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    Clinical Trial Results:
    A Phase III, Observer-Blind, Randomized, Non-influenza Vaccine Comparator-Controlled, Parallel-Group, Multi-Country Study in Children Aged 6–35 Months to Assess the Safety and Efficacy of Abbott’s Candidate Quadrivalent Influenza Vaccine

    Summary
    EudraCT number
    		 2016-004904-74
    Trial protocol
    		 SK   DK   EE   CZ   LT   BG   IT   SI   ES   FR   HR   HU   RO  
    Global end of trial date
    31 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2020
    First version publication date
    09 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INFQ3003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Abbott Biologicals B.V.
    Sponsor organisation address
    C.J. van Houtenlaan 36, Weesp, Netherlands, NL-1381 CP
    Public contact
    Public Affairs Director, Abbott Products Operations AG, hind.ounis@abbott.com
    Scientific contact
    Global Clinical Director, Abbott Healthcare Products B.V., serge.vandewitte@abbott.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001782-PIP01-15
    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
    31 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate, in children aged 6 to 35 months, the absolute efficacy of quadrivalent influenza vaccine (QIV) in the prevention of symptomatic influenza infection due to any circulating seasonal influenza strain compared with a non-influenza (child) vaccine (NIV), assessed by reverse transcription polymerase chain reaction (RT-PCR)-confirmed influenza A and/or B infection.
    Protection of trial subjects
    The study was conducted in compliance with Good Clinical Practice and the applicable national regulations to assure that the rights, safety, and well-being of the participating study subjects were protected, consistent with the ethical principles that have their origin in the Declaration of Helsinki. Following the vaccination, subjects were observed for at least 30 minutes to monitor for any immediate adverse reactions (appropriate medical treatment and supervision were readily available in case of an anaphylactic event).
    Background therapy
    		 -
    Evidence for comparator
    		 NIVs were selected as the control group for this study based on recommendations outlined in the Guideline on Influenza Vaccines by the European Medicines Agency (EMA/CHMP/VWP/457259/2014). As per the guideline, NIVs were used to avoid the use of placebo in this vulnerable population and to provide a benefit to study participation for all study subjects. The NIVs selected for the control group were vaccines that were approved for use and commonly used in routine medical practice for the respective age ranges. The selected NIV controls needed to complement the existing national/regional childhood vaccination programs and therefore the eventual usability of each of the NIVs varied by country/region.
    Actual start date of recruitment
    01 Sep 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 8 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 160
    Country: Number of subjects enrolled
    Czech Republic: 92
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Estonia: 569
    Country: Number of subjects enrolled
    Hungary: 59
    Country: Number of subjects enrolled
    Italy: 91
    Country: Number of subjects enrolled
    Lithuania: 250
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Philippines: 285
    Country: Number of subjects enrolled
    Romania: 45
    Country: Number of subjects enrolled
    Slovakia: 30
    Country: Number of subjects enrolled
    Slovenia: 6
    Country: Number of subjects enrolled
    Spain: 224
    Country: Number of subjects enrolled
    Thailand: 152
    Country: Number of subjects enrolled
    Vietnam: 21
    Worldwide total number of subjects
    2007
    EEA total number of subjects
    1540
    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)
    1341
    Children (2-11 years)
    666
    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
    		 The study was conducted at 56 centers across Europe and Asia and comprised at least 3 clinic visits and 3 telephone contacts (TCs) per completed subject. The study included 2 cohorts (Cohort 1 and Cohort 2) and was conducted over 3 influenza seasons (Northern Hemisphere [NH] 2017/2018, NH 2018/2019, and Southern Hemisphere [SH] 2019).

