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    Clinical Trial Results:
    A Phase I/II, Randomized, Observer-Blind, Multicenter Study to Evaluate Immunogenicity and Safety of Four Influenza Vaccines in Healthy Pediatric Subjects 6 to < 48 Months of Age.

    Summary
    EudraCT number
    		 2013-002081-39
    Trial protocol
    		 FI  
    Global end of trial date
    24 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    15 Mar 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    V58P16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02035696
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines & Diagnostics AG
    Sponsor organisation address
    CH, Basel, Switzerland, 4002
    Public contact
    Posting Director, Novartis Vaccines & Diagnostics, RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines & 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
    30 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Immunogenicity Objective To select an optimal dose of TIVc for pediatric subjects 6 to < 48 months of age by desirability index score (The overall desirability index is based on comparison of post-vaccination haemagglutination inhibition (HI) assay results and specific solicited adverse events following any vaccination)
    Protection of trial subjects
    Ongoing review of blinded safety data will be performed by an independent Data Monitoring Committee (DMC). Safety data will be reviewed on a regular basis as governed by the DMC Charter. If safety signals of concern are observed by the DMC, the DMC may recommend that study vaccination be halted until the DMC determines if it is appropriate to proceed with vaccination as specified in the Charter.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 7 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    Thailand: 291
    Country: Number of subjects enrolled
    Philippines: 345
    Country: Number of subjects enrolled
    Finland: 1
    Worldwide total number of subjects
    671
    EEA total number of subjects
    1
    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)
    336
    Children (2-11 years)
    335
    Adolescents (12-17 years)
    0
    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
    		 6 centers in the United States, 1 center in Finland, 2 centers in Thailand, 2 centers in Philippines

    Pre-assignment
    Screening details
    		 All enrolled Subjects 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
    Blinding implementation details
    This study was conducted in an observer-blind fashion. To maintain the observer-blind design of study, the roles and responsibilities of the “blinded” and “unblinded” team members were defined and maintained. Safety assessments and study-related procedures (except for vaccine administration done by unblinded staff) and monitoring thereof were to be performed by “blinded” team members. The database doesnt provide the option as observer blind that is the reason "Double blind" has been selected.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 TIVc-High Dose
    Arm description
    		 Subjects (6 to <48 months old) received two doses of 0.75 mL of TIVc vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mammalian cell culture-derived trivalent influenza vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IM/0.75mL

    Arm title
    		 TIVc-Full Dose
    Arm description
    		 Subjects (6 to <48 months old) received two doses of 0.50 mL of TIVc vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mammalian cell culture-derived trivalent influenza vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IM/0.50 mL

    Arm title
    		 TIVc- Half Dose
    Arm description
    		 Subjects (6 to <48 months old) received two doses of 0.25 mL of TIVc vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mammalian cell culture-derived trivalent influenza vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IM/0.25 mL

    Arm title
    		 TIVe
    Arm description
    		 Subjects aged 6 to <36 months were administered two doses of 0.25 mL TIVe and subjects aged 36 to <48 months were administered two doses 0.50 mL of TIVe vaccine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Egg Derived Trivalent Influenza Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    IM/0.25 mL- Subjects aged 6 to <36 months IM/0.50 mL- Subjects aged 36 to <48 months

    Number of subjects in period 1
    		TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Started
    174
    166
    167
    164
    Completed
    171
    163
    164
    161
    Not completed
    3
    3
    3
    3
         Consent withdrawn by subject
    3
    -
    2
    1
         Lost to follow-up
    -
    3
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TIVc-High Dose
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of 0.75 mL of TIVc vaccine.

    Reporting group title
    TIVc-Full Dose
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of 0.50 mL of TIVc vaccine.

    Reporting group title
    TIVc- Half Dose
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of 0.25 mL of TIVc vaccine.

    Reporting group title
    TIVe
    Reporting group description
    		 Subjects aged 6 to <36 months were administered two doses of 0.25 mL TIVe and subjects aged 36 to <48 months were administered two doses 0.50 mL of TIVe vaccine.

    Reporting group values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe Total
    Number of subjects
    		 174 166 167 164 671
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days - 23 months)
    		 88 83 83 82 336
        Children (2-11 years)
    		 86 83 84 82 335
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 25.3 ( 11.5 ) 25 ( 11.5 ) 25.6 ( 11.5 ) 25.3 ( 11.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 84 82 77 87 330
        Male
    		 90 84 90 77 341

    End points

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    End points reporting groups
    Reporting group title
    TIVc-High Dose
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of 0.75 mL of TIVc vaccine.

    Reporting group title
    TIVc-Full Dose
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of 0.50 mL of TIVc vaccine.

    Reporting group title
    TIVc- Half Dose
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of 0.25 mL of TIVc vaccine.

