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    Clinical Trial Results:
    Pivotal, Multicenter, Observer-Blind, Randomized Study of Influenza A (H1N1) 2009 Monovalent Subunit Vaccine With and Without Adjuvant in Children Ages 6 to <36 Months

    Summary
    EudraCT number
    		 2014-005107-24
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    06 Dec 2010

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Jul 2016
    First version publication date
    12 Apr 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Required for the re-QC because of EudraCT system glitch as possible updates to results are required. Moreover, the study is now transferred to another primary user.

    Trial information

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    Trial identification
    Sponsor protocol code
    V112_06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00996307
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Vaccines and Diagnostics Srl
    Sponsor organisation address
    350 Massachusetts Ave, Cambridge, MA, United States, 02139
    Public contact
    Posting Director, Novartis Vaccines and Diagnostics Srl, RegistryContactVaccinesUS@novartis.com
    Scientific contact
    Posting Director, Novartis Vaccines and Diagnostics Srl, 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
    21 Apr 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate hemagglutination inhibition (HI) assay results for each vaccine group after 1 and 2 doses and according to immunogenicity criteria defined by CBER recommendations. To evaluate the safety and tolerability of each A/H1N1 2009 vaccine group in this young pediatric population.
    Protection of trial subjects
    This trial was performed with the ethical principles that have their origin in the Declaration of Helsinki, that are consistent with Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines, the applicable regulatory requirements(s) for the country in which the study is conducted, and applicable standard operating procedures (SOPs).
    Background therapy
    		 Test vaccines were supplied as a single prefilled syringe containing 15μg A/H1N1 2009 antigen per 0.5mL dose. The adjuvant was supplied separately as prefilled vials containing approximately 0.7mL of MF59 at approximately 27.3mg of squalene per vial. Adjuvanted vaccines were prepared by bedside mixing of the contents in prefilled syringes of A/H1N1 2009 antigen and MF59 adjuvant. All the vaccine were administered intramuscularly (IM) at study days 1 and 22 (3 weeks after first vaccination) within the pre-specified visit windows.
    Evidence for comparator
    		 There were no reference vaccines in this study.
    Actual start date of recruitment
    01 Oct 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Regulatory reason, Safety
    Long term follow-up duration
    		 13 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Mexico: 40
    Country: Number of subjects enrolled
    United States: 614
    Worldwide total number of subjects
    654
    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)
    348
    Children (2-11 years)
    306
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 29 sites in USA and Mexico.

    Pre-assignment
    Screening details
    		 All subjects enrolled 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
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Observer-blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 3.75_(50)MF59
    Arm description
    		 3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 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
    0.25mL dose/IM

    Arm title
    		 7.5_(0)MF59
    Arm description
    		 7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 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
    0.25mL dose/IM

    Arm title
    		 7.5_(50)MF59
    Arm description
    		 7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 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
    0.38mL dose/IM

    Arm title
    		 15_(0)MF59
    Arm description
    		 15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 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
    0.5mL dose/IM

    Number of subjects in period 1
    		3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Started
    164
    165
    160
    165
    Completed
    144
    148
    146
    144
    Not completed
    20
    17
    14
    21
         Consent withdrawn by subject
    3
    2
    5
    5
         Unable to classify
    4
    -
    2
    1
         Adverse event
    -
    1
    -
    -
         Lost to follow-up
    13
    13
    7
    15
         Administrative reason
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    3.75_(50)MF59
    Reporting group description
    		 3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    7.5_(0)MF59
    Reporting group description
    		 7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    7.5_(50)MF59
    Reporting group description
    		 7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    15_(0)MF59
    Reporting group description
    		 15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Reporting group values
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59 Total
    Number of subjects
    		 164 165 160 165 654
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 21.2 ( 7.9 ) 21.6 ( 8.8 ) 21.1 ( 8.4 ) 21.3 ( 8.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 75 79 80 78 312
        Male
    		 89 86 80 87 342

    End points

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    End points reporting groups
    Reporting group title
    3.75_(50)MF59
    Reporting group description
    		 3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    7.5_(0)MF59
    Reporting group description
    		 7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    7.5_(50)MF59
    Reporting group description
    		 7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    15_(0)MF59
    Reporting group description
    		 15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    All enrolled set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects enrolled in this study.

    Subject analysis set title
    Full Analysis Set (FAS), Immunogenicity
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in the All Randomized Set who: - Actually received a study vaccination AND - Provided at least one evaluable serum sample for immunogenicity testing before and after baseline In case the study vaccination was not performed according to the subject’s randomization, subjects were to be analyzed as randomized in the FAS.

    Subject analysis set title
    Per Protocol Set (PPS), Immunogenicity
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects in the FAS who were considered “evaluable” which included subjects who: - Received all study vaccinations correctly AND - Provided evaluable serum sample for immunogenicity testing at the relevant timepoints (day 1, day 22, and/or day 43), AND - Had no major protocol deviation as pre-specified in the Analysis Plan. A major protocol deviation was defined as a protocol deviation that was considered to have a significant impact on the analysis of the subject’s antibody responses.

