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    Clinical Trial Results:
    A phase II, randomized, observer blind study to evaluate the safety and immunogenicity of three different vaccination schedules employing two formulations of the monovalent A/California/7/2009 (H1N1)v-like candidate vaccine adjuvanted with AS03 and the monovalent A/California/7/2009 (H1N1)v-like candidate vaccine formulated without adjuvant in subjects aged 10 to less than 18 years.

    Summary
    EudraCT number
    		 2009-016268-35
    Trial protocol
    		 SK   EE  
    Global end of trial date
    10 May 2011

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Apr 2023
    First version publication date
    06 May 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of full data set and alignment between registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    113883
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01035749
    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 Centre, GlaxoSmithKline Biologicals', 044 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Centre, GlaxoSmithKline Biologicals', 044 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    10 May 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether vaccination with monovalent A/California/7/2009 (H1N1)v-like vaccine (each treatment group) results in an immune response to the vaccine-homologous virus that meets or exceeds the CHMP guidance targets for pandemic vaccine seroconversion rate (SCR), rate of induction of vaccine-homologous reciprocal hemagglutination inhibition (HI) titers greater than or equal to 40 (potential seroprotection rate [SPR]) and geometric mean fold rise (GMFR) 21 days after the first dose of H1N1 vaccine in children 10 to < 18 years of age.
    Protection of trial subjects
    All subjects were supervised for atleast 30 min after vaccination/product administration with appropriate medical treatment readily available. Vaccines/products 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/products. Subjects were followed-up for 182 days after the last vaccination/product administration.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Feb 2010
    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
    Slovakia: 110
    Country: Number of subjects enrolled
    Estonia: 200
    Worldwide total number of subjects
    310
    EEA total number of subjects
    310
    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)
    110
    Adolescents (12-17 years)
    200
    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
    		 310 subjects were enrolled in the study, all of which were vaccinated and completed the Day 42 visit.

    Period 1
    Period 1 title
    At Day 42 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Flu1-F1-2D Group
    Arm description
    		 Subjects received 2 doses of Arepanrix formulation 1 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arepanrix
    Investigational medicinal product code
    Other name
    GSK2340274A
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 doses administered intramuscularly

    Investigational medicinal product name
    Saline placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose administered intramuscularly in subjects of Flu1-F1-2D Group, Flu1-F2-2D Group and Flu2-2D Group respectively at Day 21.

    Arm title
    		 Flu1-F2-2D Group
    Arm description
    		 Subjects received 2 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Saline placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose administered intramuscularly in subjects of Flu1-F1-2D Group, Flu1-F2-2D Group and Flu2-2D Group respectively at Day 21.

    Arm title
    		 Flu1-F2-3D Group
    Arm description
    		 Subjects received 3 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0, Day 21 and Day 182 (booster).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arepanrix
    Investigational medicinal product code
    Other name
    Adjuvanted A/California/7/2009 (H1N1)v-like inactivated split virion
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3 doses administered intramuscularly at Days 0, 21 and 182 (booster).

    Arm title
    		 Flu2-2D Group
    Arm description
    		 Subjects received 2 doses of Arepanrix unadjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Unadjuvanted Q-Pan H1N1 vaccine
    Investigational medicinal product code
    Other name
    unadjuvanted A/California/7/2009 (H1N1) v-like inactivated split virion
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 doses administered intramuscularly at Days 0 and 182.

    Investigational medicinal product name
    Saline placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 dose administered intramuscularly at Day 21.

    Number of subjects in period 1
    		Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Started
    66
    66
    68
    110
    Completed
    66
    66
    68
    110

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Flu1-F1-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix formulation 1 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Reporting group title
    Flu1-F2-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Reporting group title
    Flu1-F2-3D Group
    Reporting group description
    		 Subjects received 3 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0, Day 21 and Day 182 (booster).

    Reporting group title
    Flu2-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix unadjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Reporting group values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group Total
    Number of subjects
    		 66 66 68 110 310
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.6 ± 2.27 14.5 ± 2.2 14.6 ± 1.84 14.1 ± 2.13 -
    Gender categorical
    Units: Subjects
        Female
    		 37 32 38 59 166
        Male
    		 29 34 30 51 144

    End points

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    End points reporting groups
    Reporting group title
    Flu1-F1-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix formulation 1 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Reporting group title
    Flu1-F2-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Reporting group title
    Flu1-F2-3D Group
    Reporting group description
    		 Subjects received 3 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0, Day 21 and Day 182 (booster).

    Reporting group title
    Flu2-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix unadjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Primary: Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain [1]
    End point description
    Seroconversion defined as: - For initially seronegative subjects, antibody titre greater than or equal (>=) 1:40 after vaccination - For initially seropositive subjects, antibody titre after vaccination >= 4 fold the pre-vaccination antibody titre
    End point type
    Primary
    End point timeframe
    At Day 21
    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
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    65
    68
    109
    Units: Subjects
    63
    58
    61
    96
    No statistical analyses for this end point

    Primary: Number of Subjects Seroprotected for HI Antibodies against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 Number of Subjects Seroprotected for HI Antibodies against Flu A/CAL/7/09 H1N1 strain [2]
    End point description
    A seroprotected subject was defined as a subject with a serum HI titer greater than or equal to 1:40 that usually is accepted as indicating protection.
    End point type
    Primary
    End point timeframe
    At Day 0 and Day 21
    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
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    65
    68
    109
    Units: Subjects
        Day 0
    28
    35
    30
    49
        Day 21
    66
    65
    67
    107
    No statistical analyses for this end point

