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    Clinical Trial Results:
    Randomized, Double-Blind and Active-Controlled Study in Children and Adolescents Aged 3–17 Years to Assess the Safety and Immunogenicity of Abbott’s Candidate Quadrivalent Influenza Vaccine and its Non-Inferiority versus Trivalent Influenza Vaccine

    Summary
    EudraCT number
    2015-005482-23
    Trial protocol
    DE   FI   EE   HU   LT  
    Global end of trial date
    14 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Oct 2017
    First version publication date
    28 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INFQ3002
    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 Manager, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate in a population of children and adolescents 3 to 17 years of age the non-inferiority of quadrivalent influenza vaccine (QIV) with respect to post-vaccination geometric mean Hemagglutination Inhibition (HI) antibody titers against the shared strains compared with the trivalent influenza vaccines (TIV) with either the B-strain of the Victoria lineage (TIV[Vic]) or the B-strain of the Yamagata lineage (TIV[Yam]).
    Protection of trial subjects
    The study was conducted in compliance with Good Clinical Practice and the applicable national regulations so as to ensure 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.
    Background therapy
    Children and adolescents aged ≥ 9 years were considered primed subjects as well as those aged < 9 years who had received ≥ two doses of a seasonal influenza vaccine at least one month apart; children aged < 9 years who had not previously received ≥ two doses of a seasonal influenza vaccine at least one month apart were considered unprimed. Primed subjects were required to attend two clinic visits, while unprimed subjects were required to attend three clinical visits.
    Evidence for comparator
    The candidate vaccine in this study, QIV, was compared against TIV(Vic) and TIV(Yam). For all vaccines, the active drug substance consisted of approximately 15 micrograms (μg) of hemagglutinin (HA) antigen of each of the three or four viral strains recommended by the World Health Organization and Committee for Medicinal Products for Human Use for the strains recommended for the northern hemisphere 2016/2017 season. These comprised: • an A/California/7/2009 (H1N1)pdm09-like virus; referred to as the A(H1N1) strain. • an A/Hong Kong/4801/2014 (H3N2)-like virus; referred to as the A(H3N2) strain. • a B/Brisbane/60/2008-like virus; referred to as the B-Victoria strain. • a B/Phuket/3073/2013-like virus; referred to as the B-Yamagata strain. The B/Brisbane/60/2008-like virus (TIV[Vic]) was the recommended B-strain for the marketed TIV formulation (Influvac®).
    Actual start date of recruitment
    02 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 229
    Country: Number of subjects enrolled
    Estonia: 127
    Country: Number of subjects enrolled
    Finland: 450
    Country: Number of subjects enrolled
    Germany: 80
    Country: Number of subjects enrolled
    Hungary: 184
    Country: Number of subjects enrolled
    Lithuania: 130
    Worldwide total number of subjects
    1200
    EEA total number of subjects
    1200
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    978
    Adolescents (12-17 years)
    222
    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
    Twenty eight study centres in six countries (Estonia, Finland, Germany, Hungary, Lithuania, and Poland) screened and enrolled subjects. The first subject entered the study on 02 September 2016 and the last subject completed the last visit on 14 April 2017.

    Pre-assignment
    Screening details
    A total of 1,223 subjects provided informed consent and were screened for eligibility. Of these, 23 subjects failed screening and 1,200 subjects were vaccinated. Allocation was stratified 2:1 by age group: 3 to 8 years and 9 to 17 years, and in both age groups, subjects were randomly assigned to receive QIV, TIV(Vic) and TIV(Yam) in a 1:1:1 ratio.

