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    Clinical Trial Results:
    A Phase 3, observer blind, randomized, non-influenza vaccine comparator-controlled, multi-country and multi-centre study of the efficacy of GSK Biologicals’ quadrivalent, inactivated, split virion, seasonal influenza vaccine candidate, GSK2282512A (FLU Q-QIV), administered intramuscularly in healthy children 3 to 8 years of age

    Summary
    EudraCT number
    2015-001514-97
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    09 Jan 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    04 May 2016
    First version publication date
    09 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    114541
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01218308
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l'Institut, 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 May 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To evaluate the efficacy of Q-QIV in the prevention of reverse transcriptase polymerase chain reaction (RT-PCR) confirmed influenza A and or B disease presenting as influenza like illness (ILI), compared to a non-influenza vaccine comparator (Havrix) in children 3 to 8 years of age. Influenza-like illness (ILI) was defined as the presence of an oral or axillary temperature ≥37.8° C in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose or nasal congestion
    Protection of trial subjects
    All subjects were supervised closely for at least 30 minutes following vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed-up for one month (minimum 30 days) following administration of the last dose of study vaccines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Dec 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bangladesh: 1000
    Country: Number of subjects enrolled
    Lebanon: 150
    Country: Number of subjects enrolled
    Turkey: 153
    Country: Number of subjects enrolled
    Dominican Republic: 1204
    Country: Number of subjects enrolled
    Honduras: 400
    Country: Number of subjects enrolled
    Panama: 204
    Country: Number of subjects enrolled
    Thailand: 1009
    Country: Number of subjects enrolled
    Philippines: 1100
    Worldwide total number of subjects
    5220
    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)
    5220
    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
    A total of 5168 subjects have been enrolled in this study. Primed subjects had received at least 1 dose of an influenza A (H1N1) 2009 monovalent vaccine and had received 2 doses of seasonal influenza vaccine. Unprimed subjects had not received any influenza A (H1N1) 2009 monovalent vaccine or seasonal influenza vaccine.

    Pre-assignment
    Screening details
    The duration of the study was approximately 4-8 weeks to complete enrolment, with at least six months extended safety follow-up (ESFU) after first vaccination, and lasted until the end of the influenza like illness (ILI) surveillance period.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Data was collected in an observer-blinded manner. Observer-blinded indicates that during the course of the study, the subjects (and their parents/LARs), the investigator, and those responsible for the evaluation of any study endpoint (e.g. safety, reactogenicity, and immunogenicity) and review/analysis of study data were all unaware of the treatment assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    FluLaval® Quadrivalent Group
    Arm description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of FluLaval® Quadrivalent vaccine at Day 0 and, if unprimed, 2 doses of FluLaval® Quadrivalent vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.
    Arm type
    Experimental

    Investigational medicinal product name
    FluLaval® Quadrivalent
    Investigational medicinal product code
    GSK2282512A
    Other name
    Quadrivalent seasonal influenza vaccine GSK2282512A (FLU Q-QIV)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One intramuscular dose for primed subjects. Two intramuscular doses for unprimed subjects.

    Arm title
    Havrix Group
    Arm description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of Havrix™ vaccine at Day 0 and, if unprimed, 2 doses of Havrix™ vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.
    Arm type
    Active comparator

    Investigational medicinal product name
    Havrix™
    Investigational medicinal product code
    HAV Antigen
    Other name
    Havrix 720 Junior
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Two intramuscular doses (booster dose included) for primed subjects. Three intramuscular doses (booster dose included) for unprimed subjects. The booster dose was administered after the study was completed.

    Number of subjects in period 1 [1]
    FluLaval® Quadrivalent Group Havrix Group
    Started
    2584
    2584
    Completed
    2481
    2464
    Not completed
    103
    120
         Adverse event, serious fatal
    1
    1
         Protocol Violation
    -
    2
         Adverse event, non-fatal
    -
    1
         Unspecified
    14
    21
         Consent withdrawn by subject
    61
    64
         Lost to follow-up
    27
    31
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 45 subjects from 1 center were excluded from the study due to GCP-related irregularities and the data (invalidated) from this center was not included in the subsequent data analysis of this study. Of the remaining 5175 subjects, 7 subjects enrolled in the study were allocated subject numbers but the study vaccine dose was not administered.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FluLaval® Quadrivalent Group
    Reporting group description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of FluLaval® Quadrivalent vaccine at Day 0 and, if unprimed, 2 doses of FluLaval® Quadrivalent vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.

