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    Clinical Trial Results:
    A Phase III, Randomized, Observer-blind, Multicenter Study to Evaluate the Efficacy, Immunogenicity and Safety of Seqirus' Cell-Based Quadrivalent Subunit Influenza Virus Vaccine (QIVc) Compared to a Non-Influenza Vaccine when Administrated in Healthy Subjects aged 6 Months through 47 Months

    Summary
    EudraCT number
    		 2018-001857-29
    Trial protocol
    		 BG   EE   CZ   LV   PL   Outside EU/EEA   RO  
    Global end of trial date
    05 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Aug 2024
    First version publication date
    31 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V130_14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03932682
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seqirus UK Limited
    Sponsor organisation address
    Point, 29 Market Street, Maidenhead, United Kingdom,
    Public contact
    Clinical Trial Disclosures, Seqirus UK Limited, Seqirus.ClinicalTrials@seqirus.com
    Scientific contact
    Clinical Trial Disclosures, Seqirus UK Limited, Seqirus.ClinicalTrials@seqirus.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002068-PIP16-05
    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
    24 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    EFFICACY: To demonstrate the absolute vaccine efficacy of QIVc versus a non-influenza vaccine to prevent at least one of the following: - RT-PCR confirmed illness caused by any influenza Type A and/or Type B virus, regardless of antigenic match. - Culture confirmed illness caused by influenza virus strains antigenically matched to the influenza strains selected for the seasonal influenza vaccine.
    Protection of trial subjects
    This clinical study was designed, implemented, and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations including European Directive 2001/20/EC, United States Code of Federal Regulations Title 21, ICH E6(R2), 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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 May 2019
    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
    Bangladesh: 200
    Country: Number of subjects enrolled
    Bulgaria: 266
    Country: Number of subjects enrolled
    Czechia: 79
    Country: Number of subjects enrolled
    Estonia: 1246
    Country: Number of subjects enrolled
    Honduras: 298
    Country: Number of subjects enrolled
    Latvia: 5
    Country: Number of subjects enrolled
    Malaysia: 65
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    Pakistan: 561
    Country: Number of subjects enrolled
    Philippines: 1217
    Country: Number of subjects enrolled
    Poland: 437
    Country: Number of subjects enrolled
    Romania: 71
    Country: Number of subjects enrolled
    South Africa: 756
    Country: Number of subjects enrolled
    Thailand: 141
    Country: Number of subjects enrolled
    Ukraine: 367
    Worldwide total number of subjects
    5723
    EEA total number of subjects
    2104
    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)
    2532
    Children (2-11 years)
    3191
    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
    		 Subjects were enrolled from 75 centers in Bangladesh (1), Bulgaria (7), Czech Republic (5), Estonia (7), Honduras (3), Latvia (1), Malaysia (5), New Zealand (2), Pakistan (5), Philippines (12), Poland (8), Romania (4), South Africa (9), Thailand (3), Ukraine (3).

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QIVc
    Arm description
    		 Cell-based quadrivalent influenza vaccine containing 2 influenza type A strains and 2 influenza type B strains
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cell-based quadrivalent subunit influenza virus vaccine
    Investigational medicinal product code
    Other name
    Flucelvax Tetra
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Previously vaccinated subjects received one 0.5 mL dose administered intramuscularly on Day 1 Not previously vaccinated subjects received two 0.5 mL doses administered intramuscularly, one dose on Day 1 and one dose on Day 29 Previously vaccinated subjects were defined as subjects with a known history of at least 2 doses of an influenza vaccine prior to the current influenza season. Not previously vaccinated subjects were defined as subjects who have not received 2 or more doses of influenza vaccine prior to the current influenza season or subjects with unknown influenza vaccination history.

    Arm title
    		 Comparator
    Arm description
    		 Non-influenza vaccine comparator
    Arm type
    		 Non-influenza vaccine comparator

    Investigational medicinal product name
    Meningococcal Group C Polysaccharide Conjugate Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Previously vaccinated subjects received one 0.5 mL dose administered intramuscularly on Day 1 Not previously vaccinated subjects received one 0.5 mL dose administered intramuscularly on Day 1 and one dose of normal saline placebo on Day 29 Previously vaccinated subjects were defined as subjects with a known history of at least 2 doses of an influenza vaccine prior to the current influenza season. Not previously vaccinated subjects were defined as subjects who have not received 2 or more doses of influenza vaccine prior to the current influenza season or subjects with unknown influenza vaccination history.

    Number of subjects in period 1
    		QIVc Comparator
    Started
    2860
    2863
    Completed
    2794
    2766
    Not completed
    66
    97
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    37
    45
         Other
    9
    23
         Lost to follow-up
    19
    25
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QIVc
    Reporting group description
    		 Cell-based quadrivalent influenza vaccine containing 2 influenza type A strains and 2 influenza type B strains

    Reporting group title
    Comparator
    Reporting group description
    		 Non-influenza vaccine comparator

