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    Clinical Trial Results:
    A phase III, open-label, multicentre study to evaluate the immunogenicity, safety and reactogenicity study of GSK Biologicals’ quadrivalent seasonal influenza candidate vaccine GSK2321138A, administered to children who previously participated in study 115345

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2012-001230-34
    Trial protocol
    		 ES   CZ   GB   PL  
    Global end of trial date
    05 Jun 2013

    Results information
    Results version number
    		 v2
    This version publication date
    28 May 2016
    First version publication date
    02 May 2015
    Other versions
    		 v1 (removed from public view) , v3 , v4
    Version creation reason
    • Correction of full data set
    Data correction due to a system error in EudraCT – Results: Secondary endpoint -Serum neutralizing antibody titres against each of the vaccine strains after 1 dose of Fluarix Quadrivalent vaccine. In addition, some data (typos) were corrected in Adverse events section.

    Trial information

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    Trial identification
    Sponsor protocol code
    116023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01702454
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000817-PIP02-11
    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
    11 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the immune response in terms of Haemagglutination Inhibition (HI) antibody titre at Day 7 after one dose of FLU D-QIV vaccine (2012-2013 formulation) in vaccine-primed and vaccine-unprimed subjects, for all strains included in the vaccine.
    Protection of trial subjects
    All subjects were supervised closely for at least 30 minutes following vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines/products were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed-up from the time the subject consents to participate in the study until she/he is discharged.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 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
    Poland: 103
    Country: Number of subjects enrolled
    Spain: 149
    Country: Number of subjects enrolled
    United Kingdom: 83
    Country: Number of subjects enrolled
    Czech Republic: 135
    Worldwide total number of subjects
    470
    EEA total number of subjects
    470
    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)
    470
    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
    		 -

    Pre-assignment
    Screening details
    		 During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fluarix Quadrivalent Primed Group
    Arm description
    		 Subjects in this group were previously primed with 2 doses of Fluarix Quadrivalent vaccine in the primary study 115345 (NCT01439360) and received 1 dose of Fluarix Quadrivalent vaccine at Day 0 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluarix Quadrivalent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Vaccine-primed subjects received a single 0.5 mL dose administered intramuscularly at Visit 1 (Day 0). Vaccines were administered in the deltoid region.

    Arm title
    		 Fluarix Quadrivalent Unprimed Group
    Arm description
    		 Subjects in this group were unprimed in the primary study 115345 (NCT01439360) and received 2 doses of Fluarix Quadrivalent vaccine at Days 0 and 28 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluarix Quadrivalent
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Vaccine-unprimed subjects received one 0.5 mL dose administered intramuscularly at Visit 1 (Day 0) and one 0.5 mL dose administered intramuscularly at Visit 3 (Day 28). Vaccines were administered in the deltoid region.

    Number of subjects in period 1
    		Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Started
    241
    229
    Completed
    238
    221
    Not completed
    3
    8
         Consent withdrawn by subject
    -
    1
         Lost to Follow-up
    3
    6
         Migrated/moved from study area
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fluarix Quadrivalent Primed Group
    Reporting group description
    		 Subjects in this group were previously primed with 2 doses of Fluarix Quadrivalent vaccine in the primary study 115345 (NCT01439360) and received 1 dose of Fluarix Quadrivalent vaccine at Day 0 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.

    Reporting group title
    Fluarix Quadrivalent Unprimed Group
    Reporting group description
    		 Subjects in this group were unprimed in the primary study 115345 (NCT01439360) and received 2 doses of Fluarix Quadrivalent vaccine at Days 0 and 28 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.

    Reporting group values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group Total
    Number of subjects
    		 241 229 470
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.2 ( 7.54 ) 32.5 ( 7.39 ) -
    Gender categorical
    Units: Subjects
        Female
    		 114 96 210
        Male
    		 127 133 260

    End points

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    End points reporting groups
    Reporting group title
    Fluarix Quadrivalent Primed Group
    Reporting group description
    		 Subjects in this group were previously primed with 2 doses of Fluarix Quadrivalent vaccine in the primary study 115345 (NCT01439360) and received 1 dose of Fluarix Quadrivalent vaccine at Day 0 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.