    Reporting group title
    TIVe
    Reporting group description
    		 Subjects aged 6 to <36 months were administered two doses of 0.25 mL TIVe and subjects aged 36 to <48 months were administered two doses 0.50 mL of TIVe vaccine.

    Subject analysis set title
    All Enrolled Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All screened subjects who provided informed consent and provided demographic and/or other baseline screening measurements, regardless of the subject’s randomization and vaccination status in the trial and received a subject ID.

    Subject analysis set title
    Full Analysis Set (FAS), Immunogenicity Desirability – FASd
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in the All Enrolled Set who are randomized and: • Receive at least one study vaccination at day 1 and/or day 29, and • Provide immunogenicity data pre- (day 1) and postvaccination (day 50), and • Provide postvaccination solicited adverse event data from day 1 (6 hours) until day 3

    Subject analysis set title
    Full Analysis Set (FAS), FASc1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Receive at least one study vaccination and provide immunogenicity data at day 50 (HI antibody titer ≥ 1:40).

    Subject analysis set title
    FASc2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Receive at least one study vaccination and provide immunogenicity data at baseline (day 1) and day 50 (seroconversion of HI titer, seroprotection of MN titer, GMTs and ratio of GMTs).

    Subject analysis set title
    PPSd
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the FASd who: • Correctly received the vaccines (i.e., received the vaccines to which the subjects were randomized and at the scheduled time points). • Provided immunogenicity data pre- (day 1) and post vaccination (day 50). • Provided post vaccination solicited adverse event data (from day 1 (6 hours) until day 3 for at least one local reaction and at least one systemic reaction). • Had no reportable protocol deviations leading to exclusion as defined prior to unblinding/analysis. • Were not excluded due to other reasons defined prior to unblinding or analysis.

    Subject analysis set title
    PPSc1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the FASc1 who: • Correctly received the vaccines (i.e., received the vaccines to which the subjects were randomized and at the scheduled time points). • Received at least one study vaccination and provide immunogenicity data at day 50 (HI antibody titer ≥ 1:40). • Had no reportable protocol deviations leading to exclusion as defined prior to unblinding/analysis. • Were not excluded due to other reasons defined prior to unblinding or analysis.

    Subject analysis set title
    PPSc2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the FASc2 who: • Correctly receive the vaccine (i.e., receive the vaccine to which the subjects is randomized and at the scheduled time points). • Receive at least one study vaccination and provide immunogenicity data at baseline (day 1) and day 50 (seroconversion of HI titer, seroprotection of MN titer, GMTs and ratio of GMTs) • Have no reportable protocol deviations leading to exclusion (see section 6.2 of Statistical Analysis Plan version 2 issued on 03 Dec 2014) as defined prior to unblinding/analysis. • Are not excluded due to other reasons defined prior to unblinding or analysis (see section 6.2 of Statistical Analysis Plan version 2 issued on 03 Dec 2014).

    Subject analysis set title
    Solicited Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the Exposed Set with any solicited adverse event data and/or indicators of solicited adverse events.

    Subject analysis set title
    Unsolicited Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the Exposed Set with unsolicited adverse event data.

    Subject analysis set title
    Ratio of GMTs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Ratio of different doses (ie. High dose TIVc : TIVe, Full dose TIVc : TIVe, Half dose TIVc: TIVe) are compared on day 1 and day 50.

    Primary: Ratios of Geometric Mean Titer (GMT) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine

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    End point title
    		 Ratios of Geometric Mean Titer (GMT) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine
    End point description
    Immunogenicity was assessed in terms of ratios of GMTs in subjects (6 to <48 months old), measured by HI assay, day 1 to day 50 after vaccination with two doses of either TIVc or TIVe vaccine. Analysis was done on Per Protocol (PP) population i.e. all subjects in the FAS Efficacy/Immunogenicity Set who are not excluded due to reasons defined prior to unblinding or analysis.
    End point type
    Primary
    End point timeframe
    Day 50/Day 1
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    156
    145
    142
    149
    Units: Ratios
    geometric mean (confidence interval 95%)
        A/H1N1
    11 (6.18 to 20)
    8.25 (4.48 to 15)
    8.62 (4.68 to 16)
    5.27 (2.9 to 9.59)
        A/H3N2
    15 (8.79 to 24)
    15 (8.92 to 26)
    9.49 (5.61 to 16)
    17 (10 to 29)
        B strains
    5.7 (3.74 to 8.69)
    4.85 (3.13 to 7.54)
    4.45 (2.87 to 6.91)
    7.21 (4.69 to 11)
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-High Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H1N1 at Day 1.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.52
    Notes
    [1] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-High Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H1N1 at Day 50.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 3.26
    Notes
    [2] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-High Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H3N2 at Day 1.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.12
    Notes
    [3] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-High Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H3N2 at Day 50.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.8
    Notes
    [4] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-High Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain B at Day 1.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.08
    Notes
    [5] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-High Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain B at Day 50.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.03
    Notes
    [6] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-Full Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H1N1 at Day 1.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.97
    Notes
    [7] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-Full Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H1N1 at Day 50.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.27
         upper limit
    		 3.15
    Notes
    [8] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-Full Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H3N2 at Day 1.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.88
    Notes
    [9] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-Full Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H3N2 at Day 50.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.66
    Notes
    [10] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-Full Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain B at Day 1.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.03
    Notes
    [11] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc-Full Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain B at Day 50.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.84
    Notes
    [12] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc- Half Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H1N1 at Day 1.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.61
    Notes
    [13] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc- Half Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H1N1 at Day 50.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [14]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 2.7
    Notes
    [14] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc- Half Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H3N2 at Day 1.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [15]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.2
    Notes
    [15] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc- Half Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain A/H3N2 at Day 50.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [16]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.56
    Notes
    [16] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc- Half Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain B at Day 1.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [17]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.02
    Notes
    [17] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of a TIVc- Half Dose to TIVe, assessed in terms of vaccine group GMT ratios against influenza strain B at Day 50.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [18]
    Method
    Parameter type
    		 Vaccine Group Ratios
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.76
    Notes
    [18] - Non-inferiority was established if the Lower limit of the 2- sided 95% CI of the vaccine group GMT ratio ≥ 0.67.

    Primary: Percentages of Subjects (6 to <48 months old) achieving seroconversion or significant increase after receiving two doses of either TIVc or TIVe vaccine.

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    End point title
    		 Percentages of Subjects (6 to <48 months old) achieving seroconversion or significant increase after receiving two doses of either TIVc or TIVe vaccine.
    End point description
    Immunogenicity was assessed in terms number (%) of subjects (6 to <48 months old) achieving seroconversion as measured by HI antibody titer, day 50 after vaccination with two doses of either TIVc or TIVe vaccine. Seroconversion was defined as subjects with either a pre-vaccination (baseline) HI titer < 1:10 and post-vaccination HI titer ≥ 1:40 or with a pre-vaccination HI titer ≥ 1:10 and a ≥ 4-fold increase in post-vaccination HI antibody titer. Analysis was done on PP population.
    End point type
    Primary
    End point timeframe
    Day 50 post vaccination.
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    156
    145
    142
    149
    Units: Percentages of Subjects
    number (confidence interval 95%)
        A/H1N1_Day 50
    83 (77 to 89)
    82 (75 to 88)
    80 (72 to 86)
    74 (66 to 81)
        A/H3N2_Day 50
    94 (89 to 97)
    90 (84 to 95)
    87 (81 to 92)
    93 (87 to 96)
        B_Day 50
    69 (61 to 76)
    70 (61 to 77)
    63 (54 to 71)
    80 (73 to 86)
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc-High Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain A/H1N1.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [19]
    Method
    Parameter type
    		 Vaccine Group Differences]
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 18.8
    Notes
    [19] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc-High Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain A/H3N2.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [20]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 7.7
    Notes
    [20] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc-High Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc-High Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain B.
    Comparison groups
    TIVc-High Dose v TIVe
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [21]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.9
         upper limit
    		 -1.4
    Notes
    [21] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc-Full Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain A/H1N1.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [22]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 17.7
    Notes
    [22] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc-Full Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain A/H3N2.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [23]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 4.3
    Notes
    [23] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc-Full Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc-Full Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain B.
    Comparison groups
    TIVe v TIVc-Full Dose
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [24]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.1
         upper limit
    		 0
    Notes
    [24] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc- Half Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain A/H1N1.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [25]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 15.4
    Notes
    [25] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc- Half Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain A/H3N2.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [26]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.6
         upper limit
    		 1.7
    Notes
    [26] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.
    Statistical analysis title
    		 TIVc- Half Dose, TIVe
    Statistical analysis description
    Non-inferiority of immune responses of TIVc- Half Dose to TIVe, assessed in terms of Vaccine Group Differences with seroconversion against influenza strain B.
    Comparison groups
    TIVe v TIVc- Half Dose
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [27]
    Method
    Parameter type
    		 Vaccine Group Differences
    Point estimate
    -17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.3
         upper limit
    		 -6.8
    Notes
    [27] - Non-inferiority was established if the Lower limit of the 2-sided 95% CI on the difference between seroconversion rates ≥ -10%.