    Reporting group values
    		 QIVc Comparator Total
    Number of subjects
    		 2860 2863 5723
    Age categorical
    Units: Subjects
        6 months through 23 months
    		 1268 1264 2532
        24 months through 47 months
    		 1592 1599 3191
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 25.8 ( 11.9 ) 25.9 ( 11.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1418 1333 2751
        Male
    		 1442 1530 2972
    Race
    Units: Subjects
        Asian
    		 1098 1096 2194
        Black or African American
    		 348 349 697
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        White
    		 1239 1234 2473
        Other
    		 175 183 358
    Ethnic Origin
    Units: Subjects
        Hispanic or Latino
    		 155 157 312
        Not Hispanic or Latino
    		 2696 2697 5393
        Not reported
    		 2 4 6
        Unknown
    		 7 5 12
    Previous influenza vaccination
    Units: Subjects
        Previously vaccinated
    		 48 62 110
        Not previously vaccinated
    		 2812 2801 5613
    Season
    Units: Subjects
        Season 1
    		 344 349 693
        Season 2
    		 497 489 986
        Season 3
    		 525 521 1046
        Season 4
    		 496 504 1000
        Season 5
    		 998 1000 1998
    Country
    Units: Subjects
        Bangladesh
    		 101 99 200
        Bulgaria
    		 131 135 266
        Czechia
    		 41 38 79
        Estonia
    		 625 621 1246
        Honduras
    		 147 151 298
        Latvia
    		 3 2 5
        Malaysia
    		 31 34 65
        New Zealand
    		 7 7 14
        Pakistan
    		 279 282 561
        Philippines
    		 608 609 1217
        Poland
    		 217 220 437
        Romania
    		 38 33 71
        South Africa
    		 376 380 756
        Thailand
    		 72 69 141
        Ukraine
    		 184 183 367
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 16.51 ( 2.2 ) 16.61 ( 2.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    QIVc
    Reporting group description
    		 Cell-based quadrivalent influenza vaccine containing 2 influenza type A strains and 2 influenza type B strains

    Reporting group title
    Comparator
    Reporting group description
    		 Non-influenza vaccine comparator

    Subject analysis set title
    All Enrolled Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The All Enrolled Set is all screened subjects who provided informed consent and provided demographic and/or baseline screening assessments, regardless of the subject’s randomization and treatment status in the study, and received a Subject ID.

    Subject analysis set title
    All Exposed Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The All Exposed Set is all subjects in the All Enrolled Set who received a study vaccination.

    Subject analysis set title
    FAS Efficacy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS Efficacy is all subjects in the All Enrolled Set who were randomized, received at least one dose of study vaccination, and were evaluated for efficacy at more than 14 days after the last vaccination.

    Subject analysis set title
    FAS Immunogenicity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS Immunogenicity is all subjects in the All Enrolled Set who were randomized, received at least one study vaccination, and provided evaluable serum samples at both baseline (Day 1) and 28 days after last vaccination (Day 29/57).

    Subject analysis set title
    Solicited Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Solicited Safety Set is all subjects in the All Exposed Set with any solicited AE data indicating the occurrence or lack of occurrence of solicited AEs, ie, a subject does not have to have any solicited AEs to be included in this population.

    Subject analysis set title
    Unsolicited Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Unsolicited Safety Set is all subjects in the All Exposed Set with unsolicited AE data.

    Subject analysis set title
    Overall Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Overall Safety Set is all subjects in the Solicited Safety Set and/or Unsolicited Safety Set.

    Subject analysis set title
    QIVc (Season 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    QIVc immunogenicity analyses (Season 1)

    Subject analysis set title
    Comparator (Season 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparator vaccine immunogenicity analyses (Season 1)

    Subject analysis set title
    QIVc (Season 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    QIVc immunogenicity analyses (Season 2)

    Subject analysis set title
    Comparator (Season 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparator vaccine immunogenicity analyses (Season 2)

    Subject analysis set title
    QIVc (Season 3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    QIVc immunogenicity analyses (Season 3)

    Subject analysis set title
    Comparator (Season 3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparator vaccine immunogenicity analyses (Season 3)

    Subject analysis set title
    QIVc (Season 4)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    QIVc immunogenicity analyses (Season 4)

    Subject analysis set title
    Comparator (Season 4)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparator vaccine immunogenicity analyses (Season 4)

    Subject analysis set title
    QIVc (Season 5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    QIVc immunogenicity analyses (Season 5)

    Subject analysis set title
    Comparator (Season 5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparator vaccine immunogenicity analyses (Season 5)

    Primary: Efficacy Endpoint: First occurrence of RT-PCR confirmed influenza, due to any influenza Type A and/or B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine

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    End point title
    		 Efficacy Endpoint: First occurrence of RT-PCR confirmed influenza, due to any influenza Type A and/or B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine
    End point description
    First occurrence of reverse transcription-polymerase chain reaction (RT-PCR) confirmed influenza, due to any influenza Type A and/or B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine, occurring at >14 days after the last vaccination and until the end of the influenza season, in association with protocol-defined influenza-like illness (ILI) symptoms
    End point type
    Primary
    End point timeframe
    >14 days after the last vaccination and until the end of the influenza season
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2835
    Units: Cases
    number (not applicable)
        RT-PCR Confirmed Influenza (Any Strain)
    104
    173
    Statistical analysis title
    		 aVE, RT-PCR Confirmed Influenza, Any Strain
    Statistical analysis description
    Adjusted absolute vaccine efficacy (aVE) for QIVc versus comparator vaccine, estimated from a Cox proportional hazard model for time from >14 days after the last study vaccination to the onset of the first occurrence of RT-PCR confirmed influenza with vaccine group as the main effect, adjusting for previous vaccination status, sex, country, and season as random effects Analysis population: FAS Efficacy
    Comparison groups
    QIVc v Comparator
    Number of subjects included in analysis
    5691
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    41.26
    Confidence interval
         level
    		 97.98%
         sides
    2-sided
         lower limit
    		 21.55
         upper limit
    		 56.02
    Notes
    [1] - The primary objective would be achieved if efficacy was demonstrated for at least one of the two primary efficacy endpoints, that is, if the interim analysis-adjusted lower limit of the two-sided confidence interval (CI) for aVE of QIVc versus the comparator vaccine was greater than 0%.

