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    Clinical Trial Results:
    Safety and Immunogenicity of the Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Children Aged 3 to 8 Years

    Summary
    EudraCT number
    2011-005374-33
    Trial protocol
    FI  
    Global end of trial date
    25 Jun 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Feb 2016
    First version publication date
    17 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GQM02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1127-7425
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, F-69367 Lyon Cedex 07, France,
    Public contact
    Director, Clinical Development, Sanofi Pasteur SA, +33 (4) 37 37 58 50, stephanie.pepin@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, +33 (4) 37 37 58 50, stephanie.pepin@sanofipasteur.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001254-PIP01-11
    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
    02 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority of antibody (Ab) responses induced by QIV compared with the TIV.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment was also available on site in case of any immediate allergic reactions.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    12 Sep 2013
    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
    Finland: 154
    Country: Number of subjects enrolled
    Poland: 288
    Country: Number of subjects enrolled
    Mexico: 600
    Country: Number of subjects enrolled
    Taiwan: 200
    Worldwide total number of subjects
    1242
    EEA total number of subjects
    442
    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)
    1242
    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
    Study subjects were enrolled from 12 September 2013 to 13 November 2013 in 11 clinical centers in Finland, 4 in Mexico, 4 in Poland, and 3 in Taiwan.

    Pre-assignment
    Screening details
    A total of 1242 subjects who met all the inclusion criteria and none of the exclusion criteria were enrolled and vaccinated.

    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, Subject
    Blinding implementation details
    This study was blinded to the Investigator and subjects. The code could be broken by the Investigator in the event of a SAE and if identification of the vaccine received could influence SAE treatment (Responsible Medical Officer was to be notified first) by calling the IVRS/IWRS system and by the GPV department for reporting to Health authorities in the case of an SAE as described in International Conference on Harmonisation (only for the subject in question).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Quadrivalent influenza vaccine (QIV)
    Arm description
    Children aged 3-8 years who received one dose of quadrivalent influenza vaccine (QIV) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.
    Arm type
    Experimental

    Investigational medicinal product name
    Quadrivalent influenza vaccine (split-virion, inactivated) (QIV)
    Investigational medicinal product code
    481
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, intramuscular (IM) to be injected into the deltoid muscle or deep subcutaneous (SC), one dose on Day 0 and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Arm title
    TIV1
    Arm description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine that contained the B strain from the Victoria lineage (TIV1) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.
    Arm type
    Active comparator

    Investigational medicinal product name
    TIV1 (split-virion, inactivated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, intramuscular (IM) to be injected into the deltoid muscle or deep subcutaneous (SC), one dose on Day 0 and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Arm title
    TIV2
    Arm description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine containing the B strain from the Yamagata lineage (TIV2) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.
    Arm type
    Active comparator

    Investigational medicinal product name
    TIV2 (split-virion, inactivated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL dose, intramuscular (IM) to be injected into the deltoid muscle or deep subcutaneous (SC), one dose on Day 0 and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Number of subjects in period 1
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Started
    887
    181
    174
    Completed
    864
    175
    169
    Not completed
    23
    6
    5
         Protocol deviation
             2
             -
             -
         Adverse event, serious fatal
             1
             -
             -
         Consent withdrawn by subject
             19
             5
             4
         Lost to follow-up
             1
             1
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Quadrivalent influenza vaccine (QIV)
    Reporting group description
    Children aged 3-8 years who received one dose of quadrivalent influenza vaccine (QIV) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Reporting group title
    TIV1
    Reporting group description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine that contained the B strain from the Victoria lineage (TIV1) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Reporting group title
    TIV2
    Reporting group description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine containing the B strain from the Yamagata lineage (TIV2) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Reporting group values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2 Total
    Number of subjects
    887 181 174 1242
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    887 181 174 1242
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    0 0 0 0
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    5.11 ± 1.67 5.24 ± 1.68 5.18 ± 1.66 -
    Gender categorical
    Units: Subjects
        Female
    447 66 92 605
        Male
    440 115 82 637
    Primed/Unprimed status
    Units: Subjects
        Yes
    390 82 79 551
        No
    497 99 95 691

