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    Clinical Trial Results:
    A Randomized, Open Label, Single Center, Dose- and Regimen-Ranging Study to Evaluate Immunogenicity, Safety and Tolerability of Different Formulations of an Adjuvanted and Non-Adjuvanted Egg-Derived, Inactivated Novel Swine Origin A/H1N1 Monovalent Subunit Influenza Virus Vaccine in Healthy Children and Adults Ages 3 to 64 Years

    Summary
    EudraCT number
    		 2014-005185-30
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Oct 2010

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Jul 2016
    First version publication date
    30 Apr 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Required for the re-QC project because of the EudraCT system glitch and possible updates to results may be required. Moreover, a change in system user for this study is necessary.

    Trial information

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    Trial identification
    Sponsor protocol code
    V112_04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00973700
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics
    Sponsor organisation address
    350 Massachusetts Ave, Cambridge, MA, United States, 02139
    Public contact
    Posting Director, Novartis Vaccines and Diagnostics S.r.l., RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines and Diagnostics S.r.l., RegistryContactVaccinesUS@novartis.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
    08 Mar 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate vaccine 15mcg a/H1N1 S-OIV unadjuvanted hemagglutination inhibition (HI) assay results in the adult and pooled pediatric populations according to immunogenicity criteria defined by CBER recommendations.
    Protection of trial subjects
    This clinical study was designed, implemented, and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Aug 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Regulatory reason
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Costa Rica: 784
    Worldwide total number of subjects
    784
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    257
    Adolescents (12-17 years)
    135
    Adults (18-64 years)
    392
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at one center in Costa Rica.

    Pre-assignment
    Screening details
    		 All enrolled subjects were included in the trial.

    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
    		 2x7.5adj
    Arm description
    		 A/H1N1 7.5 mcg with MF59; two doses on day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Monovalent H1N1 influenza virus vaccine with MF59 adjuvant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Each dose of 0.5 mL was administered in each arm.

    Arm title
    		 7.5adj_1_8
    Arm description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 8
    Arm type
    		 Experimental

    Investigational medicinal product name
    Monovalent H1N1 influenza virus vaccine with MF59 adjuvant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL / dose

    Arm title
    		 7.5adj_1_22
    Arm description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 22
    Arm type
    		 Experimental

    Investigational medicinal product name
    Monovalent H1N1 influenza virus vaccine with MF59 adjuvant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL / dose

    Arm title
    		 15_1_22
    Arm description
    		 A/H1N1 15 mcg no MF59; one dose on days 1 and 22
    Arm type
    		 Experimental

    Investigational medicinal product name
    Monovalent H1N1 influenza virus vaccine without MF59 adjuvant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL / dose

    Arm title
    		 2x15_1_22
    Arm description
    		 A/H1N1 15 mcg no MF59; two doses on days 1 and 22
    Arm type
    		 Experimental

    Investigational medicinal product name
    Monovalent H1N1 influenza virus vaccine without MF59 adjuvant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Each dose of 0.25 mL was administered in each arm.

    Number of subjects in period 1
    		2x7.5adj 7.5adj_1_8 7.5adj_1_22 15_1_22 2x15_1_22
    Started
    56
    56
    168
    336
    168
    Completed
    49
    54
    158
    318
    158
    Not completed
    7
    2
    10
    18
    10
         Consent withdrawn by subject
    2
    2
    8
    4
    4
         Inappropriate enrollment
    -
    -
    -
    4
    -
         Unable to classify
    -
    -
    1
    2
    1
         Lost to follow-up
    5
    -
    1
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2x7.5adj
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; two doses on day 1

    Reporting group title
    7.5adj_1_8
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 8

    Reporting group title
    7.5adj_1_22
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 22

    Reporting group title
    15_1_22
    Reporting group description
    		 A/H1N1 15 mcg no MF59; one dose on days 1 and 22

    Reporting group title
    2x15_1_22
    Reporting group description
    		 A/H1N1 15 mcg no MF59; two doses on days 1 and 22

    Reporting group values
    		 2x7.5adj 7.5adj_1_8 7.5adj_1_22 15_1_22 2x15_1_22 Total
    Number of subjects
    		 56 56 168 336 168 784
    Age categorical
    Units: Subjects
        3 to <9 years
    		 0 0 56 84 56 196
        9 to 17 years
    		 0 0 56 84 56 196
        18 to 64 years
    		 56 56 56 168 56 392
    Gender categorical
    Units: Subjects
        Female (3 to <9 years)
    		 0 0 29 46 23 98
        Male (3 to <9 years)
    		 0 0 27 38 33 98
        Female (9 to 17 years)
    		 0 0 40 40 30 110
        Male (9 to 17 years)
    		 0 0 16 44 26 86
        Female (18 to 64 years)
    		 33 40 29 96 29 227
        Male (18 to 64 years)
    		 23 16 27 72 27 165

    End points

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    End points reporting groups
    Reporting group title
    2x7.5adj
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; two doses on day 1

    Reporting group title
    7.5adj_1_8
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 8

    Reporting group title
    7.5adj_1_22
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 22

    Reporting group title
    15_1_22
    Reporting group description
    		 A/H1N1 15 mcg no MF59; one dose on days 1 and 22

    Reporting group title
    2x15_1_22
    Reporting group description
    		 A/H1N1 15 mcg no MF59; two doses on days 1 and 22

    Subject analysis set title
    Per protocol set (3 to <9 years)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects included in the full analysis set (FAS), who received all the relevant doses of vaccine correctly, provided evaluable serum samples at relevant time points and had no major protocol violations as pre-specified in analysis plan prior to unblinding.

    Subject analysis set title
    As Enrolled set (3 to <9 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects (3 to <9 years) enrolled in this study.

