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    Clinical Trial Results:
    Safety and Immunogenicity of a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Child/Adolescent and Adult Subjects

    Due to a system error, the data reported in v2 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2011-005101-79
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    24 May 2012

    Results information
    Results version number
    		 v3(current)
    This version publication date
    13 Mar 2016
    First version publication date
    27 Mar 2015
    Other versions
    		 v1 , v2 (removed from public view)
    Version creation reason
    • Correction of full data set
    Correction of the Endpoint Confidence Intervals for the TIV group in the Primary Outcome 2 table.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GQM04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01481454
    WHO universal trial number (UTN)
    		 U1111-1122-2719
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    2, avenue Pont Pasteur, Lyon cedex 07, France, F-69367
    Public contact
    Director, Clinical Department, Sanofi Pasteur SA, 33 (0)437 37 58 50, stephanie.pepin@sanofipasteur.com
    Scientific contact
    Director, Clinical Department, Sanofi Pasteur SA, 33 (0)437 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
    16 Jan 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To describe the safety profile of Quadrivalent Influenza Vaccine (QIV) compared to Trivalent Influenza Vaccine (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
    19 Mar 2012
    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
    Philippines: 1390
    Country: Number of subjects enrolled
    Australia: 700
    Worldwide total number of subjects
    2090
    EEA total number of subjects
    0
    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)
    154
    Adolescents (12-17 years)
    231
    Adults (18-64 years)
    1705
    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 19 March 2012 to 28 April 2012 at 4 clinical centers in the Philippines and 6 clinical centers in Australia.

    Pre-assignment
    Screening details
    		 A total of 2090 subjects who met all inclusion criteria and none of the exclusion criteria were enrolled and randomized, 2083 subjects were 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
    		 Subject, Investigator
    Blinding implementation details
    The study was conducted double-blind for QIV lots (i.e., neither the investigator nor the subject/subject’s parent or legal representative, nor the study staff in charge of vaccination knew what lot of vaccine [QIV] was administered) for all subjects. The study was open for vaccine receipt (i.e. which vaccine [QIV or TIV] is administered).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QIV S4361
    Arm description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4361) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quadrivalent influenza vaccine (split-virion, inactivated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular to be injected into the deltoid muscle or deep subcutaneous, administered on Day 0 and 21

    Arm title
    		 QIV S4362
    Arm description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4362) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quadrivalent influenza vaccine (split-virion, inactivated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular to be injected into the deltoid muscle or deep subcutaneous, administered on Day 0 and 21

    Arm title
    		 QIV S4363
    Arm description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4363) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Quadrivalent influenza vaccine (split-virion, inactivated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular to be injected into the deltoid muscle or deep subcutaneous, administered on Day 0 and 21

    Arm title
    		 Trivalent Influenza Vaccine (TIV)
    Arm description
    		 Subjects who received Trivalent Influenza Vaccine (TIV) 2011-2012 Formulation administered on Day 0 and Day 21.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sanofi Pasteur 2011–2012 formulation TIV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use, Subcutaneous use
    Dosage and administration details
    0.5 mL, intramuscular to be injected into the deltoid muscle or deep subcutaneous, administered on Day 0 and 21

    Number of subjects in period 1 [1]
    		QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Started
    654
    664
    655
    110
    Completed
    653
    662
    653
    109
    Not completed
    1
    2
    2
    1
         Consent withdrawn by subject
    -
    1
    1
    -
         Lost to follow-up
    1
    1
    -
    -
         Protocol deviation
    -
    -
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported in the baseline period are the subjects who were enrolled and received the study vaccine.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QIV S4361
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4361) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    QIV S4362
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4362) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    QIV S4363
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4363) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    Trivalent Influenza Vaccine (TIV)
    Reporting group description
    		 Subjects who received Trivalent Influenza Vaccine (TIV) 2011-2012 Formulation administered on Day 0 and Day 21.