    Subject analysis set title
    Safety Set, Overall
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the Exposed Set who had at least one safety observation (e.g., data regarding local/systemic reactions, AEs) following study vaccination.

    Subject analysis set title
    3.75_(50)MF59 - No Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22 in subjects who did not receive a previous seasonal influenza vaccination.

    Subject analysis set title
    7.5_(0)MF59 - No Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22 in subjects who did not receive a previous seasonal influenza vaccination.

    Subject analysis set title
    7.5_(50)MF59 - No Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22 in subjects who did not receive a previous seasonal influenza vaccination.

    Subject analysis set title
    15_(0)MF59 - No Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22 in subjects who did not receive a previous seasonal influenza vaccination.

    Subject analysis set title
    3.75_(50)MF59 - Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22 in subjects who had received a previous seasonal influenza vaccination.

    Subject analysis set title
    7.5_(0)MF59 - Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22 in subjects who had received a previous seasonal influenza vaccination.

    Subject analysis set title
    7.5_(50) MF59 - Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22 who had received a previous seasonal influenza vaccination.

    Subject analysis set title
    15_(0)MF59 - Previous Vaccination
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22 who had received a previous seasonal influenza vaccination.

    Subject analysis set title
    3.75_(50)MF59 - Baseline HI <1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    7.5_(0)MF59 - Baseline HI <1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    7.5_(50)MF59 - Baseline HI <1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    15_(0)MF59 - Baseline HI <1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    3.75_(50)MF59 - Baseline HI ≥1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    7.5_(0)MF59 - Baseline HI ≥1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    7.5_(50)MF59 - Baseline HI ≥1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Subject analysis set title
    15_(0)MF59 - Baseline HI ≥1:10
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Primary: 1. Antibody Responses After the First and Second Vaccinations.

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    End point title
    		 1. Antibody Responses After the First and Second Vaccinations. [1]
    End point description
    CBER guidance (<65 years of age): The lower bound of the two-sided 95% CI for the percent of subjects achieving seroconversion for HI antibody should be ≥ 40% AND the lower bound of the two-sided 95% CI for the percent of subjects achieving an HI antibody titer ≥ 1:40 should be ≥ 70%.
    End point type
    Primary
    End point timeframe
    21 days after each vaccination
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Number of subjects analysed
    129
    124
    126
    129
    Units: Percentages of subjects
    number (confidence interval 95%)
        HI titer ≥1:40 (Baseline)
    19 (12 to 26)
    9 (5 to 15)
    15 (9 to 23)
    19 (13 to 27)
        HI titer ≥1:40 (Day 22)
    79 (71 to 86)
    37 (29 to 46)
    86 (78 to 91)
    50 (41 to 59)
        Seroconversion Day 22
    74 (65 to 81)
    32 (24 to 41)
    80 (72 to 87)
    44 (35 to 53)
        HI titer ≥1:40 (Day 43)
    100 (97 to 100)
    70 (61 to 78)
    100 (97 to 100)
    81 (74 to 88)
        Seroconversion Day 43
    98 (93 to 100)
    68 (59 to 76)
    98 (94 to 100)
    76 (68 to 83)
        HI titer ≥1:40 (Day 202; N=45,38,46,38)
    96 (85 to 99)
    50 (33 to 67)
    100 (92 to 100)
    55 (38 to 71)
        Seroconversion Day 202; N=45,38,46,38)
    89 (76 to 96)
    50 (33 to 67)
    91 (79 to 98)
    39 (24 to 57)
        HI titer ≥1:40 (Day 387; N=46,37,38,36)
    85 (71 to 94)
    27 (14 to 44)
    84 (69 to 94)
    36 (21 to 54)
        Seroconversion Day 387; N=45,38,46,38)
    76 (61 to 87)
    22 (10 to 38)
    76 (60 to 89)
    25 (12 to 42)
    No statistical analyses for this end point

    Primary: 2. Number of Participants Reporting Solicited Local and Systemic Reactions After First Vaccination.

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    End point title
    		 2. Number of Participants Reporting Solicited Local and Systemic Reactions After First Vaccination. [2]
    End point description
    Safety was measured in terms of the number of participants reporting solicited local and systemic reactions after first vaccination.
    End point type
    Primary
    End point timeframe
    Day 1 to 7
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Number of subjects analysed
    161
    161
    160 [3]
    162
    Units: Number of subjects
        Ecchymosis
    0
    0
    0
    0
        Erythema
    1
    0
    2
    1
        Swelling
    6
    9
    4
    6
        Induration
    8
    8
    13
    8
        Tenderness
    49
    42
    53
    42
        Sleepiness
    36
    28
    38
    30
        Diarrhea
    32
    28
    37
    25
        Vomiting
    13
    10
    12
    10
        Irritability
    40
    39
    45
    41
        Change in eating habits
    21
    16
    19
    18
        Persist crying
    34
    35
    35
    35
        Fever (rectal temp ≥38.5°C)
    5
    5
    9
    7
    Notes
    [3] - Actual number subjects analysed in this group was 161
    No statistical analyses for this end point

    Primary: 3. Number of Participants Reporting Solicited Local and Systemic Reactions After Second Vaccination.