    Pre-assignment
    Screening details
    		 Eligible subjects were randomly assigned to vaccination with QIV or a NIV in a 1:1 ratio. Study comprised of a primary immunization period (including Cohort 1 Year 1 and Cohort 2) and a revaccination period (including subset of subjects from Cohort 1 who were exposed to QIV in Year 1). Results data are presented for the primary immunization period.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Observer blind: the subject and their parents/legally acceptable representative (LAR), the Investigator, and those responsible for evaluation of any study endpoint (e.g., safety, reactogenicity, immunogenicity, and efficacy) and for review/analysis of study data were unaware of the treatment assignments. To maintain blinding, the vaccination was performed by authorized medical site study personnel who did not participate in any of the study clinical evaluations.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Quadrivalent Influenza Vaccine
    Arm description
    		 Each subject received 2 doses of QIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quadrivalent Influenza Vaccine
    Investigational medicinal product code
    Other name
    QIV, Influvac® Tetra
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 2 doses of 0.5 milliliters (mL) each of QIV administered by intramuscular injection in the deltoid muscle of the upper arm or in the anterolateral thigh. For the NH QIV (subunit, inactivated), the active drug substance was 15 micrograms (µg) of hemagglutinin (HA) of each of the 4 viral strains recommended for the NH season by the World Health Organization (WHO) and the Committee for Medicinal Products for Human Use as follows: • Cohort 1 Year 1 (Season NH 2017/2018) • Cohort 2 NH (Season NH 2018/2019) For the SH QIV (subunit, inactivated) the active drug substance was 15 µg of HA of each of the 4 viral strains recommended for the SH season by the WHO as follows: • Cohort 2 SH (Season SH 2019)

    Arm title
    		 Non-influenza Vaccine
    Arm description
    		 Each subject received 2 doses of a NIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination. For each subject enrolled in the NIV control group, only 1 reference product was used.
    Arm type
    		 Control vaccine

    Investigational medicinal product name
    Non-influenza Vaccine
    Investigational medicinal product code
    Other name
    NIV
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 2 doses of 0.25 to 0.5 mL each of a NIV control administered by intramuscular injection in the deltoid muscle of the upper arm or in the anterolateral thigh. Depending on the subject’s age and the routine childhood vaccination programs in each of the respective countries, the NIV controls used could be: For infants 6 to 11 months of age: • Pneumococcal conjugate vaccine or meningococcal group C conjugate vaccine. For toddlers 12 to 35 months of age: • Hepatitis A vaccine, tick borne encephalitis vaccine or varicella vaccine. Dose and administration details apply for subjects randomized to a NIV in both Cohorts 1 and 2.

    Number of subjects in period 1
    		Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Started
    1009
    998
    Vaccinated
    1005
    995
    Completed
    986
    975
    Not completed
    23
    23
         Consent withdrawn by subject
    14
    9
         Administrative
    1
    1
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    5
    10
         Protocol deviation
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine
    Reporting group description
    		 Each subject received 2 doses of QIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination.

    Reporting group title
    Non-influenza Vaccine
    Reporting group description
    		 Each subject received 2 doses of a NIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination. For each subject enrolled in the NIV control group, only 1 reference product was used.

    Reporting group values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine Total
    Number of subjects
    		 1009 998 2007
    Age categorical
    Units: Subjects
        >=6 and =<11 months
    		 200 195 395
        >=12 and =<18 months
    		 291 281 572
        >=19 and =<24 months
    		 216 217 433
        >=25 and =<35 months
    		 302 305 607
    Age continuous
    Units: Months
        arithmetic mean (standard deviation)
    		 19.4 ( 8.1 ) 19.6 ( 8.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 517 499 1016
        Male
    		 492 499 991
    Race
    Units: Subjects
        White
    		 751 733 1484
        Asian
    		 244 240 484
        Black
    		 5 6 11
        Other
    		 9 19 28
    Cohort
    Units: Subjects
        Cohort 1
    		 388 387 775
        Cohort 2 Northern Hemisphere
    		 386 379 765
        Cohort 2 Southern Hemisphere
    		 235 232 467

    End points

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    End points reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine
    Reporting group description
    		 Each subject received 2 doses of QIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination.

    Reporting group title
    Non-influenza Vaccine
    Reporting group description
    		 Each subject received 2 doses of a NIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination. For each subject enrolled in the NIV control group, only 1 reference product was used.