    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
    All syringes were identical in appearance and packaged in the correct proportions to ensure desired dosages were used and that blinding was maintained.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Quadrivalent Influenza Vaccine
    Arm description
    Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.
    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
    Primed subjects: single dose of 0.5 milliliters (mL) QIV administered by intramuscular injection on Day 1 (Visit 1). Unprimed subjects: two single doses of 0.5 mL of QIV administered by intramuscular injection on Day 1 (Visit 1) and on Day 29 (Visit 2). The HA content of the QIV batch was as follows: • A/California/7/2009 (H1N1)pdm09-like strain (A/California/7/2009, X-181) (14.4 µg HA/dose). • A/Hong Kong/4801/2014 (H3N2)-like strain (A/Hong Kong/4801/2014, X-263B) (18.6 µg HA/dose). • B/Brisbane/60/2008-like strain (B/Brisbane/60/2008, wild type) (16.2 µg HA/dose). • B/Phuket/3073/2013-like strain (B/Phuket/3073/2013, wild type) (17.5 µg HA/dose).

    Arm title
    Trivalent Influenza Vaccine (Victoria)
    Arm description
    Primed subjects received a single dose of TIV(Vic) on Day 1 and unprimed subjects received two doses of TIV(Vic) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.
    Arm type
    Active comparator

    Investigational medicinal product name
    Trivalent Influenza Vaccine (Victoria)
    Investigational medicinal product code
    Other name
    TIV(Vic), Influvac®
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Primed subjects: single dose of 0.5 mL TIV(Vic) administered by intramuscular injection on Day 1 (Visit 1). Unprimed subjects: two single doses of 0.5 mL of TIV(Vic) administered by intramuscular injection on Day 1 (Visit 1) and on Day 29 (Visit 2). The HA content of the TIV(Vic) batch was as follows: • A/California/7/2009 (H1N1)pdm09-like strain (A/California/7/2009, X-181) (14.7 µg HA/dose). • A/Hong Kong/4801/2014 (H3N2)-like strain (A/Hong Kong/4801/2014, X-263B) (18.8 µg HA/dose). • B/Brisbane/60/2008-like strain (B/Brisbane/60/2008, wild type) (15.6 µg HA/dose).

    Arm title
    Trivalent Influenza Vaccine (Yamagata)
    Arm description
    Primed subjects received a single dose of TIV(Yam) on Day 1 and unprimed subjects received two doses of TIV(Yam) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.
    Arm type
    Active comparator

    Investigational medicinal product name
    Trivalent Influenza Vaccine (Yamagata)
    Investigational medicinal product code
    Other name
    TIV(Yam)
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Primed subjects: single dose of 0.5 mL TIV(Yam) administered by intramuscular injection on Day 1 (Visit 1). Unprimed subjects: two single doses of 0.5 mL of TIV(Yam) administered by intramuscular injection on Day 1 (Visit 1) and on Day 29 (Visit 2). The HA content of the TIV(Yam) batch was as follows: • A/California/7/2009 (H1N1)pdm09-like strain (A/California/7/2009, X-181) (15.2 µg HA/dose). • A/Hong Kong/4801/2014 (H3N2)-like strain (A/Hong Kong/4801/2014, X-263B) (20.0 µg HA/dose). • B/Phuket/3073/2013-like strain (B/Phuket/3073/2013, wild type) (16.1 µg HA/dose).

    Number of subjects in period 1
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Started
    402
    404
    394
    Completed
    399
    403
    393
    Not completed
    3
    1
    1
         Consent withdrawn by subject
             2
             -
             1
         Lost to follow-up
             1
             1
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine
    Reporting group description
    Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.

    Reporting group title
    Trivalent Influenza Vaccine (Victoria)
    Reporting group description
    Primed subjects received a single dose of TIV(Vic) on Day 1 and unprimed subjects received two doses of TIV(Vic) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.

    Reporting group title
    Trivalent Influenza Vaccine (Yamagata)
    Reporting group description
    Primed subjects received a single dose of TIV(Yam) on Day 1 and unprimed subjects received two doses of TIV(Yam) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.

    Reporting group values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata) Total
    Number of subjects
    402 404 394 1200
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.4 ± 4 7.7 ± 3.9 7.6 ± 3.9 -
    Gender categorical
    Units: Subjects
        Female
    193 207 179 579
        Male
    209 197 215 621

    End points

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    End points reporting groups
    Reporting group title
    Quadrivalent Influenza Vaccine
    Reporting group description
    Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.

