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    Clinical Trial Results:
    A Phase III/IV, Stratified, Randomized, Observer Blind, Multicenter Clinical Study to Evaluate the Efficacy, Safety and Immunogenicity of a Cell-Based Quadrivalent Subunit Influenza Virus Vaccine Compared to Non-Influenza Comparator Vaccine in Subjects ≥2 years to <18 Years of Age

    Summary
    EudraCT number
    		 2016-002883-15
    Trial protocol
    		 LT   EE   ES   FI   PL  
    Global end of trial date
    30 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2020
    First version publication date
    10 Apr 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    V130_12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03165617
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seqirus UK Limited
    Sponsor organisation address
    The Point, 29 Market Street Level 3, Maidenhead, Berkshire, United Kingdom, SL6 8AA
    Public contact
    Clinical Trial Disclosure Manager , Seqirus , Seqirus.Clinicaltrials@seqirus.com
    Scientific contact
    Clinical Trial Disclosure Manager , Seqirus, Seqirus.Clinicaltrials@seqirus.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
    13 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Primary Efficacy Objective(s): To demonstrate absolute vaccine efficacy of QIVc versus a non-influenza comparator determined by first occurrence RT-PCR or culture confirmed influenza, due to any influenza Type A and B strain in subjects ≥2 years to <18 years of age. In case of successful demonstration of the primary efficacy objective: - Co-Primary Efficacy Objective(s): To demonstrate absolute vaccine efficacy of QIVc versus a non-influenza comparator determined by first occurrence RT-PCR or culture confirmed influenza, due to any influenza Type A and B strain in subjects ≥3 years to <18 years of age.
    Protection of trial subjects
    This clinical study was designed, implemented, and reported on in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare, Seqirus codes on protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, ICH 1997)
    Background therapy
    		 -
    Evidence for comparator
    		 The V130_12 followed both EU (CHMP) and US (FDA) guidelines to use noninfluenza active comparator to provide benefit to subjects randomised to the comparator group Specifically for this study the non-influenza active comparator was Meningococcal (Group ACWY) Conjugate Vaccine.
    Actual start date of recruitment
    17 May 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 195
    Country: Number of subjects enrolled
    Philippines: 1800
    Country: Number of subjects enrolled
    Thailand: 400
    Country: Number of subjects enrolled
    Poland: 298
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Estonia: 1198
    Country: Number of subjects enrolled
    Finland: 326
    Country: Number of subjects enrolled
    Lithuania: 292
    Worldwide total number of subjects
    4514
    EEA total number of subjects
    2119
    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)
    3244
    Adolescents (12-17 years)
    1270
    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
    		 This study was conducted at 39 centers in 8 countries

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

    Period 1
    Period 1 title
    Overall Study Period (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
    The study was designed as an observer-blind study. Neither the subject nor any of the investigative site staff who were involved in the subjects’ clinical evaluations or treatment were aware of the vaccine administered. Vaccine administration was shielded from the subject and blinded study personnel.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QIVc (≥2 years to <18 years)
    Arm description
    		 Cell-derived Seasonal Quadrivalent Influenza Vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    QIVc
    Investigational medicinal product code
    Other name
    cell-derived Quadrivalent Influenza Vaccine
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    All subjects received a 0.5 mL intramuscular dose of QIVc at Day 1. Participants who were not previously vaccinated received a second 0.5 mL dose at Day 29.

    Arm title
    		 Comparator (≥2 years to <18 years)
    Arm description
    		 Non-influenza comparator vaccine for intramuscular use.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Meningococcal Conjugate (Group ACWY) Vaccine
    Investigational medicinal product code
    Other name
    Men ACWY vaccine, Menveo
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    All subjects received a 0.5 mL intramuscular dose of Meningococcal (Group ACWY) Conjugate Vaccine Subjects in the this group who were not previously vaccinated received placebo (0.9% w/v saline for injection) as second vaccination for blinding purposes.

    Number of subjects in period 1
    		QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years)
    Started
    2258
    2256
    Completed
    2249
    2247
    Not completed
    9
    9
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    3
    3
         Other
    1
    3
         Lost to follow-up
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QIVc (≥2 years to <18 years)
    Reporting group description
    		 Cell-derived Seasonal Quadrivalent Influenza Vaccine

    Reporting group title
    Comparator (≥2 years to <18 years)
    Reporting group description
    		 Non-influenza comparator vaccine for intramuscular use.