    Primary: First occurrence of RT-PCR-confirmed influenza A and/or B illness of any severity due to any circulating seasonal influenza strain

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    End point title
    		 First occurrence of RT-PCR-confirmed influenza A and/or B illness of any severity due to any circulating seasonal influenza strain
    End point description
    The primary endpoint assessed the first occurrence of RT-PCR-confirmed influenza A and/or B illness of any severity due to any circulating seasonal influenza strain occurring between 28 days following the second vaccine administration and the end of the primary immunization influenza surveillance period. The number of subjects with RT-PCR-confirmed influenza A and/or B infection due to any circulating strain is presented for the full analysis (FA) sample. The analysis excluded subjects who did not receive the second vaccination, those who dropped-out or withdrew before 28 days after the second vaccination, and those with first occurrence of RT-PCR-confirmed influenza between the first vaccination and 28 days after the second vaccination.
    End point type
    Primary
    End point timeframe
    Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]) up to TC3 (end of the primary immunization influenza surveillance period).
    End point values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Number of subjects analysed
    991
    981
    Units: Subjects
    59
    117
    Statistical analysis title
    		 Absolute vaccine efficacy; primary analysis
    Statistical analysis description
    Absolute vaccine efficacy of QIV compared with NIVs in the prevention of symptomatic influenza infection due to any circulating seasonal influenza strain. Time to first occurrence was measured from Day 28 after second study vaccination. Hazard ratio (HR) was obtained from a Cox Proportional Hazards model. For purpose of the analysis, vaccine efficacy was derived as 1-HR. Model contained age group (6-11, 12-18, 19-24, 25-35 and 6-24 months), country and vaccine group (QIV or NIV) as factors.
    Comparison groups
    Non-influenza Vaccine v Quadrivalent Influenza Vaccine
    Number of subjects included in analysis
    1972
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Absolute vaccine efficacy of QIV
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.66

    Secondary: First occurrence of RT-PCR-confirmed influenza A and/or B illness of any severity due to antigenically-matching influenza strains

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    End point title
    		 First occurrence of RT-PCR-confirmed influenza A and/or B illness of any severity due to antigenically-matching influenza strains
    End point description
    A secondary endpoint assessed the first occurrence of RT-PCR-confirmed influenza A and/or B illness of any severity due to antigenically-matching influenza strains occurring between 28 days following the second vaccine administration and the end of the primary immunization influenza surveillance period. The number of subjects with RT-PCR-confirmed influenza A and/or B infection due to antigenically-matching strains is presented for the FA sample. The analysis excluded subjects who did not receive the second vaccination, those who dropped-out or withdrew before 28 days after the second vaccination, and those with first occurrence of RT-PCR-confirmed influenza between the first vaccination and 28 days after the second vaccination.
    End point type
    Secondary
    End point timeframe
    Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]) up to TC3 (end of the primary immunization influenza surveillance period).
    End point values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Number of subjects analysed
    991
    981
    Units: Subjects
    19
    56
    Statistical analysis title
    		 Absolute vaccine efficacy; secondary analysis
    Statistical analysis description
    Absolute vaccine efficacy of QIV compared with NIVs in the prevention of symptomatic influenza infection due to antigenically-matching influenza strains. Time to first occurrence was measured from Day 28 after second study vaccination. The HR was obtained from a Cox Proportional Hazards model. For purpose of the analysis, vaccine efficacy was derived as 1-HR. Model contained age group (6-11, 12-18, 19-24, 25-35 and 6-24 months), country and vaccine group (QIV or NIV) as factors.
    Comparison groups
    Quadrivalent Influenza Vaccine v Non-influenza Vaccine
    Number of subjects included in analysis
    1972
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Absolute vaccine efficacy of QIV
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.81