    Primary: Efficacy Endpoint: First occurrence of culture confirmed influenza, due to influenza Type A and/or B virus antigenically matched by ferret antigenicity testing to the influenza strains selected for the seasonal influenza vaccine

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    End point title
    		 Efficacy Endpoint: First occurrence of culture confirmed influenza, due to influenza Type A and/or B virus antigenically matched by ferret antigenicity testing to the influenza strains selected for the seasonal influenza vaccine
    End point description
    First occurrence of culture confirmed influenza, due to influenza Type A and/or B virus antigenically matched by ferret antigenicity testing to the influenza strains selected for the seasonal influenza vaccine, occurring at >14 days after the last vaccination and until the end of the influenza season, in association with protocol-defined ILI symptoms
    End point type
    Primary
    End point timeframe
    >14 days after the last vaccination and until the end of the influenza season
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2835
    Units: Cases
    number (not applicable)
        Culture Confirmed Influenza (Matched Strain)
    44
    82
    Statistical analysis title
    		 aVE, Culture Confirmed Influenza, Matched Strain
    Statistical analysis description
    Adjusted aVE for QIVc versus comparator vaccine, estimated from a Cox proportional hazard model for time from >14 days after the last study vaccination to the onset of the first occurrence of culture confirmed influenza antigenically matched to the vaccine strain with vaccine group as the main effect, adjusting for previous vaccination status, sex, country, and season as random effects Analysis population: FAS Efficacy
    Comparison groups
    QIVc v Comparator
    Number of subjects included in analysis
    5691
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    46.9
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 19.19
         upper limit
    		 65.11
    Notes
    [2] - The primary objective would be achieved if efficacy was demonstrated for at least one of the two primary efficacy endpoints, that is, if the interim analysis-adjusted lower limit of the two-sided CI for aVE of QIVc versus the comparator vaccine was greater than 0%.

    Secondary: Efficacy Endpoint: First occurrence of culture confirmed influenza caused by influenza virus strains antigenically dissimilar to the influenza strains selected for the seasonal vaccine

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    End point title
    		 Efficacy Endpoint: First occurrence of culture confirmed influenza caused by influenza virus strains antigenically dissimilar to the influenza strains selected for the seasonal vaccine
    End point description
    First occurrence of culture confirmed influenza caused by influenza virus strains antigenically dissimilar to the influenza strains selected for the seasonal vaccine occurring at >14 days after the last vaccination and until the end of the influenza season, in association with protocol-defined ILI symptoms
    End point type
    Secondary
    End point timeframe
    >14 days after the last vaccination and until the end of the influenza season
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2835
    Units: Cases
    number (not applicable)
        Culture Confirmed Influenza (Unmatched Strain)
    20
    43
    Statistical analysis title
    		 aVE, Culture Confirmed Influenza, Unmatched Strain
    Statistical analysis description
    Adjusted aVE, estimated from a Cox proportional hazard model with vaccine group as the main effect, adjusting for age group, previous vaccination status, country, and season as random effects Analysis population: FAS Efficacy
    Comparison groups
    QIVc v Comparator
    Number of subjects included in analysis
    5691
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    54.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.55
         upper limit
    		 73.26
    Notes
    [3] - The secondary efficacy objectives were not associated with any hypothesis testing

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

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    End point title
    		 Efficacy Endpoint: First occurrence of culture confirmed influenza due to any influenza Type A and/or Type B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine
    End point description
    First occurrence of culture confirmed influenza due to any influenza Type A and/or Type B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine, occurring at >14 days after the last vaccination and until the end of the influenza season, in association with protocol-defined ILI symptoms
    End point type
    Secondary
    End point timeframe
    >14 days after the last vaccination and until the end of the influenza season
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2835
    Units: Cases
    number (not applicable)
        Culture Confirmed Influenza (Any Strain)
    61
    121
    Statistical analysis title
    		 aVE, Culture Confirmed Influenza, Any Strain
    Statistical analysis description
    Adjusted aVE, estimated from a Cox proportional hazard model with vaccine group as the main effect, adjusting for age group, previous vaccination status, country, and season as random effects Analysis population: FAS Efficacy
    Comparison groups
    QIVc v Comparator
    Number of subjects included in analysis
    5691
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    50.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32.83
         upper limit
    		 63.77
    Notes
    [4] - The secondary efficacy objectives were not associated with any hypothesis testing

    Secondary: Efficacy Endpoint: First occurrence of RT-PCR confirmed moderate-to-severe influenza due to any influenza Type A and/or Type B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine

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    End point title
    		 Efficacy Endpoint: First occurrence of RT-PCR confirmed moderate-to-severe influenza due to any influenza Type A and/or Type B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine
    End point description
    First occurrence of RT-PCR confirmed moderate-to-severe influenza due to any influenza Type A and/or Type B virus regardless of antigenic match to the influenza strains selected for the seasonal influenza vaccine, occurring at >14 days after the last vaccination and until the end of the influenza season Moderate-to-severe influenza is an influenza episode complicated by one of the following diagnoses within 30 days after the ILI onset: physician confirmed lower respiratory tract illness, physician confirmed acute otitis media, or hospitalization in the ICU, physician-diagnosed serious extra-pulmonary complication of influenza or supplemental oxygen requirement for more than 8 hours
    End point type
    Secondary
    End point timeframe
    >14 days after the last vaccination and until the end of the influenza season
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2835
    Units: Cases
    number (not applicable)
        Moderate-to-Severe RT-PCR Confirmed Influenza
    0
    9
    Statistical analysis title
    		 aVE, Moderate-to-Severe RT-PCR Confirmed Influenza
    Statistical analysis description
    Adjusted aVE, estimated from a Cox proportional hazard model for time from >14 days after the last study vaccination to the onset of the first occurrence of Moderate-Severe RT-PCR confirmed influenza (any strain) with vaccine group as the main effect, adjusting for, previous vaccination status, sex, country and season as random effects Analysis population: FAS Efficacy
    Comparison groups
    QIVc v Comparator
    Number of subjects included in analysis
    5691
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -99999
         upper limit
    		 100
    Notes
    [5] - The secondary efficacy objectives were not associated with any hypothesis testing Note: The lower limit of "-99999" signifies "not estimable". (The system does not allow text to be entered in the table.)