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    End point title
    		 3. Number of Participants Reporting Solicited Local and Systemic Reactions After Second Vaccination. [4]
    End point description
    Safety was measured in terms of the number of participants reporting solicited local and systemic reactions after second vaccination.
    End point type
    Primary
    End point timeframe
    Day 22 to 28
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Number of subjects analysed
    155
    148
    157
    157
    Units: Number of subjects
        Ecchymosis (N=154,147,155,156)
    0
    0
    1
    0
        Erythema (N=155,147,157,157)
    1
    1
    4
    1
        Swelling
    2
    1
    8
    6
        Induration
    4
    3
    12
    9
        Tenderness (N=155,148,156,157)
    35
    27
    37
    32
        Sleepiness
    28
    21
    20
    17
        Diarrhea
    20
    19
    20
    15
        Vomiting
    11
    9
    14
    5
        Irritabilty
    36
    39
    32
    24
        change in eating habits
    20
    18
    14
    11
        Persist crying
    21
    22
    24
    18
        Fever (rectal temp ≥38.5°C)
    8
    5
    4
    7
    No statistical analyses for this end point

    Secondary: 4. Immunogenicity Measurement by Geometric Mean Titers (GMT).

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    End point title
    		 4. Immunogenicity Measurement by Geometric Mean Titers (GMT).
    End point description
    Immunogenicity was measured in terms of the GMT at 21 days after each vaccination.
    End point type
    Secondary
    End point timeframe
    21 days after each vaccination
    End point values
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Number of subjects analysed
    129
    124
    126
    129
    Units: Titers
    geometric mean (confidence interval 95%)
        GMT Baseline
    10 (7.94 to 14)
    7.27 (5.5 to 9.6)
    9.29 (7.06 to 12)
    11 (8.22 to 14)
        GMT Day 22
    83 (56 to 123)
    20 (14 to 31)
    92 (62 to 136)
    37 (25 to 55)
        GMT Day 43
    642 (468 to 879)
    80 (58 to 110)
    626 (457 to 858)
    151 (110 to 206)
    Statistical analysis title
    		 1. Immunogenicity measurement by GMT
    Statistical analysis description
    The two-sided confidence intervals (CIs) were calculated and assessed for non-inferiority first against the margin of 0.5 (exploratory margin) and in case of success against the margin of 0.667 (based on CBER guidance against the licensed comparator). Day 22
    Comparison groups
    3.75_(50)MF59 v 7.5_(0)MF59
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    4.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.55
         upper limit
    		 6.46
    Notes
    [5] - Log10-transformed HI antibody responses were to be modeled using analysis of variance (ANOVA) including factor for vaccine group and center. Analysis done on PPS.
    Statistical analysis title
    		 2. Immunogenicity measurement by GMT
    Statistical analysis description
    The two-sided CIs were calculated and assessed for non-inferiority first against the margin of 0.5 (exploratory margin) and in case of success against the margin of 0.667 (based on CBER guidance against the licensed comparator). Day 22
    Comparison groups
    3.75_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.42
         upper limit
    		 3.56
    Notes
    [6] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on PPS.
    Statistical analysis title
    		 3. Immunogenicity measurement by GMT
    Statistical analysis description
    The two-sided CIs were calculated and assessed for non-inferiority first against the margin of 0.5 (exploratory margin) and in case of success against the margin of 0.667 (based on CBER guidance against the licensed comparator). Day 22
    Comparison groups
    7.5_(50)MF59 v 7.5_(0)MF59
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    4.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 7.19
    Notes
    [7] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on PPS.
    Statistical analysis title
    		 4. Immunogenicity measurement by GMT
    Statistical analysis description
    The two-sided confidence intervals (CIs) were calculated and assessed for non-inferiority first against the margin of 0.5 (exploratory margin) and in case of success against the margin of 0.667 (based on CBER guidance against the licensed comparator). Day 22
    Comparison groups
    7.5_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    2.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.56
         upper limit
    		 3.96
    Notes
    [8] - Log10-transformed HI antibody responses were to be modeled using analysis of variance (ANOVA) including factor for vaccine group and center. Analysis done on PPS.
    Statistical analysis title
    		 5. Immunogenicity measurement by GMT
    Statistical analysis description
    Non-inferiority of adjuvanted vaccines was demonstrated against the non-adjuvanted vaccines in terms of antibody titers if the lower bound of the 2-sided 95% CI of GMT ratios were greater than 0.5 (exploratory margin) and also greater than 0.667 (based on CBER guidance against the licensed comparator). Day 43
    Comparison groups
    3.75_(50)MF59 v 7.5_(0)MF59
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    8.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.52
         upper limit
    		 12
    Notes
    [9] - Log10-transformed HI antibody responses were to be modeled using analysis of variance (ANOVA) including factor for vaccine group and center. Analysis done on PPS
    Statistical analysis title
    		 6. Immunogenicity measurement by GMT
    Statistical analysis description