    Reporting group title
    Havrix Group
    Reporting group description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of Havrix™ vaccine at Day 0 and, if unprimed, 2 doses of Havrix™ vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.

    Reporting group values
    FluLaval® Quadrivalent Group Havrix Group Total
    Number of subjects
    2584 2584 5168
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    5.4 ± 1.66 5.4 ± 1.65 -
    Gender categorical
    Units: Subjects
        Female
    1251 1245 2496
        Male
    1333 1339 2672

    End points

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    End points reporting groups
    Reporting group title
    FluLaval® Quadrivalent Group
    Reporting group description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of FluLaval® Quadrivalent vaccine at Day 0 and, if unprimed, 2 doses of FluLaval® Quadrivalent vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.

    Reporting group title
    Havrix Group
    Reporting group description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of Havrix™ vaccine at Day 0 and, if unprimed, 2 doses of Havrix™ vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.

    Primary: Number of subjects reporting at least one confirmed occurrence of influenza A or B.

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    End point title
    Number of subjects reporting at least one confirmed occurrence of influenza A or B. [1]
    End point description
    To confirm influenza A and/or B disease, a positive reverse transcriptase polymerase chain reaction (RT-PCR) result for influenza A or B virus from a nose and throat swab obtained concurrently with an influenza like illness (ILI) was required. ILI was defined as the presence of an oral or axillary temperature ≥ 37.8 degrees Celsius (°C) in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose or nasal congestion.
    End point type
    Primary
    End point timeframe
    From Day 14 to Day 180
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2379
    2398
    Units: Subjects
    58
    128
    No statistical analyses for this end point

    Secondary: Number of subjects reporting at least one moderate to severe occurrence of influenza A or B.

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    End point title
    Number of subjects reporting at least one moderate to severe occurrence of influenza A or B.
    End point description
    To confirm influenza A and/or B disease moderate to severe cases, a positive RT-PCR result for influenza A or B virus from a nose and throat swab obtained concurrently with an ILI was required. Moderate to severe influenza was defined as RT-PCR-confirmed ILI with: - Fever >39°C, and/or at least one of the following manifestations, - Physician-verified shortness of breath, pulmonary congestion, pneumonia, bronchiolitis, bronchitis, wheezing, croup, or acute otitis media, and/or one of the following, - Physician-diagnosed serious extra-pulmonary complication of influenza, including myositis, encephalitis, seizure, or myocarditis
    End point type
    Secondary
    End point timeframe
    From Day 14 to Day 180
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2379
    2398
    Units: Subjects
    14
    52
    No statistical analyses for this end point

    Secondary: Number of subjects reporting at least one Culture Confirmed occurrence of influenza A or B due to antigenically matched strain.

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    End point title
    Number of subjects reporting at least one Culture Confirmed occurrence of influenza A or B due to antigenically matched strain.
    End point description
    To confirm influenza A and/or B disease due to antigenically matched strain, a positive reverse transcriptase polymerase chain reaction (RT-PCR) result for influenza A or B virus from a nose and throat swab obtained concurrently with an influenza like illness (ILI) was required. ILI was defined as the presence of an oral or axillary temperature ≥ 37.8 degrees Celsius (°C) in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose or nasal congestion.
    End point type
    Secondary
    End point timeframe
    From Day 14 to Day 180
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2379
    2398
    Units: Subjects
    31
    56
    No statistical analyses for this end point

    Secondary: Number of subjects reporting at least one Culture Confirmed occurrence of influenza A or B due to any strain.