    Reporting group values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years) Total
    Number of subjects
    		 2258 2256 4514
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 1638 1606 3244
        Adolescents (12-17 years)
    		 620 650 1270
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.7 ± 4.0 8.9 ± 4.1 -
    Gender categorical
    Units: Subjects
        Female
    		 1106 1082 2188
        Male
    		 1152 1174 2326

    End points

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    End points reporting groups
    Reporting group title
    QIVc (≥2 years to <18 years)
    Reporting group description
    		 Cell-derived Seasonal Quadrivalent Influenza Vaccine

    Reporting group title
    Comparator (≥2 years to <18 years)
    Reporting group description
    		 Non-influenza comparator vaccine for intramuscular use.

    Subject analysis set title
    QIVc (≥3 years to <18 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cell-derived Seasonal Quadrivalent Influenza Vaccine

    Subject analysis set title
    Comparator (≥3 years to <18 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Non-influenza comparator vaccine for intramuscular use.

    Subject analysis set title
    QIVc (≥2 years to <9 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cell-derived Seasonal Quadrivalent Influenza Vaccine

    Subject analysis set title
    Comparator (≥2 years to <9 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Non-influenza comparator vaccine for intramuscular use.

    Subject analysis set title
    QIVc (≥4 years to <18 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cell-derived Seasonal Quadrivalent Influenza Vaccine

    Subject analysis set title
    Comparator (≥4 years to <18 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Non-influenza comparator vaccine for intramuscular use.

    Subject analysis set title
    QIVc (≥9 years to <18 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cell-derived Seasonal Quadrivalent Influenza Vaccine

    Subject analysis set title
    Comparator (≥9 years to <18 years of age)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Non-influenza comparator vaccine for intramuscular use.

    Primary: Primary Efficacy: First occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine in subjects ≥2 to <18 yrs

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    End point title
    		 Primary Efficacy: First occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine in subjects ≥2 to <18 yrs
    End point description
    The primary efficacy endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season. The success criterion used for this primary objective was as follows: The efficacy of the QIVc was demonstrated if the lower limit (LL) of the 2-sided 95% confidence interval (CI) for VE was above 20%. Dataset Used: FAS-Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination.
    End point type
    Primary
    End point timeframe
    Day 14 to Day 180 or until the end of the influenza season, whichever is longer
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years)
    Number of subjects analysed
    2257
    2252
    Units: Cases
        Any Strain
    175
    364
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain
    Statistical analysis description
    Adjusted aVE for QIVc vs. comparator. Success criteria for the primary efficacy endpoint was met if the LL of the 2-sided 95% CI of the aVE estimate was greater than 20% (primary endpoint) using the protocol definition of ILI for the entire age range (2 to <18 years of age).
    Comparison groups
    Comparator (≥2 years to <18 years) v QIVc (≥2 years to <18 years)
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    54.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 45.67
         upper limit
    		 62.12

    Primary: Co-Primary Efficacy: First occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine in subjects 3 to <18 yrs

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    End point title
    		 Co-Primary Efficacy: First occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine in subjects 3 to <18 yrs
    End point description
    The co-primary efficacy endpoints were defined as the time from the last study vaccination to the onset of the first occurrence of either RT-PCR- or culture-confirmed influenza (time-to-event analyses) due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season. The co-primary efficacy objective was to be assessed on condition that the primary efficacy objective was successfully demonstrated. The success criterion used for this co-primary objective was as follows: The efficacy of the QIVc was demonstrated if the LL of the 2-sided 95% CI for VE was above 30%. Dataset Used: FAS-Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination.
    End point type
    Primary
    End point timeframe
    Day 14 to Day 180 or until the end of the influenza season, whichever is longer
    End point values
    		 QIVc (≥3 years to <18 years of age) Comparator (≥3 years to <18 years of age)
    Number of subjects analysed
    2208
    2201
    Units: Cases
        Any Strain
    175
    351
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain
    Statistical analysis description
    Adjusted aVE for QIVc vs. comparator. Success criteria for the primary efficacy endpoint was met if the LL of the 2-sided 95% CI of the aVE estimate was greater than 30% (co-primary endpoint) using the protocol definition of ILI for the entire age range (3 to <18 years of age).
    Comparison groups
    Comparator (≥3 years to <18 years of age) v QIVc (≥3 years to <18 years of age)
    Number of subjects included in analysis
    4409
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    54.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 44.8
         upper limit
    		 61.71

    Secondary: Secondary Efficacy: First occurrence of either RT-PCR- or culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine

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    End point title
    		 Secondary Efficacy: First occurrence of either RT-PCR- or culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine
    End point description
    The endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of either RT-PCR- or culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years. Dataset Used: FAS-Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination.
    End point type
    Secondary
    End point timeframe
    Day 14 to Day 180 or until the end of the influenza season, whichever is longer
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years) QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age) QIVc (≥4 years to <18 years of age) Comparator (≥4 years to <18 years of age) QIVc (≥9 years to <18 years of age) Comparator (≥9 years to <18 years of age)
    Number of subjects analysed
    2257
    2252
    1146
    1142
    2045
    2032
    1111
    1110
    Units: Cases
        Any
    175
    364
    123
    234
    154
    310
    52
    130
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <18 Years.
    Comparison groups
    QIVc (≥2 years to <18 years) v Comparator (≥2 years to <18 years)
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    54.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 45.67
         upper limit
    		 62.12
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <9yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <9 Years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    Comparator (≥2 years to <9 years of age) v QIVc (≥2 years to <9 years of age)
    Number of subjects included in analysis
    2288
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    50.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 38.43
         upper limit
    		 60.22
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 4 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 4 to <18 Years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥4 years to <18 years of age) v Comparator (≥4 years to <18 years of age)
    Number of subjects included in analysis
    4077
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    53.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 43.38
         upper limit
    		 61.54
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 9 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 9 to <18 Years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥9 years to <18 years of age) v Comparator (≥9 years to <18 years of age)
    Number of subjects included in analysis
    2221
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    61.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47.37
         upper limit
    		 72.34

    Secondary: Secondary Efficacy: First occurrence of RT-PCR-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine

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    End point title
    		 Secondary Efficacy: First occurrence of RT-PCR-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine
    End point description
    The endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of RT-PCR-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years Dataset Used: FAS-Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination.
    End point type
    Secondary
    End point timeframe
    Day 14 to Day 180 or until the end of the influenza season, whichever is longer
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years) QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age) QIVc (≥4 years to <18 years of age) Comparator (≥4 years to <18 years of age) QIVc (≥9 years to <18 years of age) Comparator (≥9 years to <18 years of age)
    Number of subjects analysed
    2257
    2252
    1146
    1142
    2045
    2032
    1111
    1110
    Units: Cases
    175
    364
    123
    234
    154
    310
    52
    130
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <18 Years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    Comparator (≥2 years to <18 years) v QIVc (≥2 years to <18 years)
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    54.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 45.67
         upper limit
    		 62.12
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <9yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <9 Years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥2 years to <9 years of age) v Comparator (≥2 years to <9 years of age)
    Number of subjects included in analysis
    2288
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    50.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 38.43
         upper limit
    		 60.22
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 4 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 4 to <18 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥4 years to <18 years of age) v Comparator (≥4 years to <18 years of age)
    Number of subjects included in analysis
    4077
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    53.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 43.38
         upper limit
    		 61.54
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 9 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 9 to <18 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥9 years to <18 years of age) v Comparator (≥9 years to <18 years of age)
    Number of subjects included in analysis
    2221
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    61.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47.37
         upper limit
    		 72.34

    Secondary: Secondary Efficacy: First occurrence of culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine

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    End point title
    		 Secondary Efficacy: First occurrence of culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine
    End point description
    The endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of culture-confirmed influenza due to any influenza Type A or B strain regardless of antigenic match to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years. Dataset Used: FAS-Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination.
    End point type
    Secondary
    End point timeframe
    Day 14 to Day 180 or until the end of the influenza season, whichever is longer
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years) QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age) QIVc (≥4 years to <18 years of age) Comparator (≥4 years to <18 years of age) QIVc (≥9 years to <18 years of age) Comparator (≥9 years to <18 years of age)
    Number of subjects analysed
    2257
    2252
    1146
    1142
    2045
    2032
    1111
    1110
    Units: Cases
    115
    279
    79
    190
    101
    237
    36
    89
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <18 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥2 years to <18 years) v Comparator (≥2 years to <18 years)
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    60.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 51.3
         upper limit
    		 68.46
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <9yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <9 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥2 years to <9 years of age) v Comparator (≥2 years to <9 years of age)
    Number of subjects included in analysis
    2288
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    60.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 49.01
         upper limit
    		 69.83
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 4 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 4 to <18 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    Comparator (≥4 years to <18 years of age) v QIVc (≥4 years to <18 years of age)
    Number of subjects included in analysis
    4077
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    59.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 49.08
         upper limit
    		 68.05
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 9 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 9 to <18 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥9 years to <18 years of age) v Comparator (≥9 years to <18 years of age)
    Number of subjects included in analysis
    2221
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    60.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 42.14
         upper limit
    		 73.33

    Secondary: Secondary Efficacy: First occurrence of culture-confirmed influenza due to influenza Type A or B strain antigenically matched to the strains selected for the seasonal vaccine