    Secondary: Immunogenicity Endpoint: Pre- and postvaccination geometric mean titers (GMTs) (HI Assay)

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    End point title
    		 Immunogenicity Endpoint: Pre- and postvaccination geometric mean titers (GMTs) (HI Assay)
    End point description
    HI = hemagglutination inhibition Adjusted GMTs are presented Analysis population: FAS Immunogenicity Note: For the A/H3N2 strain in Seasons 1 and 3, "99999" signifies "not applicable" due to lack of agglutination of A/H3N2 in HI assay. (The system does not allow text to be entered in the table.)
    End point type
    Secondary
    End point timeframe
    Day 1 and 28 days after last vaccination
    End point values
    		 QIVc (Season 1) Comparator (Season 1) QIVc (Season 2) Comparator (Season 2) QIVc (Season 3) Comparator (Season 3) QIVc (Season 4) Comparator (Season 4) QIVc (Season 5) Comparator (Season 5)
    Number of subjects analysed
    112
    108
    107
    111
    111
    112
    87
    85
    108
    108
    Units: Geometric mean titer
    geometric mean (confidence interval 95%)
        A/H1N1 Day 1 HI GMT
    40.06 (21.41 to 74.97)
    44.28 (24.19 to 81.07)
    22.99 (9.52 to 55.49)
    27.50 (11.60 to 65.18)
    10.15 (4.45 to 23.13)
    8.72 (3.87 to 19.60)
    57.83 (34.41 to 97.19)
    58.00 (34.81 to 96.64)
    13.60 (1.97 to 93.97)
    13.94 (1.95 to 99.61)
        A/H1N1 Day 29/57 HI GMT
    126.39 (68.37 to 233.66)
    60.33 (33.32 to 109.21)
    60.77 (33.77 to 109.38)
    11.24 (6.32 to 20.02)
    49.38 (22.92 to 106.39)
    5.45 (2.56 to 11.58)
    149.01 (96.96 to 229.01)
    81.71 (53.55 to 124.68)
    362.71 (74.42 to 1767.89)
    60.84 (12.14 to 304.84)
        A/H3N2 Day 1 HI GMT
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    12.21 (5.59 to 26.70)
    14.14 (6.57 to 30.41)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    46.38 (21.09 to 101.98)
    35.62 (16.41 to 77.30)
    82.67 (19.98 to 342.16)
    120.80 (28.47 to 512.58)
        A/H3N2 Day 29/57 HI GMT
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    95.36 (43.91 to 207.07)
    8.79 (4.11 to 18.77)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    67.88 (36.64 to 125.77)
    38.85 (21.22 to 71.10)
    440.30 (127.04 to 1526.08)
    57.87 (16.29 to 205.63)
        B/Yamagata Day 1 HI GMT
    11.66 (8.26 to 16.46)
    11.53 (8.27 to 16.09)
    9.87 (6.86 to 14.22)
    8.22 (5.75 to 11.75)
    7.65 (4.25 to 13.79)
    7.54 (4.19 to 13.57)
    8.96 (6.78 to 11.84)
    9.49 (7.22 to 12.48)
    7.30 (4.19 to 12.73)
    7.35 (4.18 to 12.95)
        B/Yamagata Day 29/57 HI GMT
    18.94 (13.07 to 27.46)
    6.90 (4.82 to 9.87)
    23.65 (14.04 to 39.85)
    13.57 (8.17 to 22.53)
    13.85 (6.91 to 27.77)
    5.26 (2.63 to 10.53)
    13.80 (8.95 to 21.28)
    4.70 (3.06 to 7.22)
    53.72 (20.85 to 138.40)
    8.04 (3.07 to 21.06)
        B/Victoria Day 1 HI GMT
    7.40 (5.35 to 10.24)
    8.36 (6.11 to 11.43)
    9.37 (7.46 to 11.76)
    9.31 (7.45 to 11.63)
    8.34 (5.40 to 12.90)
    9.39 (6.12 to 14.42)
    5.82 (5.18 to 6.53)
    6.08 (5.42 to 6.82)
    7.84 (1.38 to 44.61)
    5.92 (1.01 to 34.73)
        B/Victoria Day 29/57 HI GMT
    14.97 (10.42 to 21.49)
    7.01 (4.94 to 9.95)
    16.84 (11.32 to 25.07)
    8.82 (5.97 to 13.02)
    9.54 (5.60 to 16.25)
    4.88 (2.89 to 8.26)
    23.92 (13.98 to 40.92)
    4.67 (2.73 to 7.97)
    539.53 (158.62 to 1835.19)
    45.34 (13.01 to 157.93)
    No statistical analyses for this end point

    Secondary: Immunogenicity Endpoint: Seroconversion rate (SCR) (HI Assay)