    Non-inferiority of adjuvanted vaccines was demonstrated against the non-adjuvanted vaccines in terms of antibody titers if the lower bound of the 2-sided 95% CI of GMT ratios were greater than 0.5 (exploratory margin) and also greater than 0.667 (based on CBER guidance against the licensed comparator). Day 43
    Comparison groups
    3.75_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    4.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.94
         upper limit
    		 6.15
    Notes
    [10] - Log10-transformed HI antibody responses were to be modeled using analysis of variance (ANOVA) including factor for vaccine group and center. Analysis done on PPS
    Statistical analysis title
    		 7. Immunogenicity measurement by GMT
    Statistical analysis description
    Non-inferiority of adjuvanted vaccines was demonstrated against the non-adjuvanted vaccines in terms of antibody titers if the lower bound of the 2-sided 95% CI of GMT ratios were greater than 0.5 (exploratory margin) and also greater than 0.667 (based on CBER guidance against the licensed comparator). Day 43
    Comparison groups
    7.5_(50)MF59 v 7.5_(0)MF59
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    7.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.36
         upper limit
    		 11
    Notes
    [11] - Log10-transformed HI antibody responses were to be modeled using analysis of variance (ANOVA) including factor for vaccine group and center. Analysis done on PPS.
    Statistical analysis title
    		 8. Immunogenicity measurement by GMT
    Statistical analysis description
    Non-inferiority of adjuvanted vaccines was demonstrated against the non-adjuvanted vaccines in terms of antibody titers if the lower bound of the 2-sided 95% CI of GMT ratios were greater than 0.5 (exploratory margin) and also greater than 0.667 (based on CBER guidance against the licensed comparator). Day 43
    Comparison groups
    7.5_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    4.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.86
         upper limit
    		 6.02
    Notes
    [12] - Log10-transformed HI antibody responses were to be modeled using analysis of variance (ANOVA) including factor for vaccine group and center. Analysis done on PPS
    Statistical analysis title
    		 9. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 22.
    Comparison groups
    3.75_(50)MF59 v 7.5_(0)MF59
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    3.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.37
         upper limit
    		 5.65
    Notes
    [13] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on FAS.
    Statistical analysis title
    		 10. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 22.
    Comparison groups
    3.75_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.43
         upper limit
    		 3.4
    Notes
    [14] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on FAS.
    Statistical analysis title
    		 11. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 22.
    Comparison groups
    7.5_(50)MF59 v 7.5_(0)MF59
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    4.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.85
         upper limit
    		 6.86
    Notes
    [15] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on FAS.
    Statistical analysis title
    		 12. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 22.
    Comparison groups
    7.5_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    2.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.72
         upper limit
    		 4.13
    Notes
    [16] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on FAS.
    Statistical analysis title
    		 13. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 43.
    Comparison groups
    7.5_(0)MF59 v 3.75_(50)MF59
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    7.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.54
         upper limit
    		 11
    Notes
    [17] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on FAS.
    Statistical analysis title
    		 14. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 43.
    Comparison groups
    3.75_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    4.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.23
         upper limit
    		 6.42
    Notes
    [18] - Log10-transformed HI antibody responses were to be modeled using analysis of variance (ANOVA) including factor for vaccine group and center. Analysis done on FAS.
    Statistical analysis title
    		 15. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 43.
    Comparison groups
    7.5_(0)MF59 v 7.5_(50)MF59
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    7.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.3
         upper limit
    		 11
    Notes
    [19] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on FAS.
    Statistical analysis title
    		 16. Immunogenicity measurement by GMT
    Statistical analysis description
    Superiority of the adjuvanted vaccines against the non-adjuvanted vaccines was to be tested against the margin of 1 on day 43.
    Comparison groups
    7.5_(50)MF59 v 15_(0)MF59
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    Method
    Parameter type
    		 Ratio of GMTs
    Point estimate
    4.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.09
         upper limit
    		 6.19
    Notes
    [20] - Log10-transformed HI antibody responses were to be modeled using ANOVA including factor for vaccine group and center. Analysis done on FAS.

    Secondary: 5. Antibody Responses in Subjects With and Without Seasonal Influenza Vaccination for Year 2009 to 2010.