    Primary: Differences in Number of subjects (6 to <48 months old) reporting severe solicited local and systemic reactions after vaccination with either TIVc or TIVe vaccine

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    End point title
    		 Differences in Number of subjects (6 to <48 months old) reporting severe solicited local and systemic reactions after vaccination with either TIVc or TIVe vaccine [28] [29]
    End point description
    Safety was assessed in terms of number of subjects (6 to <48 months old) reporting severe local solicited AEs and severe local systemic AEs, 3 days after vaccination with either TIVc or TIVe vaccine. Analysis was done on solicited safety data set i.e. all subjects in the exposed set who provide post-vaccination solicited adverse event data.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 3
    Notes
    [28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was reported for this outcome measure.
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was reported for this outcome measure.
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose
    Number of subjects analysed
    156
    145
    142
    Units: Desirability Index
    number (not applicable)
        Differences in % severe solicited local AEs
    0
    0
    0
        Differences in % severe solicited systemic AEs
    0.04
    0
    0
    No statistical analyses for this end point

    Secondary: Percentages of Subjects (6 to <48 months old) achieving seroconversion or significant increase after receiving two doses of either TIVc or TIVe vaccine.

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    End point title
    		 Percentages of Subjects (6 to <48 months old) achieving seroconversion or significant increase after receiving two doses of either TIVc or TIVe vaccine.
    End point description
    Immunogenicity was assessed in terms number (%) of subjects (6 to <48 months old) achieving seroconversion as measured by HI assay, day 50 after vaccination with two doses of either TIVc or TIVe vaccine. Seroconversion was defined as subjects with either a pre-vaccination (baseline) HI titer < 1:10 and post-vaccination HI titer ≥ 1:40 or with a pre-vaccination HI titer ≥ 1:10 and a ≥ 4-fold increase in post-vaccination HI antibody titer. The Center for Biologics Evaluation, Research, and Review (CBER) criterion for pediatric population is that the lower bound of the two-sided 95% confidence interval (CI) for the percentage of subjects achieving seroconversion for HI antibody should meet or exceed 40%. Analysis was done on Full analysis set.
    End point type
    Secondary
    End point timeframe
    Day 50 post vaccination
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    170
    164
    161
    159
    Units: Percentages of Subjects
    number (confidence interval 95%)
        A/H1N1
    84 (77 to 89)
    80 (74 to 86)
    82 (75 to 88)
    73 (65 to 80)
        A/H3N2
    94 (89 to 97)
    91 (85 to 95)
    88 (81 to 92)
    93 (88 to 96)
        B strain
    68 (61 to 75)
    70 (62 to 76)
    63 (55 to 70)
    79 (72 to 85)
    No statistical analyses for this end point

    Secondary: Percentages of Subjects (6 to <48 months old) achieving HI titer ≥ 1:40 after receiving two doses of either TIVc or TIVe vaccine.

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    End point title
    		 Percentages of Subjects (6 to <48 months old) achieving HI titer ≥ 1:40 after receiving two doses of either TIVc or TIVe vaccine.
    End point description
    Immunogenicity was assessed in terms of number (%) of subjects (6 to <48 months old) achieving HI titer ≥1:40 as measured by HI assay, day 50 after vaccination with two doses of either TIVc or TIVe vaccine. The CBER criterion for pediatric 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% The CHMP criterion for pediatric population is that the percentage of subjects achieving HI antibody titers ≥1:40 should be >70%. Analysis was done on FAS.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 50 post vaccination
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    170
    164
    161
    159
    Units: Percentages of Subjects
    number (confidence interval 95%)
        A/H1N1: Day 1
    28 (21 to 36)
    34 (27 to 43)
    28 (21 to 36)
    28 (21 to 35)
        A/H1N1: Day 50
    86 (79 to 91)
    87 (80 to 92)
    84 (77 to 89)
    78 (70 to 84)
        A/H3N2: Day 1
    45 (37 to 53)
    41 (33 to 50)
    47 (39 to 56)
    51 (43 to 59)
        A/H3N2: Day 50
    98 (94 to 100)
    98 (94 to 100)
    96 (92 to 99)
    99 (96 to 100)
        B: Day 1
    2 (0 to 6)
    0 (0 to 3)
    1 (0.016 to 3)
    3 (1 to 8)
        B: Day 50
    69 (61 to 76)
    70 (61 to 77)
    63 (54 to 71)
    81 (73 to 87)
    No statistical analyses for this end point

    Secondary: Geometric Mean Ratios (GMR) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine.

