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    Clinical Trial Results:
    Lot-to-Lot Consistency Study of the Investigational, Split-virion, Inactivated Influenza Vaccine, Administered by the Intradermal Route in Adults

    Summary
    EudraCT number
    2006-002369-37
    Trial protocol
    LT   ES   GB  
    Global end of trial date
    06 Jun 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Feb 2016
    First version publication date
    04 Dec 2014
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GID23
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00383539
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur SA
    Sponsor organisation address
    1541, Avenue Marcel Mérieux, Marcy L’Etoile, France, 69280
    Public contact
    Director, Clinical Development, Sanofi Pasteur SA, 33 (4) 37 37 58 50, stephanie.pepin@sanofipasteur.com
    Scientific contact
    Director, Clinical Development, Sanofi Pasteur SA, 33 (4) 37 37 58 50, stephanie.pepin@sanofipasteur.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the three different industrial lots of the intradermal (ID) investigational vaccine induce an equivalent immune response.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment were also available on site in case of any immediate allergic reactions.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    11 Sep 2006
    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
    Spain: 211
    Country: Number of subjects enrolled
    United Kingdom: 896
    Country: Number of subjects enrolled
    France: 1048
    Country: Number of subjects enrolled
    Lithuania: 100
    Worldwide total number of subjects
    2255
    EEA total number of subjects
    2255
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    2255
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study subjects were enrolled from 11 September 2006 to 31 October 2006 in 26 clinical centers (13 in France, 9 in United Kingdom, 3 in Spain, and 1 in Lithuania).

    Pre-assignment
    Screening details
    A total of 2255 subjects who met all inclusion criteria and none of the exclusion criteria were enrolled and vaccinated.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ID 9 µg Lot 1
    Arm description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 1 investigational inactivated, split-virion influenza vaccine on Day 0.
    Arm type
    Experimental

    Investigational medicinal product name
    Intradermal Influenza Vaccine
    Investigational medicinal product code
    333
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    0.1 mL, intradermal into the upper arm (deltoid area), one dose on Day 0.

    Arm title
    ID 9 µg Lot 2
    Arm description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 2 investigational inactivated, split-virion influenza vaccine on Day 0.
    Arm type
    Experimental

    Investigational medicinal product name
    Intradermal Influenza Vaccine
    Investigational medicinal product code
    333
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    0.1 mL, intradermal into the upper arm (deltoid area), one dose on Day 0.

    Arm title
    ID 9 µg Lot 3
    Arm description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 3 investigational inactivated, split-virion influenza vaccine on Day 0.
    Arm type
    Experimental

    Investigational medicinal product name
    Intradermal Influenza Vaccine
    Investigational medicinal product code
    333
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    0.1 mL, intradermal into the upper arm (deltoid area), one dose on Day 0.

    Arm title
    IM 15 µg
    Arm description
    Subjects who received one dose of intramuscular (IM) 15 µg investigational inactivated, split-virion influenza vaccine on Day 0.
    Arm type
    Active comparator

    Investigational medicinal product name
    Inactivated, split-virion, influenza vaccine
    Investigational medicinal product code
    Other name
    VAXIGRIP
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular into the upper arm (deltoid area), one dose on Day 0.

    Number of subjects in period 1
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Started
    604
    596
    603
    452
    Completed
    596
    586
    594
    443
    Not completed
    8
    10
    9
    9
         Protocol deviation
             3
             2
             2
             2
         Consent withdrawn by subject
             1
             1
             1
             2
         Lost to follow-up
             4
             7
             6
             5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ID 9 µg Lot 1
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 1 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    ID 9 µg Lot 2
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 2 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    ID 9 µg Lot 3
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 3 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    IM 15 µg
    Reporting group description
    Subjects who received one dose of intramuscular (IM) 15 µg investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group values
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg Total
    Number of subjects
    604 596 603 452 2255
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    604 596 603 452 2255
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.9 ± 12.6 43.4 ± 12.6 42.9 ± 12.4 42 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    356 345 343 268 1312
        Male
    248 251 260 184 943

    End points

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    End points reporting groups
    Reporting group title
    ID 9 µg Lot 1
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 1 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    ID 9 µg Lot 2
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 2 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    ID 9 µg Lot 3
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 3 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    IM 15 µg
    Reporting group description
    Subjects who received one dose of intramuscular (IM) 15 µg investigational inactivated, split-virion influenza vaccine on Day 0.