    Primary: HI antibody seroconversion factors against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 HI antibody seroconversion factors against Flu A/CAL/7/09 H1N1 strain [3]
    End point description
    Seroconversion factors were defined as the fold increase in serum HI GMTs post-vaccination compared to Day 0.
    End point type
    Primary
    End point timeframe
    At Day 21
    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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    65
    68
    109
    Units: Fold increase
        geometric mean (confidence interval 95%)
    35.6 (26.4 to 47.9)
    18.3 (13.1 to 25.6)
    28.9 (20.4 to 41)
    25.3 (19.2 to 33.3)
    No statistical analyses for this end point

    Secondary: HI antibody titres against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 HI antibody titres against Flu A/CAL/7/09 H1N1 strain
    End point description
    Antibody titers were expressed as GMTs.
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 21
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    65
    68
    109
    Units: Titre
    geometric mean (confidence interval 95%)
        Day 0
    24.1 (17.2 to 33.8)
    33 (22.4 to 48.7)
    23.4 (16.9 to 32.4)
    22.8 (17.4 to 29.9)
        Day 21
    858.7 (714.5 to 1032)
    603.6 (493.3 to 738.5)
    676.9 (539.1 to 850)
    578.1 (466.7 to 716.1)
    No statistical analyses for this end point

    Secondary: HI antibody titres against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 HI antibody titres against Flu A/CAL/7/09 H1N1 strain
    End point description
    Antibody titres were expressed as Geometric mean titers (GMTs).
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 42
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    65
    65
    68
    108
    Units: Titres
    geometric mean (confidence interval 95%)
        Day 0
    23.4 (16.7 to 32.9)
    33 (22.4 to 48.7)
    23.4 (16.9 to 32.4)
    22.7 (17.3 to 29.8)
        Day 42
    646.9 (532.3 to 786.2)
    469.7 (386.9 to 570.3)
    977 (833.1 to 1145.8)
    439.6 (356 to 543)
    No statistical analyses for this end point

    Secondary: HI antibody titres against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 HI antibody titres against Flu A/CAL/7/09 H1N1 strain
    End point description
    Antibody titres were expressed as GMTs.
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 182
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    64
    65
    68
    109
    Units: Titres
    geometric mean (confidence interval 95%)
        Day 0
    22.9 (16.3 to 32)
    34.8 (23.5 to 51.5)
    23.4 (16.9 to 32.4)
    22.8 (17.4 to 29.9)
        Day 182
    240.2 (188.1 to 306.6)
    176.1 (137.1 to 226)
    318.4 (257.8 to 393.1)
    177.2 (140.1 to 224)
    No statistical analyses for this end point

    Secondary: HI antibody titres against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 HI antibody titres against Flu A/CAL/7/09 H1N1 strain
    End point description
    Antibody titres were expressed as Geometric mean titers (GMTs).
    End point type
    Secondary
    End point timeframe
    At Days 0, 182 and 189
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    63
    63
    68
    108
    Units: Titres
    geometric mean (confidence interval 95%)
        Day 0
    23.4 (16.7 to 32.9)
    33.5 (22.5 to 50.1)
    23.4 (16.9 to 32.4)
    22.5 (17.2 to 29.5)
        Day 182
    237.7 (185.7 to 304.5)
    172.7 (133.7 to 223.2)
    318.4 (257.8 to 393.1)
    177.3 (140 to 224.7)
        Day 189
    589.4 (506 to 686.5)
    416.7 (352.8 to 492.2)
    552.1 (474.5 to 642.5)
    273.4 (233.2 to 320.6)
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain
    End point description
    A seroconverted subject was defined as a subject who had either a pre-vaccination titre below 1:10 and a post-vaccination titre greater than or equal to 1:40 or a pre-vaccination titre greater than or equal to 1:10 and at least a 4-fold increase in post-vaccination titre.
    End point type
    Secondary
    End point timeframe
    At Day 42
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    65
    65
    68
    108
    Units: Subjects
    62
    52
    65
    93
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain
    End point description
    A seroconverted subject was defined as a subject who had either a pre-vaccination titre below 1:10 and a post-vaccination titre greater than or equal to 1:40 or a pre-vaccination titre greater than or equal to 1:10 and at least a 4-fold increase in post-vaccination titre.
    End point type
    Secondary
    End point timeframe
    At Day 182
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    64
    65
    68
    109
    Units: Subjects
    48
    34
    56
    67
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain
    End point description
    A seroconverted subject was defined as a subject who had either a pre-vaccination titre below 1:10 and a post-vaccination titre greater than or equal to 1:40 or a pre-vaccination titre greater than or equal to 1:10 and at least a 4-fold increase in post-vaccination titre. Day 0 was used as reference activity.
    End point type
    Secondary
    End point timeframe
    At Day 189
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    63
    63
    68
    108
    Units: Subjects
    58
    47
    64
    84
    No statistical analyses for this end point

    Secondary: Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain

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    End point title
    		 Number of subjects seroconverted for HI antibodies against Flu A/CAL/7/09 H1N1 strain
    End point description
    A seroconverted subject was defined as a subject who had either a pre-vaccination titer below 1:10 and a post-vaccination titer greater than or equal to 1:40 or a pre-vaccination titer greater than or equal to 1:10 and at least a 4-fold increase in post-vaccination titer. Day 182 was used as reference activity.
    End point type
    Secondary
    End point timeframe
    At Day 189
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    63
    63
    68
    108
    Units: Subjects
    17
    18
    9
    11
    No statistical analyses for this end point

    Secondary: The number of subjects seroprotected for HI antibodies against Flu A/CAL/7/09 H1N1