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    End point title
    		 Secondary Efficacy: First occurrence of culture-confirmed influenza due to influenza Type A or B strain antigenically matched to the strains selected for the seasonal vaccine
    End point description
    The endpoint was defined as the time from the last study vaccination to the onset of the first occurrence of culture-confirmed influenza due to influenza Type A or B strain antigenically matched to the strains selected for the seasonal vaccine, that occurred more than 14 days after the last vaccination until the end of the influenza season in subjects 2 to <18 years, 2 to <9 years, 4 to <18 years, and 9 to <18 years. Dataset Used: FAS-Efficacy = All subjects in the All Enrolled Set who received at least one dose of study vaccine and were evaluated for efficacy from 14 days after the last vaccination.
    End point type
    Secondary
    End point timeframe
    Day 14 to Day 180 or until the end of the influenza season, whichever is longer
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years) QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age) QIVc (≥4 years to <18 years of age) Comparator (≥4 years to <18 years of age) QIVc (≥9 years to <18 years of age) Comparator (≥9 years to <18 years of age)
    Number of subjects analysed
    2257
    2252
    1146
    1142
    2045
    2032
    1111
    1110
    Units: Cases
    90
    236
    64
    164
    81
    200
    26
    72
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <18 Years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥2 years to <18 years) v Comparator (≥2 years to <18 years)
    Number of subjects included in analysis
    4509
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    63.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.64
         upper limit
    		 71.48
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 2 to <9yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 2 to <9 Years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥2 years to <9 years of age) v Comparator (≥2 years to <9 years of age)
    Number of subjects included in analysis
    2288
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    63.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 50.66
         upper limit
    		 72.32
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 4 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 4 to <18 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥4 years to <18 years of age) v Comparator (≥4 years to <18 years of age)
    Number of subjects included in analysis
    4077
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    61.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 50.25
         upper limit
    		 70.33
    Statistical analysis title
    		 Absolute Vaccine Efficacy, Any Strain, 9 to <18yrs
    Statistical analysis description
    Absolute Vaccine Efficacy (aVE) for 9 to <18 years. Note that no prespecified criteria for success were defined for the secondary efficacy endpoints
    Comparison groups
    QIVc (≥9 years to <18 years of age) v Comparator (≥9 years to <18 years of age)
    Number of subjects included in analysis
    2221
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 aVE
    Point estimate
    64.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 44.84
         upper limit
    		 77.51

    Secondary: Secondary Immunogenicity: Geometric Mean Titers for 4 influenza strains (HI Assay)

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    End point title
    		 Secondary Immunogenicity: Geometric Mean Titers for 4 influenza strains (HI Assay)
    End point description
    Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all “previously vaccinated” subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all “not previously vaccinated” subjects receiving 2 doses) for all 4 influenza strains using the HI assay. Dataset used: FAS Immunogenicity (HI) = All subjects in the All Enrolled Set who received at least one dose of study vaccine and provided evaluable serum samples at both baseline and after the last vaccination.
    End point type
    Secondary
    End point timeframe
    Day 1 (all subjects), Day 22 (all previously vaccinated subjects) or Day 29 and Day 50 (all not previously vaccinated subjects receiving 2 doses)
    End point values
    		 QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age)
    Number of subjects analysed
    210 [1]
    212 [2]
    Units: geometric mean titre
    geometric mean (confidence interval 95%)
        A/H1N1 Day 1 HI GMT Season 2
    50.83 (41.89 to 61.66)
    47.51 (39.15 to 57.64)
        A/H1N1 Day 22/50 HI GMT Season 2
    283.45 (249.22 to 322.38)
    49.20 (43.24 to 55.98)
        A/H3N2 Day 1 HI GMT Season 2
    97.02 (86.51 to 108.81)
    94.40 (84.19 to 105.84)
        A/H3N2 Day 22/50 HI GMT Season 2
    168.73 (150.87 to 188.70)
    96.27 (86.05 to 107.70)
        B/Victoria Day 1 HI GMT Season 2
    11.67 (9.97 to 13.67)
    11.73 (10.02 to 13.73)
        B/Victoria Day 22/50 HI GMT Season 2
    45.25 (39.73 to 51.54)
    11.94 (10.48 to 13.60)
        B/Yamagata Day 1 HI GMT Season 2
    10.87 (9.46 to 12.50)
    12.17 (10.59 to 13.99)
        B/Yamagata Day 22/50 HI GMT Season 2
    52.81 (45.77 to 60.94)
    12.34 (10.68 to 14.24)
        A/H1N1 Day 1 HI GMT Season 3
    36.62 (22.61 to 59.31)
    31.76 (19.88 to 50.74)
        A/H1N1 Day 22/50 HI GMT Season 3
    380.70 (283.12 to 511.91)
    48.22 (36.14 to 64.32)
        A/H3N2 Day 1 HI GMT Season 3
    20.85 (15.99 to 27.20)
    20.74 (16.02 to 26.85)
        A/H3N2 Day 22/50 HI GMT Season 3
    67.64 (57.03 to 80.24)
    16.73 (14.17 to 19.77)
        B/Victoria Day 1 HI GMT Season 3
    9.54 (7.25 to 12.54)
    9.41 (7.22 to 12.28)
        B/Victoria Day 22/50 HI GMT Season 3
    66.82 (51.29 to 87.04)
    11.94 (9.23 to 15.44)
        B/Yamagata Day 1 HI GMT Season 3
    23.98 (16.74 to 34.36)
    27.33 (19.27 to 38.76)
        B/Yamagata Day 22/50 HI GMT Season 3
    108.49 (85.16 to 138.22)
    21.68 (17.11 to 27.46)
    Notes
    [1] - S2 n=210; S3 n=154
    [2] - S2 n=212; S3 n=145
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: Percentage of subjects achieving seroconversion for 4 influenza strains (HI assay)