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    End point title
    		 Geometric Mean Ratios (GMR) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine.
    End point description
    Immunogenicity was assessed in terms of GMR in subjects (6 to <48 months old) as measured by HI assay, day 50 after vaccination with two doses of either TIVc or TIVe vaccine. The CHMP criterion is mean geometric ratio (GMR) >2.5. Analysis was done on FAS.
    End point type
    Secondary
    End point timeframe
    Day 50 post vaccination over day 1.
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    170
    164
    161
    159
    Units: Ratio
    number (confidence interval 95%)
        A/H1N1
    12 (7.05 to 19)
    8.58 (5.08 to 14)
    8.94 (5.28 to 15)
    5.14 (3.04 to 8.68)
        A/H3N2
    12 (7.83 to 19)
    13 (8.05 to 20)
    7.68 (4.91 to 12)
    14 (8.83 to 22)
        B.
    6.14 (4.27 to 8.84)
    5.29 (3.64 to 7.7)
    4.72 (3.24 to 6.88)
    7.57 (5.21 to 11)
    No statistical analyses for this end point

    Secondary: Percentages of Subjects (6 to <48 months old) with high post vaccination HI titers (i.e. HI titers ≥1:110, ≥1:150, ≥1:330 and ≥1:629) after receiving two doses of either TIVc or TIVe vaccine.

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    End point title
    		 Percentages of Subjects (6 to <48 months old) with high post vaccination HI titers (i.e. HI titers ≥1:110, ≥1:150, ≥1:330 and ≥1:629) after receiving two doses of either TIVc or TIVe vaccine.
    End point description
    Immunogenicity was assessed in terms of number (%) of subjects (6 to <48 months old) achieving post vaccination HI titers (i.e. HI titers ≥1:110, ≥1:150, ≥1:330 and ≥1:629) as measured by HI assay, day 50 after vaccination with two doses of either TIVc or TIVe vaccine. Analysis was done on PPS.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 50 post vaccination.
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    156
    145
    142
    149
    Units: Percentages of Subjects
    number (confidence interval 95%)
        A/H1N1: Day 1: HI titers ≥1:110
    26 (19 to 33)
    31 (24 to 39)
    26 (19 to 34)
    26 (19 to 34)
        A/H1N1: Day 50: HI titers ≥1:110
    78 (70 to 84)
    81 (73 to 87)
    72 (64 to 79)
    60 (51 to 68)
        A/H3N2: Day 1: HI titers ≥1:110
    40 (33 to 49)
    38 (30 to 46)
    42 (34 to 51)
    47 (39 to 55)
        A/H3N2: Day 50: HI titers ≥1:110
    88 (82 to 93)
    87 (80 to 92)
    82 (74 to 88)
    97 (93 to 99)
        B: Day 1: HI titers ≥1:110
    1 (0.016 to 4)
    0 (0 to 3)
    0 (0 to 3)
    0 (0 to 2)
        B: Day 50: HI titers ≥1:110
    40 (32 to 48)
    30 (23 to 39)
    25 (18 to 33)
    38 (30 to 47)
        A/H1N1: Day 1: HI titers ≥1:151
    25 (18 to 33)
    30 (23 to 39)
    26 (19 to 34)
    26 (19 to 33)
        A/H1N1: Day 50: HI titers ≥1:151
    76 (69 to 83)
    77 (70 to 84)
    71 (63 to 78)
    58 (50 to 66)
        A/H3N2: Day 1: HI titers ≥1:151
    40 (33 to 49)
    38 (30 to 46)
    42 (34 to 51)
    47 (39 to 55)
        A/H3N2: Day 50: HI titers ≥1:151
    88 (82 to 93)
    87 (80 to 92)
    81 (74 to 87)
    97 (93 to 99)
        B: Day 1: HI titers ≥1:151
    0 (0 to 2)
    0 (0 to 3)
    0 (0 to 3)
    0 (0 to 2)
        B: Day 50: HI titers ≥1:151
    39 (31 to 47)
    30 (23 to 39)
    25 (18 to 33)
    38 (30 to 47)
        A/H1N1: Day 1: HI titers ≥1:330
    12 (7 to 18)
    14 (9 to 21)
    26 (19 to 34)
    11 (6 to 17)
        A/H1N1: Day 50: HI titers ≥1:330
    51 (43 to 59)
    52 (43 to 60)
    71 (63 to 78)
    35 (27 to 43)
        A/H3N2: Day 1: HI titers ≥1:330
    16 (11 to 23)
    12 (7 to 18)
    42 (34 to 51)
    21 (15 to 28)
        A/H3N2: Day 50: HI titers ≥1:330
    62 (53 to 69)
    57 (49 to 65)
    81 (74 to 87)
    68 (60 to 76)
        B: Day 1: HI titers ≥1:330
    0 (0 to 2)
    0 (0 to 3)
    0 (0 to 3)
    0 (0 to 2)
        B: Day 50: HI titers ≥1:330
    4 (1 to 8)
    5 (2 to 10)
    24 (17 to 32)
    7 (4 to 13)
        A/H1N1: Day 1: HI titers ≥1:629
    9 (5 to 15)
    12 (7 to 18)
    12 (7 to 18)
    8 (4 to 14)
        A/H1N1: Day 50: HI titers ≥1:629
    48 (40 to 56)
    48 (40 to 57)
    44 (35 to 52)
    34 (26 to 42)
        A/H3N2: Day 1: HI titers ≥1:629
    16 (11 to 23)
    12 (7 to 18)
    13 (8 to 19)
    21 (15 to 28)
        A/H3N2: Day 50: HI titers ≥1:629
    62 (53 to 69)
    57 (48 to 65)
    52 (44 to 61)
    68 (60 to 76)
        B: Day 1: HI titers ≥1:629
    0 (0 to 2)
    0 (0 to 3)
    0 (0 to 3)
    0 (0 to 2)
        B: Day 50: HI titers ≥1:629
    4 (1 to 8)
    4 (2 to 9)
    4 (1 to 8)
    7 (3 to 12)
    No statistical analyses for this end point