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    End point title
    		 5. Antibody Responses in Subjects With and Without Seasonal Influenza Vaccination for Year 2009 to 2010.
    End point description
    Subgroup analysis based on receipt of recent seasonal vaccination. Comparison between subjects previously vaccinated versus not vaccinated with seasonal influenza vaccines.
    End point type
    Secondary
    End point timeframe
    Day 22 (three weeks after first vaccination); day 43 (three weeks after second vaccination)
    End point values
    		 3.75_(50)MF59 - No Previous Vaccination 7.5_(0)MF59 - No Previous Vaccination 7.5_(50)MF59 - No Previous Vaccination 15_(0)MF59 - No Previous Vaccination 3.75_(50)MF59 - Previous Vaccination 7.5_(0)MF59 - Previous Vaccination 7.5_(50) MF59 - Previous Vaccination 15_(0)MF59 - Previous Vaccination
    Number of subjects analysed
    81
    83
    92
    89
    48
    41
    34
    40
    Units: Percentages of subjects
    number (confidence interval 95%)
        Seroconversion (Day 22)
    73 (62 to 82)
    37 (27 to 49)
    78 (68 to 86)
    44 (33 to 55)
    75 (60 to 86)
    22 (11 to 38)
    86 (70 to 95)
    45 (29 to 62)
        Seroconversion (Day 43)
    99 (93 to 100)
    66 (55 to 76)
    98 (92 to 100)
    78 (67 to 86)
    96 (86 to 99)
    71 (54 to 84)
    100 (90 to 100)
    73 (56 to 85)
        HI titer ≥1:40 (Day 1)
    25 (16 to 36)
    12 (6 to 21)
    16 (9 to 25)
    21 (13 to 31)
    8 (2 to 20)
    2 (0.062 to 13)
    14 (5 to 30)
    15 (6 to 30)
        HI titer ≥1:40 (Day 22)
    78 (67 to 86)
    42 (31 to 54)
    84 (75 to 91)
    49 (39 to 60)
    81 (67 to 91)
    27 (14 to 43)
    91 (77 to 98)
    50 (34 to 66)
        HI titer ≥1:40 (Day 43)
    100 (96 to 100)
    67 (56 to 77)
    100 (96 to 100)
    83 (74 to 90)
    100 (93 to 100)
    76 (60 to 88)
    100 (90 to 100)
    78 (62 to 89)
    No statistical analyses for this end point

    Secondary: 6. Geometric Mean Titers (GMTs) in Subjects With and Without Seasonal Influenza Vaccination for Year 2009 to 2010.

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    End point title
    		 6. Geometric Mean Titers (GMTs) in Subjects With and Without Seasonal Influenza Vaccination for Year 2009 to 2010.
    End point description
    Subgroup analysis based on receipt of recent seasonal vaccination. Comparison between subjects previously vaccinated versus not vaccinated with seasonal influenza vaccines.
    End point type
    Secondary
    End point timeframe
    Day 22 (three weeks after first vaccination); day 43 (three weeks after second vaccination)
    End point values
    		 3.75_(50)MF59 - No Previous Vaccination 7.5_(0)MF59 - No Previous Vaccination 7.5_(50)MF59 - No Previous Vaccination 15_(0)MF59 - No Previous Vaccination 3.75_(50)MF59 - Previous Vaccination 7.5_(0)MF59 - Previous Vaccination 7.5_(50) MF59 - Previous Vaccination 15_(0)MF59 - Previous Vaccination
    Number of subjects analysed
    81
    83
    92
    89
    48
    41
    34
    40
    Units: Titers
    geometric mean (confidence interval 95%)
        Day 1
    11 (7.66 to 16)
    7.95 (5.58 to 11)
    9.94 (6.93 to 14)
    12 (8.3 to 17)
    10 (6.84 to 15)
    6.52 (4.28 to 9.94)
    8.3 (5.46 to 13)
    10 (6.58 to 15)
        Day 22
    101 (61 to 167)
    25 (15 to 41)
    105 (63 to 173)
    42 (26 to 68)
    80 (43 to 148)
    17 (8.88 to 34)
    100 (51 to 194)
    45 (23 to 87)
        Day 43
    975 (663 to 1432)
    103 (71 to 149)
    788 (538 to 1154)
    186 (129 to 271)
    389 (226 to 669)
    57 (32 to 103)
    483 (269 to 867)
    124 (69 to 224)
    No statistical analyses for this end point

    Secondary: 7. Antibody Response Based on Baseline Seropositivity.

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    End point title
    		 7. Antibody Response Based on Baseline Seropositivity.
    End point description
    Subgroup analysis based on Subjects with a pre-vaccination HI antibody titer < 1:10 and pre-vaccination HI antibody titer ≥ 1:10 Immunogenicity responses in subjects who are seropositive (A/H1N1 2009 HI titer ≥ 1:10) at Baseline (Day 1 (pre-vaccination)) as compared to those who are seronegative (HI titer < 1:10)
    End point type
    Secondary
    End point timeframe
    Day 22 (three weeks after first vaccination); day 43 (three weeks after second vaccination)
    End point values
    		 3.75_(50)MF59 - Baseline HI <1:10 7.5_(0)MF59 - Baseline HI <1:10 7.5_(50)MF59 - Baseline HI <1:10 15_(0)MF59 - Baseline HI <1:10 3.75_(50)MF59 - Baseline HI ≥1:10 7.5_(0)MF59 - Baseline HI ≥1:10 7.5_(50)MF59 - Baseline HI ≥1:10 15_(0)MF59 - Baseline HI ≥1:10
    Number of subjects analysed
    90
    96
    91
    90
    39
    28
    35
    39
    Units: Percentages of subjects
    number (confidence interval 95%)
        Seroconversion (Day 22)
    72 (62 to 81)
    31 (22 to 42)
    82 (73 to 90)
    39 (29 to 50)
    77 (61 to 89)
    36 (19 to 56)
    74 (57 to 88)
    56 (40 to 72)
        Seroconversion (Day 43)
    100 (96 to 100)
    67 (56 to 76)
    100 (96 to 100)
    77 (67 to 85)
    92 (79 to 98)
    71 (51 to 87)
    94 (81 to 99)
    74 (58 to 87)
        HI titer ≥1:40 (Day 1)
    0 (0 to 4)
    0 (0 to 4)
    0 (0 to 4)
    0 (0 to 4)
    62 (45 to 77)
    39 (22 to 59)
    54 (37 to 71)
    64 (47 to 79)
        HI titer ≥1:40 (Day 22)
    72 (62 to 81)
    31 (22 to 42)
    82 (73 to 90)
    39 (29 to 50)
    95 (83 to 99)
    57 (37 to 76)
    94 (81 to 99)
    74 (58 to 87)
        HI titer ≥1:40 (Day 43)
    100 (96 to 100)
    67 (56 to 76)
    100 (96 to 100)
    77 (67 to 85)
    100 (91 to 100)
    82 (63 to 94)
    100 (90 to 100)
    92 (79 to 98)
    No statistical analyses for this end point