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    End point title
    		 The number of subjects seroprotected for HI antibodies against Flu A/CAL/7/09 H1N1
    End point description
    A seroprotected subject was defined as a subject with a serum HI titre greater than or equal to 1:40 that usually is accepted as indicating protection.
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 42
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    65
    65
    68
    108
    Units: Subjects
        Day 0
    27
    35
    30
    48
        Day 42
    65
    64
    68
    105
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected to HI antibodies against Flu A/CAL/7/09 H1N1

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    End point title
    		 Number of subjects seroprotected to HI antibodies against Flu A/CAL/7/09 H1N1
    End point description
    A seroprotected subject was defined as a subject with a serum HI titre greater than or equal to 1:40 that usually is accepted as indicating protection.
    End point type
    Secondary
    End point timeframe
    At Day 0 and Day 182
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    64
    65
    68
    109
    Units: Subjects
        Day 0
    26
    36
    30
    49
        Day 182
    62
    61
    67
    98
    No statistical analyses for this end point

    Secondary: Number of subjects seroprotected to HI antibodies against Flu A/CAL/7/09 H1N1

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    End point title
    		 Number of subjects seroprotected to HI antibodies against Flu A/CAL/7/09 H1N1
    End point description
    A seroprotected subject was defined as a subject with a serum HI titer greater than or equal to 1:40 that usually is accepted as indicating protection.
    End point type
    Secondary
    End point timeframe
    At Day 0, Day 182 and Day 189
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    63
    63
    68
    108
    Units: Subjects
        Day 0
    26
    34
    30
    48
        Day 182
    61
    59
    67
    97
        Day 189
    63
    63
    68
    105
    No statistical analyses for this end point

    Secondary: Geometric mean fold rise (GMFR) for HI antibodies against Flu A/CAL/7/09 H1N1

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    End point title
    		 Geometric mean fold rise (GMFR) for HI antibodies against Flu A/CAL/7/09 H1N1
    End point description
    At Day 42
    End point type
    Secondary
    End point timeframe
    GMFR (also known as the seroconversion factor, SCF) was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination reciprocal HI titer for the vaccine virus.
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    65
    65
    68
    108
    Units: Fold increase
        geometric mean (confidence interval 95%)
    27.6 (20.7 to 36.7)
    14.2 (10.2 to 19.8)
    41.8 (29.4 to 59.3)
    19.3 (14.7 to 25.5)
    No statistical analyses for this end point

    Secondary: GMFR for HI antibodies against Flu A/CAL/7/09 H1N1

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    End point title
    		 GMFR for HI antibodies against Flu A/CAL/7/09 H1N1
    End point description
    GMFR (also known as the seroconversion factor, SCF) was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination reciprocal HI titer for the vaccine virus.
    End point type
    Secondary
    End point timeframe
    At Day 182
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    64
    65
    68
    109
    Units: Fold increase
        geometric mean (confidence interval 95%)
    10.5 (7.9 to 14)
    5.1 (3.7 to 6.9)
    13.6 (9.9 to 18.8)
    7.8 (5.8 to 10.3)
    No statistical analyses for this end point

    Secondary: GMFR for HI antibodies against Flu A/CAL/7/09 H1N1 using Day 0 as reference activity

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    End point title
    		 GMFR for HI antibodies against Flu A/CAL/7/09 H1N1 using Day 0 as reference activity
    End point description
    GMFR (also known as the seroconversion factor, SCF) was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination reciprocal HI titer for the vaccine virus.
    End point type
    Secondary
    End point timeframe
    At Day 189
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    63
    63
    68
    108
    Units: Fold increase
        geometric mean (confidence interval 95%)
    25.2 (17.9 to 35.3)
    12.4 (8.3 to 18.6)
    23.6 (16.6 to 33.6)
    12.1 (9.3 to 15.9)
    No statistical analyses for this end point

    Secondary: GMFR for HI antibodies against Flu A/CAL/7/09 H1N1 using Day 182 as reference activity

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    End point title
    		 GMFR for HI antibodies against Flu A/CAL/7/09 H1N1 using Day 182 as reference activity
    End point description
    GMFR (also known as the seroconversion factor, SCF) was defined as the geometric mean of the within-subject ratios of the post-vaccination reciprocal HI titer to the pre-vaccination reciprocal HI titer for the vaccine virus.
    End point type
    Secondary
    End point timeframe
    At Day 189
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    63
    63
    68
    108
    Units: Fold increase
        geometric mean (confidence interval 95%)
    2.5 (2 to 3.1)
    2.4 (1.9 to 3)
    1.7 (1.5 to 2)
    1.5 (1.3 to 1.8)
    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
    Any was defined as occurrence of any local symptom regardless of their intensity grade. Grade 3 redness and swelling was > 100 millimeter (mm) and grade 3 pain was defined as pain that prevented normal activity.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination period following each dose
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    66
    68
    110
    Units: Subjects
        Any pain
    52
    48
    61
    51
        Grade 3 pain
    2
    0
    2
    0
        Any Redness
    2
    0
    1
    0
        Grade 3 Redness
    0
    0
    0
    0
        Any Swelling
    4
    1
    6
    1
        Grade 3 Swelling
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any and grade 3 solicited local AEs