    Secondary: Geometric Mean Ratios (GMR) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine

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    End point title
    		 Geometric Mean Ratios (GMR) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine
    End point description
    Immunogenicity was assessed in terms of GMR in subjects (6 to <48 months old) as measured by MN assay, day 50 after vaccination with two doses of either TIVc or TIVe vaccine. Analysis was done on PPS.
    End point type
    Secondary
    End point timeframe
    Day 50 post vaccination over day 1.
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    156
    145
    142
    149
    Units: Ratio
    number (confidence interval 95%)
        A/H1N1
    11 (6.18 to 20)
    8.25 (4.48 to 15)
    8.62 (4.68 to 16)
    5.27 (2.9 to 9.59)
        A/H3N2
    15 (8.79 to 24)
    15 (8.92 to 26)
    9.49 (5.61 to 16)
    17 (10 to 29)
        B.
    5.7 (3.74 to 8.69)
    4.85 (3.13 to 7.54)
    4.45 (2.87 to 6.91)
    7.21 (4.69 to 11)
    No statistical analyses for this end point

    Secondary: Ratios of Geometric Mean Titer (GMT) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine as measured by HI assay.

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    End point title
    		 Ratios of Geometric Mean Titer (GMT) in subjects (6 to <48 months old) after receiving two doses of either TIVc or TIVe vaccine as measured by HI assay.
    End point description
    Immunogenicity was assessed in terms of ratios of GMTs in subjects (6 to <48 months old), measured by HI assay, day 1 to day 50 after vaccination with two doses of either TIVc or TIVe vaccine. Analysis was done on PPS population.
    End point type
    Secondary
    End point timeframe
    Day 50 /Day 1
    End point values
    		 Ratio of GMTs
    Number of subjects analysed
    156
    Units: Ratios
    number (confidence interval 95%)
        A/H1N1 (High dose TIVc:TIVe, Day 1)
    0.99 (0.65 to 1.52)
        A/H1N1 (Full dose TIVc:TIVe, Day 1)
    1.28 (0.83 to 1.97)
        A/H1N1 (Half dose TIVc:TIVe, Day 1)
    1.05 (0.68 to 1.61)
        A/H1N1 (High dose TIVc:TIVe, Day 50)
    2.09 (1.33 to 3.26)
        A/H1N1 (Full dose TIVc:TIVe, Day 50)
    2 (1.27 to 3.15)
        A/H1N1 (Half dose TIVc:TIVe, Day 50)
    1.71 (1.09 to 2.7)
        A/H3N2 (High dose TIVc:TIVe, Day 1)
    0.72 (0.46 to 1.12)
        A/H3N2 (Full dose TIVc:TIVe, Day 1)
    0.56 (0.36 to 0.88)
        A/H3N2 (Half dose TIVc:TIVe, Day 1)
    0.76 (0.48 to 1.2)
        A/H3N2 (High dose TIVc:TIVe, Day 50)
    0.6 (0.45 to 0.8)
        A/H3N2 (Full dose TIVc:TIVe, Day 50)
    0.49 (0.37 to 0.66)
        A/H3N2 (Half dose TIVc:TIVe, Day 50)
    0.42 (0.31 to 0.56)
        B (High dose TIVc:TIVe, Day 1)
    0.99 (0.91 to 1.08)
        B (Full dose TIVc:TIVe, Day 1)
    0.95 (0.88 to 1.03)
        B (Half dose TIVc:TIVe, Day 1)
    0.94 (0.86 to 1.02)
        B (High dose TIVc:TIVe, Day 50)
    0.79 (0.6 to 1.03)
        B (Full dose TIVc:TIVe, Day 50)
    0.64 (0.49 to 0.84)
        B (Half dose TIVc:TIVe, Day 50)
    0.58 (0.44 to 0.76)
    No statistical analyses for this end point

    Secondary: Number of subjects (6 to <48 months old) reporting solicited local (Grading Type I)and systemic adverse events (AEs) after two doses of either TIVc or TIVe vaccine.