    Reporting group title
    Trivalent Influenza Vaccine (Victoria)
    Reporting group description
    Primed subjects received a single dose of TIV(Vic) on Day 1 and unprimed subjects received two doses of TIV(Vic) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.

    Reporting group title
    Trivalent Influenza Vaccine (Yamagata)
    Reporting group description
    Primed subjects received a single dose of TIV(Yam) on Day 1 and unprimed subjects received two doses of TIV(Yam) (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.

    Subject analysis set title
    Trivalent Influenza Vaccine (Pooled)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Primed subjects received a single dose of TIV on Day 1 and unprimed subjects received two doses of TIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled. Reactogenicity data of the two trivalent formulations was also pooled.

    Primary: Post-vaccination geometric HI antibody titers against A(H1N1) strain

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    End point title
    Post-vaccination geometric HI antibody titers against A(H1N1) strain [1]
    End point description
    Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the A(H1N1) strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
    End point type
    Primary
    End point timeframe
    The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    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: For each A strain, the HI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    388
    774
    Units: titer
        geometric mean (standard deviation)
    548.9 ± 3.2
    622.2 ± 3.4
    Statistical analysis title
    A(H1N1) strain non-inferiority analysis
    Statistical analysis description
    Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% confidence interval (CI) for adjusted geometric mean ratios (GMRs) for the TIV versus QIV comparison, using an analysis of variance (ANOVA) model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
    Comparison groups
    Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Pooled)
    Number of subjects included in analysis
    1162
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Adjusted GMR
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.3
    Notes
    [2] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5.

    Primary: Post-vaccination geometric HI antibody titers against A(H3N2) strain

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    End point title
    Post-vaccination geometric HI antibody titers against A(H3N2) strain [3]
    End point description
    Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the A(H3N2) strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
    End point type
    Primary
    End point timeframe
    The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    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: For each A strain, the HI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    388
    774
    Units: titer
        geometric mean (standard deviation)
    1150.4 ± 3.2
    1193.9 ± 3.4
    Statistical analysis title
    A(H3N2) strain non-inferiority analysis
    Statistical analysis description
    Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
    Comparison groups
    Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Pooled)
    Number of subjects included in analysis
    1162
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    Parameter type
    Adjusted GMR
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.19
    Notes
    [4] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5.

    Primary: Post-vaccination geometric HI antibody titers against B-Victoria strain

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    End point title
    Post-vaccination geometric HI antibody titers against B-Victoria strain
    End point description
    Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the B-Victoria strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
    End point type
    Primary
    End point timeframe
    The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    388
    393
    381
    Units: titer
        geometric mean (standard deviation)
    302.6 ± 4.2
    364 ± 4.6
    104.8 ± 6.4
    Statistical analysis title
    B-Victoria strain non-inferiority analysis
    Statistical analysis description
    Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
    Comparison groups
    Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Victoria)
    Number of subjects included in analysis
    781
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    ANOVA
    Parameter type
    Adjusted GMR
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.46
    Notes
    [5] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5.

    Primary: Post-vaccination geometric HI antibody titers against B-Yamagata strain

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    End point title
    Post-vaccination geometric HI antibody titers against B-Yamagata strain
    End point description
    Non-inferiority of QIV was assessed with respect to post-vaccination geometric mean HI antibody titers against the shared strains compared with TIV(Vic) and TIV(Yam) groups; results are reported for HI titers against the B-Yamagata strain. Population for analysis was the per-protocol sample, defined through blind data review and comprised of all subjects who were included in the full analysis sample and did not present any major protocol violations.
    End point type
    Primary
    End point timeframe
    The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    388
    393
    381
    Units: titer
        geometric mean (standard deviation)
    277.6 ± 3.8
    38.6 ± 6.6
    270.7 ± 4.3
    Statistical analysis title
    B-Yamagata strain non-inferiority analysis
    Statistical analysis description
    Non-inferiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
    Comparison groups
    Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Yamagata)
    Number of subjects included in analysis
    769
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    Method
    Parameter type
    Adjusted GMR
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.19
    Notes
    [6] - The non-inferiority margin was set at 1.5. Non-inferiority of QIV to TIV would be concluded if, for all four strains, the upper limit of the 95% CI fell below 1.5.