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    End point title
    		 Number of subjects reporting any and grade 3 solicited local AEs
    End point description
    Any was defined as occurrence of any local symptom regardless of their intensity grade.Grade 3 redness and swelling was > 100 millimeter (mm) and grade 3 pain was defined as pain that prevented normal activity
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination period following booster dose
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    65
    65
    68
    110
    Units: Subjects
        Any Pain
    48
    40
    54
    49
        Grade 3 Pain
    3
    3
    4
    0
        Any Redness
    4
    1
    1
    0
        Grade 3 Redness
    0
    0
    0
    0
        Any Swelling
    6
    5
    3
    0
        Grade 3 Swelling
    1
    0
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting any, grade 3 and related solicited general AEs
    End point description
    Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, shivering, sweating and fever (Fever = axillary temperature equal to or above 38.0 degrees Celsius (°C)). Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature equal to or above (≥) 39.0°C.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination period following each dose
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    66
    68
    110
    Units: Subjects
        Any Arthralgia
    5
    7
    6
    13
        Grade 3 Arthralgia
    0
    0
    0
    0
        Related Arthralgia
    5
    6
    5
    10
        Any Fatigue
    26
    19
    24
    36
        Grade 3 Fatigue
    0
    0
    1
    1
        Related Fatigue
    23
    16
    21
    28
        Any Gastrointestinal
    5
    3
    9
    8
        Grade 3 Gastrointestinal
    0
    0
    1
    0
        Related Gastrointestinal
    3
    2
    6
    5
        Any Headache
    27
    21
    39
    45
        Grade 3 Headache
    0
    1
    0
    0
        Related Headache
    23
    16
    27
    31
        Any Myalgia
    17
    20
    28
    21
        Grade 3 Myalgia
    0
    0
    0
    0
        Related Myalgia
    16
    17
    23
    16
        Any Shivering
    6
    5
    8
    16
        Grade 3 Shivering
    0
    0
    0
    0
        Related Shivering
    6
    4
    7
    11
        Any Sweating
    6
    8
    11
    15
        Grade 3 Sweating
    0
    0
    0
    0
        Related Sweating
    6
    3
    8
    8
        Any Fever
    2
    0
    1
    3
        Grade 3 Fever
    0
    0
    0
    1
        Related Fever
    2
    0
    1
    2
    No statistical analyses for this end point

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

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    End point title
    		 Number of subjects reporting any, grade 3 and related solicited general AEs
    End point description
    Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, shivering, sweating and fever (Fever = axillary temperature equal to or above 38.0 degrees Celsius (°C)). Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature equal to or above (≥) 39.0°C.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) post-vaccination period following booster dose
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    65 [4]
    65 [5]
    68
    110
    Units: Subjects
        Any Arthralgia
    13
    8
    12
    8
        Grade 3 Arthralgia
    0
    0
    0
    0
        Related Arthralgia
    13
    5
    8
    6
        Any Fatigue
    29
    20
    28
    19
        Grade 3 Fatigue
    1
    0
    0
    0
        Related Fatigue
    27
    15
    25
    16
        Any Gastrointestinal
    4
    2
    8
    5
        GRade 3 Gastrointestinal
    1
    0
    0
    0
        Related Gastrointestinal
    4
    2
    7
    3
        Any Headache
    24
    23
    32
    25
        Grade 3 Headache
    1
    1
    0
    0
        Related Headache
    23
    16
    24
    18
        Any Myalgia
    19
    16
    17
    20
        Grade 3 Myalgia
    0
    0
    0
    0
        Related Myalgia
    19
    14
    15
    16
        Any Shivering
    9
    13
    15
    9
        Grade 3 Shivering
    0
    0
    0
    0
        Related Shivering
    9
    8
    12
    8
        Any Sweating
    5
    3
    4
    9
        Grade 3 Sweating
    0
    0
    0
    0
        Related Sweating
    5
    3
    3
    6
        Any Fever
    11
    5
    7
    2
        Grade 3 Fever
    0
    1
    0
    0
        Related Fever
    10
    1
    6
    2
    Notes
    [4] - 1 subject moved out of the study area thereby withdrawing from the study.
    [5] - 1 subject moved out of the study area thereby withdrawing from the study.
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any Medically Attended Events (MAEs

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    End point title
    		 Number of subjects reporting any Medically Attended Events (MAEs
    End point description
    MAEs were defined as events for which the subject received medical attention defined as hospitalization, an emergency room visit or a visit to or from medical personnel (medical doctor) for any reason.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Days 0-364) following the first vaccination
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    66
    68
    110
    Units: Subjects
        Any MAEs
    20
    21
    22
    34
    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
    pIMDs were defined as a subset of AEs that included both clearly autoimmune diseases and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Days 0-364) following first vaccination
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    66
    68
    110
    Units: Subjects
        Any pIMDs
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with normal and abnormal hematological and biochemical parameters assessed with respect to normal laboratory ranges