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    End point title
    		 Number of subjects (6 to <48 months old) reporting solicited local (Grading Type I)and systemic adverse events (AEs) after two doses of either TIVc or TIVe vaccine.
    End point description
    Safety was assessed in terms of number of subjects (6 to <48 months old) reporting solicited local and systemic reactions, day 1 to day 7 after vaccination with two doses of either TIVc or TIVe vaccine (By Any Vaccination). Analyses was done on solicited safety data set.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 7
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    174
    165
    167
    161
    Units: Subjects
        Any local
    64
    58
    60
    54
        Injection-site erythema
    19
    24
    24
    17
        Injection-site induration
    13
    14
    9
    8
        Injection-site ecchymosis
    9
    9
    7
    7
        Injection-site tenderness
    50
    43
    42
    45
        Any systemic
    78
    72
    69
    66
        Change in eating habits
    29
    35
    28
    29
        Sleepiness
    30
    28
    21
    24
        Irritability
    30
    31
    29
    27
        Vomiting
    21
    20
    22
    14
        Diarrhea
    31
    31
    29
    34
        Chills
    7
    5
    5
    9
        Fever (≥ 38°C)
    15
    20
    21
    21
        Prophylactic use of antipyretics/analgesics
    9
    21
    25
    13
        Therapeutic use of antipyretics/analgesics
    17
    21
    24
    22
    No statistical analyses for this end point

    Secondary: Number of subjects (6 to <48 months old) reporting unsolicited adverse events (AEs) after two doses of either TIVc or TIVe vaccine.

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    End point title
    		 Number of subjects (6 to <48 months old) reporting unsolicited adverse events (AEs) after two doses of either TIVc or TIVe vaccine.
    End point description
    Safety was assessed in terms of number of subjects (6 to <48 months old) reporting unsolicited reactions after Each /any Vaccination from Day 1 [Post Vaccination] to Day 29 [Pre Clinic Visit] and Day 29 [Post Vaccination] to Day 50 [Pre Clinic Visit] , Serious Adverse Events (SAEs), AEs leading to New Onset of Chronic Diseases (NOCD), AEs leading to withdrawal from the study and concomitant medications (day 1 to day 209) after vaccination with two doses of either TIVc or TIVe vaccine (By Any Vaccination). Analyses was done on unsolicited safety data set i.e. all subjects in the exposed set who have post-vaccination unsolicited AE data.
    End point type
    Secondary
    End point timeframe
    Unsolicited AEs after Each/any Vaccination from Day 1 to Day 29 and Day 29 to Day 50 , Day 1 to Day 209.
    End point values
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Number of subjects analysed
    174
    166
    167
    164
    Units: Subjects
        Any AEs(after any vaccination)
    102
    107
    91
    94
        Possibly/probably related AEs (after any vacc.)
    38
    43
    43
    35
        Any AEs(after each vaccination)
    79
    84
    69
    76
        Possibly/probably related AEs (after each vacc.)
    56
    64
    50
    48
        AEs leading to NOCDs
    30
    33
    31
    31
        AEs leading to withdrawal from the study
    111
    20
    18
    14
        SAEs
    4
    8
    10
    6
        Possibly/probably related SAEs
    0
    0
    0
    0
        Medically attended AEs
    0
    0
    0
    0
        New onset of chronic diseases
    0
    1
    1
    1
        Death
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited AEs were collected from day 1 to day 7 post vaccination, unsolicited AEs were collected from day 1 to day 50 post vaccination and SAEs were collected from day 1 to day 209 post vaccination.
    Adverse event reporting additional description
    Solicited AEs were collected from day 1 to day 7 post vaccination, unsolicited AEs were collected from day 1 to day 50 post vaccination. A systematic adverse event is equivalent to an event that was solicited by the diary card, whereas a non-systematic event is an unsolicited adverse event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    TIVc-High Dose
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of 0.75 mL of TIVc vaccine

    Reporting group title
    TIVc-Full Dose
    Reporting group description
    		 Subjects(6 to <48 months old) received two doses of 0.50 mL of TIVc vaccine

    Reporting group title
    TIVc- Half Dose
    Reporting group description
    		 Subjects (6 to <48 months old)received two doses of 0.25 mL of TIVc vaccine

    Reporting group title
    TIVe
    Reporting group description
    		 Subjects (6 to <48 months old) received two doses of TIVe vaccine