    Reporting group title
    Fluarix Quadrivalent Unprimed Group
    Reporting group description
    		 Subjects in this group were unprimed in the primary study 115345 (NCT01439360) and received 2 doses of Fluarix Quadrivalent vaccine at Days 0 and 28 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.

    Primary: Serum Hemagglutination Inhibition (HI) antibody titers against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine

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    End point title
    		 Serum Hemagglutination Inhibition (HI) antibody titers against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine
    End point description
    End point type
    Primary
    End point timeframe
    At Day 0 and Day 7
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    224
    209
    Units: Titer
    geometric mean (confidence interval 95%)
        H1N1, Day 0 [N=221,202]
    43.1 (33.8 to 54.9)
    14.5 (11.5 to 18.2)
        H1N1, Day 7 [N=224,209]
    445.6 (376.9 to 526.7)
    45.8 (32 to 65.5)
        H3N2, Day 0 [N=221,202]
    12.3 (10.7 to 14.1)
    16.4 (13.2 to 20.4)
        H3N2, Day 7 [N=224,209]
    135.3 (113.6 to 161.2)
    47.5 (32.6 to 69.3)
        Victoria, Day 0 [N=221,202]
    28.5 (23.8 to 34.1)
    10 (8.4 to 11.9)
        Victoria, Day 7 [N=224,209]
    193.9 (168.7 to 222.8)
    47.1 (35.2 to 63)
        Yamagata, Day 0 [N=221,202]
    11.9 (10.6 to 13.3)
    6.5 (5.9 to 7.2)
        Yamagata, Day 7 [N=224,209]
    182.6 (159 to 209.6)
    26.1 (20.9 to 32.7)
    Statistical analysis title
    		 Adjusted GMT ratio for A/Christ antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    8.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.21
         upper limit
    		 12.96
    Statistical analysis title
    		 Adjusted GMT ratio for A/Victoria antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.81
         upper limit
    		 4.02
    Statistical analysis title
    		 Adjusted GMT ratio for B/Brisbane antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    3.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.89
         upper limit
    		 5.37
    Statistical analysis title
    		 Adjusted GMT ratio for B/Hub-Wuj antibodies
    Statistical analysis description
    The B/Hub-Wuj = B/Hubei-Wujiagang/158/2009 (Yamagata) strain
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Adjusted GMT ratio
    Point estimate
    6.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.21
         upper limit
    		 8.63

    Primary: Number of seropositive subjects against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine

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    End point title
    		 Number of seropositive subjects against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine [1]
    End point description
    End point type
    Primary
    End point timeframe
    At Day 0 and Day 7
    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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    224
    209
    Units: Subjects
        H1N1, Day 0 [N=221,202]
    189
    64
        H1N1, Day 7 [N=224,209]
    220
    137
        H3N2, Day 0 [N=221,202]
    131
    79
        H3N2, Day 7 [N=224,209]
    218
    99
        Victoria, Day 0 [N=221,202]
    187
    58
        Victoria, Day 7 [N=224,209]
    224
    174
        Yamagata, Day 0 [N=221,202]
    134
    36
        Yamagata, Day 7 [N=224,209]
    222
    144
    No statistical analyses for this end point

    Primary: Number of subjects seroconverted for HI antibodies against against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine.

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    End point title
    		 Number of subjects seroconverted for HI antibodies against against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine.
    End point description
    End point type
    Primary
    End point timeframe
    At Day 7
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    221
    202
    Units: Subjects
        H1N1
    170
    65
        H3N2
    180
    73
        Victoria
    169
    78
        Yamagata
    208
    77
    Statistical analysis title
    		 Difference in SCR for A/Christ antibodies
    Statistical analysis description
    To assess the immune response in terms of haemagglutination inhibition (HI) antibody titre at Day 7 after one dose of FLU D-QIV vaccine (2012-2013 formulation) in vaccine-primed and vaccine-unprimed subjects, for all strains included in the vaccine.
    Comparison groups
    Fluarix Quadrivalent Unprimed Group v Fluarix Quadrivalent Primed Group
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentages
    Point estimate
    44.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 35.87
         upper limit
    		 52.84
    Statistical analysis title
    		 Difference in SCR for A/Victoria antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentages
    Point estimate
    45.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.58
         upper limit
    		 53.3
    Statistical analysis title
    		 Difference in SCR for B/Brisbane antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentages
    Point estimate
    37.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 28.83
         upper limit
    		 46.26
    Statistical analysis title
    		 Difference in SCR for B/Hu-Wuj antibodies
    Statistical analysis description
    B/Hu-Wuj = B/Hubei-Wujiagang/158/2009 (Yamagata)
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in percentages
    Point estimate
    56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 48.32
         upper limit
    		 63.04

    Primary: Mean geometric increase (MGI) for HI antibody titer against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine.