    End points

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    End points reporting groups
    Reporting group title
    Quadrivalent influenza vaccine (QIV)
    Reporting group description
    Children aged 3-8 years who received one dose of quadrivalent influenza vaccine (QIV) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Reporting group title
    TIV1
    Reporting group description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine that contained the B strain from the Victoria lineage (TIV1) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Reporting group title
    TIV2
    Reporting group description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine containing the B strain from the Yamagata lineage (TIV2) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Primary: Geometric Mean Titers (GMTs) of Influenza Antibodies Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Antibodies Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [1]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 28-Day 56 post-vaccination
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    819
    168
    159
    Units: Titer (1/dil)
    geometric mean (confidence interval 95%)
        A/California/07/2009 (H1N1); D0
    144 (127 to 165)
    165 (122 to 223)
    127 (95.8 to 169)
        A/California/07/2009 (H1N1); D28-D56
    979 (902 to 1064)
    1262 (1049 to 1518)
    1001 (831 to 1204)
        A/Texas/50/2012 (H3N2); D0
    209 (181 to 240)
    253 (187 to 343)
    194 (140 to 270)
        A/Texas/50/2012 (H3N2); D28-D56
    1559 (1440 to 1688)
    1978 (1696 to 2308)
    1475 (1220 to 1783)
        B/Brisbane/60/2008; D0
    61.4 (53.9 to 69.9)
    63.2 (47.6 to 84)
    45.8 (34.2 to 61.3)
        B/Brisbane/60/2008; D28-D56
    1044 (948 to 1151)
    1140 (933 to 1394)
    167 (122 to 230)
        B/Massachusetts/02/2012; D0
    47.5 (41.8 to 54)
    47.3 (35.3 to 63.5)
    35.6 (26.9 to 47)
        B/Massachusetts/02/2012; D28-D56
    1188 (1090 to 1295)
    219 (171 to 280)
    1150 (948 to 1396)
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Seroprotection Against the Influenza Antigens Before or After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Percentage of Subjects with Seroprotection Against the Influenza Antigens Before or After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [2]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method. Seroprotection was defined as subjects with titers ≥ 40 (1/dil) on D0 and, on D28 or D56.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 28-Day 56 post-vaccination
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    819
    168
    159
    Units: Percentage of subjects
    number (not applicable)
        A/California/07/2009 (H1N1); D0
    76.9
    78
    76.7
        A/California/07/2009 (H1N1); D28-D56
    98.8
    98.8
    98.7
        A/Texas/50/2012 (H3N2); D0
    78.3
    81
    76.1
        A/Texas/50/2012 (H3N2); D28-D56
    99.8
    100
    100
        B/Brisbane/60/2008; D0
    60.7
    66.1
    54.1
        B/Brisbane/60/2008; D28-D56
    98.7
    99.4
    76.1
        B/Massachusetts/02/2012; D0
    52.2
    52.1
    44.7
        B/Massachusetts/02/2012; D28-D56
    99.4
    83.3
    98.7
    No statistical analyses for this end point

