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    Clinical Trial Results:
    Immunogenicity, Reactogenicity and Safety of the Trivalent Influenza Subunit Vaccine Influvac® for the Northern Hemisphere Season 2013/2014. An Open-Label, Baseline-Controlled Study in Two Age Groups: Adult Subjects ≥ 18 and ≤ 60 Years and Elderly Subjects ≥ 61 Years of Age.

    Summary
    EudraCT number
    2013-000881-12
    Trial protocol
    DE   BE  
    Global end of trial date
    03 Aug 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Aug 2019
    First version publication date
    15 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-998
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Abbott Biologicals B.V
    Sponsor organisation address
    C.J. van Houtenlaan 36, CP Weesp, Netherlands, NL-1381
    Public contact
    Public Affairs Manager, Abbott Products Operations AG, hind.ounis@abbott.com
    Scientific contact
    Global Clinical Director, Abbott Healthcare Products B.V., serge.vandewitte@abbott.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
    03 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the immunogenicity of the trivalent influenza subunit vaccine Influvac® for the northern hemisphere season 2013/2014, three weeks after vaccination according to the Committee for Medicinal Products for Human Use (CHMP) Note for Guidance on Harmonization of Requirements for Influenza Vaccines (CPMP/BWP/214/96) in two groups: adults aged ≥ 18 and ≤ 60 years and elderly ≥ 61 years of age.
    Protection of trial subjects
    The study was conducted in compliance with Good Clinical Practice and the applicable national regulations so as to assure that the rights, safety, and well being of the participating study subjects were protected consistent with the ethical principles that have their origin in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Jul 2013
    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
    Belgium: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    63
    From 65 to 84 years
    56
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This open-label, baseline-controlled study in two groups of subjects: adults aged ≥ 18 and ≤ 60 years and elderly ≥ 61 years was performed in one study center in Belgium between 12 July 2013 and 03 August 2013.

    Pre-assignment
    Screening details
    Subjects underwent screening evaluations to determine eligibility during a period of 14 days preceding Visit 1 at an additional visit (Screening Visit) or on Day 1 (Visit 1). A total of 120 healthy adult and elderly subjects were screened and signed informed consent, and there were no screening failures.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adults Aged ≥ 18 and ≤ 60 Years
    Arm description
    On Day 1 (Visit 1) subjects aged ≥ 18 and ≤ 60 years received a single dose of Influvac® 0.5 milliliter (mL) by intramuscular (IM) injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.
    Arm type
    Experimental

    Investigational medicinal product name
    Influvac®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of 0.5 mL Influvac® (influenza virus surface antigens (haemagglutinin and neuramidase) of the following strains: A (H1N1), A (H3N2) and B) by IM injection on Day 1 (Visit 1).

    Arm title
    Elderly Aged ≥ 61 Years
    Arm description
    On Day 1 (Visit 1) subjects aged ≥ 61 years received a single dose of Influvac® 0.5 mL by IM injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.
    Arm type
    Experimental

    Investigational medicinal product name
    Influvac®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of 0.5 mL Influvac® (influenza virus surface antigens (haemagglutinin and neuramidase) of the following strains: A (H1N1), A (H3N2) and B) by IM injection on Day 1 (Visit 1).

    Number of subjects in period 1
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Started
    60
    60
    Completed
    60
    59
    Not completed
    0
    1
         Adverse event, serious
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adults Aged ≥ 18 and ≤ 60 Years
    Reporting group description
    On Day 1 (Visit 1) subjects aged ≥ 18 and ≤ 60 years received a single dose of Influvac® 0.5 milliliter (mL) by intramuscular (IM) injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.

    Reporting group title
    Elderly Aged ≥ 61 Years
    Reporting group description
    On Day 1 (Visit 1) subjects aged ≥ 61 years received a single dose of Influvac® 0.5 mL by IM injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.

    Reporting group values
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years Total
    Number of subjects
    60 60 120
    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)
    40.1 ± 12.1 71.8 ± 5.1 -
    Gender categorical
    Units: Subjects
        Female
    34 29 63
        Male
    26 31 57

    End points

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    End points reporting groups
    Reporting group title
    Adults Aged ≥ 18 and ≤ 60 Years
    Reporting group description
    On Day 1 (Visit 1) subjects aged ≥ 18 and ≤ 60 years received a single dose of Influvac® 0.5 milliliter (mL) by intramuscular (IM) injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.

    Reporting group title
    Elderly Aged ≥ 61 Years
    Reporting group description
    On Day 1 (Visit 1) subjects aged ≥ 61 years received a single dose of Influvac® 0.5 mL by IM injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.