    Subject analysis set title
    Per protocol set (9 to 17 years)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects included in the FAS, who received all the relevant doses of vaccine correctly, provided evaluable serum samples at relevant time points and had no major protocol violations as pre-specified in analysis plan prior to unblinding.

    Subject analysis set title
    As Enrolled set (9 to 17 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects (9 to 17 years) enrolled in this study.

    Subject analysis set title
    Safety set (3 to <9 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who actually received a study vaccination and provided post-baseline safety data.

    Subject analysis set title
    Per protocol set (18 to 64 years)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects included in the FAS, who received all the relevant doses of vaccine correctly, provided evaluable serum samples at relevant time points and had no major protocol violations as pre-specified in analysis plan prior to unblinding.

    Subject analysis set title
    Safety set (18 to 64 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who actually received a study vaccination and provided post-baseline safety data

    Subject analysis set title
    Safety set (9 to 17 years)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who actually received a study vaccination and provided post-baseline safety data.

    Subject analysis set title
    As Enrolled set (18 to 64 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects (18 to 64 years) enrolled in this study.

    Primary: 1. Percentage of Subjects With Seroconversion and HI Titer ≥1:40 in Children 3 to 17 Years of Age.

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    End point title
    		 1. Percentage of Subjects With Seroconversion and HI Titer ≥1:40 in Children 3 to 17 Years of Age. [1] [2]
    End point description
    Seroconversion: The percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer >1:40 or a prevaccination HI titer >1:10 and a minimum four-fold rise in post-vaccination HI antibody titer. The analyses were performed on the Per-Protocol Set (PPS).
    End point type
    Primary
    End point timeframe
    Day 1 to day 387
    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: No statistical analyses for this end point
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point
    End point values
    		 15_1_22
    Number of subjects analysed
    149
    Units: Percentages of subjects
    number (confidence interval 95%)
        HI Titer ≥40 on day 1
    26 (19 to 33)
        HI Titer ≥40 on day 22
    83 (76 to 89)
        HI Titer ≥40 on day 29
    95 (91 to 98)
        HI Titer ≥40 on day 43
    92 (86 to 96)
        HI Titer ≥40 on day 217 (N=129)
    88 (81 to 93)
        HI Titer ≥40 on day 387 (N=136)
    80 (72 to 86)
        Seroconversion on day 22
    79 (71 to 85)
        Seroconversion on day 29
    92 (86 to 96)
        Seroconversion on day 43
    87 (81 to 92)
        Seroconversion on day 217 (N=129)
    71 (62 to 78)
        Seroconversion on day 387 (N=136)
    63 (54 to 71)
    No statistical analyses for this end point

    Primary: 2. Percentage of Subjects With Seroconversion and HI Titer ≥1:40 in Adults 18 to 64 Years of Age.

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    End point title
    		 2. Percentage of Subjects With Seroconversion and HI Titer ≥1:40 in Adults 18 to 64 Years of Age. [3] [4]
    End point description
    Seroconversion: The percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer >1:40 or a prevaccination HI titer >1:10 and a minimum four-fold rise in post-vaccination HI antibody titer. The analyses were performed on the Per-Protocol Set (PPS).
    End point type
    Primary
    End point timeframe
    Day 1 to day 387
    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: No statistical analyses for this end point
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point
    End point values
    		 15_1_22
    Number of subjects analysed
    132
    Units: Percentages of subjects
    number (confidence interval 95%)
        HI Titer ≥40 on day 1
    18 (12 to 26)
        HI Titer ≥40 on day 8
    93 (87 to 97)
        HI Titer ≥40 on day 15
    99 (96 to 100)
        HI Titer ≥40 on day 22
    98 (95 to 100)
        HI Titer ≥40 on day 29
    99 (96 to 100)
        HI Titer ≥40 on day 43
    100 (97 to 100)
        HI Titer ≥40 on day 217 (N=111)
    91 (84 to 96)
        HI Titer ≥40 on day 387 (N=120)
    84 (76 to 90)
        Seroconversion on day 8
    86 (78 to 91)
        Seroconversion on day 15
    94 (88 to 97)
        Seroconversion on day 22
    94 (88 to 97)
        Seroconversion on day 29
    95 (90 to 98)
        Seroconversion on day 43
    95 (90 to 98)
        Seroconversion on day 217 (N=111)
    81 (73 to 88)
        Seroconversion on day 387 (N=120)
    75 (66 to 82)
    No statistical analyses for this end point

    Secondary: 3. Percentage of Subjects With Seroconversion and HI Titer ≥1:40, in 3 to <9 Years and 9 to 17 Years.