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    End point title
    		 Secondary Immunogenicity: Percentage of subjects achieving seroconversion for 4 influenza strains (HI assay)
    End point description
    Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all “previously vaccinated” subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all “not previously vaccinated” subjects receiving 2 doses) for all 4 influenza strains using the HI assay. Seroconversion was defined as: either a prevaccination HI titer <1:10 and a postvaccination HI titer ≥1:40 or a prevaccination HI titer ≥1:10 and a ≥4 fold increase in postvaccination HI titer) Dataset used: FAS Immunogenicity = All subjects in the All Enrolled Set who received at least one dose of study vaccine and provided evaluable serum samples at both baseline and after the last vaccination. Data
    End point type
    Secondary
    End point timeframe
    Day 22 (all previously vaccinated subjects) or Day 29 and Day 50 (all not previously vaccinated subjects receiving 2 doses)
    End point values
    		 QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age)
    Number of subjects analysed
    210 [3]
    212 [4]
    Units: percentage of participants
    number (confidence interval 95%)
        A/H1N1 Season 2
    59.5 (52.55 to 66.22)
    1.9 (0.52 to 4.80)
        A/H3N2 Season 2
    19.0 (13.97 to 25.02)
    1.9 (0.52 to 4.80)
        B/Victoria Season 2
    40.0 (33.32 to 46.97)
    2.9 (1.06 to 6.11)
        B/Yamagata Season 2
    49.5 (42.57 to 56.49)
    4.8 (2.31 to 8.58)
        A/H1N1 Season 3
    74.0 (66.35 to 80.75)
    6.2 (2.88 to 11.46)
        A/H3N2 Season 3
    51.9 (43.76 to 60.06)
    1.4 (0.17 to 4.89)
        B/Victoria Season 3
    58.4 (50.23 to 66.32)
    3.4 (1.13 to 7.86)
        B/Yamagata Season 3
    58.4 (50.23 to 66.32)
    1.4 (0.17 to 4.89)
    Notes
    [3] - S1 n=210; S2 n=154
    [4] - S1 n=212; S2 n=145
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: Geometric mean ratio for 4 influenza strains (HI assay)

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    End point title
    		 Secondary Immunogenicity: Geometric mean ratio for 4 influenza strains (HI assay)
    End point description
    Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all “previously vaccinated” subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all “not previously vaccinated” subjects receiving 2 doses) for all 4 influenza strains using the HI assay. Geometric mean ratios (GMRs) measure the ratio in immunogenicity titers within subject\ Dataset used: FAS Immunogenicity = All subjects in the All Enrolled Set who received at least one dose of study vaccine and provided evaluable serum samples at both baseline and after the last vaccination.
    End point type
    Secondary
    End point timeframe
    Day 22/Day 1 (all previously vaccinated subjects) or Day 29/Day 1 and Day 50/Day 1 (all not previously vaccinated subjects receiving 2 doses)
    End point values
    		 QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age)
    Number of subjects analysed
    210 [5]
    212 [6]
    Units: ratio
    number (confidence interval 95%)
        A/H1N1 Season 2
    5.76 (5.06 to 6.55)
    1.00 (0.88 to 1.14)
        A/H3N2 Season 2
    1.74 (1.56 to 1.95)
    0.99 (0.89 to 1.11)
        B/Victoria Season 2
    3.79 (3.33 to 4.32)
    1.00 (0.88 to 1.14)
        B/Yamagata Season 2
    4.63 (4.01 to 5.34)
    1.08 (0.94 to 1.25)
        A/H1N1 Season 3
    9.73 (7.24 to 13.09)
    1.23 (0.92 to 1.64)
        A/H3N2 Season 3
    4.14 (3.49 to 4.91)
    1.02 (0.87 to 1.21)
        B/Victoria Season 3
    7.01 (5.38 to 9.14)
    1.25 (0.97 to 1.62)
        B/Yamagata Season 3
    5.27 (4.14 to 6.72)
    1.05 (0.83 to 1.33)
    Notes
    [5] - S1 n=210; S2 n=154
    [6] - S1 n=212; S2 n=145
    No statistical analyses for this end point