    Reporting group values
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV) Total
    Number of subjects
    		 654 664 655 110 2083
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 42 44 45 21 152
        Adolescents (12-17 years)
    		 67 67 63 33 230
        Adults (18-64 years)
    		 545 553 547 56 1701
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.4 ( 14.6 ) 33.7 ( 14.8 ) 33.5 ( 14.5 ) 25.2 ( 14.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 382 387 398 53 1220
        Male
    		 272 277 257 57 863
    Influenza vaccination 2011
    Units: Subjects
        Yes
    		 162 145 136 26 469
        No
    		 485 512 511 83 1591
        Unknown
    		 7 7 8 1 23
    Influenza vaccination 2010
    Units: Subjects
        Yes
    		 120 110 108 22 360
        No
    		 526 543 536 86 1691
        Unknown
    		 8 11 11 2 32
    Influenza vaccination 2009
    Units: Subjects
        Yes
    		 134 138 138 18 428
        No
    		 507 509 502 89 1607
        Unknown
    		 13 17 15 3 48

    End points

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    End points reporting groups
    Reporting group title
    QIV S4361
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4361) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    QIV S4362
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4362) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    QIV S4363
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4363) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    Trivalent Influenza Vaccine (TIV)
    Reporting group description
    		 Subjects who received Trivalent Influenza Vaccine (TIV) 2011-2012 Formulation administered on Day 0 and Day 21.

    Primary: Geometric Mean Titers (GMTs) of influenza Antibodies Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Subjects Aged 18 to 60 Years

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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 in Subjects Aged 18 to 60 Years [1]
    End point description
    Immunogenicity was assessed using the hemagglutination inhibition (HAI) assay.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    543
    551
    545
    56
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        A/California/7/2009 (H1N1); Day 0
    101 (87.5 to 117)
    95.3 (82.1 to 111)
    94.2 (81.3 to 109)
    141 (91.9 to 215)
        A/Victoria/210/2009 (H3N2); Day 0
    115 (100 to 132)
    103 (89.2 to 118)
    102 (88.4 to 117)
    115 (74.9 to 177)
        B/Brisbane/60/2008; Day 0
    113 (99.5 to 129)
    103 (90.8 to 118)
    97.3 (85.6 to 111)
    91.1 (62.3 to 133)
        B/Florida/04/2006; Day 0
    320 (281 to 363)
    302 (264 to 345)
    309 (271 to 353)
    400 (278 to 576)
        A/California/7/2009 (H1N1); Day 21
    878 (795 to 970)
    834 (757 to 919)
    967 (876 to 1068)
    934 (670 to 1301)
        A/Victoria/210/2009 (H3N2); Day 21
    760 (690 to 838)
    734 (666 to 809)
    845 (763 to 937)
    846 (602 to 1188)
        B/Brisbane/60/2008; Day 21
    1033 (945 to 1129)
    1054 (963 to 1154)
    1043 (950 to 1145)
    851 (606 to 1195)
        B/Florida/04/2006; Day 21
    2537 (2336 to 2756)
    2650 (2427 to 2894)
    2609 (2401 to 2836)
    1264 (854 to 1871)
    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 in Subjects Aged 9 to 17 Years