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    End point title
    		 3. Percentage of Subjects With Seroconversion and HI Titer ≥1:40, in 3 to <9 Years and 9 to 17 Years. [5]
    End point description
    Seroconversion: The percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer >1:40 or a prevaccination HI titer >1:10 and a minimum four-fold rise in post-vaccination HI antibody titer. The analyses were performed on the PPS.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 387
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point
    End point values
    		 7.5adj_1_22 15_1_22 2x15_1_22
    Number of subjects analysed
    46
    75
    47
    Units: Percentages of subjects
    number (confidence interval 95%)
        HI Titer ≥40 on day 1 (3 to <9 yrs)
    24 (13 to 39)
    23 (14 to 34)
    23 (12 to 38)
        HI Titer ≥40 on day 22 (3 to <9 yrs)
    93 (82 to 99)
    71 (59 to 81)
    79 (64 to 89)
        HI Titer ≥40 on day 29 (3 to <9 yrs)
    100 (92 to 100)
    92 (83 to 97)
    96 (85 to 99)
        HI Titer ≥40 on day 43 (3 to <9 yrs)
    100 (92 to 100)
    85 (75 to 92)
    96 (85 to 99)
        HI Titer ≥40 on day 217 (3 to <9 yrs; N=41,66,40)
    100 (91 to 100)
    80 (69 to 89)
    78 (62 to 89)
        HI Titer ≥40 on day 387 (3 to <9 yrs; N=43,70,42)
    93 (81 to 99)
    73 (61 to 83)
    62 (46 to 76)
        Seroconversion on day 22 (3 to <9 yrs)
    91 (79 to 98)
    69 (58 to 79)
    79 (64 to 89)
        Seroconversion on day 29 (3 to <9 yrs)
    98 (88 to 100)
    92 (83 to 97)
    96 (85 to 99)
        Seroconversion on day 43 (3 to <9 yrs)
    96 (85 to 99)
    84 (74 to 91)
    94 (82 to 99)
        Seroconversion on day 217 (3 to <9 yrs;N=41,66,40)
    88 (74 to 96)
    65 (52 to 76)
    65 (48 to 79)
        Seroconversion on day 387 (3 to <9 yrs;N=43,70,42
    77 (61 to 88)
    56 (43 to 68)
    50 (34 to 66)
        HI Titer ≥40 on day 1 (9 to 17 yrs; N=45,74,52)
    42 (28 to 58)
    28 (19 to 40)
    33 (20 to 47)
        HI Titer ≥40 on day 22 (9 to 17 yrs; N=45,74,52)
    98 (88 to 100)
    96 (89 to 99)
    100 (93 to 100)
        HI Titer ≥40 on day 29 (9 to 17 yrs; N=45,74,52)
    100 (92 to 100)
    99 (93 to 100)
    100 (93 to 100)
        HI Titer ≥40 on day 43 (9 to 17 yrs; N=45,74,52)
    100 (92 to 100)
    99 (93 to 100)
    100 (93 to 100)
        HI Titer ≥40 on day 217 (9 to 17 yrs; N=37,63,45)
    100 (91 to 100)
    95 (87 to 99)
    98 (88 to 100)
        HI Titer ≥40 on day 387 (9 to 17 yrs; N=37,66,47)
    89 (75 to 97)
    88 (78 to 95)
    89 (77 to 96)
        Seroconversion on day 22 (9 to 17 yrs; N=45,74,52)
    87 (73 to 95)
    88 (78 to 94)
    94 (84 to 99)
        Seroconversion on day 29 (9 to 17 yrs; N=45,74,52)
    89 (76 to 96)
    92 (83 to 97)
    94 (84 to 99)
        Seroconversion on day 43 (9 to 17 yrs; N=45,74,52)
    84 (71 to 94)
    98 (89 to 100)
    92 (81 to 98)
        Seroconversion on day 217 (9 to 17 yrs;N=37,63,45)
    68 (50 to 82)
    76 (64 to 86)
    76 (60 to 87)
        Seroconversion on day 387 (9 to 17 yrs;N=37,66,47)
    59 (42 to 75)
    70 (57 to 80)
    70 (55 to 83)
    No statistical analyses for this end point

    Secondary: 4. HI GMRs, in 3 to <9 Years and 9 to 17 Years.

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    End point title
    		 4. HI GMRs, in 3 to <9 Years and 9 to 17 Years. [6]
    End point description
    Geometric Mean Ratios (GMRs) of HI antibody assay (ratio of post-vaccination versus pre-vaccination HI titers). The analyses were performed on the PPS.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 387
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point
    End point values
    		 7.5adj_1_22 15_1_22 2x15_1_22
    Number of subjects analysed
    46
    75
    47
    Units: Ratio
    geometric mean (confidence interval 95%)
        GMR on day 22 (3 to <9 yrs)
    31 (19 to 50)
    12 (8.51 to 18)
    16 (10 to 26)
        GMR on day 29 (3 to <9 yrs)
    169 (110 to 260)
    35 (25 to 49)
    53 (35 to 82)
        GMR on day 43 (3 to <9 yrs)
    120 (75 to 192)
    22 (15 to 32)
    44 (27 to 69)
        GMR on day 217 (3 to <9 yrs; N=41,66,40)
    19 (12 to 30)
    7.79 (5.46 to 11)
    8.07 (5.11 to 13)
        GMR on day 387 (3 to <9 yrs; N=43,70,42)
    14 (8.27 to 24)
    6.9 (4.58 to 10)
    5.94 (3.5 to 10)
        GMR on day 22 (9 to 17 yrs; N=45,74,52)
    42 (24 to 74)
    52 (34 to 81)
    66 (39 to 111)
        GMR on day 29 (9 to 17 yrs; N=45,74,52)
    63 (36 to 109)
    70 (45 to 108)
    79 (47 to 132)
        GMR on day 43 (9 to 17 yrs; N=45,74,52)
    44 (25 to 77)
    48 (31 to 75)
    59 (35 to 100)
        GMR on day 217 (9 to 17 yrs; N=37,63,45)
    10 (5.66 to 18)
    17 (11 to 26)
    13 (7.92 to 23)
        GMR on day 387 (9 to 17 yrs; N=37,66,47)
    7.22 (3.77 to 14)
    16 (9.53 to 25)
    13 (7.53 to 24)
    No statistical analyses for this end point

    Secondary: 5. HI GMRs, in adults 18 to 64 Years.