    Primary: Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies Before and After Vaccination with One of Three Lots of Inactivated, Split-Virion Influenza Vaccine Administered by Intradermal Route

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies Before and After Vaccination with One of Three Lots of Inactivated, Split-Virion Influenza Vaccine Administered by Intradermal Route
    End point description
    Influenza vaccine antibodies were assessed using the hemagglutination inhibition technique.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 post vaccination
    End point values
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Number of subjects analysed
    418
    418
    414
    452
    Units: Titers
    geometric mean (confidence interval 95%)
        A/New Caledonia/20/99 (H1N1; Day 0)
    18.8 (16.4 to 21.5)
    20 (17.3 to 23)
    19.7 (17.1 to 22.8)
    0 (0 to 0)
        A/Wisconsin 67/2005(H3N2; Day 0)
    24.1 (20.9 to 27.8)
    24.9 (21.4 to 29)
    22.4 (19.5 to 25.8)
    0 (0 to 0)
        B/Malaysia 25/06/2004 (Day 0)
    10.9 (10.1 to 11.9)
    10.4 (9.62 to 11.3)
    10.4 (9.56 to 11.3)
    0 (0 to 0)
        A/New Caledonia/20/99 (H1N1; Day 21)
    186 (162 to 214)
    183 (159 to 211)
    176 (152 to 204)
    0 (0 to 0)
        A/Wisconsin 67/2005(H3N2; Day 21)
    269 (236 to 307)
    298 (260 to 340)
    268 (234 to 308)
    0 (0 to 0)
        B/Malaysia 25/06/2004 (Day 21)
    67.6 (61 to 74.9)
    75.4 (67.4 to 84.3)
    62.4 (55.8 to 69.7)
    0 (0 to 0)
    Statistical analysis title
    Equivalence of ID Vaccine Lot 1 and Lot 2 (H1N1)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 1 v ID 9 µg Lot 2
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [1]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    0.006
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.065
         upper limit
    0.078
    Notes
    [1] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 1 and Lot 3 (H1N1)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 1 v ID 9 µg Lot 3
    Number of subjects included in analysis
    832
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [2]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    0.023
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.051
         upper limit
    0.096
    Notes
    [2] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 2 and Lot 3 (H1N1)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 2 v ID 9 µg Lot 3
    Number of subjects included in analysis
    832
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [3]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    0.017
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.057
         upper limit
    0.09
    Notes
    [3] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 1 and Lot 2 (H3N2)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 1 v ID 9 µg Lot 2
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [4]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.044
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.113
         upper limit
    0.025
    Notes
    [4] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 1 and Lot 3 (H3N2)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 3 v ID 9 µg Lot 1
    Number of subjects included in analysis
    832
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [5]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    0.001
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.068
         upper limit
    0.07
    Notes
    [5] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 2 and Lot 3 (H3N2)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 3 v ID 9 µg Lot 2
    Number of subjects included in analysis
    832
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [6]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    0.045
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.025
         upper limit
    0.115
    Notes
    [6] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 1 and Lot 2 (B)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 2 v ID 9 µg Lot 1
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [7]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.047
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.102
         upper limit
    0.008
    Notes
    [7] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 1 and Lot 3 (B)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 1 v ID 9 µg Lot 3
    Number of subjects included in analysis
    832
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [8]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    0.035
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.09
    Notes
    [8] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.
    Statistical analysis title
    Equivalence of ID Vaccine Lot 2 and Lot 3 (B)
    Statistical analysis description
    Equivalence among the three lots was demonstrated if all individual null hypotheses were rejected i.e. if the equivalence was demonstrated for each pair of lots and for each strain. The global hypotheses were: H0Global: Equivalence between the three lots is not demonstrated for at least one strain H1Global: Equivalence between the three lots is demonstrated for all strains
    Comparison groups
    ID 9 µg Lot 3 v ID 9 µg Lot 2
    Number of subjects included in analysis
    832
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [9]
    Method
    Log transformation
    Parameter type
    Mean difference (final values)
    Point estimate
    0.082
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.139
    Notes
    [9] - The statistical methodology was based on the use of the two-sided 90% confidence interval (CI) of the differences of the means of the log10 transformed post-vaccination titers between pairs of lots. The CI for differences was calculated using normal approximation of log-transformed titers. Equivalence between the two lots was demonstrated if, the two-sided 90% CI of the difference lies between -0.176 and 0.176.