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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 in Subjects Aged 9 to 17 Years [2]
    End point description
    Immunogenicity was assessed using the hemagglutination inhibition (HAI) assay.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    109
    111
    108
    54
    Units: Titers (1/dil)
    geometric mean (confidence interval 95%)
        A/California/7/2009 (H1N1); Day 0
    154 (114 to 209)
    127 (94.2 to 172)
    124 (93.4 to 164)
    312 (207 to 470)
        A/Victoria/210/2009 (H3N2); Day 0
    208 (156 to 277)
    220 (164 to 295)
    195 (145 to 263)
    178 (108 to 294)
        B/Brisbane/60/2008; Day 0
    74.6 (55.4 to 100)
    85.7 (64.1 to 115)
    66 (49.6 to 87.9)
    98.9 (66.4 to 147)
        B/Florida/04/2006; Day 0
    230 (162 to 327)
    177 (125 to 250)
    202 (144 to 284)
    223 (132 to 378)
        A/California/7/2009 (H1N1); Day 21
    1554 (1262 to 1913)
    1313 (1056 to 1632)
    2045 (1687 to 2479)
    2006 (1586 to 2538)
        A/Victoria/210/2009 (H3N2); Day 21
    1491 (1269 to 1752)
    1668 (1407 to 1978)
    1493 (1247 to 1788)
    1720 (1262 to 2343)
        B/Brisbane/60/2008; Day 21
    1845 (1485 to 2293)
    1738 (1438 to 2100)
    1687 (1336 to 2130)
    1644 (1147 to 2357)
        B/Florida/04/2006; Day 21
    3932 (3278 to 4717)
    3466 (2833 to 4240)
    4432 (3787 to 5185)
    849 (557 to 1294)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 18 to 60 Years With Seroprotection Against Influenza Antigens Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    		 Percentage of Subjects Aged 18 to 60 Years With Seroprotection Against Influenza Antigens Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [3]
    End point description
    Immunogenicity was assessed using the hemagglutination inhibition (HAI) assay. Seroprotection was defined as titers ≥ 40 (1/dil) on Day 21.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    543
    551
    545
    56
    Units: Percentage of subjects
    number (not applicable)
        A/California/7/2009 (H1N1); Day 0
    73.4
    72.1
    73.5
    80.4
        A/Victoria/210/2009 (H3N2); Day 0
    77.7
    74
    73
    75
        B/Brisbane/60/2008; Day 0
    77.4
    75.3
    72.1
    69.6
        B/Florida/04/2006; Day 0
    92.3
    92
    90.8
    96.4
        A/California/7/2009 (H1N1); Day 21
    99.3
    99.3
    99.3
    100
        A/Victoria/210/2009 (H3N2); Day 21
    99.1
    99.1
    98.9
    100
        B/Brisbane/60/2008; Day 21
    100
    100
    100
    100
        B/Florida/04/2006; Day 21
    100
    100
    100
    98.2
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 9 to 17 Years With Seroprotection Against Influenza Antigens Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    		 Percentage of Subjects Aged 9 to 17 Years With Seroprotection Against Influenza Antigens Before and After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [4]
    End point description
    Immunogenicity was assessed using the hemagglutination inhibition (HAI) assay. Seroprotection was defined as titers ≥ 40 (1/dil) on Day 21.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    109
    110
    108
    54
    Units: Percentage of subjects
    number (not applicable)
        A/California/7/2009 (H1N1); Day 0
    86.2
    85.5
    86.1
    90.7
        A/Victoria/210/2009 (H3N2); Day 0
    89.9
    88.2
    85.2
    81.5
        B/Brisbane/60/2008; Day 0
    67
    72.7
    64.8
    81.5
        B/Florida/04/2006; Day 0
    82.6
    82.9
    84.3
    79.6
        A/California/7/2009 (H1N1); Day 21
    98.2
    98.2
    100
    100
        A/Victoria/210/2009 (H3N2); Day 21
    100
    100
    100
    100
        B/Brisbane/60/2008; Day 21
    99.1
    100
    99.1
    100
        B/Florida/04/2006; Day 21
    99.1
    99.1
    100
    100
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 18 to 60 Years 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 Aged 18 to 60 Years Achieving Seroconversion or Significant increase Against Influenza Antigens after Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [5]
    End point description
    Immunogenicity was assessed using the hemagglutination inhibition (HAI) assay. Seroconversion for subjects with a pre-vaccination titer < 10 (1/dil): post-injection titer ≥ 40 (1/dil) on Day 21, or significant increase for subjects with a pre-vaccination titer ≥ 10 (1/dil): ≥ 4-fold increase from pre- to post-injection titer on Day 21.
    End point type
    Primary
    End point timeframe
    Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    543
    551
    545
    56
    Units: Percentage of subjects
    number (not applicable)
        A/California/7/2009 (H1N1)
    59.8
    62.4
    68.6
    46.4
        A/Victoria/210/2009 (H3N2)
    56.5
    58.1
    63.2
    58.9
        B/Brisbane/60/2008
    63.4
    66.5
    69.5
    55.4
        B/Florida/04/2006
    64.6
    65.6
    67.3
    44.6
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 9 to 17 Years 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 Aged 9 to 17 Years 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 assessed using the hemagglutination inhibition (HAI) assay. Seroconversion for subjects with a pre-vaccination titer < 10 (1/dil): post-injection titer ≥ 40 (1/dil) on Day 21, or significant increase for subjects with a pre-vaccination titer ≥ 10 (1/dil): ≥ 4-fold increase from pre- to post-injection titer on Day 21.
    End point type
    Primary
    End point timeframe
    Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    109
    111
    108
    54
    Units: Percentage of subjects
    number (not applicable)
        A/California/7/2009 (H1N1)
    75.2
    73.6
    84.3
    70.4
        A/Victoria/210/2009 (H3N2)
    56.9
    61.8
    66.7
    63
        B/Brisbane/60/2008
    84.4
    80.9
    86.1
    79.6
        B/Florida/04/2006
    81.7
    83.8
    88.9
    50
    No statistical analyses for this end point