    Primary: Percentage of Subjects Achieving Seroconversion or Significant increase Against Influenza Antigens After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Percentage of Subjects Achieving Seroconversion or Significant increase Against Influenza Antigens After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [3]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method. Seroconversion was defined as subjects with pre-vaccination titer < 10 (1/dil) on D0, post-vaccination titer ≥40 (1/dil) or significant increase was for subjects with pre-vaccination titer ≥ 10 (1/dil), ≥ 4-fold increase of the titer after vaccination (post/pre).
    End point type
    Primary
    End point timeframe
    Day 28-Day 56 post-vaccination
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    819
    168
    159
    Units: Percentage of subjects
    number (not applicable)
        A/California/07/2009 (H1N1)
    65.6
    64.3
    67.9
        A/Texas/50/2012 (H3N2)
    65
    68.5
    66.7
        B/Brisbane/60/2008
    84.9
    89.9
    40.3
        B/Massachusetts/02/2012
    88.4
    45.5
    90.6
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) of Influenza Antibodies In Primed Subjects Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Antibodies In Primed Subjects Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [4]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 28-Day 56 post-vaccination
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    381
    80
    72
    Units: Titer (1/dil)
    geometric mean (confidence interval 95%)
        A/California/07/2009 (H1N1); D0
    178 (151 to 210)
    220 (154 to 316)
    150 (103 to 220)
        A/California/07/2009 (H1N1); D28-D56
    829 (732 to 940)
    1067 (811 to 1404)
    927 (707 to 1215)
        A/Texas/50/2012 (H3N2); D0
    264 (219 to 318)
    321 (217 to 476)
    179 (111 to 287)
        A/Texas/50/2012 (H3N2); D28-D56
    1313 (1160 to 1486)
    1549 (1205 to 1990)
    1119 (846 to 1479)
        B/Brisbane/60/2008; D0
    84.3 (70.8 to 100)
    96.4 (69.1 to 134)
    53.1 (35.9 to 78.6)
        B/Brisbane/60/2008; D28-D56
    927 (799 to 1075)
    1022 (750 to 1392)
    236 (152 to 368)
        B/Massachusetts/02/2012; D0
    82.4 (68.8 to 98.8)
    97.9 (65 to 147)
    49.4 (34.4 to 71)
        B/Massachusetts/02/2012; D28-D56
    1132 (984 to 1302)
    392 (288 to 535)
    1082 (785 to 1490)
    No statistical analyses for this end point

    Primary: Percentage of Primed Subjects with Seroprotection Against the Influenza Antigens Before or After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Percentage of Primed Subjects with Seroprotection Against the Influenza Antigens Before or After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [5]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method. Seroprotection was defined as subjects with titers ≥ 40 (1/dil) on D0 and, on D28 or D56.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 28-Day 56 post-vaccination
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    381
    80
    72
    Units: Percentage of subjects
    number (not applicable)
        A/California/07/2009 (H1N1); D0
    83.7
    85
    81.9
        A/California/07/2009 (H1N1); D28-D56
    97.9
    98.8
    97.2
        A/Texas/50/2012 (H3N2); D0
    84.8
    86.3
    76.4
        A/Texas/50/2012 (H3N2); D28-D56
    99.5
    100
    100
        B/Brisbane/60/2008; D0
    68.5
    78.8
    59.7
        B/Brisbane/60/2008; D28-D56
    97.6
    98.8
    86.1
        B/Massachusetts/02/2012; D0
    63.9
    67.1
    52.8
        B/Massachusetts/02/2012; D28-D56
    98.7
    97.5
    97.2
    No statistical analyses for this end point

    Primary: Percentage of Primed Subjects Achieving Seroconversion or Significant increase Against Influenza Antigens After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

    Close Top of page
    End point title
    Percentage of Primed Subjects Achieving Seroconversion or Significant increase Against Influenza Antigens After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [6]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method. Seroconversion was defined as subjects with pre-vaccination titer < 10 (1/dil) on D0, post-vaccination titer ≥40 (1/dil) or significant increase was for subjects with pre-vaccination titer ≥ 10 (1/dil), ≥ 4-fold increase of the titer after vaccination (post/pre).
    End point type
    Primary
    End point timeframe
    Day 28-Day 56 post-vaccination
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    381
    80
    72
    Units: Percentage of subjects
    number (not applicable)
        A/California/07/2009 (H1N1)
    55.9
    51.3
    61.1
        A/Texas/50/2012 (H3N2)
    54.3
    53.8
    62.5
        B/Brisbane/60/2008
    77.7
    86.3
    50
        B/Massachusetts/02/2012
    82.4
    48.1
    90.3
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) of Influenza Antibodies in Unprimed Subjects Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Antibodies in Unprimed Subjects Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [7]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 28-Day 56 post-vaccination
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    438
    88
    87
    Units: Titer (1/dil)
    geometric mean (confidence interval 95%)
        A/California/07/2009 (H1N1); D0
    120 (98.7 to 147)
    127 (79.5 to 204)
    111 (73.1 to 168)
        A/California/07/2009 (H1N1); D28-D56
    1131 (1015 to 1261)
    1469 (1144 to 1887)
    1066 (823 to 1379)
        A/Texas/50/2012 (H3N2); D0
    170 (138 to 209)
    204 (130 to 322)
    208 (131 to 330)
        A/Texas/50/2012 (H3N2); D28-D56
    1810 (1637 to 2001)
    2471 (2068 to 2952)
    1854 (1438 to 2390)
        B/Brisbane/60/2008; D0
    46.6 (38.7 to 56.2)
    43.1 (27.7 to 67.1)
    40.5 (26.3 to 62.2)
        B/Brisbane/60/2008; D28-D56
    1159 (1020 to 1316)
    1260 (968 to 1641)
    125 (80 to 197)
        B/Massachusetts/02/2012; D0
    29.5 (24.9 to 34.9)
    24.6 (16.9 to 35.9)
    27.1 (17.9 to 40.9)
        B/Massachusetts/02/2012; D28-D56
    1239 (1114 to 1378)
    129 (91 to 182)
    1211 (952 to 1540)
    No statistical analyses for this end point