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    End point title
    Number of subjects reporting at least one Culture Confirmed occurrence of influenza A or B due to any strain.
    End point description
    To confirm influenza A and/or B disease due to any strain, a positive reverse transcriptase polymerase chain reaction (RT-PCR) result for influenza A or B virus from a nose and throat swab obtained concurrently with an influenza like illness (ILI) was required. ILI was defined as the presence of an oral or axillary temperature ≥ 37.8 degrees Celsius (°C) in the presence of at least one of the following symptoms on the same day: cough, sore throat, runny nose or nasal congestion.
    End point type
    Secondary
    End point timeframe
    From Day 14 to Day 180
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2379
    2398
    Units: Subjects
    50
    112
    No statistical analyses for this end point

    Secondary: Titers for serum Hemagglutination Inhibition (HI) antibodies against 4 strains of influenza disease.

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    End point title
    Titers for serum Hemagglutination Inhibition (HI) antibodies against 4 strains of influenza disease.
    End point description
    Titers are presented as geometric mean titers (GMTs). The reference cut-off value was the seropositivity cut-off of 1:10. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At Day 0 [PRE] and 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST]
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    457
    122
    Units: Titers
    geometric mean (confidence interval 95%)
        H1N1, PRE [N=457;117]
    15.3 (13.6 to 17.3)
    16.1 (12.6 to 20.5)
        H1N1, POST [N=457;121]
    318.8 (291 to 349.2)
    16.1 (12.8 to 20.2)
        H3N2, PRE [N=457;117]
    24.3 (21.9 to 27)
    28.6 (23.5 to 34.8)
        H3N2, POST [N=457;122]
    264.7 (244.3 to 286.8)
    30.3 (24.8 to 36.9)
        Victoria, PRE [N=457;117]
    13.7 (12.2 to 15.4)
    15.6 (12.2 to 20.1)
        Victoria, POST [N=457;120]
    239.9 (214.6 to 268.2)
    17.8 (13.7 to 23.1)
        Yamagata, PRE [N=457;117]
    16.2 (14.3 to 18.4)
    18.8 (14.4 to 24.5)
        Yamagata, POST [N=457;117]
    361.5 (330.7 to 395.3)
    19.2 (14.9 to 24.7)
    No statistical analyses for this end point

    Secondary: Number of seroconverted subjects against 4 strains of influenza disease.

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    End point title
    Number of seroconverted subjects against 4 strains of influenza disease.
    End point description
    A seroconverted subject was defined as a vaccinated subject who had either a pre-vaccination titer < 1:10 and a post-vaccination titer ≥ 1:40 or a pre-vaccination titer ≥ 1:10 and at least a four-fold increase in post-vaccination titer. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST]
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    457
    117
    Units: Subjects
        H1N1, POST
    438
    1
        H3N2, POST
    385
    2
        Victoria, POST
    425
    3
        Yamagata, POST
    435
    1
    No statistical analyses for this end point

    Secondary: Number of seroprotected subjects against 4 strains of influenza disease.

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    End point title
    Number of seroprotected subjects against 4 strains of influenza disease.
    End point description
    A seroprotected subject was defined as a vaccinated subject who had a serum HI titer ≥ 1:40. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At Day 0 [PRE] and 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST]
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    457
    122
    Units: Subjects
        H1N1, PRE [N=457;117]
    151
    37
        H1N1, POST [N=457;121]
    451
    39
        H3N2, PRE [N=457;117]
    205
    63
        H3N2, POST [N=457;122]
    445
    63
        Victoria, PRE [N=457;117]
    127
    35
        Victoria, POST [N=457;120]
    443
    38
        Yamagata, PRE [N=457;117]
    159
    45
        Yamagata, POST [N=457;117]
    452
    45
    No statistical analyses for this end point

    Secondary: Seroconversion factor for Hemagglutination Inhibition (HI) antibodies against 4 strains of influenza disease.