    Primary: Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies after Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Subjects Aged 18 to 60 Years

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    End point title
    		 Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies after Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Subjects Aged 18 to 60 Years [7]
    End point description
    Immunogenicity was assessed using the hemagglutination inhibition (HAI) assay. Geometric mean titer ratio is the geometric mean of the individual post-vaccination/pre-vaccination titer of influenza antibodies.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    543
    551
    545
    56
    Units: Titer Ratios
    geometric mean (confidence interval 95%)
        A/California/7/2009 (H1N1)
    8.67 (7.48 to 10)
    8.75 (7.56 to 10.1)
    10.33 (8.86 to 11.9)
    6.64 (4.05 to 10.9)
        A/Victoria/210/2009 (H3N2)
    6.62 (5.79 to 7.57)
    7.16 (6.24 to 8.22)
    8.3 (7.19 to 9.59)
    7.34 (4.5 to 11.9)
        B/Brisbane/60/2008
    9.12 (7.93 to 10.5)
    10.2 (8.87 to 11.7)
    10.7 (9.33 to 12.3)
    9.34 (5.63 to 15.5)
        B/Florida/04/2006
    7.94 (6.97 to 9.04)
    8.77 (7.67 to 10)
    8.43 (7.43 to 9.59)
    3.16 (2.25 to 4.44)
    No statistical analyses for this end point

    Primary: Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies after Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Subjects Aged 9 to 17 Years