    Serious adverse events
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 174 (2.30%)
    8 / 166 (4.82%)
    10 / 167 (5.99%)
    6 / 164 (3.66%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 174 (0.57%)
    2 / 166 (1.20%)
    1 / 167 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 174 (0.57%)
    2 / 166 (1.20%)
    1 / 167 (0.60%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 166 (0.00%)
    0 / 167 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 166 (1.20%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 166 (0.00%)
    0 / 167 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 166 (1.20%)
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand-Foot-And-Mouth Disease
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital Cellulitis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 166 (0.60%)
    0 / 167 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 166 (1.20%)
    2 / 167 (1.20%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 166 (0.00%)
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TIVc-High Dose TIVc-Full Dose TIVc- Half Dose TIVe
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    135 / 174 (77.59%)
    123 / 166 (74.10%)
    132 / 167 (79.04%)
    118 / 164 (71.95%)
    Nervous system disorders
    Somnolence
    alternative assessment type: Systematic
         subjects affected / exposed
    30 / 174 (17.24%)
    28 / 166 (16.87%)
    21 / 167 (12.57%)
    24 / 164 (14.63%)
         occurrences all number
    38
    34
    29
    30
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    7 / 174 (4.02%)
    5 / 166 (3.01%)
    7 / 167 (4.19%)
    9 / 164 (5.49%)
         occurrences all number
    7
    7
    8
    11
    Influenza like illness
         subjects affected / exposed
    20 / 174 (11.49%)
    38 / 166 (22.89%)
    35 / 167 (20.96%)
    37 / 164 (22.56%)
         occurrences all number
    22
    44
    40
    46
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    30 / 174 (17.24%)
    36 / 166 (21.69%)
    32 / 167 (19.16%)
    29 / 164 (17.68%)
         occurrences all number
    40
    47
    42
    40
    Injection site haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 174 (5.17%)
    10 / 166 (6.02%)
    8 / 167 (4.79%)
    7 / 164 (4.27%)
         occurrences all number
    12
    13
    8
    7
    Injection site induration
    alternative assessment type: Systematic
         subjects affected / exposed
    13 / 174 (7.47%)
    16 / 166 (9.64%)
    12 / 167 (7.19%)
    10 / 164 (6.10%)
         occurrences all number
    17
    18
    13
    11
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed
    56 / 174 (32.18%)
    48 / 166 (28.92%)
    47 / 167 (28.14%)
    47 / 164 (28.66%)
         occurrences all number
    84
    65
    66
    66
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    22 / 174 (12.64%)
    28 / 166 (16.87%)
    32 / 167 (19.16%)
    22 / 164 (13.41%)
         occurrences all number
    27
    35
    34
    30
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    32 / 174 (18.39%)
    32 / 166 (19.28%)
    30 / 167 (17.96%)
    36 / 164 (21.95%)
         occurrences all number
    47
    41
    38
    46
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    21 / 174 (12.07%)
    20 / 166 (12.05%)
    22 / 167 (13.17%)
    14 / 164 (8.54%)
         occurrences all number
    26
    24
    30
    17
    Psychiatric disorders
    Eating disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    29 / 174 (16.67%)
    35 / 166 (21.08%)
    28 / 167 (16.77%)
    29 / 164 (17.68%)
         occurrences all number
    35
    43
    39
    36
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed
    34 / 174 (19.54%)
    37 / 166 (22.29%)
    34 / 167 (20.36%)
    29 / 164 (17.68%)
         occurrences all number
    48
    52
    41
    34
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 174 (3.45%)
    11 / 166 (6.63%)
    12 / 167 (7.19%)
    12 / 164 (7.32%)
         occurrences all number
    8
    14
    14
    13
    Gastroenteritis
         subjects affected / exposed
    17 / 174 (9.77%)
    17 / 166 (10.24%)
    15 / 167 (8.98%)
    15 / 164 (9.15%)
         occurrences all number
    19
    19
    16
    19
    Impetigo
         subjects affected / exposed
    6 / 174 (3.45%)
    8 / 166 (4.82%)
    10 / 167 (5.99%)
    6 / 164 (3.66%)
         occurrences all number
    7
    8
    13
    6
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    19 / 174 (10.92%)
    17 / 166 (10.24%)
    22 / 167 (13.17%)
    25 / 164 (15.24%)
         occurrences all number
    24
    22
    29
    33
    Rhinitis
    alternative assessment type: Systematic
         subjects affected / exposed
    22 / 174 (12.64%)
    30 / 166 (18.07%)
    19 / 167 (11.38%)
    26 / 164 (15.85%)
         occurrences all number
    31
    41
    23
    33
    Upper respiratory tract infection
         subjects affected / exposed
    48 / 174 (27.59%)
    44 / 166 (26.51%)
    53 / 167 (31.74%)
    41 / 164 (25.00%)
         occurrences all number
    79
    62
    68
    82

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
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