    Primary: Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies Before and After Vaccination with Either One of Three Lots of Inactivated, Split-Virion Influenza Vaccine Administered by Intradermal or by Intramuscular Route

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    End point title
    Geometric Mean Titers (GMTs) of Influenza Vaccine Antibodies Before and After Vaccination with Either One of Three Lots of Inactivated, Split-Virion Influenza Vaccine Administered by Intradermal or by Intramuscular Route [10]
    End point description
    Influenza vaccine antibodies were assessed using the hemagglutination inhibition technique.
    End point type
    Primary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 post vaccination
    Notes
    [10] - 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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome.
    End point values
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Number of subjects analysed
    604
    596
    414
    421
    Units: Titers
    geometric mean (confidence interval 95%)
        A/New Caledonia/20/99 (H1N1; Day 0)
    0 (0 to 0)
    0 (0 to 0)
    19.5 (18 to 21.1)
    19.2 (16.6 to 22.3)
        A/Wisconsin 67/2005(H3N2; Day 0)
    0 (0 to 0)
    0 (0 to 0)
    23.8 (21.9 to 25.8)
    24.1 (20.9 to 27.9)
        B/Malaysia 25/06/2004 (Day 0)
    0 (0 to 0)
    0 (0 to 0)
    10.6 (10.1 to 11.1)
    10.4 (9.65 to 11.3)
        A/New Caledonia/20/99 (H1N1; Day 21)
    0 (0 to 0)
    0 (0 to 0)
    182 (168 to 197)
    187 (162 to 216)
        A/Wisconsin 67/2005(H3N2; Day 21)
    0 (0 to 0)
    0 (0 to 0)
    278 (257 to 301)
    274 (244 to 309)
        B/Malaysia 25/06/2004 (Day 21)
    0 (0 to 0)
    0 (0 to 0)
    68.3 (64.1 to 72.7)
    69.8 (62.7 to 77.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Seroconversion Against Each Influenza Vaccine Antigen Following Vaccination with Inactivated, Split-Virion Influenza Vaccine Administered by Either Intradermal (1 of 3 lots) or by Intramuscular Route

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    End point title
    Percentage of Subjects Achieving Seroconversion Against Each Influenza Vaccine Antigen Following Vaccination with Inactivated, Split-Virion Influenza Vaccine Administered by Either Intradermal (1 of 3 lots) or by Intramuscular Route
    End point description
    Influenza vaccine antibodies were assessed using the hemagglutination inhibition technique. Seroconversion was defined as subjects with a pre-vaccination anti-HA antibody individual titer <10 (1/dil): post-vaccination anti-HA antibody individual titer ≥40 (1/dil) or significant increase in subjects with a pre-vaccination anti-HA antibody individual titer ≥10 (1/dil): ≥ four-fold increase from pre- to post-vaccination anti-HA antibody individual titer on Day 21.
    End point type
    Secondary
    End point timeframe
    Day 21 post-vaccination
    End point values
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Number of subjects analysed
    217
    224
    231
    230
    Units: Percentage of subjects
    number (not applicable)
        A/New Caledonia/20/99 (H1N1)
    81.3
    79.5
    78
    77.9
        A/Wisconsin 67/2005 (H3N2)
    84.7
    86.8
    88.1
    90.8
        B/Malaysia 25/06/2004
    66.4
    65.6
    64.1
    66.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Seroprotection Against Each Influenza Antigen Before and After Vaccination with Inactivated, Split-Virion Influenza Vaccine Administered by Either Intradermal (1 of 3 lots) or Intramuscular Route