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    End point title
    		 Geometric Mean Titer Ratios (GMTRs) of Influenza Antibodies after Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route in Subjects Aged 9 to 17 Years [8]
    End point description
    Immunogenicity was assessed using the hemagglutination inhibition (HAI) assay. Geometric mean titer ratio is the geometric mean of the individual post-vaccination/pre-vaccination titer of influenza antibodies.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    109
    111
    108
    54
    Units: Titer Ratios
    geometric mean (confidence interval 95%)
        A/California/7/2009 (H1N1)
    10.1 (7.67 to 13.3)
    10.3 (7.81 to 13.6)
    16.5 (12.6 to 21.6)
    6.43 (4.35 to 9.5)
        A/Victoria/210/2009 (H3N2)
    7.16 (5.21 to 9.83)
    7.58 (5.61 to 10.2)
    7.65 (5.8 to 10.1)
    9.64 (5.75 to 16.1)
        B/Brisbane/60/2008
    24.7 (18 to 34.1)
    20.3 (15.1 to 27.2)
    25.6 (19 to 34.4)
    16.6 (10.7 to 25.8)
        B/Florida/04/2006
    17.1 (12.5 to 23.4)
    19.6 (14.5 to 26.5)
    21.9 (16.1 to 29.9)
    3.8 (2.69 to 5.37)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 18 to 60 Years Reporting Solicited Injection-site or Systemic Reaction After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    		 Percentage of Subjects Aged 18 to 60 Years Reporting Solicited Injection-site or Systemic Reaction After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [9]
    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 (9-11 years): Pain – Incapacitating, unable to perform usual activities; Erythema, Swelling, Induration, and Ecchymosis - ≥50 mm. Grade 3 Solicited Injection site reactions (12-60 years): Pain – Significant, prevents daily activity; Erythema, Swelling, Induration, and Ecchymosis - >100 mm. Grade 3 Solicited systemic reactions (9-60 years): 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
    [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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    546
    554
    548
    56
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    48.3
    48.5
    52
    46.4
        Grade 3 Injection site Pain
    0
    0.5
    0.4
    1.8
        Injection site Erythema
    5.7
    7.2
    5.1
    5.4
        Grade 3 Injection site Erythema
    0
    0.2
    0
    0
        Injection site Swelling
    5.9
    6
    6
    1.8
        Grade 3 Injection site Swelling
    0
    0
    0
    0
        Injection site Induration
    4.8
    5.2
    5.5
    3.6
        Grade 3 Injection site Induration
    0
    0
    0
    0
        Injection site Ecchymosis
    0.2
    2
    0.9
    0
        Grade 3 Injection site Ecchymosis
    0
    0.2
    0
    0
        Fever
    1.3
    1.6
    1.1
    1.8
        Grade 3 Fever
    0
    0
    0
    0
        Headache
    27
    26.2
    27.9
    23.2
        Grade 3 Headache
    2.2
    0.5
    0.7
    0
        Malaise
    21.8
    20.8
    17.9
    12.5
        Grade 3 Malaise
    1.3
    1.1
    0.5
    0
        Myalgia
    20.7
    19.2
    16.4
    7.1
        Grade 3 Myalgia
    1.1
    0.5
    0.4
    0
        Shivering
    5.3
    2.7
    3.1
    1.8
        Grade 3 Shivering
    0.6
    0.2
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 9 to 17 Years Reporting Solicited Injection-site or Systemic Reaction After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    		 Percentage of Subjects Aged 9 to 17 Years Reporting Solicited Injection-site or Systemic Reaction After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [10]
    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 (9-11 years): Pain – Incapacitating, unable to perform usual activities; Erythema, Swelling, Induration, and Ecchymosis - ≥50 mm. Grade 3 Solicited Injection site reactions (12-60 years): Pain – Significant, prevents daily activity; Erythema, Swelling, Induration, and Ecchymosis - >100 mm. Grade 3 Solicited systemic reactions (9-60 years): 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
    [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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    109
    111
    109
    55
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    57.8
    53.2
    51.4
    54.5
        Grade 3 Injection site Pain
    0
    0
    0
    0
        Injection site Erythema
    10.1
    12.6
    10.1
    5.5
        Grade 3 Injection site Erythema
    0.9
    1.8
    0
    0
        Injection site Swelling
    15.6
    9.9
    12.8
    7.3
        Grade 3 Injection site Swelling
    0.9
    0
    0
    0
        Injection site Induration
    9.2
    5.4
    10.1
    7.3
        Grade 3 Injection site Induration
    0.9
    0.9
    0
    1.8
        Injection site Ecchymosis
    1.8
    1.8
    1.8
    1.8
        Grade 3 Injection site Ecchymosis
    0
    0
    0
    0
        Fever
    4.6
    1.8
    2.8
    9.1
        Grade 3 Fever
    0
    0
    0.9
    0
        Headache
    31.2
    28.8
    29.4
    23.6
        Grade 3 Headache
    0.9
    0
    0
    0
        Malaise
    25.7
    18
    22
    16.4
        Grade 3 Malaise
    0.9
    0
    0.9
    0
        Myalgia
    32.1
    21.6
    19.3
    12.7
        Grade 3 Myalgia
    0.9
    0
    0
    0
        Shivering
    2.8
    5.4
    3.7
    0
        Grade 3 Shivering
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 18 to 60 Years Reporting Solicited Reactions Listed in the EMA Note for Guidance within 3 Days After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    		 Percentage of Subjects Aged 18 to 60 Years Reporting Solicited Reactions Listed in the EMA Note for Guidance within 3 Days After Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [11]
    End point description
    Solicited injection site reactions: Injection site Induration ≥5 cm for at least 4 consecutive days and Injection site Ecchymosis. Solicited systemic reactions: Pyrexia (recorded temperature > 38°C) for at least 1 day, Malaise, and Shivering.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 3 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    546
    554
    548
    56
    Units: Percentage of subjects
    number (not applicable)
        Reaction listed in the EMA recommendations
    23.5
    20.8
    20.1
    14.3
        Injection site Induration ≥5 cm for 4 days
    0
    0
    0
    0
        Injection site Ecchymosis
    4.4
    3.8
    4.2
    1.8
        Pyrexia (temp. > 38°C) for at least 1 day
    0.6
    0.9
    0.9
    1.8
        Malaise
    19.8
    18.1
    15.7
    10.7
        Shivering
    4.2
    2.4
    2.6
    1.8
    No statistical analyses for this end point

