176 (164 to 189)
    45 (41 to 49)
    Statistical analysis title
    		 Superiority of QIVc to TIV1c regarding B2 antibody
    Statistical analysis description
    Superiority of immune responses of QIVc to TIV1c in terms of ratios of GMT against influenza strain B2
    Comparison groups
    TIV1c (≥4 to <18 years) v QIVc (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Ratios of GMT (Day 22/Day 50)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.29
    Variability estimate
    Standard deviation

    Secondary: 9.Number (%) of subjects achieving seroconversion against B2 strain after one or two doses of either QIVc or TIV1c

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    End point title
    		 9.Number (%) of subjects achieving seroconversion against B2 strain after one or two doses of either QIVc or TIV1c [10]
    End point description
    Immunogenicity of QIVc to comparator TIV1c in terms of number (%) of subjects (Previously vaccinated and Not previously vaccinated) showing seroconversion or significant increase in HI antibody titers, against influenza strain B2, three weeks after last vaccination with QIVc or TIV1c Superiority criterion was established if the upper bound of the two-sided 95% CI for the difference between seroconversion rates (% seroconversion TIV1c – % seroconversion QIVc) for HI antibody does not exceed the margin of 0 points
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    Notes
    [10] - 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: Statistics only for applicable arms
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    Units: Percentages of subjects
    number (confidence interval 95%)
        Day 22/Day 50(N=1108,563)
    73 (70 to 76)
    26 (23 to 30)
    Statistical analysis title
    		 superiority of QIVc to TIV1c regarding B2 antibody
    Statistical analysis description
    Superiority of immune responses of QIVc to TIV1c in terms of seroconversion rates against influenza strain B2
    Comparison groups
    QIVc (≥4 to <18 years) v TIV1c (≥4 to <18 years)
    Number of subjects included in analysis
    1752
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference b/w SC rates(Day 22/Day 50)
    Point estimate
    -47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.1
         upper limit
    		 -42.1
    Variability estimate
    Standard deviation

    Secondary: 10.GMT in subjects after receiving one or two doses of either QIVc, TIV2c against B1 strain

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    End point title
    		 10.GMT in subjects after receiving one or two doses of either QIVc, TIV2c against B1 strain [11]
    End point description
    Immunogenicity of QIVc to comparator TIV2c was assessed in terms of ratios of GMT in subjects (Previously vaccinated and Not previously vaccinated) measured by HI assay, three weeks after last vaccination with one or two doses of either QIVc or TIV2c Superiority was established if the upper bound of the two-sided 95% CI for the ratio of GMTs (GMT TIV2c /GMT QIVc) for HI antibody does not exceed the superiority margin of 1
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    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: Statistics only for applicable arms
    End point values
    		 QIVc (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    581
    Units: Titers
    geometric mean (confidence interval 95%)
        Day1(N=1112,557)
    25 (23 to 27)
    24 (22 to 27)
        Day 22/Day 50(N=1112,557)
    154 (145 to 163)
    59 (54 to 64)
    Statistical analysis title
    		 Superiority of QIVc to TIV2c regarding B1 antibody
    Statistical analysis description
    Superiority of immune responses of QIVc to TIV2c in terms of ratios of GMT against influenza strain B1
    Comparison groups
    QIVc (≥4 to <18 years) v TIV2c (≥4 to <18 years)
    Number of subjects included in analysis
    1740
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Ratios of GMT (Day 22/Day 50)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.42
    Variability estimate
    Standard deviation

    Secondary: 11.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc or TIV2c

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    End point title
    		 11.Number (%) of subjects achieving seroconversion after one or two doses of either QIVc or TIV2c [12]
    End point description
    Immunogenicity of QIVc to comparator TIV2c in terms of number (%) of subjects (Previously vaccinated and Not previously vaccinated) showing seroconversion or significant increase in HI antibody titers, against influenza strain B1, three weeks after last vaccination with QIVc or TIV2c Superiority was established if the upper bound of the two-sided 95% CI for the difference between seroconversion rates (% seroconversion TIV2c – % seroconversion QIVc) for HI antibody does not exceed the margin of 0 points
    End point type
    Secondary
    End point timeframe
    Three weeks post vaccination (Day 22 for previously vaccinated and Day 50 for Not previously vaccinated subjects)
    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: Statistics only for applicable arms
    End point values
    		 QIVc (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    581
    Units: Percentages of subjects
    number (confidence interval 95%)
        Day 22/Day 50(N=1112,557)
    67 (64 to 70)
    33 (29 to 37)
    Statistical analysis title
    		 superiority of QIVc to TIV2c regarding B1 antibody
    Statistical analysis description
    Superiority of immune responses of QIVc to TIV2c in terms of seroconversion rates against influenza strain B1
    Comparison groups
    QIVc (≥4 to <18 years) v TIV2c (≥4 to <18 years)
    Number of subjects included in analysis
    1740
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference b/w SC rates(Day 22/Day 50)
    Point estimate
    -34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.8
         upper limit
    		 -29.3
    Variability estimate
    Standard deviation