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    End point title
    		 5. HI GMRs, in adults 18 to 64 Years.
    End point description
    Geometric Mean Ratios (GMRs) of HI antibody assay (ratio of post-vaccination versus pre-vaccination HI titers). The analyses were performed on the PPS.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 387
    End point values
    		 2x7.5adj 7.5adj_1_8 7.5adj_1_22 15_1_22 2x15_1_22
    Number of subjects analysed
    41
    45
    45
    132
    47
    Units: Ratio
    geometric mean (confidence interval 95%)
        GMR on day 8
    48 (28 to 85)
    35 (21 to 60)
    57 (33 to 97)
    43 (32 to 59)
    63 (37 to 106)
        GMR on day 15
    115 (70 to 189)
    181 (113 to 292)
    200 (124 to 322)
    138 (104 to 182)
    123 (77 to 197)
        GMR on day 22
    79 (48 to 130)
    100 (63 to 160)
    123 (77 to 197)
    85 (64 to 111)
    72 (45 to 113)
        GMR on day 29
    56 (35 to 89)
    76 (49 to 118)
    160 (103 to 248)
    83 (64 to 107)
    66 (43 to 101)
        GMR on day 43
    44 (27 to 71)
    64 (40 to 101)
    101 (63 to 161)
    76 (58 to 100)
    65 (41 to 102)
        GMR on day 217 (N=0,0,35,111,34)
    0 (0 to 0)
    0 (0 to 0)
    30 (18 to 48)
    16 (12 to 20)
    16 (10 to 27)
        GMR on day 387 (N=38,40,38,120,42)
    6.61 (3.92 to 11)
    11 (6.81 to 19)
    21 (12 to 36)
    12 (8.99 to 16)
    9.21 (5.61 to 15)
    No statistical analyses for this end point

    Secondary: 6. Percentage of Subjects With Seroconversion and HI Titer ≥1:40, in Adults 18 to 64 Years.

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    End point title
    		 6. Percentage of Subjects With Seroconversion and HI Titer ≥1:40, in Adults 18 to 64 Years.
    End point description
    Seroconversion: The percentage of subjects with either a pre-vaccination HI titer < 1:10 and a post-vaccination HI titer >1:40 or a prevaccination HI titer >1:10 and a minimum four-fold rise in post-vaccination HI antibody titer. The analyses were performed on the PPS.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 387
    End point values
    		 2x7.5adj 7.5adj_1_8 7.5adj_1_22 15_1_22 2x15_1_22
    Number of subjects analysed
    41
    45
    45
    132
    47
    Units: Percentages of subjects
    number (confidence interval 95%)
        HI Titer ≥40 on day 1
    20 (9 to 35)
    22 (11 to 37)
    13 (5 to 27)
    18 (12 to 26)
    21 (11 to 36)
        HI Titer ≥40 on day 8
    100 (91 to 100)
    91 (79 to 98)
    96 (85 to 99)
    93 (87 to 97)
    96 (85 to 99)
        HI Titer ≥40 on day 15
    100 (91 to 100)
    100 (92 to 100)
    98 (88 to 100)
    99 (96 to 100)
    100 (92 to 100)
        HI Titer ≥40 on day 22
    100 (91 to 100)
    98 (88 to 100)
    98 (88 to 100)
    98 (95 to 100)
    98 (89 to 100)
        HI Titer ≥40 on day 29
    100 (91 to 100)
    98 (88 to 100)
    100 (92 to 100)
    99 (96 to 100)
    100 (92 to 100)
        HI Titer ≥40 on day 43
    98 (87 to 100)
    100 (92 to 100)
    98 (88 to 100)
    100 (97 to 100)
    100 (92 to 100)
        HI Titer ≥40 on day 217 (N=0,0,35,111,34)
    0 (0 to 0)
    0 (0 to 0)
    97 (85 to 100)
    91 (84 to 96)
    97 (85 to 100)
        HI Titer ≥40 on day 387 (N=38,40,38,120,42)
    76 (60 to 89)
    90 (76 to 97)
    92 (79 to 98)
    84 (76 to 90)
    83 (69 to 93)
        Seroconversion on day 8
    95 (83 to 99)
    80 (65 to 90)
    93 (82 to 99)
    86 (78 to 91)
    94 (82 to 99)
        Seroconversion on day 15
    98 (87 to 100)
    100 (92 to 100)
    98 (88 to 100)
    94 (88 to 97)
    98 (89 to 100)
        Seroconversion on day 22
    95 (83 to 99)
    91 (79 to 98)
    96 (85 to 99)
    94 (88 to 97)
    96 (85 to 99)
        Seroconversion on day 29
    95 (83 to 99)
    93 (82 to 99)
    98 (88 to 100)
    95 (90 to 98)
    98 (89 to 100)
        Seroconversion on day 43
    85 (71 to 94)
    93 (82 to 99)
    96 (85 to 99)
    95 (90 to 98)
    98 (89 to 100)
        Seroconversion on day 217 (N=0,0,35,111,34)
    0 (0 to 0)
    0 (0 to 0)
    94 (81 to 99)
    81 (73 to 88)
    88 (73 to 97)
        Seroconversion on day 387 (N=38,40,38,120,42)
    66 (49 to 80)
    80 (64 to 91)
    87 (72 to 96)
    75 (66 to 82)
    69 (53 to 82)
    No statistical analyses for this end point

    Secondary: 7. Number of Subjects With at Least One Reactogenicity Sign, in 3 to <9 Years of Age.