    Primary: Percentage of Unprimed Subjects with Seroprotection Against the Influenza Antigens Before or After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Percentage of Unprimed Subjects with Seroprotection Against the Influenza Antigens Before or After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [8]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method. Seroprotection was defined as subjects with titers ≥ 40 (1/dil) on D0 and, on D28 or D56.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 28-Day 56 post-vaccination
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    438
    88
    87
    Units: Percentage of subjects
    number (not applicable)
        A/California/07/2009 (H1N1); D0
    71
    71.6
    72.4
        A/California/07/2009 (H1N1); D28-D56
    99.5
    98.9
    100
        A/Texas/50/2012 (H3N2); D0
    72.6
    76.1
    75.9
        A/Texas/50/2012 (H3N2); D28-D56
    100
    100
    100
        B/Brisbane/60/2008; D0
    53.9
    54.5
    49.4
        B/Brisbane/60/2008; D28-D56
    99.5
    100
    67.8
        B/Massachusetts/02/2012; D0
    42
    38.6
    37.9
        B/Massachusetts/02/2012; D28-D56
    100
    70.5
    100
    No statistical analyses for this end point

    Primary: Percentage of Unprimed Subjects Achieving Seroconversion or Significant increase Against Influenza Antigens After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Percentage of Unprimed Subjects Achieving Seroconversion or Significant increase Against Influenza Antigens After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [9]
    End point description
    Immunogenicity was evaluated using the hemagglutination inhibition (HAI) method. Seroconversion was defined as subjects with pre-vaccination titer < 10 (1/dil) on D0, post-vaccination titer ≥40 (1/dil) or significant increase was for subjects with pre-vaccination titer ≥ 10 (1/dil), ≥ 4-fold increase of the titer after vaccination (post/pre).
    End point type
    Primary
    End point timeframe
    Day 28-Day 56 post-vaccination
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    438
    88
    87
    Units: Percentage of subjects
    number (not applicable)
        A/California/07/2009 (H1N1)
    74
    76.1
    73.6
        A/Texas/50/2012 (H3N2)
    74.2
    81.8
    70.1
        B/Brisbane/60/2008
    91.1
    93.2
    32.2
        B/Massachusetts/02/2012
    93.6
    43.2
    90.8
    No statistical analyses for this end point