    Primary: Percentage of Subjects With Seroprotection for Hemagglutination Inhibition (HI) and Single Radial Hemolysis (SRH) Antibody Titers

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    End point title
    Percentage of Subjects With Seroprotection for Hemagglutination Inhibition (HI) and Single Radial Hemolysis (SRH) Antibody Titers [1]
    End point description
    The pre-vaccination (blood sample taken at Day 1) and the post-vaccination (blood sample taken at Day 22) seroprotection rates for each strain are presented. Seroprotection was defined as an HI antibody titer ≥ 40 and a SRH antibody titer ≥ 25 millimeter square (mm^2). The HI assay was performed for all three strains (A (H3N2), A (H1N1), and B strains) and the SRH assay was performed for the B strain only. The CHMP Note for Guidance defined a (the CHMP criteria for immunogenicity) seroprotection rate of > 70% for adults and > 60% for elderly as meeting the requirements for sufficient immunogenicity. The confidence intervals (CI) were calculated based on the Clopper-Pearson method. The efficacy sample set included all vaccinated subjects for whom both the pre- and the post-vaccination HI/SRH antibody titers were available, who did not present an intercurrent respiratory infection (IRI) diagnosed as influenza and who did not present any major protocol deviation.
    End point type
    Primary
    End point timeframe
    Pre-vaccination at Day 1 (Visit 1) and Post-vaccination at Day 22 (Visit 3)
    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: Descriptive statistical analysis was performed for the outcome measure.
    End point values
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Number of subjects analysed
    60
    58
    Units: percentage of subjects
    number (confidence interval 95%)
        HI antibody titer: A (H3N2) strain; Day 1
    61.7 (48.21 to 73.93)
    84.5 (72.58 to 92.65)
        HI antibody titer: A (H3N2) strain; Day 22
    98.3 (91.06 to 99.96)
    100 (93.84 to 100)
        HI antibody titer: A (H1N1) strain; Day 1
    51.7 (38.39 to 64.77)
    81.0 (68.59 to 90.13)
        HI antibody titer: A (H1N1) strain; Day 22
    96.7 (88.47 to 99.59)
    100 (93.84 to 100)
        HI antibody titer: B strain; Day 1
    50.0 (36.81 to 63.19)
    29.3 (18.09 to 42.73)
        HI antibody titer: B strain; Day 22
    83.3 (71.48 to 91.71)
    67.2 (53.66 to 78.99)
        SRH antibody titer: B strain; Day 1
    68.3 (55.04 to 79.74)
    65.5 (51.88 to 77.51)
        SRH antibody titer: B strain; Day 22
    96.7 (88.47 to 99.59)
    93.1 (83.27 to 98.09)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Seroconversion or Significant Increase in HI and SRH Antibody Titers

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    End point title
    Percentage of Subjects With Seroconversion or Significant Increase in HI and SRH Antibody Titers [2]
    End point description
    The post-vaccination seroconversion or significant increase rates for each strain are presented. For the HI assay, seroconversion was defined as a pre-vaccination HI antibody titer < 10 and a post-vaccination HI antibody titer ≥ 40, and a significant increase was defined as a pre-vaccination HI antibody titer ≥ 10 and a post-vaccination relative increase of ≥ 4-fold. For the SRH assay, seroconversion or a significant increase was defined as a post-vaccination SRH antibody titer ≥ 25 mm^2 and a post-vaccination relative increase of 1.5-fold if the pre-vaccination SRH antibody titer was > 4 mm^2. The HI assay was performed for all three strains (A (H3N2), A (H1N1), and B strains) and the SRH assay was performed for the B strain only. The CHMP Note for Guidance defined a (CHMP criteria for immunogenicity) seroconversion or significant increase in titer of > 40% for adults and > 30% for elderly as meeting the requirements for sufficient immunogenicity. Efficacy sample set were analysed.
    End point type
    Primary
    End point timeframe
    Post-vaccination at Day 22 (Visit 3)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis was performed for the outcome measure.
    End point values
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Number of subjects analysed
    60
    58
    Units: percentage of subjects
    number (confidence interval 95%)
        HI antibody titer: A (H3N2) strain
    66.7 (53.31 to 78.31)
    41.4 (28.60 to 55.07)
        HI antibody titer: A (H1N1) strain
    60.0 (46.54 to 72.44)
    37.9 (25.51 to 51.63)
        HI antibody titer: B strain
    53.3 (40.00 to 66.33)
    32.8 (21.01 to 46.34)
        SRH antibody titer: B strain
    53.3 (40.00 to 66.33)
    44.8 (31.74 to 58.46)
    No statistical analyses for this end point