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    End point title
    		 7. Number of Subjects With at Least One Reactogenicity Sign, in 3 to <9 Years of Age. [7]
    End point description
    Number of subjects with specified solicited local and systemic reactions in adult subjects (3 to <9 years of age). Postvac: postvaccination Analges: analgesics Antipyr: antipyretics The analyses were performed on the safety set. Note: 1) postvac 1 = after the first vaccination and 2) postvac 2 = after the second vaccination
    End point type
    Secondary
    End point timeframe
    7 days after each vaccination
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point
    End point values
    		 7.5adj_1_22 15_1_22 2x15_1_22
    Number of subjects analysed
    55
    84
    54
    Units: Number of subjects
        Local Reactions postvac. 1
    25
    31
    20
        Erythema postvac. 1
    1
    0
    0
        Induration postvac. 1
    0
    3
    1
        Swelling postvac. 1
    3
    4
    3
        Tenderness postvac. 1
    21
    23
    17
        Pain postvac. 1
    21
    25
    17
        Systemic Reaction postvac. 1
    24
    28
    17
        Headache postvac. 1
    7
    12
    9
        Fatigue postvac. 1
    6
    8
    5
        Myalgia postvac. 1
    4
    8
    6
        Arthralgia postvac. 1
    0
    2
    2
        Chills postvac. 1
    3
    1
    2
        Nausea postvac. 1
    5
    7
    4
        Vomiting postvac. 1
    0
    1
    2
        Diarrhea postvac. 1
    0
    0
    1
        Other Reactions postvac. 1
    10
    10
    6
        Analges/Antipyr Used postvac. 1 (N=55,83,54)
    9
    8
    6
        Stayed Home postvac. 1 (N=55,83,54)
    1
    2
    0
        Body Temp > 40 C postvac. 1
    0
    0
    0
        Local Reactions postvac. 2 (N=55,83,54)
    20
    29
    21
        Erythema postvac. 2 (N=55,83,54)
    3
    1
    1
        Induration postvac. 2 (N=55,83,54)
    8
    1
    2
        Swelling postvac. 2 (N=55,83,54)
    8
    0
    2
        Tenderness postvac. 2 (N=55, 83, 54)
    15
    27
    16
        Pain postvac. 2 (N=55,83,54)
    18
    23
    19
        Systemic Reaction postvac. 2 (N=55,83,54)
    13
    22
    18
        Headache postvac. 2 (N=55,83,54)
    5
    12
    3
        Fatigue postvac. 2 (N=55,83,54)
    1
    5
    2
        Myalgia postvac. 2 (N=55,83,54)
    3
    2
    5
        Arthralgia postvac. 2 (N=55,83,54)
    0
    2
    5
        Chills postvac. 2 (N=55,83,54)
    2
    2
    1
        Nausea postvac. 2 (N=55,83,54)
    5
    5
    1
        Vomiting postvac. 2 (N=55,83,54)
    0
    1
    3
        Diarrhea postvac. 2 (N=55,83,54)
    0
    1
    2
        Other Reactions postvac. 2 (N=55,83,54)
    5
    7
    7
        Analges/Antipyr Used postvac. 2 (N=55,83,54)
    4
    6
    7
        Stayed Home postvac. 2 (N=55,82,54)
    1
    2
    0
        Body Temp > 40 C postvac. 2 (N=55,83,54)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: 8. Number of Subjects With at Least One Reactogenicity Sign, in 9 to 17 Years of Age.

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    End point title
    		 8. Number of Subjects With at Least One Reactogenicity Sign, in 9 to 17 Years of Age. [8]
    End point description
    Number of subjects with specified solicited local and systemic reactions in adult subjects (9 to 17 years of age). Postvac: postvaccination Analges: analgesics Antipyr: antipyretics The analyses were performed on the safety set. Note: 1) postvac 1 = after the first vaccination and 2) postvac 2 = after the second vaccination.
    End point type
    Secondary
    End point timeframe
    7 days after each vaccination
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point
    End point values
    		 7.5adj_1_22 15_1_22 2x15_1_22
    Number of subjects analysed
    53
    84
    57
    Units: Number of subjects
        Local Reactions postvac. 1
    37
    36
    29
        Erythema postvac. 1
    1
    1
    0
        Induration postvac. 1
    1
    6
    1
        Swelling postvac. 1
    1
    4
    3
        Tenderness postvac. 1
    26
    23
    21
        Pain postvac. 1
    32
    30
    25
        Systemic Reaction postvac. 1
    24
    36
    16
        Headache postvac. 1
    17
    20
    8
        Fatigue postvac. 1
    9
    13
    11
        Myalgia postvac. 1
    11
    15
    11
        Arthralgia postvac. 1
    2
    2
    0
        Chills postvac. 1
    1
    2
    1
        Nausea postvac. 1
    3
    7
    5
        Vomiting postvac. 1
    0
    1
    0
        Diarrhea postvac. 1
    2
    0
    0
        Other Reactions postvac. 1
    11
    10
    8
        Analges/Antipyr Used postvac. 1
    10
    10
    7
        Stayed Home postvac. 1
    2
    1
    2
        Body Temp > 40 C postvac. 1
    0
    0
    0
        Local Reactions postvac. 2 (N=52,84,55)
    31
    36
    27
        Erythema postvac. 2 (N=52,84,55)
    0
    3
    1
        Induration postvac. 2 (N=52,84,55)
    2
    3
    4
        Swelling postvac. 2 (N=52,84,55)
    2
    5
    3
        Tenderness postvac. 2 (N=52,84, 55)
    20
    25
    25
        Pain postvac. 2 (N=52,84,55)
    27
    30
    26
        Systemic Reaction postvac. 2 (N=52,84,55)
    18
    29
    14
        Headache postvac. 2 (N=52,84,55)
    12
    16
    8
        Fatigue postvac. 2 (N=52,84,55)
    3
    6
    9
        Myalgia postvac. 2 (N=52,84,55)
    8
    9
    7
        Arthralgia postvac. 2 (N=52,84,55)
    0
    4
    4
        Chills postvac. 2 (N=52,84,55)
    2
    2
    3
        Nausea postvac. 2 (N=52,84,55)
    3
    7
    2
        Vomiting postvac. 2 (N=52,84,55)
    1
    0
    0
        Diarrhea postvac. 2 (N=52,84,55)
    2
    3
    0
        Other Reactions postvac. 2 (N=52,84,55)
    1
    10
    4
        Analges/Antipyr Used postvac. 2 (N=52,84,55)
    1
    9
    4
        Stayed Home postvac. 2 (N=52,84,55)
    0
    1
    0
        Body Temp > 40 C postvac. 2 (N=52,84,55)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: 9. Number of Subjects With at Least One Reactogenicity Sign, in 18 to 64 Years of Age.