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    End point title
    		 Number of subjects with normal and abnormal hematological and biochemical parameters assessed with respect to normal laboratory ranges
    End point description
    Subjects were categorized according to their results at pre-vaccination (PRE), Day 21, Day 42, Day 182 and Day 189 which were within normal, above normal, below the normal ranges or unknown. The laboratory parameters assessed were Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), Total Bilirubin, Creatinine, Hematocrit, Hemoglobin, Platelets, Blood urea nitrogen (BUN) and White blood cells (WBCs).
    End point type
    Secondary
    End point timeframe
    At Days 0, 21, 42, 182 and 189
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66 [6]
    66 [7]
    68
    110
    Units: Subjects
        ALAT, Day 0 Unknown
    0
    0
    0
    0
        ALAT, Day 0 Below
    0
    0
    0
    0
        ALAT, Day 0 Within
    65
    65
    66
    108
        ALAT, Day 0 Above
    1
    1
    2
    2
        ALAT, Day 21 Unknown
    0
    0
    0
    0
        ALAT, Day 21 Below
    0
    0
    0
    0
        ALAT, Day 21 Within
    64
    64
    64
    108
        ALAT, Day 21 Above
    2
    2
    4
    2
        ALAT, Day 42 Unknown
    0
    0
    0
    0
        ALAT, Day 42 Below
    0
    0
    0
    0
        ALAT, Day 42 Within
    64
    66
    66
    104
        ALAT, Day 42 Above
    2
    0
    2
    6
        ALAT, Day 182 Unknown
    0
    0
    0
    0
        ALAT, Day 182 Below
    0
    0
    0
    0
        ALAT, Day 182 Within
    64
    62
    67
    109
        ALAT, Day 182 Above
    1
    3
    1
    1
        ALAT, Day 189 Unknown
    0
    0
    0
    0
        ALAT, Day 189 Below
    0
    0
    0
    0
        ALAT, Day 189 Within
    64
    61
    67
    110
        ALAT, Day 189 Above
    1
    4
    1
    0
        ASAT, Day 0 Unknown
    0
    0
    0
    0
        ASAT, Day 0 Below
    0
    0
    0
    0
        ASAT, Day 0 Within
    63
    62
    64
    108
        ASAT, Day 0 Above
    3
    4
    4
    2
        ASAT, Day 21 Unknown
    0
    0
    0
    0
        ASAT, Day 21 Below
    0
    0
    0
    0
        ASAT, Day 21 Within
    61
    61
    63
    104
        ASAT, Day 21 Above
    5
    5
    5
    6
        ASAT, Day 42 Unknown
    0
    0
    0
    0
        ASAT, Day 42 Below
    0
    0
    0
    0
        ASAT, Day 42 Within
    65
    60
    67
    103
        ASAT, Day 42 Above
    1
    6
    1
    7
        ASAT, Day 182 Unknown
    0
    0
    0
    0
        ASAT, Day 182 Below
    0
    0
    0
    0
        ASAT, Day 182 Within
    63
    61
    67
    110
        ASAT, Day 182 Above
    2
    4
    1
    0
        ASAT, Day 189 Unknown
    0
    0
    0
    0
        ASAT, Day 189 Below
    0
    0
    0
    0
        ASAT, Day 189 Within
    64
    62
    67
    110
        ASAT, Day 189 Above
    1
    3
    1
    0
        Total Bilirubin, Day 0 Unknown
    0
    0
    0
    0
        Total Bilirubin, Day 0 Below
    0
    0
    0
    0
        Total Bilirubin, Day 0 Within
    21
    22
    19
    36
        Total Bilirubin, Day 0 Above
    3
    1
    5
    3
        Total Bilirubin, Day 21 Unknown
    0
    0
    0
    0
        Total Bilirubin, Day 21 Below
    0
    0
    0
    0
        Total Bilirubin, Day 21 Within
    23
    21
    21
    34
        Total Bilirubin, Day 21 Above
    1
    2
    3
    5
        Total Bilirubin, Day 42 Unknown
    0
    0
    0
    0
        Total Bilirubin, Day 42 Below
    0
    0
    0
    0
        Total Bilirubin, Day 42 Within
    22
    21
    20
    37
        Total Bilirubin, Day 42 Above
    2
    2
    4
    2
        Total Bilirubin, Day 182 Unknown
    0
    0
    0
    0
        Total Bilirubin, Day 182 Below
    0
    0
    0
    0
        Total Bilirubin, Day 182 Within
    22
    21
    21
    36
        Total Bilirubin, Day 182 Above
    2
    2
    3
    3
        Total Bilirubin, Day 189 Unknown
    0
    0
    0
    0
        Total Bilirubin, Day 189 Below
    0
    0
    1
    0
        Total Bilirubin, Day 189 Within
    22
    22
    21
    35
        Total Bilirubin, Day 189 Above
    2
    1
    2
    4
        Creatinine, Day 0 Unknown
    0
    0
    0
    0
        Creatinine, Day 0 Below
    4
    2
    4
    5
        Creatinine, Day 0 Within
    41
    47
    46
    77
        Creatinine, Day 0 Above
    21
    17
    18
    28
        Creatinine, Day 21 Unknown
    0
    0
    0
    0
        Creatinine, Day 21 Below
    4
    5
    4
    8
        Creatinine, Day 21 Within
    46
    48
    45
    74
        Creatinine, Day 21 Above
    16
    13
    19
    28
        Creatinine, Day 42 Unknown
    0
    0
    0
    0
        Creatinine, Day 42 Below
    4
    3
    6
    7
        Creatinine, Day 42 Within
    42
    48
    43
    80
        Creatinine, Day 42 Above
    20
    15
    19
    23
        Creatinine, Day 182 Unknown
    0
    0
    0
    0
        Creatinine, Day 182 Below
    6
    5
    5
    5
        Creatinine, Day 182 Within
    51
    52
    53
    94
        Creatinine, Day 182 Above
    8
    8
    10
    11
        Creatinine, Day 189 Unknown
    0
    0
    0
    0
        Creatinine, Day 189 Below
    4
    6
    3
    6
        Creatinine, Day 189 Within
    53
    54
    52
    91
        Creatinine, Day 189 Above
    8
    5
    13
    13
        Hematocrit, Day 0 Unknown
    0
    0
    0
    0
        Hematocrit, Day 0 Below
    6
    6
    9
    11
        Hematocrit, Day 0 Within
    60
    59
    59
    99
        Hematocrit, Day 0 Above
    0
    1
    0
    0