    Secondary: Post-vaccination geometric HI antibody titers against the alternate lineage B-strain (Victoria lineage)

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    End point title
    Post-vaccination geometric HI antibody titers against the alternate lineage B-strain (Victoria lineage)
    End point description
    Superiority of QIV to TIV(Vic) and TIV(Yam) was assessed with respect to post-vaccination geometric HI antibody titers against the alternate lineage B-strain; results are reported for HI titers against the B-Victoria strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers).
    End point type
    Secondary
    End point timeframe
    The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    396
    399
    389
    Units: titer
        geometric mean (standard deviation)
    306.7 ± 4.2
    361.4 ± 4.6
    104.5 ± 6.4
    Statistical analysis title
    B-Victoria strain superiority analysis
    Statistical analysis description
    Superiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
    Comparison groups
    Trivalent Influenza Vaccine (Yamagata) v Quadrivalent Influenza Vaccine
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted GMR
    Point estimate
    2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.36
         upper limit
    3.64
    Notes
    [7] - Superiority of QIV to TIV against the alternate lineage B-strains would be concluded if for both strains: GMR > 1 and p-value <0.05.

    Secondary: Post-vaccination geometric HI antibody titers against the alternate lineage B-strain (Yamagata lineage)

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    End point title
    Post-vaccination geometric HI antibody titers against the alternate lineage B-strain (Yamagata lineage)
    End point description
    Superiority of QIV to TIV(Vic) and TIV(Yam) was assessed with respect to post-vaccination geometric HI antibody titers against the alternate lineage B-strain; results are reported for HI titers against the B-Yamagata strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers).
    End point type
    Secondary
    End point timeframe
    The HI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    396
    399
    389
    Units: titer
        geometric mean (standard deviation)
    280.8 ± 3.8
    38.3 ± 6.5
    269 ± 4.3
    Statistical analysis title
    B-Yamagata strain superiority analysis
    Statistical analysis description
    Superiority was analyzed by calculating for each of the two A-strains and each of the two B-strains a two-sided 95% CI for adjusted GMRs for the TIV versus QIV comparison, using an ANOVA model for the log transformed titers at Day 29/Day 57 with age group, center and priming status included as covariates in the model.
    Comparison groups
    Quadrivalent Influenza Vaccine v Trivalent Influenza Vaccine (Victoria)
    Number of subjects included in analysis
    795
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    < 0.0001
    Method
    ANOVA
    Parameter type
    Adjusted GMR
    Point estimate
    7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.83
         upper limit
    9.03
    Notes
    [8] - Superiority of QIV to TIV against the alternate lineage B-strains would be concluded if for both strains: GMR > 1 and p-value <0.05.

    Secondary: Post-vaccination geometric mean fold increases in HI, Virus Neutralization (VN) and Neuraminidase Inhibition (NI) antibody titers against A(H1N1) strain

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    End point title
    Post-vaccination geometric mean fold increases in HI, Virus Neutralization (VN) and Neuraminidase Inhibition (NI) antibody titers against A(H1N1) strain [9]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the A(H1N1) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    396
    786
    Units: titer (fold increase)
    geometric mean (standard deviation)
        HI titers (n=396; 786)
    6.6 ± 4.2
    6.9 ± 4.4
        VN titers (n=59; 118)
    2.5 ± 2.2
    2.4 ± 2.1
        NI titers (n=59; 118)
    4.8 ± 3.6
    4.9 ± 3.4
    No statistical analyses for this end point

    Secondary: Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against A(H3N2) strain

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    End point title
    Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against A(H3N2) strain [10]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the A(H3N2) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    396
    786
    Units: titer (fold increase)
    geometric mean (standard deviation)
        HI titers (n=396; 786)
    16.2 ± 5.3
    18.6 ± 5.2
        VN titers (n=59; 118)
    3.4 ± 2.3
    3.4 ± 2.4
        NI titers (n=59; 118)
    2.4 ± 2.8
    2.2 ± 3.2
    No statistical analyses for this end point