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    End point title
    		 9. Number of Subjects With at Least One Reactogenicity Sign, in 18 to 64 Years of Age.
    End point description
    Number of subjects with specified solicited local and systemic reactions in adult subjects (18 to 64 years of age). Postvac: postvaccination Analges: analgesics Antipyr: antipyretics The analyses were performed on the safety set. Note: 1) postvac 1 = after the first vaccination and 2) postvac 2 = after the second vaccination
    End point type
    Secondary
    End point timeframe
    7 days after each vaccination
    End point values
    		 2x7.5adj 7.5adj_1_8 7.5adj_1_22 15_1_22 2x15_1_22
    Number of subjects analysed
    54
    56
    56
    159
    54
    Units: Number of subjects
        Local Reactions postvac. 1
    39
    26
    38
    56
    19
        Erythema postvac. 1
    3
    0
    2
    2
    1
        Induration postvac. 1
    5
    4
    5
    6
    3
        Swelling postvac. 1
    3
    3
    5
    4
    2
        Tenderness postvac. 1
    33
    21
    26
    35
    14
        Pain postvac. 1
    36
    23
    32
    41
    16
        Systemic Reaction postvac. 1
    34
    31
    31
    71
    22
        Headache postvac. 1
    26
    18
    22
    42
    12
        Fatigue postvac. 1
    17
    16
    16
    32
    15
        Myalgia postvac. 1
    21
    13
    16
    28
    12
        Arthralgia postvac. 1
    4
    1
    6
    10
    2
        Chills postvac. 1
    4
    3
    6
    6
    4
        Nausea postvac. 1
    7
    9
    8
    16
    3
        Vomiting postvac. 1
    0
    0
    0
    1
    1
        Diarrhea postvac. 1
    2
    1
    0
    8
    3
        Other Reactions postvac. 1
    14
    7
    12
    13
    5
        Analges/Antipyr Used postvac. 1
    14
    6
    12
    13
    4
        Stayed Home postvac. 1 (N=53,55,56,157,54)
    2
    1
    2
    0
    1
        Body Temp > 40 C postvac. 1
    0
    0
    0
    0
    0
        Local Reactions postvac. 2 (N=0,55,56,158,53)
    0
    21
    28
    56
    17
        Erythema postvac. 2 (N=0,55,56,158,53)
    0
    1
    2
    5
    1
        Induration postvac. 2 (N=0,55,56,158,53)
    0
    3
    4
    4
    3
        Swelling postvac. 2 (N=0,55,56,158,53)
    0
    2
    5
    7
    5
        Tenderness postvac. 2 (N=0,55,56,158,53)
    0
    16
    24
    48
    16
        Pain postvac. 2 (N=0,55,56,158,53)
    0
    19
    24
    45
    15
        Systemic Reaction postvac. 2 (N=0,55,56,158,53)
    0
    26
    28
    53
    14
        Headache postvac. 2 (N=0,55,56,158,53)
    0
    18
    18
    25
    11
        Fatigue postvac. 2 (N=0,55,56,158,53)
    0
    14
    13
    24
    10
        Myalgia postvac. 2 (N=0,55,56,158,53
    0
    9
    14
    26
    7
        Arthralgia postvac. 2 (N=0,55,56,158,53)
    0
    5
    7
    16
    4
        Chills postvac. 2 (N=0,55,56,158,53)
    0
    8
    5
    5
    8
        Nausea postvac. 2 (N=0,55,56,158,53)
    0
    8
    5
    7
    3
        Vomiting postvac. 2 (N=0,55,56,158,53)
    0
    1
    0
    2
    1
        Diarrhea postvac. 2 (N=0,55,56,158,53)
    0
    1
    0
    4
    1
        Other Reactions postvac. 2 (N=0,55,56,158,53)
    0
    8
    7
    11
    7
        Analges/Antipyr Used postvac. 2 (N=0,55,56,158,53)
    0
    7
    7
    11
    6
        Stayed Home postvac. 2 (N=0,55,56,158,53)
    0
    2
    0
    1
    2
        Body Temp > 40 C postvac. 2 (N=0,55,56,158,53)
    0
    0
    0
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) and serious adverse events (SAEs) were collected throughout the duration of the study (day 1 to day 387).
    Adverse event reporting additional description
    Data provided in Other Adverse Events (>5%) were collected. The data included solicited local and systemic reactions that persisted for more than 7 days after each study vaccination. The number of participants at risk is not the same with the numbers provided in the participant flow module as these numbers are analyzed by age and group.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    2x7.5adj (18 to 64 Yrs)
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; two doses on day 1

    Reporting group title
    7.5adj_1_8 (18 to 64 Yrs)
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 8

    Reporting group title
    7.5adj_1_22 (18 to 64 Yrs)
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 22

    Reporting group title
    15_1_22 (18 to 64 Yrs)
    Reporting group description
    		 A/H1N1 15 mcg no MF59; one dose on days 1 and 22

    Reporting group title
    2x15_1_22 (18 to 64 Yrs)
    Reporting group description
    		 A/H1N1 15 mcg no MF59; two doses on days 1 and 22

    Reporting group title
    7.5adj_1_22 (9 to 17 Yrs)
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 22

    Reporting group title
    15_1_22 (9 to 17 Yrs)
    Reporting group description
    		 A/H1N1 15 mcg no MF59; one dose on days 1 and 22

    Reporting group title
    2x15_1_22 (9 to 17 Yrs)
    Reporting group description
    		 A/H1N1 15 mcg no MF59; two doses on days 1 and 22

    Reporting group title
    7.5adj_1_22 (3 to <9 Yrs)
    Reporting group description
    		 A/H1N1 7.5 mcg with MF59; one dose on days 1 and 22