    Primary: Geometric Mean Titers (GMTs) of Influenza Antibodies Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Antibodies Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [10]
    End point description
    Immunogenicity was evaluated using the virus seroneutralization (SN) method.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 28-Day 56 post-vaccination
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    431
    86
    83
    Units: Titer (1/dil)
    geometric mean (confidence interval 95%)
        A/California/07/2009 (H1N1); D0
    414 (335 to 512)
    580 (357 to 945)
    508 (314 to 820)
        A/California/07/2009 (H1N1); D28-D56
    3499 (3138 to 3902)
    4409 (3460 to 5617)
    4517 (3581 to 5698)
        A/Texas/50/2012 (H3N2); D0
    94.5 (81.8 to 109)
    102 (75.4 to 137)
    97.1 (70.5 to 134)
        A/Texas/50/2012 (H3N2); D28-D56
    475 (430 to 525)
    571 (466 to 699)
    513 (411 to 641)
        B/Brisbane/60/2008; D0
    66.7 (56 to 79.4)
    62.8 (42.8 to 92.2)
    57.9 (37.9 to 88.6)
        B/Brisbane/60/2008; D28-D56
    905 (788 to 1039)
    980 (722 to 1329)
    203 (139 to 298)
        B/Massachusetts/02/2012; D0
    38 (32.2 to 44.7)
    33.7 (22.9 to 49.7)
    37.8 (26 to 55)
        B/Massachusetts/02/2012; D28-D56
    731 (638 to 838)
    131 (94.4 to 181)
    952 (709 to 1279)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After First Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After First Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [11]
    End point description
    Solicited injection site: Pain, Erythema, Swelling, Induration and Ecchymosis. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Shivering. Grade 3 Solicited Injection site reactions: Pain – Incapacitating, unable to perform usual activities; Erythema, Swelling, Induration, and Ecchymosis - ≥50 mm. Grade 3 Solicited systemic reactions: Fever - ≥39˚C; Headache, Malaise, Myalgia, and Shivering – Significant, prevents daily activities.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 7 post-vaccination
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    884
    181
    172
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    46.7
    51.1
    43
        Grade 3 Injection site Pain
    0.8
    1.1
    1.2
        Injection site Erythema
    15.6
    19.2
    16.3
        Grade 3 Injection site Erythema
    2.3
    3.8
    0.6
        Injection site Swelling
    16.4
    19.2
    15.1
        Grade 3 Injection site Swelling
    1.7
    1.6
    0
        Injection site Induration
    13.3
    13.7
    11
        Grade 3 Injection site Induration
    1
    1.1
    0.6
        Injection site Ecchymosis
    4.8
    5.5
    2.9
        Grade 3 Injection site Ecchymosis
    0.2
    0
    0
        Fever
    6.2
    5.6
    2.9
        Grade 3 Fever
    0.2
    0.6
    0
        Headache
    20.5
    16.5
    15.1
        Grade 3 Headache
    0.9
    1.1
    1.2
        Malaise
    25.7
    19.8
    24.4
        Grade 3 Malaise
    1.2
    1.1
    1.7
        Myalgia
    22.9
    21.4
    24.4
        Grade 3 Myalgia
    1
    0
    1.2
        Shivering
    9.3
    9.3
    6.4
        Grade 3 Shivering
    0.7
    0.5
    0.6
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Second Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    Percentage of Subjects Reporting Solicited Injection-site or Systemic Reaction After Second Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [12]
    End point description
    Solicited injection site: Pain, Erythema, Swelling, Induration and Ecchymosis. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Shivering. Grade 3 Solicited Injection site reactions: Pain – Incapacitating, unable to perform usual activities; Erythema, Swelling, Induration, and Ecchymosis - ≥50 mm. Grade 3 Solicited systemic reactions: Fever - ≥39˚C; Headache, Malaise, Myalgia, and Shivering – Significant, prevents daily activities.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 7 post-vaccination
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Number of subjects analysed
    491
    99
    96
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    45.9
    46.3
    43
        Grade 3 Injection site Pain
    1.2
    3.2
    0
        Injection site Erythema
    14.6
    13.7
    11.8
        Grade 3 Injection site Erythema
    1.5
    1.1
    0
        Injection site Swelling
    13.1
    13.7
    8.6
        Grade 3 Injection site Swelling
    1.2
    1.1
    0
        Injection site Induration
    11.4
    9.5
    7.5
        Grade 3 Injection site Induration
    0.8
    0
    0
        Injection site Ecchymosis
    3.5
    2.1
    6.5
        Grade 3 Injection site Ecchymosis
    0.2
    0
    0
        Fever
    5.5
    4.2
    4.3
        Grade 3 Fever
    1.5
    0
    0
        Headache
    17
    16.8
    11.8
        Grade 3 Headache
    1.2
    0
    0
        Malaise
    18.3
    15.8
    22.6
        Grade 3 Malaise
    1.5
    0
    1.1
        Myalgia
    20.4
    16.8
    15.1
        Grade 3 Myalgia
    0.8
    1.1
    0
        Shivering
    6
    3.2
    2.2
        Grade 3 Shivering
    0.6
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from Day 0 (post-vaccination) up to Day 28 post-vaccination.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Quadrivalent influenza vaccine (QIV)
    Reporting group description
    Children aged 3-8 years who received one dose of quadrivalent influenza vaccine (QIV) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Reporting group title
    TIV1
    Reporting group description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine that contained the B strain from the Victoria lineage (TIV1) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Reporting group title
    TIV2
    Reporting group description
    Children aged 3-8 years who received one dose of trivalent influenza vaccine containing the B strain from the Yamagata lineage (TIV2) and if previously unvaccinated, a second dose of vaccine was administered on Day 28.