    Secondary: 12.Number of subjects reporting solicited adverse events (AEs) after one or two doses of either QIVc, TIV1c or TIV2c by age sub-strata

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    End point title
    		 12.Number of subjects reporting solicited adverse events (AEs) after one or two doses of either QIVc, TIV1c or TIV2c by age sub-strata
    End point description
    Safety was assessed in terms of number of subjects (Previously vaccinated and Not previously vaccinated) reporting solicited local and systemic reactions, day 1 to 7 after last vaccination with one or two doses of either QIVc, TIV1c or TIV2c.For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c.
    End point type
    Secondary
    End point timeframe
    Day 1 to 7 after last vaccination
    End point values
    		 QIVc _First Vaccine (≥4 to <6 years) TIV1c_First Vaccine (≥4 to <6 years) TIV2c _First Vaccine (≥4 to <6 years) QIVc _Second Vaccine (≥4 to <6 years) TIV1c_Second Vaccine (≥4 to <6 years) TIV2c _Second Vaccine (≥4 to <6 years) QIVc _First Vaccine (≥6 to <9 years) TIV1c_First Vaccine (≥6 to <9 years) TIV2c _First Vaccine (≥6 to <9 years) QIVc _Second Vaccine (≥6 to <9 years) TIV1c_Second Vaccine (≥6 to <9 years) TIV2c _Second Vaccine (≥6 to <9 years) QIVc (≥9 to <18 years) TIV1c (≥9 to <18 years) TIV2c (≥9 to <18 years)
    Number of subjects analysed
    182
    91
    93
    98
    39
    47
    372
    185
    186
    205
    112
    116
    579
    294
    282
    Units: Subjects
        Any local
    103
    51
    47
    52
    17
    17
    237
    124
    116
    102
    64
    66
    377
    175
    156
        Tenderness
    83
    41
    40
    49
    15
    15
    1
    0
    0
    0
    0
    0
    0
    0
    0
        Ecchymosis
    16
    10
    7
    6
    3
    2
    35
    17
    14
    9
    9
    7
    24
    16
    13
        Erythema
    32
    21
    16
    17
    3
    7
    83
    43
    38
    29
    17
    19
    110
    51
    43
        Induration
    24
    18
    12
    11
    2
    4
    59
    35
    24
    25
    18
    12
    88
    43
    36
        Pain
    0
    0
    0
    0
    0
    0
    201
    105
    107
    95
    61
    62
    334
    150
    142
        Any systemic
    51
    18
    17
    30
    9
    9
    117
    67
    65
    46
    30
    27
    232
    121
    94
        Change of eating habits
    19
    6
    6
    9
    3
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Sleepiness
    34
    11
    9
    13
    3
    5
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Chills
    10
    2
    1
    4
    2
    1
    16
    6
    8
    2
    3
    0
    43
    17
    10
        Irritability
    29
    9
    9
    15
    6
    6
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Nausea
    0
    0
    0
    0
    0
    0
    29
    9
    10
    7
    6
    4
    55
    24
    21
        Myalgia
    0
    0
    0
    0
    0
    0
    43
    26
    19
    18
    11
    11
    94
    50
    41
        Arthralgia
    0
    0
    0
    0
    0
    0
    13
    10
    7
    6
    5
    4
    36
    19
    22
        Headache
    0
    0
    0
    0
    0
    0
    52
    24
    23
    9
    8
    7
    127
    68
    50
        Fatigue
    0
    0
    0
    0
    0
    0
    47
    26
    33
    18
    12
    10
    104
    46
    44
        Vomiting
    8
    2
    2
    3
    0
    0
    12
    6
    6
    7
    2
    1
    10
    4
    5
        Diarrhea
    8
    2
    2
    3
    1
    2
    13
    11
    9
    4
    4
    1
    22
    11
    9
        Loss of appetite
    0
    0
    0
    0
    0
    0
    33
    10
    15
    6
    9
    8
    51
    25
    25
        Body temperature(>=38C)
    7
    4
    3
    4
    1
    0
    16
    5
    4
    6
    2
    2
    7
    8
    4
        Analgesics-Preventive
    13
    1
    1
    2
    1
    0
    14
    6
    8
    7
    4
    4
    15
    6
    8
        Analgesics-Treatment
    12
    4
    3
    2
    2
    1
    27
    13
    10
    15
    4
    10
    24
    20
    14
    No statistical analyses for this end point

    Secondary: 13.Number of subjects reporting unsolicited adverse events (AEs) after one or two doses of either QIVc, TIV1c or TIV2c by overall age group