    Reporting group title
    15_1_22 (3 to <9 Yrs)
    Reporting group description
    		 A/H1N1 15 mcg no MF59; one dose on days 1 and 22

    Reporting group title
    2x15_1_22 (3 to <9 Yrs)
    Reporting group description
    		 A/H1N1 15 mcg no MF59; two doses on days 1 and 22

    Serious adverse events
    		 2x7.5adj (18 to 64 Yrs) 7.5adj_1_8 (18 to 64 Yrs) 7.5adj_1_22 (18 to 64 Yrs) 15_1_22 (18 to 64 Yrs) 2x15_1_22 (18 to 64 Yrs) 7.5adj_1_22 (9 to 17 Yrs) 15_1_22 (9 to 17 Yrs) 2x15_1_22 (9 to 17 Yrs) 7.5adj_1_22 (3 to <9 Yrs) 15_1_22 (3 to <9 Yrs) 2x15_1_22 (3 to <9 Yrs)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 56 (0.00%)
    1 / 56 (1.79%)
    4 / 159 (2.52%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    2 / 55 (3.64%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 56 (1.79%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    1 / 159 (0.63%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    1 / 159 (0.63%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinoplasty
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion threatened
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    High risk pregnancy
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Sexual abuse
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    1 / 159 (0.63%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    1 / 159 (0.63%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    1 / 159 (0.63%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    1 / 84 (1.19%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 2x7.5adj (18 to 64 Yrs) 7.5adj_1_8 (18 to 64 Yrs) 7.5adj_1_22 (18 to 64 Yrs) 15_1_22 (18 to 64 Yrs) 2x15_1_22 (18 to 64 Yrs) 7.5adj_1_22 (9 to 17 Yrs) 15_1_22 (9 to 17 Yrs) 2x15_1_22 (9 to 17 Yrs) 7.5adj_1_22 (3 to <9 Yrs) 15_1_22 (3 to <9 Yrs) 2x15_1_22 (3 to <9 Yrs)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 54 (90.74%)
    41 / 56 (73.21%)
    48 / 56 (85.71%)
    119 / 159 (74.84%)
    35 / 54 (64.81%)
    46 / 53 (86.79%)
    67 / 84 (79.76%)
    43 / 57 (75.44%)
    40 / 55 (72.73%)
    61 / 84 (72.62%)
    41 / 54 (75.93%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 56 (5.36%)
    1 / 56 (1.79%)
    1 / 159 (0.63%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    1
    3
    1
    1
    1
    0
    0
    1
    0
    0
    0
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    27 / 54 (50.00%)
    21 / 56 (37.50%)
    27 / 56 (48.21%)
    56 / 159 (35.22%)
    17 / 54 (31.48%)
    21 / 53 (39.62%)
    29 / 84 (34.52%)
    11 / 57 (19.30%)
    11 / 55 (20.00%)
    21 / 84 (25.00%)
    11 / 54 (20.37%)
         occurrences all number
    31
    49
    57
    91
    30
    39
    48
    22
    12
    31
    15
    General disorders and administration site conditions
    Chills
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 54 (7.41%)
    9 / 56 (16.07%)
    8 / 56 (14.29%)
    10 / 159 (6.29%)
    11 / 54 (20.37%)
    3 / 53 (5.66%)
    4 / 84 (4.76%)
    4 / 57 (7.02%)
    4 / 55 (7.27%)
    2 / 84 (2.38%)
    2 / 54 (3.70%)
         occurrences all number
    5
    11
    12
    12
    14
    3
    4
    5
    6
    3
    3
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    17 / 54 (31.48%)
    20 / 56 (35.71%)
    22 / 56 (39.29%)
    45 / 159 (28.30%)
    18 / 54 (33.33%)
    11 / 53 (20.75%)
    15 / 84 (17.86%)
    14 / 57 (24.56%)
    6 / 55 (10.91%)
    11 / 84 (13.10%)
    6 / 54 (11.11%)
         occurrences all number
    20
    34
    36
    73
    30
    13
    23
    26
    7
    16
    9
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 56 (1.79%)
    3 / 56 (5.36%)
    6 / 159 (3.77%)
    2 / 54 (3.70%)
    1 / 53 (1.89%)
    4 / 84 (4.76%)
    1 / 57 (1.75%)
    3 / 55 (5.45%)
    1 / 84 (1.19%)
    1 / 54 (1.85%)
         occurrences all number
    5
    1
    4
    7
    3
    1
    4
    1
    4
    1
    1
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed
    39 / 54 (72.22%)
    31 / 56 (55.36%)
    42 / 56 (75.00%)
    79 / 159 (49.69%)
    23 / 54 (42.59%)
    42 / 53 (79.25%)
    52 / 84 (61.90%)
    37 / 57 (64.91%)
    32 / 55 (58.18%)
    43 / 84 (51.19%)
    29 / 54 (53.70%)
         occurrences all number
    130
    79
    113
    173
    108
    116
    117
    160
    75
    102
    116
    Injection site swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 56 (3.57%)
    2 / 56 (3.57%)
    5 / 159 (3.14%)
    2 / 54 (3.70%)
    1 / 53 (1.89%)
    2 / 84 (2.38%)
    1 / 57 (1.75%)
    3 / 55 (5.45%)
    2 / 84 (2.38%)
    2 / 54 (3.70%)
         occurrences all number
    2
    2
    2
    5
    2
    1
    2
    1
    3
    2
    2
    Pyrexia
         subjects affected / exposed
    2 / 54 (3.70%)
    4 / 56 (7.14%)
    6 / 56 (10.71%)
    12 / 159 (7.55%)
    2 / 54 (3.70%)
    3 / 53 (5.66%)
    3 / 84 (3.57%)
    6 / 57 (10.53%)
    8 / 55 (14.55%)
    10 / 84 (11.90%)
    10 / 54 (18.52%)
         occurrences all number
    2
    5
    8
    13
    2
    4
    3
    8
    8
    13
    12
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 56 (3.57%)
    1 / 56 (1.79%)
    13 / 159 (8.18%)
    3 / 54 (5.56%)