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    End point title
    		 Mean geometric increase (MGI) for HI antibody titer against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine. [2]
    End point description
    End point type
    Primary
    End point timeframe
    At Day 7
    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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    221
    202
    Units: Fold increase
    geometric mean (confidence interval 95%)
        H1N1
    10.3 (8.5 to 12.4)
    3.2 (2.6 to 3.9)
        H3N2
    10.9 (9.4 to 12.6)
    2.9 (2.4 to 3.6)
        Victoria
    6.7 (5.9 to 7.6)
    4.6 (3.8 to 5.5)
        Yamagata
    15.2 (13.3 to 17.3)
    4 (3.3 to 4.9)
    No statistical analyses for this end point

    Primary: Number of subjects seroprotected for anti-HA antibodies against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine.

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    End point title
    		 Number of subjects seroprotected for anti-HA antibodies against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine.
    End point description
    End point type
    Primary
    End point timeframe
    At Day 0 and Day 7
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    224
    209
    Units: Subjects
        H1N1, Day 0 [N=221,202]
    89
    61
        H1N1, Day 7 [N=224,209]
    217
    72
        H3N2, Day 0 [N=221,202]
    37
    74
        H3N2, Day 7 [N=224,209]
    193
    81
        Victoria, Day 0 [N=221,202]
    72
    39
        Victoria, Day 7 [N=224,209]
    217
    84
        Yamagata, Day 0 [N=221,202]
    27
    12
        Yamagata, Day 7 [N=224,209]
    216
    83
    Statistical analysis title
    		 Difference in SPR for A/Christ antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in SPR
    Point estimate
    62.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 55.27
         upper limit
    		 68.89
    Statistical analysis title
    		 Difference in SPR for A/Victoria antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in SPR
    Point estimate
    47.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 39.08
         upper limit
    		 55.06
    Statistical analysis title
    		 Difference in SPR for B/Brisbane antibodies
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in SPR
    Point estimate
    56.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 49.44
         upper limit
    		 63.43
    Statistical analysis title
    		 Difference in SPR for B/Hub-Wuj antibodies
    Statistical analysis description
    The B/Hub-Wuj = B/Hubei-Wujiagang/158/2009 (Yamagata)
    Comparison groups
    Fluarix Quadrivalent Primed Group v Fluarix Quadrivalent Unprimed Group
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in SPR
    Point estimate
    56.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 49.41
         upper limit
    		 63.49

    Secondary: Number of subjects with HI antibody titers against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine.

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    End point title
    		 Number of subjects with HI antibody titers against each of the four vaccine strains after 1 dose of Fluarix Quadrivalent vaccine.
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 7
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    224
    209
    Units: Subjects
        H1N1 (<1:10), Day 0 [N=221,202]
    32
    138
        H1N1 (<1:10), Day 7 [N=224,209]
    4
    72
        H3N2 (<1:10), Day 0 [N=221,202]
    90
    123
        H3N2 (<1:10), Day 7 [N=224,209]
    6
    110
        Victoria (<1:10), Day 0 [N=221,202]
    34
    144
        Victoria (<1:10), Day 7 [N=224,209]
    0
    35
        Yamagata (<1:10), Day 0 [N=221,202]
    87
    166
        Yamagata (<1:10), Day 7 [N=224,209]
    2
    65
        H1N1 (1:10 to <1:40), Day 0 [N=221,202]
    100
    3
        H1N1 (1:10 to <1:40), Day 7 [N=224,209]
    3
    65
        H3N2 (1:10 to <1:40), Day 0 [N=221,202]
    94
    5
        H3N2 (1:10 to <1:40), Day 7 [N=224,209]
    25
    18
        Victoria (1:10 to <1:40), Day 0 [N=221,202]
    115
    19
        Victoria (1:10 to <1:40), Day 7 [N=224,209]
    7
    90
        Yamagata (1:10 to <1:40), Day 0 [N=221,202]
    107
    24
        Yamagata (1:10 to <1:40), Day 7 [N=224,209]
    6
    61
        H1N1 (≥1: 40), Day 0 [N=221,202]
    89
    61
        H1N1 (≥1: 40), Day 7 [N=224,209]
    217
    72
        H3N2 (≥1: 40), Day 0 [N=221,202]
    37
    74
        H3N2 (≥1: 40), Day 7 [N=224,209]
    193
    81
        Victoria (≥1: 40), Day 0 [N=221,202]
    72
    39
        Victoria (≥1: 40), Day 7 [N=224,209]
    217
    84
        Yamagata (≥1: 40), Day 0 [N=221,202]
    27
    12
        Yamagata (≥1: 40), Day 7 [N=224,209]
    216
    83
    No statistical analyses for this end point