    Secondary: 8. Geometric Mean Titers (GMTs) Based on Baseline Seropositivity.

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    End point title
    		 8. Geometric Mean Titers (GMTs) Based on Baseline Seropositivity.
    End point description
    Subgroup analysis based on Subjects with a pre-vaccination HI antibody titer < 1:10 and pre-vaccination HI antibody titer ≥ 1:10 Immunogenicity responses in subjects who are seropositive (A/H1N1 2009 HI titer ≥ 1:10) at Baseline (Day 1 (pre-vaccination)) as compared to those who are seronegative (HI titer < 1:10).
    End point type
    Secondary
    End point timeframe
    Day 22 (three weeks after first vaccination); day 43 (three weeks after second vaccination)
    End point values
    		 3.75_(50)MF59 - Baseline HI <1:10 7.5_(0)MF59 - Baseline HI <1:10 7.5_(50)MF59 - Baseline HI <1:10 15_(0)MF59 - Baseline HI <1:10 3.75_(50)MF59 - Baseline HI ≥1:10 7.5_(0)MF59 - Baseline HI ≥1:10 7.5_(50)MF59 - Baseline HI ≥1:10 15_(0)MF59 - Baseline HI ≥1:10
    Number of subjects analysed
    90
    96
    91
    90
    39
    28
    35
    39
    Units: Titers
    geometric mean (confidence interval 95%)
        Day 1
    5.06 (4.98 to 5.14)
    5.07 (4.99 to 5.15)
    5.01 (4.93 to 5.09)
    5.06 (4.98 to 5.14)
    53 (34 to 83)
    35 (21 to 58)
    47 (29 to 76)
    69 (44 to 108)
        Day 22
    42 (29 to 61)
    15 (11 to 22)
    60 (42 to 88)
    17 (12 to 24)
    266 (137 to 517)
    67 (31 to 145)
    313 (154 to 639)
    248 (126 to 487)
        Day 43
    566 (398 to 804)
    65 (46 to 93)
    577 (404 to 825)
    96 (67 to 137)
    660 (390 to 1117)
    167 (90 to 308)
    811 (462 to 1426)
    420 (246 to 717)
    No statistical analyses for this end point

    Secondary: 9. Antibody Persistence by Geometric Mean Titers (GMT).

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    End point title
    		 9. Antibody Persistence by Geometric Mean Titers (GMT).
    End point description
    Immunogenicity was assessed in terms of Geometric Mean Titers (GMT at 6 months (Day 202)and 12 months (Day 387) after second vaccination.
    End point type
    Secondary
    End point timeframe
    6 months (Day 202) and 12 months (Day 387) after second vaccination
    End point values
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Number of subjects analysed
    129
    124
    126
    129
    Units: Titers
    geometric mean (confidence interval 95%)
        GMT (Day 1)
    10 (7.94 to 14)
    7.27 (5.5 to 9.6)
    9.29 (7.06 to 12)
    11 (8.22 to 14)
        GMT (Day 202; N=45,38,46,38)
    176 (111 to 280)
    33 (20 to 54)
    205 (133 to 316)
    42 (25 to 69)
        GMT (Day 387; N=46,37,38,36)
    92 (52 to 162)
    15 (8.24 to 28)
    85 (48 to 151)
    25 (13 to 46)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study
    Adverse event reporting additional description
    Local, systemic, and other reactions were collected from Study days 1 to 7 and 22 to 28. Serious adverse events (SAEs), medically attended visits, new onset of chronic diseases and AEs that lead to subject’s withdrawal were collected from Day 1 (post-consent) through Day 387 (12 months following second vaccination)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    3.75_(50)MF59
    Reporting group description
    		 3.75 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    7.5_(0)MF59
    Reporting group description
    		 7.5 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    7.5_(50)MF59
    Reporting group description
    		 7.5 μg A/H1N1 antigen with 50% MF59 adjuvant administered on study day 1 and day 22.

    Reporting group title
    15_(0)MF59
    Reporting group description
    		 15 μg A/H1N1 antigen without MF59 adjuvant administered on study day 1 and day 22.