    Secondary: Pre- and post-vaccination geometric mean hemagglutination inhibition (HI) antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Pre- and post-vaccination geometric mean hemagglutination inhibition (HI) antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the geometric mean titer with respect to the HI assay. The pre-first vaccination and post-second vaccination geometric mean HI antibody titers against each of the indicated vaccine strains are presented for the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 or a NIV during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-vaccination: Visit 1 (Day 1). Post-vaccination: Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    End point values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Number of subjects analysed
    348
    343
    Units: Titer
    geometric mean (standard deviation)
        A(H3N2): pre-vaccination (n=346, 337)
    12.5 ( 5.8 )
    12.6 ( 5.8 )
        A(H3N2): post-vaccination (n=348, 341)
    341.4 ( 6.7 )
    12.9 ( 5.7 )
        A(H1N1): pre-vaccination (n=344, 337)
    9.4 ( 3.4 )
    8.6 ( 3.3 )
        A(H1N1): post-vaccination (n=347, 338)
    71.1 ( 4.4 )
    12.0 ( 4.1 )
        B/Victoria: pre-vaccination (n=347, 337)
    5.6 ( 1.7 )
    5.2 ( 1.4 )
        B/Victoria: post-vaccination (n=348, 341)
    11.1 ( 4.0 )
    5.3 ( 1.5 )
        B/Yamagata: pre-vaccination (n=344, 337)
    5.0 ( 1.1 )
    5.1 ( 1.2 )
        B/Yamagata: post-vaccination (n=347, 338)
    10.8 ( 3.1 )
    5.6 ( 1.7 )
    No statistical analyses for this end point

    Secondary: Pre- and post-vaccination geometric mean virus neutralization (VN) antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Pre- and post-vaccination geometric mean virus neutralization (VN) antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage [1]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the geometric mean titer with respect to the VN assay. The pre-first vaccination and post-second vaccination geometric mean VN antibody titers against each of the indicated vaccine strains are presented for the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-vaccination: Visit 1 (Day 1). Post-vaccination: Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    Notes
    [1] - 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: The VN and NI assays were only performed for a random subset of subjects who were vaccinated with QIV from Cohort 1. Subjects vaccinated with a NIV are therefore not applicable for reporting of this end point.
    End point values
    		 Quadrivalent Influenza Vaccine
    Number of subjects analysed
    102
    Units: Titer
    geometric mean (standard deviation)
        A(H3N2): pre-vaccination (n=102)
    8.5 ( 1.6 )
        A(H3N2): post-vaccination (n=102)
    22.2 ( 3.7 )
        A(H1N1): pre-vaccination (n=102)
    7.3 ( 1.2 )
        A(H1N1): post-vaccination (n=102)
    12.7 ( 2.3 )
        B/Victoria: pre-vaccination (n=102)
    7.9 ( 1.6 )
        B/Victoria: post-vaccination (n=102)
    20.0 ( 3.3 )
        B/Yamagata: pre-vaccination (n=102)
    7.9 ( 1.5 )
        B/Yamagata: post-vaccination (n=102)
    41.5 ( 2.7 )
    No statistical analyses for this end point

    Secondary: Pre- and post-vaccination geometric mean neuraminidase inhibition (NI) antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Pre- and post-vaccination geometric mean neuraminidase inhibition (NI) antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage [2]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the geometric mean titer with respect to the NI assay. The pre-first vaccination and post-second vaccination geometric mean NI antibody titers against each of the indicated vaccine strains are presented for the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    Pre-vaccination: Visit 1 (Day 1). Post-vaccination: Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    Notes
    [2] - 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: The VN and NI assays were only performed for a random subset of subjects who were vaccinated with QIV from Cohort 1. Subjects vaccinated with a NIV are therefore not applicable for reporting of this end point.
    End point values
    		 Quadrivalent Influenza Vaccine
    Number of subjects analysed
    102
    Units: Titer
    geometric mean (standard deviation)
        A(H3N2): pre-vaccination (n=102)
    7.8 ( 2.5 )
        A(H3N2): post-vaccination (n=102)
    22.8 ( 5.2 )
        A(H1N1): pre-vaccination (n=102)
    5.7 ( 1.9 )
        A(H1N1): post-vaccination (n=102)
    60.1 ( 3.2 )
        B/Victoria: pre-vaccination (n=101)
    6.4 ( 2.3 )
        B/Victoria: post-vaccination (n=102)
    39.9 ( 4.0 )
        B/Yamagata: pre-vaccination (n=102)
    5.4 ( 1.4 )
        B/Yamagata: post-vaccination (n=102)
    8.4 ( 2.7 )
    No statistical analyses for this end point