    Secondary: Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against B-Victoria strain

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    End point title
    Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against B-Victoria strain
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the B-Victoria strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    396
    399
    387
    Units: titer (fold incease)
    geometric mean (standard deviation)
        HI titers (n=396; 399; 387)
    11.9 ± 4.7
    10.4 ± 4.7
    3.6 ± 4.3
        VN titers (n=59; 59; 59)
    5.1 ± 2.8
    6.4 ± 2.9
    1.9 ± 2.5
        NI titers (n=59; 59; 59)
    2.3 ± 3.3
    2.1 ± 2.2
    2.1 ± 2.4
    No statistical analyses for this end point

    Secondary: Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against B-Yamagata strain

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    End point title
    Post-vaccination geometric mean fold increases in HI, VN and NI antibody titers against B-Yamagata strain
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the geometric mean fold increase with respect to HI, VN and NI antibody titers; results are reported for antibody titers against the B-Yamagata strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    396
    399
    387
    Units: titer (fold increase)
    geometric mean (standard deviation)
        HI titers (n=396; 399; 387)
    16.7 ± 5.1
    2.5 ± 3.8
    14.9 ± 5.9
        VN titers (n=59; 59; 59)
    5.8 ± 2.8
    1.8 ± 2
    5.5 ± 2.8
        NI titers (n=59; 59; 59)
    2.3 ± 2.7
    1.5 ± 2.1
    2.3 ± 2.5
    No statistical analyses for this end point

    Secondary: Seroconversion rates based on HI, VN and NI antibody titers against A(H1N1) strain

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    End point title
    Seroconversion rates based on HI, VN and NI antibody titers against A(H1N1) strain [11]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the A(H1N1) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    396
    786
    Units: percentage of subjects
    number (not applicable)
        HI titers (n=396; 786)
    60.1
    60.4
        VN titers (n=59; 118)
    66.1
    61.9
        NI titers (n=59; 118)
    57.6
    68.6
    No statistical analyses for this end point

    Secondary: Seroconversion rates based on HI, VN and NI antibody titers against A(H3N2) strain

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    End point title
    Seroconversion rates based on HI, VN and NI antibody titers against A(H3N2) strain [12]
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the A(H3N2) strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For each A strain, the HI, VN and NI titer data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    396
    786
    Units: percentage of subjects
    number (not applicable)
        HI titers (n=396; 786)
    80.6
    81.6
        VN titers (n=59; 118)
    76.3
    67.8
        NI titers (n=59; 118)
    33.9
    33.9
    No statistical analyses for this end point

    Secondary: Seroconversion rates based on HI, VN and NI antibody titers against B-Victoria strain

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    End point title
    Seroconversion rates based on HI, VN and NI antibody titers against B-Victoria strain
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the B-Victoria strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    396
    399
    387
    Units: percentage of subjects
    number (not applicable)
        HI titers (n=396; 399; 387)
    76.5
    72.7
    39.5
        VN titers (n=59; 59; 59)
    76.3
    79.7
    25.4
        NI titers (n=59; 59; 59)
    39.0
    32.2
    32.2
    No statistical analyses for this end point

    Secondary: Seroconversion rates based on HI, VN and NI antibody titers against B-Yamagata strain

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    End point title
    Seroconversion rates based on HI, VN and NI antibody titers against B-Yamagata strain
    End point description
    Characterization of the immunogenicity of each of the strains in QIV and TIV was assessed by deriving the seroconversion rates with respect to HI, VN and NI antibody titers. Seroconversion (defined as becoming seropositive if seronegative at enrollment, or [at least] a 4-fold rise in titer if seropositive at enrollment) rates are presented as percentage of subjects and are reported for antibody titers against the B-Yamagata strain. Population for analysis was the full analysis sample and comprised of all subjects who were included in the safety sample and had post-vaccination primary efficacy data (i.e., HI titers). Note: VN and NI titers were assessed only for a random subset of subjects (comprising of approximately 15% of the overall randomized population). n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    The HI, VN and NI titers were measured on Day 29 (Visit 2) post-vaccination for primed subjects and on Day 57 (Visit 3) post-vaccination for unprimed subjects.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Victoria) Trivalent Influenza Vaccine (Yamagata)
    Number of subjects analysed
    396
    399
    387
    Units: percentage of subjects
    number (not applicable)
        HI titers (n=396; 399; 387)
    79.3
    28.1
    73.1
        VN titers (n=59; 59; 59)
    81.4
    33.9
    71.2
        NI titers (n=59; 59; 59)
    42.4
    22.0
    37.3
    No statistical analyses for this end point