    Serious adverse events
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 162 (3.09%)
    6 / 164 (3.66%)
    1 / 162 (0.62%)
    10 / 166 (6.02%)
         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
    Accidental exposure to product
         subjects affected / exposed
    2 / 162 (1.23%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    0 / 166 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    1 / 166 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Complex partial seizures
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (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
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    1 / 166 (0.60%)
         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
    Constipation
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    1 / 166 (0.60%)
         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
    Intussusception
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (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
    Vomiting
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (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
    Asthma
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    1 / 166 (0.60%)
         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
    Hypoxia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    2 / 166 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    1 / 166 (0.60%)
         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
    Mental status changes
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    0 / 166 (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
    Nephrotic syndrome
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (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
    Abdominal abscess
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (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
    Atypical pneumonia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    1 / 166 (0.60%)
         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
    Cellulitis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    1 / 162 (0.62%)
    0 / 166 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    0 / 166 (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
    Genital abscess
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    1 / 166 (0.60%)
         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
    Otitis media
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 164 (0.61%)
    0 / 162 (0.00%)
    0 / 166 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    3 / 166 (1.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 164 (0.00%)
    1 / 162 (0.62%)
    0 / 166 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 164 (0.00%)
    0 / 162 (0.00%)
    2 / 166 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 164 (1.22%)
    0 / 162 (0.00%)
    0 / 166 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 3.75_(50)MF59 7.5_(0)MF59 7.5_(50)MF59 15_(0)MF59
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 162 (88.89%)
    152 / 164 (92.68%)
    141 / 162 (87.04%)
    142 / 166 (85.54%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    51 / 162 (31.48%)
    41 / 164 (25.00%)
    48 / 162 (29.63%)
    39 / 166 (23.49%)
         occurrences all number
    71
    58
    66
    53
    General disorders and administration site conditions
    Crying
         subjects affected / exposed
    47 / 162 (29.01%)
    46 / 164 (28.05%)
    48 / 162 (29.63%)
    42 / 166 (25.30%)
         occurrences all number
    62
    72
    64
    60
    Injection site pain
         subjects affected / exposed
    60 / 162 (37.04%)
    51 / 164 (31.10%)
    60 / 162 (37.04%)
    50 / 166 (30.12%)
         occurrences all number
    87
    69
    95
    76
    Pyrexia
         subjects affected / exposed
    53 / 162 (32.72%)
    52 / 164 (31.71%)
    54 / 162 (33.33%)
    53 / 166 (31.93%)
         occurrences all number
    72
    81
    88
    77
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    9 / 162 (5.56%)
    4 / 164 (2.44%)
    7 / 162 (4.32%)
    5 / 166 (3.01%)
         occurrences all number
    10
    4
    7
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    57 / 162 (35.19%)
    52 / 164 (31.71%)
    63 / 162 (38.89%)
    45 / 166 (27.11%)
         occurrences all number
    83
    85
    82
    62
    Vomiting
         subjects affected / exposed
    33 / 162 (20.37%)
    37 / 164 (22.56%)
    33 / 162 (20.37%)
    24 / 166 (14.46%)
         occurrences all number
    47
    48
    41
    30
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    7 / 162 (4.32%)
    8 / 164 (4.88%)
    5 / 162 (3.09%)
    9 / 166 (5.42%)
         occurrences all number
    7
    11
    8
    18
    Bronchial Hyperreactivity
         subjects affected / exposed
    6 / 162 (3.70%)
    9 / 164 (5.49%)
    10 / 162 (6.17%)
    7 / 166 (4.22%)
         occurrences all number
    8
    10
    14
    9
    Cough
         subjects affected / exposed
    45 / 162 (27.78%)
    54 / 164 (32.93%)
    46 / 162 (28.40%)
    54 / 166 (32.53%)
         occurrences all number
    68
    75
    58
    73
    Nasal congestion
         subjects affected / exposed
    11 / 162 (6.79%)
    11 / 164 (6.71%)
    14 / 162 (8.64%)
    11 / 166 (6.63%)
         occurrences all number
    11
    11
    14
    12
    Rhinitis allergic
         subjects affected / exposed
    8 / 162 (4.94%)
    10 / 164 (6.10%)
    5 / 162 (3.09%)
    3 / 166 (1.81%)
         occurrences all number
    12
    10
    6
    3
    Rhinorrhoea
         subjects affected / exposed
    26 / 162 (16.05%)