    Secondary: Serum neutralising antibody titers against each of the vaccine strains after 1 dose of Fluarix Quadrivalent vaccine

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    End point title
    		 Serum neutralising antibody titers against each of the vaccine strains after 1 dose of Fluarix Quadrivalent vaccine
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 7
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    107
    109
    Units: Titer
    geometric mean (confidence interval 95%)
        H1N1, Day 0 [N=97,90]
    138.2 (97.4 to 196.2)
    48.3 (33.9 to 68.7)
        H1N1, Day 7 [N=107, 96]
    1500.9 (1172.7 to 1920.9)
    139.4 (78.8 to 246.8)
        H3N2, Day 0 [N=99,96]
    66.5 (55.9 to 79.2)
    82.8 (60.6 to 113.1)
        H3N2, Day 7 [N=104,100]
    422.9 (342.3 to 522.4)
    325.1 (187.1 to 564.7)
        Victoria, Day 0 [N=107,109]
    38.6 (29.7 to 50.3)
    22.2 (18.6 to 26.5)
        Victoria, Day 7 [N=107, 108]
    193.7 (154.7 to 242.6)
    47 (30.3 to 72.9)
        Yamagata, Day 0 [N=107,107]
    36.9 (34.2 to 39.8)
    30.8 (29 to 32.6)
        Yamagata, Day 7 [N=107,107]
    182.7 (157.7 to 211.8)
    51.7 (42.2 to 63.4)
    No statistical analyses for this end point

    Secondary: Serum anti-neuraminidase antibody titers against each of the vaccine strains after 1 dose of Fluarix Quadrivalent vaccine

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    End point title
    		 Serum anti-neuraminidase antibody titers against each of the vaccine strains after 1 dose of Fluarix Quadrivalent vaccine
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 7
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    107
    109
    Units: Titer
    geometric mean (confidence interval 95%)
        H1N1, Day 0 [N=106,106]
    34.6 (25.3 to 47.3)
    24.1 (18.6 to 31.1)
        H1N1, Day 7 [N=106, 109]
    293.9 (247.2 to 349.3)
    41.3 (28.9 to 59)
        H3N2, Day 0 [N=107,106]
    38.4 (33.7 to 43.7)
    58.8 (47.2 to 73.4)
        H3N2, Day 7 [N=107, 109]
    189.4 (155.9 to 230.2)
    114.2 (84.1 to 155.2)
        Victoria, Day 0 [N=106,106]
    17.4 (14.2 to 21.3)
    14.3 (12.4 to 16.5)
        Victoria, Day 7 [N=106,109]
    90.6 (74.1 to 110.8)
    27.6 (19.4 to 39.1)
        Yamagata, Day 0 [N=106, 106]
    25.3 (21.6 to 29.6)
    15.4 (13.2 to 18)
        Yamagata, Day 7 [N=106,109]
    222 (185.7 to 265.4)
    40.6 (29.5 to 55.7)
    No statistical analyses for this end point

    Secondary: Vaccine response rate (VRR) for neutralising antibody titers against each of the four vaccine strains.