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    End point title
    Percentage of Subjects with Seroprotection Against Each Influenza Antigen Before and After Vaccination with Inactivated, Split-Virion Influenza Vaccine Administered by Either Intradermal (1 of 3 lots) or Intramuscular Route
    End point description
    Influenza vaccine antibodies were assessed using the hemagglutination inhibition technique. Seroprotection was defined as titers ≥40 (1/dil) on Day 21.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and Day 21 post-vaccination
    End point values
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Number of subjects analysed
    441
    428
    428
    436
    Units: Percentage of subjects
    number (not applicable)
        A/New Caledonia/20/99 (H1N1; Day 0)
    33.2
    31.4
    33.6
    31.2
        A/New Caledonia/20/99 (H1N1; Day 21)
    88.2
    88.1
    85.3
    86.2
        A/Wisconsin 67/2005 (H3N2; Day 0)
    38.3
    38.8
    36
    38.1
        A/Wisconsin 67/2005 (H3N2; Day 21)
    92.5
    94.4
    93.7
    95.4
        B/Malaysia 25/06/2004 (B; Day 0)
    11.1
    10
    9.9
    8.5
        B/Malaysia 25/06/2004 (B; Day 21)
    74.3
    73.4
    70.9
    74.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Solicited Injection Site or Systemic Reaction Following Vaccination with One of Three Lots of Inactivated, Split-Virion Influenza Vaccine Administered by Intradermal or by Intramuscular Route

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    End point title
    Percentage of Subjects Reporting Solicited Injection Site or Systemic Reaction Following Vaccination with One of Three Lots of Inactivated, Split-Virion Influenza Vaccine Administered by Intradermal or by Intramuscular Route
    End point description
    Solicited injection site: Pain, Erythema, Swelling, Induration, Ecchymosis, and Pruritus. Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Shivering. Severe injection site: Pain and Pruritus – Incapacitating, unable to perform usual activities, may have/or required medical care or absenteeism; Erythema, Swelling, Induration, and Ecchymosis – ≥5 cm. Severe systemic reactions: Fever – >39.6°C rectal; Headache, Malaise, Myalgia, and Shivering – Prevents daily activities.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 7 post-vaccination
    End point values
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Number of subjects analysed
    604
    592
    600
    452
    Units: Percentage of subjects
    number (not applicable)
        Injection site Pain
    46.2
    41.8
    41.4
    48.4
        Severe Injection site Pain
    0.2
    0
    0.2
    0.2
        Injection site Erythema
    82.8
    84.4
    86
    25.5
        Severe Injection site Erythema
    18.6
    22.6
    17.2
    4.7
        Injection site Swelling
    61.5
    62.1
    62
    20.7
        Severe Injection site Swelling
    6.9
    8.2
    6.9
    2.7
        Injection site Induration
    63.4
    58.5
    60.5
    26.1
        Severe Injection site Induration
    5.2
    6
    4.7
    1.8
        Injection site Ecchymosis
    10.5
    9.9
    9.5
    9.9
        Severe Injection site Ecchymosis
    0.5
    0.7
    0.7
    0.7
        Injection site Pruritus
    45.3
    44.5
    44.6
    13.1
        Severe Injection site Pruritus
    0.8
    0.7
    0
    0.2
        Fever
    3.2
    5
    3.5
    3.4
        Severe Fever
    0
    0.3
    0.2
    0.4
        Headache
    30.3
    29.5
    27.7
    30
        Severe Headache
    1.5
    1.2
    1.2
    1.6
        Malaise
    18.6
    18.2
    17.9
    19.4
        Severe Malaise
    2
    1.2
    1.9
    1.6
        Myalgia
    23.6
    22.5
    24.5
    29.5
        Severe Myalgia
    2
    0.7
    0.7
    1.6
        Shivering
    10.5
    8.1
    9.6
    7.4
        Severe Shivering
    1
    0.5
    0.2
    0.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from Day 0 (post-vaccination) up to Day 21 post-vaccination.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    7.1
    Reporting groups
    Reporting group title
    ID 9 µg Lot 1
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 1 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    ID 9 µg Lot 2
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 2 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    ID 9 µg Lot 3
    Reporting group description
    Subjects who received one dose of intradermal (ID) 9 µg Lot 3 investigational inactivated, split-virion influenza vaccine on Day 0.