    Secondary: Post-vaccination geometric mean fold increases in HI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Post-vaccination geometric mean fold increases in HI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the geometric mean fold increase with respect to HI titers. The post-vaccination geometric mean fold increase in HI antibody titers against each of the indicated vaccine strains are presented for the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 or a NIV during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    End point values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Number of subjects analysed
    348
    343
    Units: Titer (fold increase)
    geometric mean (standard deviation)
        A(H3N2) (n=346, 335)
    27.4 ( 4.1 )
    1.0 ( 2.0 )
        A(H1N1) (n=344, 332)
    7.7 ( 4.7 )
    1.3 ( 4.1 )
        B/Victoria (n=347, 335)
    2.0 ( 3.7 )
    1.0 ( 1.3 )
        B/Yamagata (n=344, 332)
    2.2 ( 3.1 )
    1.1 ( 1.7 )
    No statistical analyses for this end point

    Secondary: Post-vaccination geometric mean fold increases in VN antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Post-vaccination geometric mean fold increases in VN antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage [3]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the geometric mean fold increase with respect to VN titers. The post-vaccination geometric mean fold increase in VN antibody titers against each of the indicated vaccine strains are presented for the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    Notes
    [3] - 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: The VN and NI assays were only performed for a random subset of subjects who were vaccinated with QIV from Cohort 1. Subjects vaccinated with a NIV are therefore not applicable for reporting of this end point.
    End point values
    		 Quadrivalent Influenza Vaccine
    Number of subjects analysed
    102
    Units: Titer (fold increase)
    geometric mean (standard deviation)
        A(H3N2) (n=102)
    2.6 ( 2.8 )
        A(H1N1) (n=102)
    1.7 ( 2.1 )
        B/Victoria (n=102)
    2.5 ( 2.6 )
        B/Yamagata (n=102)
    5.3 ( 2.4 )
    No statistical analyses for this end point

    Secondary: Post-vaccination geometric mean fold increases in NI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Post-vaccination geometric mean fold increases in NI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage [4]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the geometric mean fold increase with respect to NI titers. The post-vaccination geometric mean fold increase in NI antibody titers against each of the indicated vaccine strains are presented for the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    Notes
    [4] - 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: The VN and NI assays were only performed for a random subset of subjects who were vaccinated with QIV from Cohort 1. Subjects vaccinated with a NIV are therefore not applicable for reporting of this end point.
    End point values
    		 Quadrivalent Influenza Vaccine
    Number of subjects analysed
    102
    Units: Titer (fold increase)
    geometric mean (standard deviation)
        A(H3N2) (n=102)
    2.9 ( 2.8 )
        A(H1N1) (n=102)
    10.5 ( 2.7 )
        B/Victoria (n=101)
    6.2 ( 2.8 )
        B/Yamagata (n=102)
    1.6 ( 2.2 )
    No statistical analyses for this end point

    Secondary: Seroconversion rates based on HI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Seroconversion rates based on HI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the seroconversion rate with respect to HI titers. Seroconversion was defined as becoming seropositive (titer ≥ 10) if seronegative (titer < 10) at enrollment, or (at least) a 4-fold rise in titer if seropositive (titer ≥ 10) at enrollment. Seroconversion rates for HI are presented as the percentage of seroconverted subjects against each of the indicated vaccine strains. Analysis was performed on the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 or a NIV during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    End point values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Number of subjects analysed
    348
    343
    Units: Percentage of subjects
    number (not applicable)
        A(H3N2) (n=346, 335)
    92.5
    3.6
        A(H1N1) (n=344, 332)
    74.4
    21.4
        B/Victoria (n=347, 335)
    26.5
    1.2
        B/Yamagata (n=344, 332)
    35.5
    3.9
    No statistical analyses for this end point