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    End point title
    		 Immunogenicity Endpoint: Seroconversion rate (SCR) (HI Assay)
    End point description
    The SCR is defined as the percentage of subjects with 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 Analysis population: FAS Immunogenicity Note: For the A/H3N2 strain in Seasons 1 and 3, "99999" signifies "not applicable" due to lack of agglutination of A/H3N2 in HI assay". For the B/Victoria strain in the Comparator group in Season 3, the 95% CI values of "-99999 to 99999" signify "not estimable". (The system does not allow text to be entered in the table.)
    End point type
    Secondary
    End point timeframe
    Day 1 and 28 days after last vaccination
    End point values
    		 QIVc (Season 1) Comparator (Season 1) QIVc (Season 2) Comparator (Season 2) QIVc (Season 3) Comparator (Season 3) QIVc (Season 4) Comparator (Season 4) QIVc (Season 5) Comparator (Season 5)
    Number of subjects analysed
    112
    108
    107
    111
    111
    112
    87
    85
    108
    108
    Units: Percentage of participants
    number (confidence interval 95%)
        A/H1N1 SCR HI Titer
    45.54 (36.10 to 55.22)
    12.04 (6.57 to 19.70)
    57.01 (47.08 to 66.54)
    3.60 (0.99 to 8.97)
    68.47 (58.96 to 76.96)
    2.68 (0.56 to 7.63)
    29.89 (20.54 to 40.65)
    4.71 (1.30 to 11.61)
    75.00 (65.75 to 82.83)
    12.96 (7.27 to 20.79)
        A/H3N2 SCR HI Titer
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    70.09 (60.48 to 78.56)
    6.31 (2.57 to 12.56)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    44.83 (34.15 to 55.87)
    28.24 (19.00 to 39.04)
    84.26 (76.00 to 90.55)
    15.74 (9.45 to 24.00)
        B/Yamagata SCR HI Titer
    37.50 (28.53 to 47.15)
    3.70 (1.02 to 9.21)
    24.30 (16.53 to 33.54)
    6.31 (2.57 to 12.56)
    23.42 (15.91 to 32.41)
    0.90 (0.02 to 4.92)
    29.89 (20.54 to 40.65)
    1.18 (0.03 to 6.38)
    66.67 (56.95 to 75.45)
    3.70 (1.02 to 9.21)
        B/Victoria SCR HI Titer
    24.11 (16.53 to 33.10)
    2.78 (0.58 to 7.90)
    13.08 (7.34 to 20.98)
    0.90 (0.02 to 4.92)
    9.91 (5.05 to 17.04)
    0 (-99999 to 99999)
    42.53 (31.99 to 53.59)
    3.53 (0.73 to 9.97)
    80.56 (71.83 to 87.54)
    8.33 (3.88 to 15.23)
    No statistical analyses for this end point

    Secondary: Immunogenicity Endpoint: Geometric mean ratio (GMR) (HI Assay)

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    End point title
    		 Immunogenicity Endpoint: Geometric mean ratio (GMR) (HI Assay)
    End point description
    The GMR is defined as the geometric mean of the fold increase of postvaccination HI titer over the prevaccination HI titer. Adjusted GMRs are presented. Analysis population: FAS Immunogenicity Note: For the A/H3N2 strain in Seasons 1 and 3, "99999" signifies "not applicable" due to lack of agglutination of A/H3N2 in HI assay". (The system does not allow text to be entered in the table.)
    End point type
    Secondary
    End point timeframe
    Day 1 and 28 days after last vaccination
    End point values
    		 QIVc (Season 1) Comparator (Season 1) QIVc (Season 2) Comparator (Season 2) QIVc (Season 3) Comparator (Season 3) QIVc (Season 4) Comparator (Season 4) QIVc (Season 5) Comparator (Season 5)
    Number of subjects analysed
    112
    108
    107
    111
    111
    112
    87
    85
    108
    108
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        A/H1N1 GMR HI Titer
    3.36 (1.69 to 6.66)
    1.53 (0.79 to 2.95)
    3.71 (2.04 to 6.73)
    0.67 (0.37 to 1.20)
    6.28 (2.91 to 13.56)
    0.70 (0.33 to 1.50)
    2.59 (1.51 to 4.45)
    1.42 (0.83 to 2.41)
    19.20 (3.61 to 102.12)
    3.20 (0.58 to 17.52)
        A/H3N2 GMR HI Titer
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    7.43 (2.95 to 18.75)
    0.62 (0.25 to 1.54)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    1.81 (0.86 to 3.81)
    1.19 (0.57 to 2.48)
    7.14 (1.81 to 28.16)
    0.80 (0.20 to 3.24)
        B/Yamagata GMR HI Titer
    2.52 (1.75 to 3.63)
    0.92 (0.65 to 1.31)
    3.38 (2.02 to 5.67)
    1.96 (1.18 to 3.25)
    1.95 (0.91 to 4.15)
    0.75 (0.35 to 1.59)
    2.03 (1.32 to 3.13)
    0.68 (0.44 to 1.04)
    8.04 (3.12 to 20.72)
    1.20 (0.46 to 3.15)
        B/Victoria GMR HI Titer
    2.01 (1.37 to 2.96)
    0.90 (0.62 to 1.30)
    1.79 (1.15 to 2.79)
    0.94 (0.61 to 1.46)
    1.43 (0.83 to 2.44)
    0.71 (0.42 to 1.21)
    4.44 (2.62 to 7.55)
    0.85 (0.51 to 1.43)
    32.55 (8.85 to 119.71)
    2.95 (0.78 to 11.09)
    No statistical analyses for this end point

    Secondary: Immunogenicity Endpoint: Pre- and postvaccination GMTs (MN Assay)