    Primary: Geometric Mean Fold Increase (MFI) in HI and SRH Antibody Titers

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    End point title
    Geometric Mean Fold Increase (MFI) in HI and SRH Antibody Titers [3]
    End point description
    The post-vaccination (blood sample taken at Day 22) geometric MFI for each strain are presented. Geometric MFI was defined as the geometric mean of the intra-individual increases, that is post-vaccination HI or SRH antibody titer/pre-vaccination HI or SRH antibody titer. The HI assay was performed for all three strains (A (H3N2), A (H1N1), and B strains) and the SRH assay was performed for the B strain only. The CHMP Note for Guidance defined a (the CHMP criteria for immunogenicity) MFI of > 2.5 for adults and > 2.0 for elderly as meeting the requirements for sufficient immunogenicity. The efficacy sample set included all vaccinated subjects for whom both the pre- and the post-vaccination HI/SRH antibody titers were available, who did not present an IRI diagnosed as influenza and who did not present any major protocol deviation.
    End point type
    Primary
    End point timeframe
    Post-vaccination at Day 22 (Visit 3)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis was performed for the outcome measure.
    End point values
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Number of subjects analysed
    60
    58
    Units: antibody titer
    geometric mean (confidence interval 95%)
        HI antibody titer: A (H3N2) strain
    8.43 (5.65 to 12.56)
    3.06 (2.28 to 4.09)
        HI antibody titer: A (H1N1) strain
    9.59 (6.06 to 15.18)
    3.07 (2.30 to 4.09)
        HI antibody titer: B strain
    4.40 (3.13 to 6.18)
    2.88 (2.01 to 4.12)
        SRH antibody titer: B strain
    1.95 (1.60 to 2.38)
    1.77 (1.46 to 2.15)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Solicited Systemic Reactions

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    End point title
    Percentage of Subjects With Solicited Systemic Reactions
    End point description
    A subject diary was used to record pre-specified systemic reactions which occurred during the 72 hours after vaccination (solicited reactogenicity). Systemic reactions were assessed for the following categories: fever (≥ 38.0°C), increased sweating, headache, malaise, fatigue, and shivering. These reactions were rated on a four-point scale (none, mild, moderate, severe): none: lack of reactogenicity/inconvenience, mild: presence of mild reactogenicity/inconvenience that did not interfere with normal daily activities, moderate: reactogenicity/inconvenience that had an impact on normal daily activities, and severe: reactogenicity/inconvenience which prevented normal daily activities. Data is presented for the Safety sample set which included all vaccinated subjects for whom both the pre- and the post-vaccination HI/SRH titers were available.
    End point type
    Secondary
    End point timeframe
    Up to 72 hours post-vaccination on Day 1 (Visit 1)
    End point values
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Number of subjects analysed
    60
    60
    Units: percentage of subjects
    number (not applicable)
        Fever ≥ 38°C
    0
    0
        Increased sweating
    1.7
    1.7
        Headache
    10.0
    0
        Malaise
    1.7
    1.7
        Fatigue
    16.7
    5.0
        Shivering
    1.7
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Solicited Local Reactions

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    End point title
    Percentage of Subjects With Solicited Local Reactions
    End point description
    A subject diary was used to record pre-specified local (vaccination site) reactions occurred which during the 72 hours after vaccination (solicited reactogenicity). Local reactions were assessed for the following categories: redness, swelling, itching, warmth, tenderness (pain or discomfort upon touch), pain, impairment of movement of the arm, induration, and ecchymosis (blue spots). These reactions were rated on a four-point scale (none, mild, moderate, severe): none: lack of reactogenicity/inconvenience, mild: presence of mild reactogenicity/inconvenience that did not interfere with normal daily activities, moderate: reactogenicity/inconvenience that had an impact on normal daily activities, and severe: reactogenicity/inconvenience which prevented normal daily activities. Data is presented for the Safety sample set which included all vaccinated subjects for whom both the pre- and the post-vaccination HI/SRH titers were available.
    End point type
    Secondary
    End point timeframe
    Up to 72 hours post-vaccination on Day 1 (Visit 1)
    End point values
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Number of subjects analysed
    60
    60
    Units: percentage of subjects
    number (not applicable)
        Redness
    3.3
    1.7
        Swelling
    10.0
    0
        Itching
    1.7
    0
        Warmth
    6.7
    1.7
        Tenderness (pain or discomfort upon touch)
    31.7
    3.3
        Pain
    28.3
    0
        Impairment of movement of the arm
    16.7
    3.3
        Induration (hardening)
    10.0
    0
        Ecchymosis (blue spots)
    1.7
    1.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From administration of study vaccination (Day 1) up to Day 22.
    Adverse event reporting additional description
    Safety sample set included the sample of all vaccinated subjects for whom both the pre- and the post-vaccination HI/SRH titers were available.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Adults Aged ≥ 18 and ≤ 60 Years
    Reporting group description
    On Day 1 (Visit 1) subjects aged ≥ 18 and ≤ 60 years received a single dose of Influvac® 0.5 mL by IM injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.

    Reporting group title
    Elderly Aged ≥ 61 Years
    Reporting group description
    On Day 1 (Visit 1) subjects aged ≥ 61 years received a single dose of Influvac® 0.5 mL by IM injection into the upper arm, after taking a blood sample for baseline antibody titers against each of the vaccine antigens.

    Serious adverse events
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Adults Aged ≥ 18 and ≤ 60 Years Elderly Aged ≥ 61 Years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 60 (11.67%)
    4 / 60 (6.67%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    3
    1
    Malaise
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    Vaccination site erythema
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    Vaccination site pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    Vaccination site warmth
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    Rash generalised
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0

    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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