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    End point title
    		 Vaccine response rate (VRR) for neutralising antibody titers against each of the four vaccine strains.
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 7 post dose 1
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    107
    108
    Units: Subjects
        H1N1 [N=97,89]
    74
    36
        H3N2 [N=97,94]
    72
    48
        Victoria [N=107,108]
    78
    24
        Yamagata [N=107,105]
    45
    15
    No statistical analyses for this end point

    Secondary: VRR for anti-neuraminidase antibody titers against each of the four vaccine strains.

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    End point title
    		 VRR for anti-neuraminidase antibody titers against each of the four vaccine strains.
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 7 post dose 1
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    107
    106
    Units: Subjects
        H1N1 [N=105,106]
    75
    31
        H3N2 [N=107,106]
    75
    31
        Victoria [N=105,106]
    79
    24
        Yamagata [N=105,106]
    90
    29
    No statistical analyses for this end point

    Secondary: MGI for neutralising antibodies titres against each of the four vaccine strains.

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    End point title
    		 MGI for neutralising antibodies titres against each of the four vaccine strains.
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 7
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    107
    108
    Units: Fold increase
    geometric mean (confidence interval 95%)
        H1N1 [N=97, 89]
    10.6 (8.2 to 13.7)
    3.1 (2.3 to 4.2)
        H3N2 [N=97, 94]
    6.4 (5.4 to 7.6)
    4.5 (3.2 to 6.2)
        Victoria [N=107,108]
    5 (4.3 to 5.8)
    2.1 (1.6 to 2.8)
        Yamagata [N=107,105]
    5 (4.3 to 5.7)
    1.7 (1.4 to 2)
    No statistical analyses for this end point

    Secondary: MGI for anti-neuraminidase antibodies titers against each of the four vaccine strains.

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    End point title
    		 MGI for anti-neuraminidase antibodies titers against each of the four vaccine strains.
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 7 post dose 1
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    107
    106
    Units: Fold increase
    geometric mean (confidence interval 95%)
        H1N1 [N=105,106]
    8.3 (6.5 to 10.7)
    1.8 (1.5 to 2.1)
        H3N2 [N=105,106]
    5.2 (4.4 to 6)
    1.9 (1.5 to 2.4)
        Victoria [N=105,106]
    8.8 (7.5 to 10.2)
    2.7 (2.1 to 3.4)
        Yamagata [N=107,106]
    4.9 (4.2 to 5.8)
    2 (1.7 to 2.3)
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any and grade 3 solicited local adverse events (AEs)

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    End point title
    		 Number of subjects reporting any and grade 3 solicited local adverse events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    During a 7-day (Day 0 to 6) follow-up period after first vaccination
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    239
    228
    Units: Subjects
        Any Pain
    96
    61
        Grade 3 Pain
    2
    1
        Any Redness
    82
    48
        Grade 3 Redness
    2
    0
        Any Swelling
    49
    25
        Grade 3 Swelling
    2
    0
    No statistical analyses for this end point

    Secondary: Duration of solicited symptoms

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    End point title
    		 Duration of solicited symptoms
    End point description
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination Dose 1 period
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    96
    61
    Units: Days
    median (full range (min-max))
        Drowsiness
    1 (1 to 7)
    1 (1 to 4)
        Irritability/fussiness
    2 (1 to 7)
    2 (1 to 7)
        Loss of appetite
    2 (1 to 7)
    2 (1 to 5)
        Pain
    1 (1 to 5)
    1 (1 to 5)
        Redness
    2 (1 to 7)
    2 (1 to 6)
        Swelling
    2 (1 to 5)
    1 (1 to 5)
        Temperature
    1 (1 to 5)
    2 (1 to 6)
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, grade 3 and related solicited general symptoms.