    4 / 53 (7.55%)
    5 / 84 (5.95%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    3 / 84 (3.57%)
    5 / 54 (9.26%)
         occurrences all number
    2
    4
    1
    13
    5
    4
    5
    0
    1
    3
    5
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 54 (12.96%)
    13 / 56 (23.21%)
    11 / 56 (19.64%)
    21 / 159 (13.21%)
    5 / 54 (9.26%)
    6 / 53 (11.32%)
    12 / 84 (14.29%)
    6 / 57 (10.53%)
    8 / 55 (14.55%)
    10 / 84 (11.90%)
    5 / 54 (9.26%)
         occurrences all number
    7
    23
    17
    28
    8
    6
    16
    11
    10
    14
    5
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 56 (0.00%)
    3 / 159 (1.89%)
    1 / 54 (1.85%)
    1 / 53 (1.89%)
    3 / 84 (3.57%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    2 / 84 (2.38%)
    5 / 54 (9.26%)
         occurrences all number
    0
    1
    0
    5
    2
    1
    3
    1
    0
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 56 (3.57%)
    1 / 56 (1.79%)
    8 / 159 (5.03%)
    3 / 54 (5.56%)
    0 / 53 (0.00%)
    4 / 84 (4.76%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
    6 / 84 (7.14%)
    4 / 54 (7.41%)
         occurrences all number
    2
    2
    1
    9
    3
    0
    4
    1
    0
    7
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 54 (7.41%)
    6 / 56 (10.71%)
    10 / 56 (17.86%)
    24 / 159 (15.09%)
    4 / 54 (7.41%)
    2 / 53 (3.77%)
    5 / 84 (5.95%)
    5 / 57 (8.77%)
    0 / 55 (0.00%)
    4 / 84 (4.76%)
    7 / 54 (12.96%)
         occurrences all number
    4
    6
    14
    32
    7
    2
    7
    5
    0
    4
    7
    Back pain
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    3 / 56 (5.36%)
    2 / 159 (1.26%)
    2 / 54 (3.70%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    0 / 84 (0.00%)
    0 / 54 (0.00%)
         occurrences all number
    0
    1
    4
    3
    3
    0
    0
    0
    0
    0
    0
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    21 / 54 (38.89%)
    17 / 56 (30.36%)
    22 / 56 (39.29%)
    42 / 159 (26.42%)
    17 / 54 (31.48%)
    18 / 53 (33.96%)
    20 / 84 (23.81%)
    14 / 57 (24.56%)
    5 / 55 (9.09%)
    10 / 84 (11.90%)
    9 / 54 (16.67%)
         occurrences all number
    28
    25
    34
    73
    22
    22
    26
    22
    8
    12
    13
    Pain in extremity
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 56 (5.36%)
    2 / 56 (3.57%)
    1 / 159 (0.63%)
    1 / 54 (1.85%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
    1 / 84 (1.19%)
    0 / 54 (0.00%)
         occurrences all number
    1
    3
    2
    1
    1
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 54 (18.52%)
    6 / 56 (10.71%)
    8 / 56 (14.29%)
    24 / 159 (15.09%)
    6 / 54 (11.11%)
    7 / 53 (13.21%)
    12 / 84 (14.29%)
    11 / 57 (19.30%)
    4 / 55 (7.27%)
    17 / 84 (20.24%)
    11 / 54 (20.37%)
         occurrences all number
    11
    7
    8
    26
    7
    7
    15
    12
    6
    20
    15
    Tonsillitis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    3 / 55 (5.45%)
    3 / 84 (3.57%)
    6 / 54 (11.11%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    4
    3
    6
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 56 (3.57%)
    5 / 56 (8.93%)
    6 / 159 (3.77%)
    0 / 54 (0.00%)
    1 / 53 (1.89%)
    3 / 84 (3.57%)
    3 / 57 (5.26%)
    4 / 55 (7.27%)
    7 / 84 (8.33%)
    6 / 54 (11.11%)
         occurrences all number
    1
    2
    6
    7
    0
    1
    3
    3
    5
    9
    7
    Varicella
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
    0 / 159 (0.00%)
    0 / 54 (0.00%)
    0 / 53 (0.00%)
    0 / 84 (0.00%)
    0 / 57 (0.00%)
    1 / 55 (1.82%)
    0 / 84 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2009
    - Follow-up extended from 6 months to 12 months after last vaccination. - Addition of children to Cohort E with subsequent increase in sample size from 672 to 784 and shift in randomization ratio in groups C, D, and E from 1:1:0 to 2:3:2. - Vaccine Group E design changed from a single 30 μg dose to 2 x 15 μg doses administered in two locations on Day 1 and Day 22. - Removal of injection site ecchymosis, arthralgia, chills, malaise, and sweating as solicited adverse events. Addition of injection site tenderness, vomiting, and diarrhea as solicited adverse events. - Safety laboratory assessments according to standardized toxicity scales. - Medically attended visits added as a safety endpoint. - Full Analysis Set for interim analyses on Day 8, 15, 22, 29 and 43. - Assent to be performed for individuals ages 10 years and older. - No Diary cards to be completed for individuals under 13 years. - Physical assessment procedures at Visit 1 and subsequent visits defined in greater detail. - Procedures for monthly telephone contacts with subjects from Visit 7 through Visit 16 added. - Exclusion criterion added, to specify subjects who received or intended to receive influenza vaccine within 1 week before or after each study vaccination.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21285531
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