    Secondary: Seroconversion rates based on VN antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Seroconversion rates based on VN antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage [5]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the seroconversion rate with respect to VN titers. Seroconversion was defined as becoming seropositive (titer ≥ 10) if seronegative (titer < 10) at enrollment, or (at least) a 4-fold rise in titer if seropositive (titer ≥ 10) at enrollment. Seroconversion rates for VN are presented as the percentage of seroconverted subjects against each of the indicated vaccine strains. Analysis was performed on the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    Notes
    [5] - 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: The VN and NI assays were only performed for a random subset of subjects who were vaccinated with QIV from Cohort 1. Subjects vaccinated with a NIV are therefore not applicable for reporting of this end point.
    End point values
    		 Quadrivalent Influenza Vaccine
    Number of subjects analysed
    102
    Units: Percentage of subjects
    number (not applicable)
        A(H3N2) (n=102)
    71.6
        A(H1N1) (n=102)
    51.0
        B/Victoria (n=102)
    68.6
        B/Yamagata (n=102)
    93.1
    No statistical analyses for this end point

    Secondary: Seroconversion rates based on NI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage

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    End point title
    		 Seroconversion rates based on NI antibody titers against the influenza A and B strains: A(H3N2), A(H1N1), B/Victoria lineage and B/Yamagata lineage [6]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV was assessed by deriving the seroconversion rate with respect to NI titers. Seroconversion was defined as becoming seropositive (titer ≥ 10) if seronegative (titer < 10) at enrollment, or (at least) a 4-fold rise in titer if seropositive (titer ≥ 10) at enrollment. Seroconversion rates for NI are presented as the percentage of seroconverted subjects against each of the indicated vaccine strains. Analysis was performed on the immunogenicity sample for subjects in Cohort 1 (i.e., received QIV recommended for the NH season 2017/2018 during the primary immunogenicity period). n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    At Visit 3 (28-33 days after second vaccination [equivalent to 56-66 days after Day 1]).
    Notes
    [6] - 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: The VN and NI assays were only performed for a random subset of subjects who were vaccinated with QIV from Cohort 1. Subjects vaccinated with a NIV are therefore not applicable for reporting of this end point.
    End point values
    		 Quadrivalent Influenza Vaccine
    Number of subjects analysed
    102
    Units: Percentage of subjects
    number (not applicable)
        A(H3N2) (n=102)
    66.7
        A(H1N1) (n=102)
    97.1
        B/Victoria (n=101)
    93.1
        B/Yamagata (n=102)
    34.3
    No statistical analyses for this end point

    Secondary: Percentage of subjects with solicited systemic reactions

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    End point title
    		 Percentage of subjects with solicited systemic reactions
    End point description
    A subject diary was used to record pre-specified systemic reactions occurring during the first 7 days after vaccination (solicited reactogenicity). The diary was completed by the parents/LAR, as appropriate. The following systemic reactions were assessed: fever, irritability/fussiness, drowsiness, sweating, diarrhea/vomiting and loss of appetite. The percentage of subjects with solicited systemic reactions during the primary immunization period are presented for the safety sample. n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    Period of 7 days after each of the 2 study vaccinations (first vaccination at Visit 1 [Day 1] and second vaccination at Visit 2 [28-33 days after Day 1]).
    End point values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Number of subjects analysed
    1005
    995
    Units: Percentage of subjects
    number (not applicable)
        Fever (n=999, 985)
    19.3
    18.1
        Irritability/fussiness (n=1000, 985)
    30.2
    33.6
        Drowsiness (n=1000, 985)
    17.5
    17.3
        Sweating (n=1000, 985)
    12.4
    11.5
        Diarrhea/vomiting (n=1000, 985)
    19.8
    18.0
        Loss of appetite (n=1000, 985)
    19.3
    21.9
    No statistical analyses for this end point