        Hematocrit, Day 21 Unknown
    0
    0
    0
    0
        Hematocrit, Day 21 Below
    6
    6
    6
    13
        Hematocrit, Day 21 Within
    59
    60
    61
    95
        Hematocrit, Day 21 Above
    1
    0
    1
    2
        Hematocrit, Day 42 Unknown
    0
    0
    0
    0
        Hematocrit, Day 42 Below
    9
    6
    7
    13
        Hematocrit, Day 42 Within
    57
    60
    61
    96
        Hematocrit, Day 42 Above
    0
    0
    0
    1
        Hematocrit, Day 182 Unknown
    0
    0
    0
    0
        Hematocrit, Day 182 Below
    10
    3
    6
    8
        Hematocrit, Day 182 Within
    55
    61
    62
    102
        Hematocrit, Day 182 Above
    0
    1
    0
    0
        Hematocrit, Day 189 Unknown
    0
    0
    0
    0
        Hematocrit, Day 189 Below
    8
    3
    4
    8
        Hematocrit, Day 189 Within
    57
    62
    64
    102
        Hematocrit, Day 189 Above
    0
    0
    0
    0
        Hemoglobin, Day 0 Unknown
    0
    0
    0
    0
        Hemoglobin, Day 0 Below
    10
    8
    8
    17
        Hemoglobin, Day 0 Within
    56
    57
    58
    92
        Hemoglobin, Day 0 Above
    0
    1
    2
    1
        Hemoglobin, Day 21 Unknown
    0
    0
    0
    0
        Hemoglobin, Day 21 Below
    11
    9
    7
    15
        Hemoglobin, Day 21 Within
    54
    56
    59
    93
        Hemoglobin, Day 21 Above
    1
    1
    2
    2
        Hemoglobin, Day 42 Unknown
    0
    0
    0
    0
        Hemoglobin, Day 42 Below
    14
    8
    9
    13
        Hemoglobin, Day 42 Within
    51
    57
    58
    97
        Hemoglobin, Day 42 Above
    1
    1
    1
    0
        Hemoglobin, Day 182 Unknown
    0
    0
    0
    0
        Hemoglobin, Day 182 Below
    10
    4
    6
    12
        Hemoglobin, Day 182 Within
    54
    60
    62
    98
        Hemoglobin, Day 182 Above
    1
    1
    0
    0
        Hemoglobin, Day 189 Unknown
    0
    0
    0
    0
        Hemoglobin, Day 189 Below
    9
    3
    4
    14
        Hemoglobin, Day 189 Within
    55
    61
    64
    96
        Hemoglobin, Day 189 Above
    1
    1
    0
    0
        Platelets, Day 0 Unknown
    0
    0
    0
    0
        Platelets, Day 0 Below
    0
    0
    0
    0
        Platelets, Day 0 Within
    24
    23
    24
    39
        Platelets, Day 0 Above
    0
    0
    0
    0
        Platelets, Day 21 Unknown
    0
    0
    0
    0
        Platelets, Day 21 Below
    1
    0
    0
    1
        Platelets, Day 21 Within
    23
    23
    24
    37
        Platelets, Day 21 Above
    0
    0
    0
    1
        Platelets, Day 42 Unknown
    0
    0
    0
    0
        Platelets, Day 42 Below
    0
    0
    0
    0
        Platelets, Day 42 Within
    24
    23
    24
    39
        Platelets, Day 42 Above
    0
    0
    0
    0
        Platelets, Day 182 Unknown
    0
    0
    0
    0
        Platelets, Day 182 Below
    1
    0
    0
    0
        Platelets, Day 182 Within
    22
    23
    24
    39
        Platelets, Day 182 Above
    1
    0
    0
    0
        Platelets, Day 189 Unknown
    0
    0
    0
    0
        Platelets, Day 189 Below
    0
    1
    0
    0
        Platelets, Day 189 Within
    23
    22
    24
    39
        Platelets, Day 189 Above
    1
    0
    0
    0
        BUN, Day 0 Unknown
    0
    0
    0
    0
        BUN, Day 0 Below
    3
    1
    3
    0
        BUN, Day 0 Within
    60
    62
    63
    106
        BUN, Day 0 Above
    1
    0
    0
    0
        BUN, Day 21 Unknown
    0
    0
    0
    0
        BUN, Day 21 Below
    1
    1
    0
    0
        BUN, Day 21 Within
    63
    62
    66
    106
        BUN, Day 21 Above
    0
    0
    0
    0
        BUN, Day 42 Unknown
    0
    0
    0
    0
        BUN, Day 42 Below
    0
    2
    1
    0
        BUN, Day 42 Within
    64
    60
    65
    105
        BUN, Day 42 Above
    0
    1
    0
    1
        BUN, Day 182 Unknown
    0
    0
    0
    0
        BUN, Day 182 Below
    0
    1
    2
    0
        BUN, Day 182 Within
    63
    61
    64
    106
        BUN, Day 182 Above
    0
    0
    0
    0
        BUN, Day 189 Unknown
    0
    0
    0
    0
        BUN, Day 189 Below
    1
    3
    2
    2
        BUN, Day 189 Within
    62
    59
    64
    104
        BUN, Day 189 Above
    0
    0
    0
    0
        WBCs, Day 0 Unknown
    0
    0
    0
    0
        WBCs, Day 0 Below
    0
    3
    0
    1
        WBCs, Day 0 Within
    64
    54
    62
    104
        WBCs, Day 0 Above
    2
    9
    6
    5
        WBCs, Day 21 Unknown
    0
    0
    0
    0
        WBCs, Day 21 Below
    3
    0
    1
    2
        WBCs, Day 21 Within
    56
    60
    60
    103
        WBCs, Day 21 Above
    7
    6
    7
    5
        WBCs, Day 42 Unknown
    0
    0
    0
    0
        WBCs, Day 42 Below
    1
    0
    0
    2
        WBCs, Day 42 Within
    63
    64
    64
    103
        WBCs, Day 42 Above
    2
    2
    4
    5
        WBCs, Day 182 Unknown
    0
    0
    0
    0
        WBCs, Day 182 Below
    1
    1
    2
    0
        WBCs, Day 182 Within
    62
    60
    64
    106
        WBCs, Day 182 Above
    2
    4
    2
    4
        WBCs, Day 189 Unknown
    0
    0
    0
    0
        WBCs, Day 189 Below
    0
    2
    1
    1
        WBCs, Day 189 Within
    62
    60
    61
    105
        WBCs, Day 189 Above
    3
    3
    6
    4
    Notes
    [6] - 1 subject moved out of the study area thereby withdrawing from the study at Days 182 and 189.
    [7] - 1 subject moved out of the study area thereby withdrawing from the study at Days 182 and 189.
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any unsolicited AEs