    Secondary: Proportion (percentage) of subjects with solicited systemic reactions

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    End point title
    Proportion (percentage) of subjects with solicited systemic reactions [13]
    End point description
    A subject diary was used to record pre-specified systemic reactions occurring during the first 7 days after vaccination (solicited reactogenicity). Population for analysis was the safety sample and comprised of all subjects who were vaccinated and had at least one post-vaccination safety observation. Solicited systemic reactions were assessed only in children aged 3-5 years for the following categories: Irritability/fussiness, Drowsiness, Diarrhea/vomiting, and Loss of appetite; and only in children aged 6-17 years for: Headache, Fatigue/tiredness, Gastrointestinal symptoms, Myalgia/muscle pain, Arthralgia/joint pain, Malaise, and Shivering; Fever and Sweating were assessed for both age groups. Note: n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    Solicited events were recorded during the first 7 days after vaccination (up to Day 7).
    Notes
    [13] - 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 reactogenicity data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    402
    795
    Units: percentage of subjects
    number (not applicable)
        Fever (n=402; 795)
    4.2
    2.6
        Irritability/fussiness (n=176; 314)
    21.0
    17.8
        Drowsiness (n=176; 314)
    15.9
    12.7
        Diarrhea/vomiting (n=176; 314)
    6.8
    7.3
        Loss of appetite (n=176; 314)
    13.1
    11.1
        Headache (n=229; 489)
    24.0
    20.9
        Fatigue/tiredness (n=229; 489)
    23.6
    22.1
        Gastrointestinal symptoms (n=229; 489)
    14.8
    10.0
        Myalgia/muscle pain (n=229; 489)
    14.8
    15.3
        Arthralgia/joint pain (n=229; 489)
    6.1
    4.9
        Malaise (n=229; 488)
    14.8
    12.3
        Sweating (n=401; 794)
    4.2
    3.7
        Shivering (n=229; 489)
    4.4
    3.5
    No statistical analyses for this end point

    Secondary: Proportion (percentage) of subjects with solicited local reactions

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    End point title
    Proportion (percentage) of subjects with solicited local reactions [14]
    End point description
    A subject diary was used to record pre-specified injection site (local) reactions occurring during the first 7 days after vaccination (solicited reactogenicity).Population for analysis was the safety sample and comprised of all subjects who were vaccinated and had at least one post-vaccination safety observation. Note: n = Number of subjects with non-missing data.
    End point type
    Secondary
    End point timeframe
    Solicited events were recorded during the first 7 days after vaccination (up to Day 7).
    Notes
    [14] - 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 reactogenicity data of the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.
    End point values
    Quadrivalent Influenza Vaccine Trivalent Influenza Vaccine (Pooled)
    Number of subjects analysed
    402
    795
    Units: percentage of subjects
    number (not applicable)
        Vaccination site erythema (n=402; 794)
    19.4
    16.6
        Swelling (n=402; 795)
    13.4
    10.7
        Induration (n=402; 795)
    11.4
    10.1
        Vaccination site pain (n=402; 794)
    59.0
    52.5
        Vaccination site ecchymosis (n=402; 795)
    6.5
    4.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For serious adverse events (SAEs): Day 1 up to end of safety follow-up period (up to Day 183). For non-serious adverse events (AEs): Day 1 up to Day 29 (primed subjects) or up to Day 57 (unprimed subjects).
    Adverse event reporting additional description
    All AEs are reported as treatment-emergent AEs during the immunization period plus safety follow-up period for SAEs and during the immunization period only for non-serious AEs. Population for analysis was the safety sample and comprised of all subjects who were vaccinated and had at least one post-vaccination safety observation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Trivalent Influenza Vaccine (Pooled)
    Reporting group description
    Primed subjects received a single dose of TIV on Day 1 and unprimed subjects received two doses of TIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm. The safety data of the subjects vaccinated with the two trivalent formulations, TIV(Vic) and TIV(Yam), were pooled.