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    End point title
    		 Immunogenicity Endpoint: Pre- and postvaccination GMTs (MN Assay)
    End point description
    MN = microneutralization Adjusted GMTs are presented Analysis population: FAS Immunogenicity
    End point type
    Secondary
    End point timeframe
    Day 1 and 28 days after last vaccination
    End point values
    		 QIVc (Season 1) Comparator (Season 1) QIVc (Season 2) Comparator (Season 2) QIVc (Season 3) Comparator (Season 3) QIVc (Season 4) Comparator (Season 4) QIVc (Season 5) Comparator (Season 5)
    Number of subjects analysed
    112
    108
    107
    111
    111
    112
    87
    85
    108
    108
    Units: Geometric mean titer
    geometric mean (confidence interval 95%)
        A/H1N1 Day 1 MN GMT
    22.06 (9.53 to 51.07)
    31.10 (13.83 to 69.92)
    57.54 (18.79 to 176.16)
    55.89 (18.69 to 167.19)
    61.40 (16.51 to 228.37)
    43.43 (11.93 to 158.11)
    32.15 (19.17 to 53.90)
    35.32 (21.25 to 58.71)
    113.94 (36.64 to 354.34)
    115.49 (36.41 to 366.35)
        A/H1N1 Day 29/57 MN GMT
    329.08 (196.16 to 552.06)
    36.24 (21.97 to 59.79)
    473.15 (247.69 to 903.85)
    66.69 (35.39 to 125.71)
    459.87 (157.55 to 1342.31)
    19.32 (6.76 to 55.21)
    86.91 (58.51 to 129.11)
    46.51 (31.53 to 68.60)
    352.09 (110.01 to 1126.90)
    86.61 (26.51 to 282.92)
        A/H3N2 Day 1 MN GMT
    6.92 (4.91 to 9.76)
    6.29 (4.51 to 8.76)
    4.96 (4.19 to 5.88)
    4.80 (4.07 to 5.67)
    7.02 (3.18 to 15.51)
    8.33 (3.82 to 18.16)
    17.70 (10.34 to 30.31)
    15.77 (9.29 to 26.76)
    26.08 (7.79 to 87.37)
    25.98 (7.59 to 88.87)
        A/H3N2 Day 29/57 MN GMT
    27.55 (18.70 to 40.58)
    10.95 (7.52 to 15.94)
    12.04 (7.60 to 19.08)
    5.31 (3.38 to 8.34)
    57.93 (28.43 to 118.06)
    10.49 (5.21 to 21.09)
    35.99 (18.52 to 69.94)
    14.78 (7.70 to 28.34)
    139.97 (41.52 to 471.84)
    30.22 (8.78 to 104.08)
        B/Yamagata Day 1 MN GMT
    76.91 (53.50 to 110.55)
    66.14 (46.60 to 93.87)
    65.25 (35.87 to 118.70)
    60.03 (33.41 to 107.86)
    15.33 (7.73 to 30.41)
    15.26 (7.78 to 29.93)
    53.41 (32.42 to 88.00)
    54.11 (33.12 to 88.41)
    51.81 (23.27 to 115.35)
    45.20 (20.02 to 102.06)
        B/Yamagata Day 29/57 MN GMT
    278.89 (202.31 to 384.46)
    88.67 (65.06 to 120.84)
    283.42 (183.07 to 438.79)
    126.59 (82.43 to 194.41)
    55.17 (27.19 to 111.92)
    19.24 (9.59 to 38.59)
    84.60 (55.74 to 128.38)
    52.11 (34.57 to 78.55)
    169.24 (75.01 to 381.86)
    49.34 (21.58 to 112.85)
        B/Victoria Day 1 MN GMT
    6.07 (4.82 to 7.65)
    6.64 (5.31 to 8.30)
    4.99 (4.16 to 5.99)
    5.18 (4.33 to 6.18)
    9.09 (4.80 to 17.24)
    10.71 (5.71 to 20.09)
    8.79 (6.40 to 12.07)
    7.72 (5.66 to 10.55)
    15.97 (2.53 to 100.98)
    12.20 (1.87 to 79.68)
        B/Victoria Day 29/57 MN GMT
    14.23 (10.95 to 18.51)
    7.00 (5.44 to 9.02)
    5.29 (4.03 to 6.92)
    5.26 (4.04 to 6.85)
    26.81 (14.06 to 51.12)
    9.65 (5.12 to 18.20)
    121.02 (59.56 to 245.87)
    5.99 (2.99 to 11.97)
    938.65 (230.67 to 3819.51)
    39.32 (9.41 to 164.32)
    No statistical analyses for this end point

    Secondary: Immunogenicity Endpoint: SCR (MN Assay)

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    End point title
    		 Immunogenicity Endpoint: SCR (MN Assay)
    End point description
    The SCR is defined as the percentage of subjects with either a prevaccination MN titer <1:10 and a postvaccination MN titer ≥1:40, or a prevaccination MN titer ≥1:10 and a ≥4-fold increase in postvaccination MN titer Analysis population: FAS Immunogenicity
    End point type
    Secondary
    End point timeframe
    Day 1 and 28 days after last vaccination
    End point values
    		 QIVc (Season 1) Comparator (Season 1) QIVc (Season 2) Comparator (Season 2) QIVc (Season 3) Comparator (Season 3) QIVc (Season 4) Comparator (Season 4) QIVc (Season 5) Comparator (Season 5)
    Number of subjects analysed
    112
    108
    107
    111
    111
    112
    87
    85
    108
    108
    Units: Percentage of participants
    number (confidence interval 95%)
        A/H1N1 SCR MN Titer
    73.21 (64.02 to 81.14)
    2.78 (0.58 to 7.90)
    74.77 (65.45 to 82.67)
    4.50 (1.48 to 10.20)
    87.39 (79.74 to 92.93)
    4.46 (1.47 to 10.11)
    32.18 (22.56 to 43.06)
    7.06 (2.63 to 14.73)
    68.52 (58.88 to 77.12)
    15.74 (9.45 to 24.00)
        A/H3N2 SCR MN Titer
    38.39 (29.36 to 48.06)
    4.63 (1.52 to 10.47)
    20.56 (13.36 to 29.46)
    1.80 (0.22 to 6.36)
    57.66 (47.92 to 66.98)
    1.79 (0.22 to 6.30)
    33.33 (23.58 to 44.25)
    10.59 (4.96 to 19.15)
    71.30 (61.80 to 79.59)
    15.74 (9.45 to 24.00)
        B/Yamagata SCR MN Titer
    46.43 (36.95 to 56.10)
    0.93 (0.02 to 5.05)
    30.84 (22.27 to 40.50)
    3.60 (0.99 to 8.97)
    36.94 (27.97 to 46.62)
    4.46 (1.47 to 10.11)
    19.54 (11.81 to 29.43)
    4.71 (1.30 to 11.61)
    54.63 (44.76 to 64.24)
    7.41 (3.25 to 14.07)
        B/Victoria SCR MN Titer
    20.54 (13.49 to 29.20)
    0.93 (0.02 to 5.05)
    0.93 (0.02 to 5.10)
    2.70 (0.56 to 7.70)
    25.23 (17.46 to 34.35)
    0.89 (0.02 to 4.87)
    87.36 (78.50 to 93.52)
    7.06 (2.63 to 14.73)
    94.44 (88.30 to 97.93)
    9.26 (4.53 to 16.37)
    No statistical analyses for this end point