    Reporting group title
    IM 15 µg
    Reporting group description
    Subjects who received one dose of intramuscular (IM) 15 µg investigational inactivated, split-virion influenza vaccine on Day 0.

    Serious adverse events
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    1 / 603 (0.17%)
    1 / 452 (0.22%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    0 / 603 (0.00%)
    1 / 452 (0.22%)
         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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    1 / 603 (0.17%)
    0 / 452 (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
    Blood and lymphatic system disorders
    Necrotising granulomatous lymphadenitis
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    1 / 603 (0.17%)
    0 / 452 (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
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    1 / 603 (0.17%)
    0 / 452 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    1 / 603 (0.17%)
    0 / 452 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    1 / 603 (0.17%)
    0 / 452 (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
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 604 (0.00%)
    0 / 596 (0.00%)
    1 / 603 (0.17%)
    0 / 452 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ID 9 µg Lot 1 ID 9 µg Lot 2 ID 9 µg Lot 3 IM 15 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    495 / 604 (81.95%)
    493 / 596 (82.72%)
    509 / 603 (84.41%)
    215 / 452 (47.57%)
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    181 / 598 (30.27%)
    172 / 583 (29.50%)
    164 / 592 (27.70%)
    133 / 444 (29.95%)
         occurrences all number
    181
    172
    164
    133
    General disorders and administration site conditions
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    276 / 598 (46.15%)
    244 / 584 (41.78%)
    245 / 592 (41.39%)
    215 / 444 (48.42%)
         occurrences all number
    276
    244
    245
    215
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    495 / 598 (82.78%)
    493 / 584 (84.42%)
    509 / 592 (85.98%)
    113 / 444 (25.45%)
         occurrences all number
    495
    493
    509
    113
    Injection site swelling
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    368 / 598 (61.54%)
    362 / 583 (62.09%)
    367 / 592 (61.99%)
    92 / 444 (20.72%)
         occurrences all number
    368
    362
    367
    92
    Injection site induration
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    379 / 598 (63.38%)
    341 / 583 (58.49%)
    358 / 592 (60.47%)
    116 / 444 (26.13%)
         occurrences all number
    379
    341
    358
    116
    Injection site ecchymosis
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    63 / 598 (10.54%)
    58 / 583 (9.95%)
    56 / 592 (9.46%)
    44 / 444 (9.91%)
         occurrences all number
    63
    58
    56
    44
    Injection site pruritus
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    271 / 598 (45.32%)
    260 / 584 (44.52%)
    264 / 592 (44.59%)
    58 / 444 (13.06%)
         occurrences all number
    271
    260
    264
    58
    Fever
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    19 / 598 (3.18%)
    29 / 584 (4.97%)
    21 / 592 (3.55%)
    15 / 445 (3.37%)
         occurrences all number
    19
    29
    21
    15
    Malaise
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    111 / 598 (18.56%)
    106 / 583 (18.18%)
    106 / 592 (17.91%)
    86 / 444 (19.37%)
         occurrences all number
    111
    106
    106
    86
    Shivering
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    63 / 598 (10.54%)
    47 / 583 (8.06%)
    57 / 592 (9.63%)
    33 / 444 (7.43%)
         occurrences all number
    63
    47
    57
    33
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed [11]
    141 / 598 (23.58%)
    131 / 583 (22.47%)
    145 / 592 (24.49%)
    131 / 444 (29.50%)
         occurrences all number
    141
    131
    145
    131
    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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [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: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was a solicited adverse event recorded in a diary card within 7 days of vaccination; the total number (N) reflects those subjects for which the diary cards were returned and for which data were available for the event during the period.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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