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    End point title
    		 Number of subjects reporting any, grade 3 and related solicited general symptoms.
    End point description
    End point type
    Secondary
    End point timeframe
    During the 7 days (Days 0 – 6) post dose 1 vaccination
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    238
    224
    Units: Subjects
        Any Drowsiness
    54
    44
        Grade 3 Drowsiness
    5
    1
        Related Drowsiness
    36
    28
        Any Irritability/Fussiness
    77
    59
        Grade 3 Irritability/Fussiness
    5
    5
        Related Irritability/Fussiness
    51
    43
        Any Loss of appetite
    51
    46
        Grade 3 Loss of appetite
    8
    5
        Related Loss of appetite
    31
    31
        Any Temperature
    13
    26
        Grade 3 Temperature
    2
    1
        Related Temperature
    6
    15
    No statistical analyses for this end point

    Secondary: Number of subjects reporting AEs with Medically Attended Visits (MAV)

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    End point title
    		 Number of subjects reporting AEs with Medically Attended Visits (MAV)
    End point description
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 0 – Day 179)
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    241
    229
    Units: Subjects
        Any MAV
    149
    130
        Grade 3 MAV
    5
    8
        Related MAV
    0
    1
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Potential Immune-Mediated Diseases (pIMDs)

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    End point title
    		 Number of subjects reporting Potential Immune-Mediated Diseases (pIMDs)
    End point description
    End point type
    Secondary
    End point timeframe
    During the entire study period (Days 0 - 179)
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    241
    229
    Units: Subjects
        Any pIMD
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any, grade 3 and related unsolicited AEs.

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    End point title
    		 Number of subjects reporting any, grade 3 and related unsolicited AEs.
    End point description
    End point type
    Secondary
    End point timeframe
    Within 28 days (Days 0-27) after first vaccination
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    241
    229
    Units: Subject
        Any Unsolicted AEs
    66
    66
        Grade 3 Unsolicted AEs
    6
    7
        Related Unsolicted AEs
    5
    3
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any and related serious adverse events (SAEs)

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    End point title
    		 Number of subjects reporting any and related serious adverse events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 0 – Day 179)
    End point values
    		 Fluarix Quadrivalent Primed Group Fluarix Quadrivalent Unprimed Group
    Number of subjects analysed
    241
    229
    Units: Subjects
        Any SAE(s)
    7
    8
        Related SAE(s)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events: From Day 0 to Day 179; Solicited local and general symptoms: During the 7-day (Days 0-6) post-vaccination period; Unsolicited symptoms: During the 28-day (Day 0-27) post-vaccination period.
    Adverse event reporting additional description
    For the frequent adverse events, the number of participants at risk included those from Total Vaccinated cohort who had the symptom sheet completed.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Fluarix Quadrivalent Unprimed Group
    Reporting group description
    		 Subjects in this group were unprimed in the primary study 115345 (NCT01439360) and received 2 doses of Fluarix Quadrivalent vaccine at Days 0 and 28 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.

    Reporting group title
    Fluarix Quadrivalent Primed Group
    Reporting group description
    		 Subjects in this group were previously primed with 2 doses of Fluarix Quadrivalent vaccine in the primary study 115345 (NCT01439360) and received 1 dose of Fluarix Quadrivalent vaccine at Day 0 in the current study. The vaccine was administered intramuscularly in the deltoid region of arm.

    Serious adverse events
    		 Fluarix Quadrivalent Unprimed Group Fluarix Quadrivalent Primed Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 229 (3.49%)
    7 / 241 (2.90%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis bacterial
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 241 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fluarix Quadrivalent Unprimed Group Fluarix Quadrivalent Primed Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 229 (26.64%)
    96 / 241 (39.83%)
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    61 / 228 (26.75%)
    96 / 239 (40.17%)
         occurrences all number
    61
    96
    Redness
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    48 / 228 (21.05%)
    82 / 239 (34.31%)
         occurrences all number
    48
    82
    Swelling
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    25 / 228 (10.96%)
    49 / 239 (20.50%)
         occurrences all number
    25
    49
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    44 / 224 (19.64%)
    54 / 238 (22.69%)
         occurrences all number
    44
    54
    Irritability/Fussines
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    59 / 224 (26.34%)
    77 / 238 (32.35%)
         occurrences all number
    59
    77
    Loss of Appetite
         subjects affected / exposed [6]
    46 / 224 (20.54%)
    51 / 238 (21.43%)
         occurrences all number
    46
    51
    Temperature
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    26 / 224 (11.61%)
    13 / 238 (5.46%)
         occurrences all number
    26
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 229 (5.68%)
    9 / 241 (3.73%)
         occurrences all number
    13
    9
    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: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed.
    [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: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed.
    [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: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed.
    [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: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed.
    [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: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed.
    [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: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed.
    [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: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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