    Secondary: Immunogenicity Endpoint: GMR (MN Assay)

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    End point title
    		 Immunogenicity Endpoint: GMR (MN Assay)
    End point description
    The GMR is defined as the geometric mean of the fold increase of postvaccination MN titer over the prevaccination MN titer. Adjusted GMRs are presented. Analysis population: FAS Immunogenicity
    End point type
    Secondary
    End point timeframe
    Day 1 and 28 days after vaccination
    End point values
    		 QIVc (Season 1) Comparator (Season 1) QIVc (Season 2) Comparator (Season 2) QIVc (Season 3) Comparator (Season 3) QIVc (Season 4) Comparator (Season 4) QIVc (Season 5) Comparator (Season 5)
    Number of subjects analysed
    112
    108
    107
    111
    111
    112
    87
    85
    108
    108
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        A/H1N1 GMR MN Titer
    16.16 (9.52 to 27.45)
    1.70 (1.02 to 2.83)
    8.12 (4.19 to 15.75)
    1.15 (0.60 to 2.20)
    17.55 (5.72 to 53.86)
    0.81 (0.27 to 2.44)
    2.37 (1.54 to 3.67)
    1.23 (0.80 to 1.88)
    3.47 (1.07 to 11.24)
    0.85 (0.26 to 2.81)
        A/H3N2 GMR MN Titer
    3.28 (2.23 to 4.84)
    1.32 (0.91 to 1.92)
    2.14 (1.35 to 3.40)
    0.93 (0.59 to 1.46)
    5.92 (2.79 to 12.56)
    1.01 (0.48 to 2.13)
    2.74 (1.39 to 5.38)
    1.16 (0.60 to 2.26)
    4.40 (1.30 to 14.88)
    0.95 (0.27 to 3.28)
        B/Yamagata GMR MN Titer
    3.93 (2.81 to 5.49)
    1.30 (0.94 to 1.79)
    3.05 (1.95 to 4.75)
    1.38 (0.89 to 2.13)
    3.15 (1.47 to 6.71)
    1.10 (0.52 to 2.32)
    1.82 (1.15 to 2.88)
    1.11 (0.71 to 1.75)
    3.81 (1.56 to 9.33)
    1.19 (0.48 to 2.95)
        B/Victoria GMR MN Titer
    2.17 (1.67 to 2.82)
    1.07 (0.83 to 1.37)
    1.04 (0.77 to 1.40)
    1.01 (0.75 to 1.35)
    2.74 (1.37 to 5.47)
    0.92 (0.47 to 1.83)
    16.90 (8.36 to 34.19)
    0.86 (0.43 to 1.72)
    31.51 (7.19 to 138.05)
    1.42 (0.31 to 6.37)
    No statistical analyses for this end point

    Secondary: Safety Endpoint: Percentage of subjects with solicited local and systemic adverse events (AEs) was assessed for 7 days following each vaccination in the QIVc group and the comparator group

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    End point title
    		 Safety Endpoint: Percentage of subjects with solicited local and systemic adverse events (AEs) was assessed for 7 days following each vaccination in the QIVc group and the comparator group
    End point description
    Analysis population: Solicited Safety Set
    End point type
    Secondary
    End point timeframe
    7 days following each vaccination
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2813
    2790
    Units: Percentage of subjects
    number (not applicable)
        Solicited AEs
    55.8
    60.8
        Solicited Local AEs
    32.3
    40.4
        Solicited Systemic AEs
    40.9
    42.5
        Analgesic/Antipyretic Use
    14.5
    15.0
    No statistical analyses for this end point

    Secondary: Safety Endpoint: Percentage of subjects with any unsolicited AEs was assessed in the QIVc group and in the comparator group until 28 days after each vaccination

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    End point title
    		 Safety Endpoint: Percentage of subjects with any unsolicited AEs was assessed in the QIVc group and in the comparator group until 28 days after each vaccination
    End point description
    Analysis population: Unsolicited Safety Set
    End point type
    Secondary
    End point timeframe
    28 days following each vaccination
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2841
    Units: Percentage of participants
    number (not applicable)
        Any AE
    42.5
    45.4
        Any related AE
    4.2
    3.6
    No statistical analyses for this end point

    Secondary: Safety Endpoint: Percentage of subjects with serious adverse events (SAEs), new onset of chronic disease (NOCD), AEs leading to withdrawal from the study or vaccination

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    End point title
    		 Safety Endpoint: Percentage of subjects with serious adverse events (SAEs), new onset of chronic disease (NOCD), AEs leading to withdrawal from the study or vaccination
    End point description
    Analysis population: Unsolicited Safety Set
    End point type
    Secondary
    End point timeframe
    Day 1 through Study Completion
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2841
    Units: Percentage of subjects
    number (not applicable)
        SAE
    2.2
    3.0
        Related SAE
    0
    0.04
        NOCD
    0.7
    0.4
        AE leading to study withdrawal
    0
    0
        AE leading to study vaccine withdrawal
    0
    0.1
    No statistical analyses for this end point

    Secondary: Safety Endpoint: Percentage of subjects with medically-attended AEs within 30 days after influenza-like illness (ILI) onset