    Primary: Percentage of Subjects Aged 9 to 17 Years Reporting Solicited Reactions Listed in the EMA Note for Guidance within 3 Days after Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route

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    End point title
    		 Percentage of Subjects Aged 9 to 17 Years Reporting Solicited Reactions Listed in the EMA Note for Guidance within 3 Days after Vaccination with a Quadrivalent Influenza Vaccine Administered via the Intramuscular Route [12]
    End point description
    Solicited injection site reactions: Injection site Induration ≥5 cm for at least 4 consecutive days and Injection site Ecchymosis. Solicited systemic reactions: Pyrexia (recorded temperature > 38°C) for at least 1 day, Malaise, and Shivering.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 3 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
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Number of subjects analysed
    109
    111
    109
    55
    Units: Percentage of subjects
    number (not applicable)
        Reaction listed in the EMA recommendations
    25.7
    20.7
    22.9
    20
        Injection site Induration ≥5 cm for 4 days
    0.9
    0
    0
    0
        Injection site Ecchymosis
    4.6
    1.8
    1.8
    1.8
        Pyrexia (temp. > 38°C) for at least 1 day
    2.8
    1.8
    0.9
    3.6
        Malaise
    21.1
    17.1
    20.2
    14.5
        Shivering
    2.8
    5.4
    2.8
    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 up to Day 21 after vaccination.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    QIV S4361
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4361) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    QIV S4362
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4362) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    QIV S4363
    Reporting group description
    		 Subjects who received Quadrivalent Influenza Vaccine (Lot QIV S4363) 2011-2012 Formulation + B/Florida strain from the Yamagata lineage administered on Day 0 and Day 21.

    Reporting group title
    Trivalent Influenza Vaccine (TIV)
    Reporting group description
    		 Subjects who received Trivalent Influenza Vaccine (TIV) 2011-2012 Formulation administered on Day 0 and Day 21.

    Serious adverse events
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 655 (0.92%)
    5 / 665 (0.75%)
    2 / 657 (0.30%)
    0 / 111 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Meniscus lesion
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 665 (0.00%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 665 (0.15%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 665 (0.15%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleurisy
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 665 (0.00%)
    1 / 657 (0.15%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 665 (0.00%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 665 (0.15%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 665 (0.00%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 665 (0.00%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 665 (0.00%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leptospirosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 665 (0.00%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 665 (0.15%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 665 (0.15%)
    0 / 657 (0.00%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 665 (0.00%)
    1 / 657 (0.15%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 QIV S4361 QIV S4362 QIV S4363 Trivalent Influenza Vaccine (TIV)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    263 / 655 (40.15%)
    268 / 665 (40.30%)
    285 / 657 (43.38%)
    30 / 111 (27.03%)
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    147 / 655 (22.44%)
    145 / 665 (21.80%)
    153 / 657 (23.29%)
    13 / 111 (11.71%)
         occurrences all number
    147
    145
    153
    13
    General disorders and administration site conditions
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed
    263 / 655 (40.15%)
    268 / 665 (40.30%)
    285 / 657 (43.38%)
    30 / 111 (27.03%)
         occurrences all number
    263
    268
    285
    30
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    31 / 655 (4.73%)
    40 / 665 (6.02%)
    28 / 657 (4.26%)
    3 / 111 (2.70%)
         occurrences all number
    31
    40
    28
    3
    Injection site swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    32 / 655 (4.89%)
    33 / 665 (4.96%)
    33 / 657 (5.02%)
    4 / 111 (3.60%)
         occurrences all number
    32
    33
    33
    4
    Malaise
    alternative assessment type: Systematic
         subjects affected / exposed
    119 / 655 (18.17%)
    115 / 665 (17.29%)
    98 / 657 (14.92%)
    9 / 111 (8.11%)
         occurrences all number
    119
    115
    98
    9
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    113 / 655 (17.25%)
    106 / 665 (15.94%)
    90 / 657 (13.70%)
    7 / 111 (6.31%)
         occurrences all number
    113
    106
    90
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2012
    Included all child/adolescent subjects for the seroneutralization analysis and a subset of child/adolescent subjects for the anti-neuraminidase analysis.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25843270
    For support, Contact us.
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