    Secondary: Secondary Immunogenicity: Percentage of subjects with HI titer ≥1:40 for 4 influenza strains (HI assay)

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    End point title
    		 Secondary Immunogenicity: Percentage of subjects with HI titer ≥1:40 for 4 influenza strains (HI assay)
    End point description
    Immunogenicity was characterized by HI assay 3 weeks after the last vaccination in a subset of subjects 2 to <9 years of age enrolled in Season 2 (n=432) and Season 3 (n=319) who were immunized and had immunogenicity data at the assessed timepoints (FAS Immunogenicity). Immunogenicity was assessed at baseline (Day 1; all subjects in immunogenicity subset), at Day 22 (all “previously vaccinated” subjects receiving a single dose of the study vaccine), and at Days 29 and 50 (all “not previously vaccinated” subjects receiving 2 doses) for all 4 influenza strains using the HI assay. The measures for assessing immunogenicity as determined by HI were as follows: Percentage of subjects with an HI titer ≥1:40 on Day 22 (all “previously vaccinated” subjects receiving a single vaccine dose) or Days 29 and 50 (all “not previously vaccinated” subjects receiving 2 doses) for all 4 influenza strains. Dataset used: FAS Immunogenicity = All subjects in the All Enrolled Set who received at least
    End point type
    Secondary
    End point timeframe
    Day 1 (all subjects), Day 22 (all “previously vaccinated” subjects receiving a single vaccine dose) or Days 29 and 50 (all “not previously vaccinated”subjects receiving 2 doses)
    End point values
    		 QIVc (≥2 years to <9 years of age) Comparator (≥2 years to <9 years of age)
    Number of subjects analysed
    210 [7]
    212 [8]
    Units: percentage of participants
    number (confidence interval 95%)
        A/H1N1 Season 2
    88.6 (83.47 to 92.54)
    58.6 (51.59 to 65.31)
        A/H3N2 Season 2
    90.0 (85.12 to 93.70)
    92.4 (87.92 to 95.58)
        B/Victoria Season 2
    54.3 (47.29 to 61.16)
    24.3 (18.65 to 30.66)
        B/Yamagata Season 2
    63.8 (56.91 to 70.31)
    21.4 (16.08 to 27.60)
        A/H1N1 Season 3
    94.8 (90.02 to 97.73)
    55.2 (46.70 to 63.43)
        A/H3N2 Season 3
    74.0 (66.35 to 80.75)
    24.8 (18.03 to 32.68)
        B/Victoria Season 3
    68.8 (60.88 to 76.04)
    13.1 (8.08 to 19.70)
        B/Yamagata Season 3
    79.2 (71.95 to 85.33)
    46.2 (37.90 to 54.67)
    Notes
    [7] - Season 2 QIVc N = 210 Season 2 Comp N = 212 Season 3 QIVc N = 154 Season 3 Comp N = 145
    [8] - Season 2 QIVc N = 210 Season 2 Comp N = 212 Season 3 QIVc N = 154 Season 3 Comp N = 145
    No statistical analyses for this end point

    Secondary: Secondary Safety: Percentage of subjects with solicited local and systemic adverse events for 7 days after vaccination

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    End point title
    		 Secondary Safety: Percentage of subjects with solicited local and systemic adverse events for 7 days after vaccination
    End point description
    The secondary safety objective was to assess the safety and tolerability of QIVc. The measures for assessing safety and tolerability were as follows: Percentage of subjects with solicited local and systemic adverse events (AEs) for 7 days after vaccination on Day 1 (for “previously vaccinated” subjects) or for 7 days after vaccination on Day 1 and Day 29 (for “not previously vaccinated” subjects) in the QIVc group and the non-influenza comparator vaccine group. Dataset used: Solicited Safety Set = All subjects in the Exposed Set who had gone through any assessment of local and systemic site reaction and/or assessment of any use of analgesics/antipyretics. Note: Other solicited adverse events refer to use of analgesics / antipyretics for prophylaxis or treatment.
    End point type
    Secondary
    End point timeframe
    7 days after vaccination on Day 1 (for “previously vaccinated” subjects) or for 7 days after vaccination on Day 1 and Day 29 (for “not previously vaccinated” subjects)
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years)
    Number of subjects analysed
    2255
    2254
    Units: Percentage
    number (not applicable)
        Solicited AEs
    51.4
    48.6
        Solicited Local AEs
    36.8
    33.6
        Solicited Systemic AEs
    31.4
    30.5
        Other
    8.6
    7.3
    No statistical analyses for this end point

    Secondary: Secondary Safety: Percentage of subjects with unsolicited AEs for 21 days after vaccination