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    End point title
    		 Number of subjects reporting any unsolicited AEs
    End point description
    Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as any symptom regardless of intensity or relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 42-day (Days 0-41) follow up period after first vaccination.
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    66
    68
    110
    Units: Subjects
        Any AEs
    13
    19
    22
    39
    No statistical analyses for this end point

    Secondary: Number of subjects reporting any unsolicited AEs

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    End point title
    		 Number of subjects reporting any unsolicited AEs
    End point description
    Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as any symptom regardless of intensity or relationship to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 21-day (Days 0-20) follow-up period after booster vaccination.
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    65 [8]
    65 [9]
    68
    110
    Units: Subjects
        Any AEs
    4
    7
    3
    6
    Notes
    [8] - 1 subject moved out of the study area thereby withdrawing from the study.
    [9] - 1 subject moved out of the study area thereby withdrawing from the study.
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects Reporting Serious Adverse Events (SAEs)
    End point description
    SAEs: medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 0 to Day 364)
    End point values
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Number of subjects analysed
    66
    66
    68
    110
    Units: Number
        Any SAE(s)
    2
    2
    1
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were assessed throughout the study period (Days 0-364). Systematically frequent AEs were assessed 7 days after each vaccination and non-systematically frequent AEs were assessed 42 days after first vaccination and 21 days after booster vaccination.
    Adverse event reporting additional description
    1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    ​14.0
    Reporting groups
    Reporting group title
    Flu1-F1-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix formulation 1 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Reporting group title
    Flu1-F2-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Reporting group title
    Flu1-F2-3D Group
    Reporting group description
    		 Subjects received 3 doses of Arepanrix formulation 2 adjuvanted vaccine on Day 0, Day 21 and Day 182 (booster).

    Reporting group title
    Flu2-2D Group
    Reporting group description
    		 Subjects received 2 doses of Arepanrix unadjuvanted vaccine on Day 0 and Day 182 (booster) and one dose of saline placebo on Day 21.