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    End point title
    		 Safety Endpoint: Percentage of subjects with medically-attended AEs within 30 days after influenza-like illness (ILI) onset
    End point description
    Analysis population: Unsolicited Safety Set
    End point type
    Secondary
    End point timeframe
    30 days following ILI onset
    End point values
    		 QIVc Comparator
    Number of subjects analysed
    2856
    2841
    Units: Percentage of participants
    number (not applicable)
        Medically-attended AE within 30 days of ILI onset
    28.9
    32.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through Study Completion
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    QIVc
    Reporting group description
    		 Cell-based quadrivalent influenza vaccine containing 2 influenza type A strains and 2 influenza type B strains

    Reporting group title
    Comparator
    Reporting group description
    		 Non-influenza vaccine comparator

    Serious adverse events
    		 QIVc Comparator
    Total subjects affected by serious adverse events
         subjects affected / exposed
    64 / 2856 (2.24%)
    84 / 2841 (2.96%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    1
    2
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    2 / 2856 (0.07%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Accidental exposure to product
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 2856 (0.00%)
    2 / 2841 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed
    1 / 2856 (0.04%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular dysfunction
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (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
    Febrile convulsion
         subjects affected / exposed
    5 / 2856 (0.18%)
    3 / 2841 (0.11%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         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
    Anaemia
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intussusception
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 2856 (0.04%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (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
    Asthma
         subjects affected / exposed
    2 / 2856 (0.07%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (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
    Pneumonia
         subjects affected / exposed
    15 / 2856 (0.53%)
    24 / 2841 (0.84%)
         occurrences causally related to treatment / all
    0 / 15
    1 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    8 / 2856 (0.28%)
    12 / 2841 (0.42%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dengue fever
         subjects affected / exposed
    6 / 2856 (0.21%)
    7 / 2841 (0.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    4 / 2856 (0.14%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 2856 (0.11%)
    6 / 2841 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    2 / 2856 (0.07%)
    3 / 2841 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    2 / 2856 (0.07%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    2 / 2856 (0.07%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    2 / 2856 (0.07%)
    2 / 2841 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 2856 (0.07%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typhoid fever
         subjects affected / exposed
    2 / 2856 (0.07%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebic dysentery
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (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 / 2856 (0.04%)
    3 / 2841 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 2856 (0.04%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 2856 (0.04%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Norovirus infection
         subjects affected / exposed
    1 / 2856 (0.04%)
    2 / 2841 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (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 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 2856 (0.04%)
    2 / 2841 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    0 / 2856 (0.00%)
    2 / 2841 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         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 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (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 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         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
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 2856 (0.00%)
    3 / 2841 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 2856 (0.07%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 2856 (0.04%)
    0 / 2841 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 2856 (0.00%)
    1 / 2841 (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 Comparator
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1121 / 2856 (39.25%)
    1176 / 2841 (41.39%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    576 / 2856 (20.17%)
    634 / 2841 (22.32%)
         occurrences all number
    852
    933
    Rhinitis
         subjects affected / exposed
    282 / 2856 (9.87%)
    290 / 2841 (10.21%)
         occurrences all number
    324
    319
    Nasopharyngitis
         subjects affected / exposed
    255 / 2856 (8.93%)
    255 / 2841 (8.98%)
         occurrences all number
    371
    397
    Respiratory tract infection
         subjects affected / exposed
    162 / 2856 (5.67%)
    158 / 2841 (5.56%)
         occurrences all number
    190
    185

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2018
    Version 1.0 to Version 2.0 The main reasons for the protocol amendment were: 1. Omission of the option of placebo only as the comparator vaccine; all subjects in the comparator group were to receive Neisseria meningitidis serogroup C polysaccharide conjugate vaccine. 2. Modification of an exclusion criterion to exclude subjects with prior documented Neisseria meningitidis serogroup C disease from the study. 3. Reduction in the volume of blood drawn per time point from a maximum of 7 mL per blood draw to a maximum of 5 mL per blood draw. 4. Revision of the description of the route of temperature measurement to indicate that there was not a preferred route of measurement.
    03 Sep 2020
    Version 2.0 to Version 3.0 The main reasons for the protocol amendment were: 1. Removal of constraints on a minimum number of subjects to be recruited or a minimum number of influenza seasons in which the study would be conducted. 2. Addition of exploratory objectives to characterize immune response by other assays and use genotypic methods to characterize strains of circulating influenza virus from NP swabs collected during the study. 3. Inclusion of other study assessments, in addition to collection of a NP swab specimen, at home visits when deemed necessary and agreed to by the Sponsor, eg, during the COVID-19 pandemic situation. 4. Permitting Remote Source Data Verification when deemed necessary, eg, during the COVID-19 pandemic situation. 5. Modification of the description of the residual amount of MDCK cell protein and protein other than HA in alignment with the Package Insert/SmPC for Flucelvax Quadrivalent/Flucelvax Tetra. 6. Harmonization of the text in Section 8.6 Interim Analysis of the protocol to state that the DMC may recommend to stop the study for efficacy when at least one efficacy objective met the success criteria, and adjusting the CI and overall alpha for hypothesis testing for the primary objectives during the interim analysis to meet the overall coverage of 97.5% CI and alpha being 1.25% (one sided), respectively.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Mar 2020
    The Northern Hemisphere (NH) 2019/2020 study season was shortened in duration due to the onset of the COVID-19 pandemic in March 2020 and conduct of the study was cancelled for the Southern Hemisphere (SH) 2020 season. The study was restarted for the NH 2020/2021 influenza season.
    11 Sep 2020
    02 Sep 2021
    The NH 2020/2021 season was conducted; however, the SH 2021 and NH 2021/2022 study seasons were cancelled due to the significant reduction in global influenza activity observed with the pandemic. The study was restarted for the NH 2022/2023 influenza season.
    14 Sep 2022

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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