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    End point title
    		 Secondary Safety: Percentage of subjects with unsolicited AEs for 21 days after vaccination
    End point description
    The secondary safety objective was to assess the safety and tolerability of QIVc. The measures for assessing safety and tolerability were as follows: Percentage of subjects with unsolicited AEs assessed from Day 1 to Day 22 (for “previously vaccinated” subjects) or from Day 1 to Day 50 (for “not previously vaccinated” subjects) in the QIVc group and the non-influenza comparator vaccine group. Dataset used: Unsolicited Safety Set = All subjects in the Exposed Set who had gone through any AE assessments, ie, a subject did not have to have any AEs to be included in this population.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 22 (for “previously vaccinated” subjects) or from Day 1 to Day 50 (for “not previously vaccinated” subjects)
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years)
    Number of subjects analysed
    2258
    2255
    Units: Percentage
    number (not applicable)
        Any AE
    28.0
    27.9
        Any AE (Mild)
    24.4
    24.6
        Any AE (Moderate)
    4.8
    4.5
        Any AE (Severe)
    0.5
    0.5
        Related AE
    4.3
    3.9
    No statistical analyses for this end point

    Secondary: Secondary Safety: Percentage of subjects with SAEs, AEs leading to withdrawal from vaccination and/or the study, MAAEs, and NOCDs reported

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    End point title
    		 Secondary Safety: Percentage of subjects with SAEs, AEs leading to withdrawal from vaccination and/or the study, MAAEs, and NOCDs reported
    End point description
    The secondary safety objective was to assess the safety and tolerability of QIVc. The measures for assessing safety and tolerability were as follows: Percentage of subjects with SAEs, AEs leading to withdrawal from vaccination and/or the study, New Onset of Chronic Diseases (NOCDs), medical attended AEs (MAAE) within 30 days of ILI, AEs leading to death reported during the subject’s entire participation in the study (ie, from Day 1 to Day 181 [for “previously vaccinated” subjects] or from Day 1 to Day 209 [for “not previously vaccinated” subjects]), or until the end of influenza season, whichever was longer, and all medications associated with these events. Medically-attended AEs were collected through the first 30 days after the first occurrence of influenza-like illness. Dataset used: Unsolicited Safety Set = All subjects in the Exposed Set who had gone through any AE assessments, ie, a subject did not have to have any AEs to be included in this popul
    End point type
    Secondary
    End point timeframe
    from Day 1 to Day 181 [for “previously vaccinated” subjects] or from Day 1 to Day 209 [for “not previously vaccinated” subjects]), or until the end of influenza season, whichever was longer
    End point values
    		 QIVc (≥2 years to <18 years) Comparator (≥2 years to <18 years)
    Number of subjects analysed
    2258
    2255
    Units: percentage
    number (not applicable)
        SAE
    1.1
    1.3
        Related SAE
    0
    0
        AE leading to study withdrawal
    0
    0
        MAAE
    27.2
    30.1
        NOCD
    0.4
    0.5
        Death
    0
    0.04
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through end of study
    Adverse event reporting additional description
    Nonserious Unsolicited AEs and SAEs are reported
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    QIVc
    Reporting group description
    		 A single dose of approximately 0.5 mL of QIVc was administered on Day 1. (QIVc = Quadrivalent Influenza Vaccine, cell-based ). For those subjects who were not previously vaccinated, a second dose was administered on Day 29. For subjects randomized in the QIVc-arm, the second dose was QIVc.)

    Reporting group title
    Non-influenza Comparator Vaccine
    Reporting group description
    		 A single dose of approximately 0.5 mL of non-influenza comparator vaccine was administered on Day 1. (Non-nfluenza comparator vaccine is (meningococcal [Groups A, C, W-135, and Y] oligosaccharide diphtheria CRM197 conjugate vaccine [Men ACWY]. For those not previously vaccinated, a second dose was administered on Day 29. For subjects randomized in the non-influenza comparator group, the second dose was a placebo (saline for injection).

    Serious adverse events
    		 QIVc Non-influenza Comparator Vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 2258 (1.11%)
    30 / 2255 (1.33%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder developmental
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Loss of consciousness
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status migrainosus
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Unevaluable event
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anorexia nervosa
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    1 / 2258 (0.04%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 2258 (0.22%)
    3 / 2255 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    2 / 2258 (0.09%)
    2 / 2255 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    2 / 2258 (0.09%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 2258 (0.04%)
    2 / 2255 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 2258 (0.04%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue haemorrhagic fever
         subjects affected / exposed
    1 / 2258 (0.04%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal gastroenteritis
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 2258 (0.04%)
    0 / 2255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 2258 (0.00%)
    2 / 2255 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 2258 (0.00%)
    3 / 2255 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 2258 (0.00%)
    1 / 2255 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 QIVc Non-influenza Comparator Vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    871 / 2258 (38.57%)
    963 / 2255 (42.71%)
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    791 / 2258 (35.03%)
    894 / 2255 (39.65%)
         occurrences all number
    1194
    1252
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    97 / 2258 (4.30%)
    121 / 2255 (5.37%)
         occurrences all number
    111
    135
    Upper respiratory tract infection
         subjects affected / exposed
    216 / 2258 (9.57%)
    216 / 2255 (9.58%)
         occurrences all number
    298
    270