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    End point title
    		 13.Number of subjects reporting unsolicited adverse events (AEs) after one or two doses of either QIVc, TIV1c or TIV2c by overall age group
    End point description
    Safety was assessed in terms of number of subjects (Previously vaccinated and Not previously vaccinated) reporting unsolicited AEs (day 1 to 22 for Previously vaccinated and day 1 to day 50 for Not previously vaccinated subjects), serious adverse events (SAEs), medically attended AEs, AEs leading to withdrawal from the study, new onset of chronic diseases (NOCDs), and concomitant medications (day 1 to day 181 for Previously vaccinated and day 1 to day 210 for Not previously vaccinated subjects) after receiving one or two doses of either QIVc, TIV1c or TIV2c. For H1N1, H3N2 and B1 strain, the comparison is between QIVc and TIV1c and for B2 i.e. alternate B strain, the comparison is between QIVc and TIV2c.
    End point type
    Secondary
    End point timeframe
    Day 1 to 210 post vaccination
    End point values
    		 QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years) TIV2c (≥4 to <18 years)
    Number of subjects analysed
    1159
    593
    581
    Units: Subjects
        Any AE
    279
    139
    152
        Possibly/probably related AE
    56
    34
    31
        SAE
    6
    7
    2
        Possibly/probably related SAE
    0
    0
    0
        AE leading to study withdrawal
    0
    1
    0
        Medically attended AE
    310
    156
    153
        NOCD
    20
    11
    11
        Death
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were collected from day 1 to day 181 for previously vaccinated subjects and day 1 to day 210 for not previously vaccinated subjects
    Adverse event reporting additional description
    Solicited AEs were collected from day 1 to day 7 after last vaccination, unsolicited AEs were collected from day 1 to day 22 for previously vaccinated subjects and day 1 to day 50 for not previously vaccinated subjects.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    TIV2c (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV2c that contains an alternate B strain compared to what is recommended for 2013-2014

    Reporting group title
    QIVc (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived quadrivalent influenza vaccine (QIVc)

    Reporting group title
    TIV1c (≥4 to <18 years)
    Reporting group description
    		 Subjects received one or two doses of cell derived trivalent influenza vaccine TIV1c (H1N1, H3N2, B1) recommended for 2013-2014 season

    Serious adverse events
    		 TIV2c (≥4 to <18 years) QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 570 (0.35%)
    6 / 1149 (0.52%)
    7 / 579 (1.21%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 1149 (0.09%)
    0 / 579 (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
    Forearm fracture
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hippocampal sclerosis
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 1149 (0.09%)
    0 / 579 (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
    Partial seizures
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 1149 (0.09%)
    0 / 579 (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
    Immune system disorders
    Anaphylactic reaction.
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 1149 (0.09%)
    0 / 579 (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
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 1149 (0.00%)
    0 / 579 (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
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 1149 (0.09%)
    0 / 579 (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
    Depression
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 1149 (0.09%)
    0 / 579 (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
    Intentional self-injury
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oppositional defiant disorder
         subjects affected / exposed
    0 / 570 (0.00%)
    1 / 1149 (0.09%)
    0 / 579 (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
    Suicidal ideation
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess of eyelid
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 570 (0.18%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 570 (0.00%)
    0 / 1149 (0.00%)
    1 / 579 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    		 TIV2c (≥4 to <18 years) QIVc (≥4 to <18 years) TIV1c (≥4 to <18 years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    392 / 570 (68.77%)
    840 / 1149 (73.11%)
    417 / 579 (72.02%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    88 / 570 (15.44%)
    204 / 1149 (17.75%)
    105 / 579 (18.13%)
         occurrences all number
    111
    264
    132
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    315 / 570 (55.26%)
    664 / 1149 (57.79%)
    324 / 579 (55.96%)
         occurrences all number
    376
    789
    381
    Fatigue
         subjects affected / exposed
    82 / 570 (14.39%)
    165 / 1149 (14.36%)
    82 / 579 (14.16%)
         occurrences all number
    107
    193
    97
    Chills
         subjects affected / exposed
    21 / 570 (3.68%)
    73 / 1149 (6.35%)
    29 / 579 (5.01%)
         occurrences all number
    23
    81
    31
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    42 / 570 (7.37%)
    95 / 1149 (8.27%)
    40 / 579 (6.91%)
         occurrences all number
    51
    110
    44
    Psychiatric disorders
    Eating disorders
         subjects affected / exposed
    51 / 570 (8.95%)
    115 / 1149 (10.01%)
    49 / 579 (8.46%)
         occurrences all number
    7
    29
    11
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    66 / 570 (11.58%)
    150 / 1149 (13.05%)
    84 / 579 (14.51%)
         occurrences all number
    78
    168
    89
    Arthralgia
         subjects affected / exposed
    33 / 570 (5.79%)
    63 / 1149 (5.48%)
    35 / 579 (6.04%)
         occurrences all number
    38
    69
    42

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2014
    (1) inclusion of safety analysis based on age groups and time periods as detailed in SAP.(2) clarification regarding clinic visit and safety call visit windows.(3) correction of how the IRT system assigns Subject Identifiers.(4) correction of sequence for enrollment and randomization.(5) clarification on use of diary cards assigned to subject based on age at time of enrollment

    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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