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    End point title
    Seroconversion factor for Hemagglutination Inhibition (HI) antibodies against 4 strains of influenza disease.
    End point description
    The seroconversion factor (SCF) was defined as the fold increase in serum Hemagglutination Inhibition (HI) geometric mean titers (GMTs) post vaccination compared to Day 0. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At 28 days post vaccination (Day 28 for primed subjects and day 56 for unprimed subjects) [POST]
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    457
    117
    Units: fold increase
    geometric mean (confidence interval 95%)
        H1N1, POST
    20.8 (19 to 22.8)
    1 (0.9 to 1.1)
        H3N2, POST
    10.9 (9.8 to 12.1)
    1 (0.9 to 1.2)
        Victoria, POST
    17.5 (16 to 19.1)
    1.1 (1 to 1.3)
        Yamagata, POST
    22.3 (20.1 to 24.8)
    1 (1 to 1.1)
    No statistical analyses for this end point

    Secondary: Haemagglutination Inhibition (HI) antibody titers against each of the 4 vaccine strains

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    End point title
    Haemagglutination Inhibition (HI) antibody titers against each of the 4 vaccine strains
    End point description
    HI antibody titres were expressed as Geometric mean titers (GMTs). The vaccine strains assessed were Flu A/California/7/2009 (H1N1), Flu A/Victoria/210/09 (H3N2), Flu B/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    On Day 0 and at least 6 months after first vaccination (Month 6)
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    444
    112
    Units: Titer
    geometric mean (confidence interval 95%)
        H1N1, PRE [N=444;112]
    15.5 (13.8 to 17.6)
    16.5 (12.9 to 21.2)
        H1N1, POST [N=444;112]
    138.6 (122.6 to 156.6)
    23.2 (17.9 to 30.1)
        H3N2, PRE [N=444;112]
    24.6 (22.1 to 27.4)
    29.1 (23.8 to 35.5)
        H3N2, POST [N=443;112]
    136.5 (124.3 to 149.9)
    43.6 (34.9 to 54.5)
        Victoria, PRE [N=444;112]
    13.7 (12.2 to 15.4)
    15.1 (11.8 to 19.5)
        Victoria, POST [N=443;112]
    110.2 (97.1 to 125)
    19.7 (15 to 25.8)
        Yamagata, PRE [N=444;112]
    16.1 (14.2 to 18.4)
    18.7 (14.3 to 24.6)
        Yamagata, POST [N=444;112]
    157 (143.1 to 172.3)
    21.8 (16.5 to 28.9)
    No statistical analyses for this end point

    Secondary: Number of seroconverted subjects for HI antibody titers against each of the 4 vaccine influenza strains.

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    End point title
    Number of seroconverted subjects for HI antibody titers against each of the 4 vaccine influenza strains.
    End point description
    A seroconverted subject was defined as a vaccinated subject with either a pre-vaccination titer less than (<) 1:10 and a post-vaccination titer greater than or equal to (≥) 1:40, or a pre-vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination titer. The vaccine strains assessed were Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At least 6 months after first vaccination (Month 6)
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    444
    112
    Units: Subjects
        H1N1, POST [N=444;112]
    349
    9
        H3N2, POST [N=443;112]
    290
    10
        Victoria, POST [N=443;112]
    323
    12
        Yamagata, POST [N=444;112]
    354
    8
    No statistical analyses for this end point

    Secondary: Number of seroprotected subjects for HI antibody titers against each of the 4 vaccine influenza strains.

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    End point title
    Number of seroprotected subjects for HI antibody titers against each of the 4 vaccine influenza strains.
    End point description
    A seroprotected subject was defined as a vaccinated subject with a serum HI titer greater than or equal to (≥) 1:40 that usually is accepted as indicating protection in adults. The vaccine strains assessed were Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At Day 0 and at least 6 months after first vaccination (Month 6)
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    444
    112
    Units: Subjects
        H1N1, PRE [N=444;112]
    148
    36
        H1N1, POST [N=444;112]
    383
    49
        H3N2, PRE [N=444;112]
    204
    60
        H3N2, POST [N=443;112]
    412
    71
        Victoria, PRE [N=444;112]
    123
    32
        Victoria, POST [N=443;112]
    374
    39
        Yamagata, PRE [N=444;112]
    153
    43
        Yamagata, POST [N=444;112]
    427
    49
    No statistical analyses for this end point

    Secondary: Seroconversion factors for HI antibodies against 4 strains of influenza disease.