    Serious adverse events
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 66 (3.03%)
    2 / 66 (3.03%)
    1 / 68 (1.47%)
    5 / 110 (4.55%)
         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
    Alcohol poisoning
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 68 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 68 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 68 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    0 / 68 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 66 (0.00%)
    0 / 68 (0.00%)
    0 / 110 (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
    Renal and urinary disorders
    Facial bones fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 66 (1.52%)
    0 / 68 (0.00%)
    0 / 110 (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
    Cystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 66 (1.52%)
    0 / 66 (0.00%)
    0 / 68 (0.00%)
    0 / 110 (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
    Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 66 (0.00%)
    1 / 66 (1.52%)
    0 / 68 (0.00%)
    0 / 110 (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
    Appendicitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 66 (0.00%)
    0 / 66 (0.00%)
    1 / 68 (1.47%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         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
    		 Flu1-F1-2D Group Flu1-F2-2D Group Flu1-F2-3D Group Flu2-2D Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 66 (90.91%)
    59 / 66 (89.39%)
    67 / 68 (98.53%)
    94 / 110 (85.45%)
    General disorders and administration site conditions
    Pain (Primary phase)
    Additional description: AE reported during the primary phase of the study
         subjects affected / exposed
    52 / 66 (78.79%)
    48 / 66 (72.73%)
    61 / 68 (89.71%)
    51 / 110 (46.36%)
         occurrences all number
    52
    48
    61
    51
    Swelling (Primary phase)
    Additional description: AE reported during the Primary phase of the study
         subjects affected / exposed
    6 / 66 (9.09%)
    5 / 66 (7.58%)
    6 / 68 (8.82%)
    1 / 110 (0.91%)
         occurrences all number
    6
    5
    6
    1
    Redness
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
         subjects affected / exposed [1]
    4 / 65 (6.15%)
    1 / 65 (1.54%)
    1 / 68 (1.47%)
    0 / 110 (0.00%)
         occurrences all number
    4
    1
    1
    0
    Arthralgia (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE reported during the Booster phase of the study.
         subjects affected / exposed [2]
    13 / 65 (20.00%)
    8 / 65 (12.31%)
    12 / 68 (17.65%)
    8 / 110 (7.27%)
         occurrences all number
    13
    8
    12
    8
    Fatigue (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE reported during the Booster phase of the study.
         subjects affected / exposed [3]
    29 / 65 (44.62%)
    20 / 65 (30.77%)
    28 / 68 (41.18%)
    36 / 110 (32.73%)
         occurrences all number
    29
    20
    28
    36
    Headache (Primary phase)
    Additional description: AE reported during the Primary phase of the study.
         subjects affected / exposed
    27 / 66 (40.91%)
    21 / 66 (31.82%)
    39 / 68 (57.35%)
    45 / 110 (40.91%)
         occurrences all number
    27
    21
    39
    45
    Myalgia (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE reported during the Booster phase of the study.
         subjects affected / exposed [4]
    19 / 65 (29.23%)
    16 / 65 (24.62%)
    17 / 68 (25.00%)
    20 / 110 (18.18%)
         occurrences all number
    19
    16
    17
    20
    Shivering (Primary phase)
    Additional description: AE reported during the Primary phase of the study.
         subjects affected / exposed
    6 / 66 (9.09%)
    5 / 66 (7.58%)
    8 / 68 (11.76%)
    16 / 110 (14.55%)
         occurrences all number
    6
    5
    8
    16
    Sweating (Primary phase)
    Additional description: AE was reported during the Primary phase of the study.
         subjects affected / exposed
    6 / 66 (9.09%)
    8 / 66 (12.12%)
    11 / 68 (16.18%)
    15 / 110 (13.64%)
         occurrences all number
    6
    8
    11
    15
    Pain (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE reported during the Booster phase of the study
         subjects affected / exposed [5]
    48 / 65 (73.85%)
    40 / 65 (61.54%)
    54 / 68 (79.41%)
    49 / 110 (44.55%)
         occurrences all number
    48
    40
    54
    49
    Swelling (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE reported during the Booster phase of the study.
         subjects affected / exposed [6]
    6 / 65 (9.23%)
    5 / 65 (7.69%)
    3 / 68 (4.41%)
    0 / 110 (0.00%)
         occurrences all number
    6
    5
    3
    0
    Arthralgia (Primary phase)
    Additional description: AE reported during the Primary phase of the study.
         subjects affected / exposed
    5 / 66 (7.58%)
    7 / 66 (10.61%)
    6 / 68 (8.82%)
    13 / 110 (11.82%)
         occurrences all number
    5
    7
    6
    13
    Fatigue (Primary phase)
    Additional description: AE was reported during the Primary phase of the study.
         subjects affected / exposed
    26 / 66 (39.39%)
    19 / 66 (28.79%)
    24 / 68 (35.29%)
    36 / 110 (32.73%)
         occurrences all number
    26
    19
    24
    36
    Headache (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE reported during the Booster phase of the study.
         subjects affected / exposed [7]
    24 / 65 (36.92%)
    23 / 65 (35.38%)
    32 / 68 (47.06%)
    25 / 110 (22.73%)
         occurrences all number
    24
    23
    32
    25
    Myalgia (Primary phase)
    Additional description: AE reported during the Primary phase of the study.
         subjects affected / exposed
    17 / 66 (25.76%)
    20 / 66 (30.30%)
    28 / 68 (41.18%)
    21 / 110 (19.09%)
         occurrences all number
    17
    20
    28
    21
    Shivering (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE reported during the Booster phase of the study.
         subjects affected / exposed [8]
    9 / 65 (13.85%)
    13 / 65 (20.00%)
    15 / 68 (22.06%)
    9 / 110 (8.18%)
         occurrences all number
    9
    13
    15
    9
    Sweating (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE was reported during the Booster phase of the study.
         subjects affected / exposed [9]
    5 / 65 (7.69%)
    3 / 65 (4.62%)
    4 / 68 (5.88%)
    9 / 110 (8.18%)
         occurrences all number
    5
    3
    4
    9
    Gastrointestinal disorders
    Gastrointestinal (Primary phase)
    Additional description: AE reported during the Primary phase of the study.
         subjects affected / exposed
    5 / 66 (7.58%)
    3 / 66 (4.55%)
    9 / 68 (13.24%)
    8 / 110 (7.27%)
         occurrences all number
    5
    3
    9
    8
    Gastrointestinal (Booster phase)
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively. AE was reported during the Booster phase of the study.
         subjects affected / exposed [10]
    4 / 65 (6.15%)
    2 / 65 (3.08%)
    8 / 68 (11.76%)
    5 / 110 (4.55%)
         occurrences all number
    4
    2
    8
    5
    Infections and infestations
    Fever
    Additional description: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
         subjects affected / exposed [11]
    11 / 65 (16.92%)
    5 / 65 (7.69%)
    7 / 68 (10.29%)
    2 / 110 (1.82%)
         occurrences all number
    11
    5
    7
    2
    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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.
    [11] - 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: 1 subject moved out of the study area thereby withdrawing from the study in Flu1-F1-2D Group and Flu1-F2-2D Group, respectively.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2009
    The protocol was amended for the following reasons: •On the basis of early concordant data from several manufacturers and the United States National Institutes of Health (NIH), it appears that a single 15g dose of unadjuvanted 2009 pandemic H1N1 influenza vaccine is well-tolerated and induces a robust immune response in healthy adults between the ages of three and 64 years. The dose groups were amended in response to these reports and a preliminary finding in children from 6 months to < 36 months of age demonstrating the potency of half-volume vaccine (1.9g HA adjuvanted with AS03B) following a single dose of vaccine: 98% seroconversion rate in children 6 months to < 36 months of age following a single dose of half-volume vaccine. •The age range of eligible subjects was changed to align with European Medicines Agency (EMEA) guideline for pandemic H1N1 vaccine. •Passive surveillance for influenza-like illness (ILI) was added to the study objectives in response to a request from EMEA. Nose and throat swab specimens were collected from subjects with any ILI in order to describe the occurrence of laboratory-confirmed H1N1 cases from the first dose (Day 0) through Day 182 and to genetically sequence viruses causing illness in case of non-study evidence for genetic drift. •Persistence of immune responses were evaluated on Day 182 to assess possible advantages to use of the full adult dose (Group A) or longer term advantages to two primary doses (Group C). Booster vaccination on Day 182 allowed an assessment of the effectiveness of primary vaccination(s) based on the presence or absence of anamnestic immune responses on Day 189. •The design incorporated four groups instead of five groups and the sample size decreased from 300 to 280 subjects. Randomization ratio changed from 1:1:1:1:2 to 3:3:3:5.

    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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