    Secondary: Percentage of subjects with solicited local reactions

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    End point title
    		 Percentage of subjects with solicited local reactions
    End point description
    A subject diary was used to record pre-specified vaccination site (local) reactions occurring during the first 7 days after vaccination (solicited reactogenicity). The diary was completed by the parents/LAR, as appropriate. The following vaccination site reactions were assessed: erythema, swelling, induration, vaccination site pain and ecchymosis. Percentages of subjects with solicited local reactions during the primary immunization period are presented for the safety sample. n = number of subjects with non-missing data for each parameter analyzed.
    End point type
    Secondary
    End point timeframe
    Period of 7 days after each of the 2 study vaccinations (first vaccination at Visit 1 [Day 1] and second vaccination at Visit 2 [28-33 days after Day 1]).
    End point values
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Number of subjects analysed
    1005
    995
    Units: Percentage of subjects
    number (not applicable)
        Vaccination site erythema (n=1000, 985)
    11.6
    19.6
        Vaccination site swelling (n=1000, 985)
    4.3
    7.2
        Vaccination site induration (n=1000, 985)
    4.4
    10.4
        Vaccination site pain (n=1000, 985)
    22.6
    27.0
        Vaccination site ecchymosis (n=1000, 985)
    4.0
    4.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are reported for the primary immunization period from Day 1 up to the final safety follow-up TC. Overall time frame of between 6 and 8 months after first vaccination.
    Adverse event reporting additional description
    The safety sample consisted of all subjects who were in the all subjects vaccinated sample and had at least 1 post-vaccination safety observation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine
    Reporting group description
    		 Each subject received 2 doses of QIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination.

    Reporting group title
    Non-influenza Vaccine
    Reporting group description
    		 Each subject received 2 doses of a NIV. The first vaccination was administered on Day 1 (Visit 1), followed by a second vaccination 28 to 33 days after Day 1 (Visit 2). The final safety follow-up (TC3) was planned between 6 and 8 months after the first vaccination. For each subject enrolled in the NIV control group, only 1 reference product was used.