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    End point title
    Seroconversion factors for HI antibodies against 4 strains of influenza disease.
    End point description
    Seroconversion factors were defined as the fold increase in serum HI GMTs post-vaccination compared to Day 0. The 4 influenza strains assessed were the Flu A/California/7/09 (H1N1), Flu A/Victoria/210/09 (H3N2), FluB/Brisbane/60/08 (Victoria) and Flu B/Florida/4/06 (Yamagata).
    End point type
    Secondary
    End point timeframe
    At least 6 months after first vaccination (Month 6)
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    444
    112
    Units: Fold increase
    geometric mean (confidence interval 95%)
        H1N1, POST [N=444;112]
    8.9 (8.1 to 9.8)
    1.4 (1.2 to 1.6)
        H3N2, POST [N=443;112]
    5.5 (5 to 6.1)
    1.5 (1.2 to 1.8)
        Victoria, POST [N=443;112]
    8 (7.3 to 8.9)
    1.3 (1.1 to 1.6)
        Yamagata, POST [N=444;112]
    9.7 (8.7 to 10.8)
    1.2 (1 to 1.4)
    No statistical analyses for this end point

    Secondary: Number of subjects with any, grade 3 and related solicited local symptoms.

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    End point title
    Number of subjects with any, grade 3 and related solicited local symptoms.
    End point description
    Assessed solicited local symptoms were pain, redness and swelling at the injection site. Any = Incidence of a particular symptom regardless of intensity grade. Grade 3 pain = Cried when limb was moved/spontaneously painful for subjects < 5 years of age or significant pain at rest that prevented normal, everyday activities for subjects ≥ 5 years of age. Grade 3 redness/swelling = Redness/swelling above 100 millimeters (mm) of the injection site. All solicited local symptoms were considered related to vaccination.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) follow-up period after any vaccination
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2546
    2551
    Units: Subjects
        Any Pain
    1251
    888
        Grade 3 Pain
    36
    20
        Any Redness
    17
    5
        Grade 3 Redness
    0
    0
        Any Swelling
    46
    10
        Grade 3 Swelling
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with any, grade 3 and related solicited general symptoms in subjects below 5 years of age.

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    End point title
    Number of subjects with any, grade 3 and related solicited general symptoms in subjects below 5 years of age.
    End point description
    Assessed solicited general symptoms were drowsiness, irritability, loss of appetite and temperature. Any = Occurrence of any solicited general symptom regardless of intensity grade and relation to vaccination. Any temperature = Axillary temperature ≥ 38.0 °C. Grade 3 Drowsiness = Drowsiness that prevented normal activity. Grade 3 Irritability = Crying that could not be comforted/prevented normal activity. Grade 3 Loss of appetite = not eating at all. Related = General symptom assessed by the investigator as causally related to the study vaccination. Grade 3 temperature = Axillary temperature ≥ 39.0°C.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) follow-up period after any vaccination
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    899
    896
    Units: Subjects
        Any Drowsiness
    100
    93
        Grade 3 Drowsiness
    5
    4
        Related Drowsiness
    57
    61
        Any Irritability
    102
    91
        Grade 3 Irritability
    5
    4
        Related Irritability
    60
    59
        Any Loss of appetite
    119
    120
        Grade 3 Loss of appetite
    6
    7
        Related Loss of appetite
    55
    61
        Any Temperature
    74
    74
        Grade 3 Temperature
    21
    18
        Related Temperature
    35
    35
    No statistical analyses for this end point

    Secondary: Number of subjects with any, grade 3 and related solicited general symptoms in subjects of 5 years of age and above.

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    End point title
    Number of subjects with any, grade 3 and related solicited general symptoms in subjects of 5 years of age and above.
    End point description
    Assessed solicited general symptoms were fatigue, gastrointestinal symptoms (Gastro.), headache, joint pain at other location (Joint pain), muscle aches, shivering and temperature. Any = Occurrence of any solicited general symptom regardless of intensity grade or relation to vaccination. Any temperature = Axillary temperature ≥ 38.0 °C. Grade 3 symptom = Symptom that prevented normal activity. Related = Symptom assessed by the investigator as causally related to the vaccination. Grade 3 temperature = Axillary temperature ≥ 39.0°C.
    End point type
    Secondary
    End point timeframe
    During the 7-day (Days 0-6) follow-up period after any vaccination
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    1648
    1654
    Units: Subjects
        Any Fatigue
    188
    145
        Grade 3 Fatigue
    1
    6
        Related Fatigue
    101
    78
        Any Gastro.
    133
    146
        Grade 3 Gastro.
    9
    9
        Related Gastro.
    68
    54
        Any Headache
    243
    217
        Grade 3 Headache
    9
    14
        Related Headache
    154
    125
        Any Joint pain
    143
    93
        Grade 3 Joint pain
    3
    2
        Related Joint pain
    98
    54
        Any Muscle aches
    257
    194
        Grade 3 Muscle aches
    3
    5
        Related Muscle aches
    162
    109
        Any Shivering
    63
    59
        Grade 3 Shivering
    2
    2
        Related Shivering
    32
    26
        Any Temperature
    72
    82
        Grade 3 Temperature
    21
    17
        Related Temperature
    46
    37
    No statistical analyses for this end point