    24 / 164 (14.63%)
    27 / 162 (16.67%)
    32 / 166 (19.28%)
         occurrences all number
    30
    32
    32
    41
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    10 / 162 (6.17%)
    12 / 164 (7.32%)
    8 / 162 (4.94%)
    4 / 166 (2.41%)
         occurrences all number
    10
    12
    8
    4
    Psychiatric disorders
    Eating disorder
         subjects affected / exposed
    33 / 162 (20.37%)
    30 / 164 (18.29%)
    30 / 162 (18.52%)
    23 / 166 (13.86%)
         occurrences all number
    49
    40
    35
    32
    Irritability
         subjects affected / exposed
    58 / 162 (35.80%)
    62 / 164 (37.80%)
    60 / 162 (37.04%)
    52 / 166 (31.33%)
         occurrences all number
    90
    102
    97
    79
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    10 / 162 (6.17%)
    12 / 164 (7.32%)
    9 / 162 (5.56%)
    13 / 166 (7.83%)
         occurrences all number
    12
    15
    10
    13
    Bronchitis
         subjects affected / exposed
    5 / 162 (3.09%)
    6 / 164 (3.66%)
    9 / 162 (5.56%)
    7 / 166 (4.22%)
         occurrences all number
    6
    6
    11
    7
    Conjunctivitis
         subjects affected / exposed
    27 / 162 (16.67%)
    22 / 164 (13.41%)
    18 / 162 (11.11%)
    22 / 166 (13.25%)
         occurrences all number
    30
    25
    19
    25
    Croup infectious
         subjects affected / exposed
    11 / 162 (6.79%)
    12 / 164 (7.32%)
    7 / 162 (4.32%)
    12 / 166 (7.23%)
         occurrences all number
    14
    13
    7
    15
    Ear infection
         subjects affected / exposed
    5 / 162 (3.09%)
    10 / 164 (6.10%)
    6 / 162 (3.70%)
    8 / 166 (4.82%)
         occurrences all number
    9
    11
    12
    16
    Gastroenteritis
         subjects affected / exposed
    12 / 162 (7.41%)
    9 / 164 (5.49%)
    4 / 162 (2.47%)
    8 / 166 (4.82%)
         occurrences all number
    13
    11
    6
    8
    Nasopharyngitis
         subjects affected / exposed
    23 / 162 (14.20%)
    20 / 164 (12.20%)
    13 / 162 (8.02%)
    20 / 166 (12.05%)
         occurrences all number
    39
    36
    20
    30
    Otitis media
         subjects affected / exposed
    56 / 162 (34.57%)
    38 / 164 (23.17%)
    37 / 162 (22.84%)
    45 / 166 (27.11%)
         occurrences all number
    90
    69
    65
    75
    Otitis media acute
         subjects affected / exposed
    14 / 162 (8.64%)
    10 / 164 (6.10%)
    12 / 162 (7.41%)
    12 / 166 (7.23%)
         occurrences all number
    22
    15
    16
    23
    Pharyngitis
         subjects affected / exposed
    18 / 162 (11.11%)
    16 / 164 (9.76%)
    12 / 162 (7.41%)
    17 / 166 (10.24%)
         occurrences all number
    23
    22
    15
    21
    Pharyngitis streptococcal
         subjects affected / exposed
    7 / 162 (4.32%)
    7 / 164 (4.27%)
    10 / 162 (6.17%)
    5 / 166 (3.01%)
         occurrences all number
    9
    8
    12
    5
    Rhinitis
         subjects affected / exposed
    14 / 162 (8.64%)
    11 / 164 (6.71%)
    13 / 162 (8.02%)
    13 / 166 (7.83%)
         occurrences all number
    25
    20
    18
    19
    Sinusitis
         subjects affected / exposed
    11 / 162 (6.79%)
    16 / 164 (9.76%)
    8 / 162 (4.94%)
    13 / 166 (7.83%)
         occurrences all number
    13
    19
    9
    15
    Upper respiratory tract infection
         subjects affected / exposed
    62 / 162 (38.27%)
    54 / 164 (32.93%)
    51 / 162 (31.48%)
    64 / 166 (38.55%)
         occurrences all number
    99
    100
    82
    95
    Viral infection
         subjects affected / exposed
    18 / 162 (11.11%)
    14 / 164 (8.54%)
    12 / 162 (7.41%)
    17 / 166 (10.24%)
         occurrences all number
    21
    19
    15
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2009
    - Solicited local injection site reactions will be evaluated using CBER toxicity scales and solicited systemic reactions will be evaluated using a standardized severity scale employed in other Novartis Vaccines and Diagnostics studies in children in this age range. The previous version of the protocol included the DAIDS toxicity tables for use of solicited local and systemic reactions. - Types of solicited local reactions changed from: erythema, induration, edema, pruritus, and injection site tenderness to erythema, ecchymosis, induration, swelling, and tenderness at injection site. Types of solicited systemic reactions changed from: acute systemic allergic reaction, body pain, fatigue, malaise, chills, arthralgia, vomiting, diarrhea, and anorexia to sleepiness, diarrhea, vomiting, irritability, change in eating habits, persistent crying, and fever - Preferred route of body temperature measurement switched from oral measurement to rectal as the preferred route with axillary measurement as the back-up. -. Adjusted serious adverse events reporting to include subjects with confirmed “potentially life threatening” graded local and systemic reactions and laboratory abnormalities
    03 Feb 2010
    Added the secondary objective: To evaluate antibody persistence at 6 and 12 months post last study vaccination to evaluate immunogenicity against drifted strains (cross protection) and antibody persistence.
    08 Feb 2010
    - Increased visit windows for Visit 10 and Visit 16 additional blood draws to -7/+14 days - References to 6 and 12 months post-vaccination were replaced by day 202 and day 387 to be consistent with the inclusion of subjects receiving only one vaccination for optional blood draws at Visit 10 (Day 202) and Visit 16 (Day 387).

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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