    Serious adverse events
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 1005 (3.68%)
    54 / 995 (5.43%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical poisoning
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Carbohydrate metabolism disorder
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryostenosis congenital
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Niemann-Pick disease
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    5 / 1005 (0.50%)
    3 / 995 (0.30%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         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
    Influenza like illness
         subjects affected / exposed
    7 / 1005 (0.70%)
    10 / 995 (1.01%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 1005 (0.00%)
    2 / 995 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         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
    Asthma
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         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
    Angioedema
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermal sinus
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 1005 (0.60%)
    6 / 995 (0.60%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1005 (0.10%)
    2 / 995 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    2 / 1005 (0.20%)
    3 / 995 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 1005 (0.10%)
    3 / 995 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    2 / 1005 (0.20%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    8 / 1005 (0.80%)
    3 / 995 (0.30%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parasitic gastroenteritis
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (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 / 1005 (0.10%)
    2 / 995 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 1005 (0.10%)
    2 / 995 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 1005 (0.00%)
    2 / 995 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1005 (0.10%)
    2 / 995 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis bacterial
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 1005 (0.10%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 1005 (0.10%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    1 / 1005 (0.10%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         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
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chikungunya virus infection
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpangina
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 1005 (0.10%)
    0 / 995 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 1005 (0.20%)
    5 / 995 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 1005 (0.00%)
    1 / 995 (0.10%)
         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: 1%
    Non-serious adverse events
    		 Quadrivalent Influenza Vaccine Non-influenza Vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    586 / 1005 (58.31%)
    616 / 995 (61.91%)
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    412 / 1005 (41.00%)
    443 / 995 (44.52%)
         occurrences all number
    657
    741
    Pyrexia
         subjects affected / exposed
    36 / 1005 (3.58%)
    25 / 995 (2.51%)
         occurrences all number
    43
    33
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 1005 (1.59%)
    21 / 995 (2.11%)
         occurrences all number
    16
    22
    Vomiting
         subjects affected / exposed
    11 / 1005 (1.09%)
    13 / 995 (1.31%)
         occurrences all number
    12
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    42 / 1005 (4.18%)
    47 / 995 (4.72%)
         occurrences all number
    47
    51
    Rhinorrhoea
         subjects affected / exposed
    13 / 1005 (1.29%)
    7 / 995 (0.70%)
         occurrences all number
    14
    9
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    11 / 1005 (1.09%)
    8 / 995 (0.80%)
         occurrences all number
    13
    8
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    65 / 1005 (6.47%)
    74 / 995 (7.44%)
         occurrences all number
    106
    96
    Rhinitis
         subjects affected / exposed
    57 / 1005 (5.67%)
    74 / 995 (7.44%)
         occurrences all number
    66
    82
    Nasopharyngitis
         subjects affected / exposed
    44 / 1005 (4.38%)
    56 / 995 (5.63%)
         occurrences all number
    58
    79
    Tonsillitis
         subjects affected / exposed
    23 / 1005 (2.29%)
    15 / 995 (1.51%)
         occurrences all number
    25
    16
    Pharyngitis
         subjects affected / exposed
    15 / 1005 (1.49%)
    19 / 995 (1.91%)
         occurrences all number
    15
    22
    Laryngitis
         subjects affected / exposed
    9 / 1005 (0.90%)
    12 / 995 (1.21%)
         occurrences all number
    11
    12
    Viral upper respiratory tract infection
         subjects affected / exposed
    36 / 1005 (3.58%)
    35 / 995 (3.52%)
         occurrences all number
    44
    42
    Viral infection
         subjects affected / exposed
    26 / 1005 (2.59%)
    20 / 995 (2.01%)
         occurrences all number
    29
    22
    Respiratory tract infection viral
         subjects affected / exposed
    18 / 1005 (1.79%)
    21 / 995 (2.11%)
         occurrences all number
    21
    26
    Otitis media
         subjects affected / exposed
    35 / 1005 (3.48%)
    45 / 995 (4.52%)
         occurrences all number
    40
    57
    Otitis media acute
         subjects affected / exposed
    34 / 1005 (3.38%)
    33 / 995 (3.32%)
         occurrences all number
    41
    40
    Bronchitis
         subjects affected / exposed
    58 / 1005 (5.77%)
    44 / 995 (4.42%)
         occurrences all number
    67
    57
    Pneumonia
         subjects affected / exposed
    17 / 1005 (1.69%)
    22 / 995 (2.21%)
         occurrences all number
    22
    27
    Gastroenteritis
         subjects affected / exposed
    48 / 1005 (4.78%)
    46 / 995 (4.62%)
         occurrences all number
    54
    51
    Conjunctivitis
         subjects affected / exposed
    23 / 1005 (2.29%)
    30 / 995 (3.02%)
         occurrences all number
    25
    36
    Respiratory tract infection
         subjects affected / exposed
    20 / 1005 (1.99%)
    30 / 995 (3.02%)
         occurrences all number
    30
    44
    Hand-foot-and-mouth disease
         subjects affected / exposed
    23 / 1005 (2.29%)
    18 / 995 (1.81%)
         occurrences all number
    23
    18
    Pharyngitis streptococcal
         subjects affected / exposed
    7 / 1005 (0.70%)
    16 / 995 (1.61%)
         occurrences all number
    10
    31

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2017
    Protocol amendment 1 incorporated the following changes: exclusion criteria changes (2 added and 2 others revised), clarification for the selection of control vaccines for different age groups, clarification of Investigator instructions in case of immediate (serious) adverse reactions, and addition of specific guidance on the reporting of suspected unexpected serious adverse reactions.
    21 Feb 2018
    Protocol amendment 2 incorporated the following changes: the planned interim analysis was removed due to lower than planned recruitment of subjects into Cohort 1, number of countries and sites was expanded to enable recruitment of up to 2,000 subjects in Cohort 2, and clarification regarding adverse events of special interest.
    12 Jul 2018
    Protocol amendment 3 incorporated the following changes: enrollment of Cohort 2 was extended into an additional influenza season.

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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