    Secondary: Number of subjects with any, grade 3 and related unsolicited adverse events (AEs).

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    End point title
    Number of subjects with any, grade 3 and related unsolicited adverse events (AEs).
    End point description
    Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any = Any unsolicited AE regardless of intensity or relationship to vaccination. Grade 3 = Unsolicited AE that prevented normal activity. Related = Unsolicited AE assessed by the investigator as causally related to the vaccination.
    End point type
    Secondary
    End point timeframe
    During the 28-day (Days 0-27) follow-up period after vaccination
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2584
    2584
    Units: Subjects
        Any unsolicited AE(s)
    843
    855
        Grade 3 unsolicited AE(s)
    25
    20
        Related unsolicited AE(s)
    30
    37
    No statistical analyses for this end point

    Secondary: Number of subjects with any and related medically attended adverse events (MAEs).

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    End point title
    Number of subjects with any and related medically attended adverse events (MAEs).
    End point description
    MAEs were defined as AEs that resulted in medical attention (defined as hospitalization, an emergency room visit or a visit to or from medical personnel for any reason). Any = Any MAE regardless of intensity or relationship to vaccination. Related = MAE assessed by the investigator as causally related to the vaccination.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 0 - Day 180)
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2584
    2584
    Units: Subjects
        Any MAE(s)
    792
    749
        Related MAE(s)
    6
    13
    No statistical analyses for this end point

    Secondary: Number of subjects with any and related potential immune-mediated diseases (pIMDs).

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    End point title
    Number of subjects with any and related potential immune-mediated diseases (pIMDs).
    End point description
    pIMDs were defined as a subset of AEs that included both clearly autoimmune diseases (AID) and also other inflammatory and/or neurologic disorders which may or may not have an autoimmune etiology. Any = Any pIMD(s) regardless of intensity or relationship to vaccination. Related = pIMDs assessed by the investigator as causally related to the vaccination.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 0 - Day 180)
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2584
    2584
    Units: Subjects
        Any pIMD(s)
    0
    1
        Related pIMD(s)
    0
    0
    No statistical analyses for this end point

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

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    End point title
    Number of subjects with any and related serious adverse events (SAEs).
    End point description
    Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. Any = Any SAE(s) regardless of intensity or relationship to vaccination. Related = SAEs assessed by the investigator as causally related to the vaccination.
    End point type
    Secondary
    End point timeframe
    During the entire study period (Day 0 - Day 180)
    End point values
    FluLaval® Quadrivalent Group Havrix Group
    Number of subjects analysed
    2584
    2584
    Units: Subjects
        Any SAE(s)
    36
    24
        Related SAE(s)
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: during the entire study period (Day 0-Day 180); Unsolicited AEs: during the 28-day (Day 0-Day 27) follow-up period after vaccination; Solicited local/general symptoms: during the 7-day (Day 0-Day 6) follow-up period after any vaccination.
    Adverse event reporting additional description
    For the systematically assessed other non-serious AEs, the number of participants at risk included those from Total Vaccinated cohort whose symptom sheet had been completed.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    FluLaval® Quadrivalent Group
    Reporting group description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of FluLaval® Quadrivalent vaccine at Day 0 and, if unprimed, 2 doses of FluLaval® Quadrivalent vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.