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2016
    This amendment included updates to support regulatory submissions in additional global regions and to satisfy CHMP requests made after review of the study synopsis. These changes consisted of the following: extending the age range include subjects ≥2 years of age; a co-primary objective was added to the revised protocol, for evaluation of efficacy in subjects 2 to <18 years of age; secondary endpoints were aligned with the cohort distribution of 3 to <18, 2 to <18, 3 to <9, 2 to <9, and 9 to <18 years of age, to allow for evaluation per age cohort; monitoring of ILI cases was to continue until the end of the influenza season in the revised protocol, instead of until the end of study participation; blood drawn from the immunogenicity subset was lowered from 10 mL to 7 mL per visit to reduce subject burden; pregnancy testing was scheduled to occur prior to each vaccination; the end of study definition was adapted for reporting purposes and the number of immunogenicity subset subjects was clarified as 666 subjects.
    30 Nov 2017
    This amendment described an adjustment of the assumptions underlying the sample size calculation to maintain the protocol-defined power for demonstration of the efficacy objective in subjects 3 to <18 years of age. The assumed event rate in non-influenza comparator arm was updated from 4% to 8% and additional updated assumptions included: reducing the original absolute VE (aVE) assumption from 60% to 50%; the co-primary aVE assumption (aVE = 55%) was changed to aVE = 45%; the primary and co-primary endpoints were reversed; adjustments to the sample size and the required number of influenza events were needed in order to maintain study power. The number of influenza-confirmed cases needed to proceed to final analysis increased from 144 to 381. An interim analysis was planned after the majority of the cases for the second influenza season were collected; the total number of healthy subjects planned to be enrolled was updated from 6368 to 7692; allocation strategy was changed from a 2:1 to a 1:1; immunogenicity subset enrollment was to be performed during the second and subsequent seasons, and not limited to the second season only; given the changes in subject allocation for the immunogenicity subset, and because of the descriptive nature of the secondary immunogenicity objective, the immunogenicity sampling strategy was further clarified. Sample size for secondary immunogenicity objectives has been modified and redistributed in the revised protocol and as a consequence of changes in the allocation ratio and enrollment was to be performed during the second and subsequent seasons, the number of subjects was increased.
    20 Jun 2018
    Multiple reasons for this amendment included: 1) adjusting the timing, scope and conditionality of the interim analysis (IA), 2) enrolment in a third season was planned despite the fact the total number of cases approached the minimal number of cases estimated for analysis, 3) Added 2 age cohorts to evalute efficacy, immunogenicity, and safety Compliance to EU GDPR was also added to Data Management 4) an exploratory objective has been added to further describe vaccine efficacy against antigenically matched A/H3N2 influenza cases and the microneutralization assay may be used to characterize the immune response of QIVc. 1. The prespecified interim analysis after the second season was removed and updated to an interim analysis performed a) when a sufficient number of influenza-confirmed cases have occurred and b) conditional to the needs of the Sponsor. 2. The test for futility was removed from the interim analysis, as vaccine efficacy and influenza strain distribution could vary widely between influenza seasons. 3. Enrolment in a third season was planned and reasons provided in the amendment. 4. The following exploratory efficacy objective was added: To describe the absolute vaccine efficacy of QIVc versus a non-influenza comparator determined by occurrence of culture confirmed illness caused by influenza H3N2 virus strains antigenically matched to the influenza H3N2 A/Singapore/GP2050/2015 (cell seed) strain. 5. Although antigenic characterization of influenza viruses using HI assay was still successful for the antigenic characterization of influenza A(H1N1) and B-viruses, problems had arisen for A(H3N2) viruses mainly due to evolutionary changes in agglutination properties. As an alternative, a MN assay might be used to evaluate the immunogenicity of QIVc.
    13 Dec 2018
    This amendment included changes to address regulatory feedback in regards to the intended use of microneutralization assay data and to reduce the overall number of planned subgroup analyses. Specifically, to reflect regulatory feedback, the microneutralization (MN) assay was kept for Exploratory Immunogenicity Endpoints and removed from the Secondary Immunogenicity Endpoints and total number of age categories for subgroup analyses was reduced.

    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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