    Reporting group title
    Quadrivalent Influenza Vaccine
    Reporting group description
    Primed subjects received a single dose of QIV on Day 1 and unprimed subjects received two doses of QIV (Day 1 and Day 29). Each dose contained approximately 15 μg HA antigen per virus strain, given intramuscularly in the deltoid muscle of the upper arm.

    Serious adverse events
    Trivalent Influenza Vaccine (Pooled) Quadrivalent Influenza Vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 798 (0.88%)
    4 / 402 (1.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 798 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ewing's sarcoma
         subjects affected / exposed
    0 / 798 (0.00%)
    1 / 402 (0.25%)
         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 / 798 (0.13%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 798 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (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
    1 / 798 (0.13%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 798 (0.50%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (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
    0 / 798 (0.00%)
    1 / 402 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 798 (0.13%)
    0 / 402 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Trivalent Influenza Vaccine (Pooled) Quadrivalent Influenza Vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 798 (14.04%)
    48 / 402 (11.94%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    13 / 798 (1.63%)
    4 / 402 (1.00%)
         occurrences all number
    14
    4
    Cough
         subjects affected / exposed
    24 / 798 (3.01%)
    7 / 402 (1.74%)
         occurrences all number
    25
    7
    Rhinorrhoea
         subjects affected / exposed
    9 / 798 (1.13%)
    0 / 402 (0.00%)
         occurrences all number
    10
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 798 (1.75%)
    4 / 402 (1.00%)
         occurrences all number
    15
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    19 / 798 (2.38%)
    10 / 402 (2.49%)
         occurrences all number
    21
    10
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    37 / 798 (4.64%)
    19 / 402 (4.73%)
         occurrences all number
    39
    20
    Nasopharyngitis
         subjects affected / exposed
    20 / 798 (2.51%)
    7 / 402 (1.74%)
         occurrences all number
    21
    7
    Otitis media
         subjects affected / exposed
    5 / 798 (0.63%)
    7 / 402 (1.74%)
         occurrences all number
    5
    9
    Rhinitis
         subjects affected / exposed
    11 / 798 (1.38%)
    2 / 402 (0.50%)
         occurrences all number
    11
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Mar 2016
    The amendment was implemented to include feedback from the protocol review conducted by the centralized Voluntary Harmonization Procedure. Updates comprised: • The person who was authorized and in the position to break the blinding in case of a serious adverse event (SAE) was specified. • It was clarified that the use of prohibited medications did not affect the contraindications for the second study vaccination in unprimed subjects. • Major protocol deviations, considered for the exclusion of subjects from the per protocol subject sample, were defined and specified. • It was emphasized that all attempts to contact the subject/parent(s)/legally acceptable representative (LAR) of drop-outs after study vaccination had to be documented in the source documents. • The reactogenicity grading scale for local solicited reactions was adapted for use in the pediatric populations. • AE reporting methods were clarified, to state that all AEs, including those not considered related to the study vaccine, were to be reported. • The analysis of safety was updated to state that all solicited local reactions were to be considered as related to the vaccine. • The analysis of efficacy was updated to state that the serology data were to include serological baseline status. • The benefit-risk considerations were updated to state that subjects who received TIV with the alternate B-strain lineage may have less benefit compared with those who received TIV with the recommended B-strain lineage or QIV with both B-strain lineages. • The study assessments and flow chart were updated to state that parents/LARs should have been reminded to inform the study site in case of an SAE not treated at site.

    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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