    Reporting group title
    Havrix Group
    Reporting group description
    Subjects between 3 and 8 years of age at the time of first vaccination received, if primed, 1 dose of Havrix™ vaccine at Day 0 and, if unprimed, 2 doses of Havrix™ vaccine at Days 0 and 28. The vaccine was administered intramuscularly in the deltoid muscle of the non-dominant arm.

    Serious adverse events
    FluLaval® Quadrivalent Group Havrix Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 2584 (1.39%)
    24 / 2584 (0.93%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    3 / 2584 (0.12%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal scratch
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Optic nerve glioma
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 2584 (0.04%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drowning
         subjects affected / exposed
    1 / 2584 (0.04%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Influenza like illness
         subjects affected / exposed
    1 / 2584 (0.04%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    6 / 2584 (0.23%)
    3 / 2584 (0.12%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 2584 (0.15%)
    3 / 2584 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 2584 (0.04%)
    3 / 2584 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    2 / 2584 (0.08%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 2584 (0.04%)
    2 / 2584 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 2584 (0.12%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    1 / 2584 (0.04%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 2584 (0.08%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebic dysentery
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpangina
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 2584 (0.04%)
    0 / 2584 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visceral leishmaniasis
         subjects affected / exposed
    0 / 2584 (0.00%)
    1 / 2584 (0.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    FluLaval® Quadrivalent Group Havrix Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1251 / 2584 (48.41%)
    888 / 2584 (34.37%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    145 / 2584 (5.61%)
    137 / 2584 (5.30%)
         occurrences all number
    145
    137
    General disorders and administration site conditions
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    1215 / 2546 (47.72%)
    888 / 2551 (34.81%)
         occurrences all number
    1215
    888
    Drowsiness
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    100 / 899 (11.12%)
    93 / 896 (10.38%)
         occurrences all number
    100
    93
    Irritability
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    102 / 899 (11.35%)
    91 / 896 (10.16%)
         occurrences all number
    102
    91
    Loss of appetite
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    119 / 899 (13.24%)
    120 / 896 (13.39%)
         occurrences all number
    119
    120
    Temperature
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    74 / 899 (8.23%)
    74 / 896 (8.26%)
         occurrences all number
    74
    74
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    188 / 1648 (11.41%)
    145 / 1654 (8.77%)
         occurrences all number
    188
    145
    Gastro.
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    133 / 1648 (8.07%)
    146 / 1654 (8.83%)
         occurrences all number
    133
    146
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    243 / 1648 (14.75%)
    217 / 1654 (13.12%)
         occurrences all number
    243
    217
    Joint pain
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    143 / 1648 (8.68%)
    93 / 1654 (5.62%)
         occurrences all number
    143
    93
    Muscle aches
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    257 / 1648 (15.59%)
    194 / 1654 (11.73%)
         occurrences all number
    257
    194
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    213 / 2584 (8.24%)
    231 / 2584 (8.94%)
         occurrences all number
    213
    231
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed on Total Vaccinated cohort which included all subjects with the vaccine administration documented and symptom sheet completed only on subjects that reported the specific symptom. Subjects who missed reporting symptoms (solicited/unsolicited or concomitant medications) were treated as subjects without symptoms (solicited/unsolicited or concomitant medications, respectively).

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2011
    The overall rationale for this amendment is two-fold. First, the protocol is being amended to implement changes to the protocol of the study’s first year (in progress). Second, the amendment also facilitates the use of the protocol for a potential extension of the study to a second year, based on the outcome of a benefit interim analysis planned for the end of the first year.
    28 Jul 2011
    The original protocol indicated that the study would conclude at the end of the extended safety follow-up (ESFU) visit. This amended protocol recommends that wherever possible, the ESFU visit (provided it occurs at least six months after the first vaccination) should be scheduled to coincide with the end of the ILI surveillance period so that it will not be necessary to have a separate final contact with subjects at the end of ILI surveillance. However, in the event that subjects in a particular country complete the ESFU visit prior to the end of the ILI surveillance period, this amendment to the protocol adds a final phone contact at the end of the ILI surveillance period to conclude the study. This final phone contact will enable the collection of essential subject data from the subjects for whom the ILI surveillance continues after the ESFU visit and the phone contact will also enable study conclusion for these subjects.

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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