    Serious adverse events
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 884 (1.58%)
    3 / 182 (1.65%)
    1 / 172 (0.58%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Extradural haematoma
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 884 (0.11%)
    1 / 182 (0.55%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Strabismus
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Adenoiditis
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 884 (0.11%)
    1 / 182 (0.55%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpangina
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 884 (0.11%)
    0 / 182 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 884 (0.00%)
    1 / 182 (0.55%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 884 (0.00%)
    0 / 182 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Quadrivalent influenza vaccine (QIV) TIV1 TIV2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    412 / 884 (46.61%)
    93 / 182 (51.10%)
    74 / 172 (43.02%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    65 / 884 (7.35%)
    20 / 182 (10.99%)
    11 / 172 (6.40%)
         occurrences all number
    70
    22
    11
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    181 / 882 (20.52%)
    16 / 95 (16.84%)
    26 / 172 (15.12%)
         occurrences all number
    181
    16
    26
    General disorders and administration site conditions
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    412 / 882 (46.71%)
    93 / 182 (51.10%)
    74 / 172 (43.02%)
         occurrences all number
    412
    93
    74
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    138 / 882 (15.65%)
    35 / 182 (19.23%)
    28 / 172 (16.28%)
         occurrences all number
    138
    35
    28
    Injection site swelling
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    145 / 882 (16.44%)
    35 / 182 (19.23%)
    26 / 172 (15.12%)
         occurrences all number
    145
    35
    26
    Injection site ecchymosis
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    42 / 882 (4.76%)
    10 / 182 (5.49%)
    6 / 93 (6.45%)
         occurrences all number
    42
    10
    6
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    54 / 877 (6.16%)
    10 / 180 (5.56%)
    4 / 93 (4.30%)
         occurrences all number
    54
    10
    4
    Malaise
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    227 / 882 (25.74%)
    36 / 182 (19.78%)
    42 / 172 (24.42%)
         occurrences all number
    227
    36
    42
    Shivering
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    82 / 882 (9.30%)
    17 / 182 (9.34%)
    11 / 172 (6.40%)
         occurrences all number
    82
    17
    11
    Skin and subcutaneous tissue disorders
    Injection site induration
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    117 / 882 (13.27%)
    25 / 182 (13.74%)
    19 / 172 (11.05%)
         occurrences all number
    117
    25
    19
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    202 / 882 (22.90%)
    39 / 182 (21.43%)
    42 / 172 (24.42%)
         occurrences all number
    202
    39
    42
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    83 / 884 (9.39%)
    13 / 182 (7.14%)
    16 / 172 (9.30%)
         occurrences all number
    96
    14
    18
    Upper respiratory tract infection
         subjects affected / exposed
    54 / 884 (6.11%)
    12 / 182 (6.59%)
    8 / 172 (4.65%)
         occurrences all number
    58
    15
    10
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2014
    A first analysis on vaccination period data (D0-D56) was added.

    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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