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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, single-centre phase IIb trial as part of the EU-funded UNISEC project to assess the immunogenicity and safety of different formulations and dosing regimens of FLU-v vaccine administered subcutaneously in healthy adults aged 18-60 years.

    Summary
    EudraCT number
    2015-001932-38
    Trial protocol
    NL  
    Global end of trial date
    18 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Apr 2019
    First version publication date
    12 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FLU-v-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02962908
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    PepTcell
    Sponsor organisation address
    Central Point, 45 Beech Street, London, United Kingdom, EC2Y 8AD
    Public contact
    Gregory Stoloff, PepTcell Limited (trading as SEEK), 44 207 153 6575, gregory.stoloff@seekacure.com
    Scientific contact
    Dr Olga Pleguezuelos, PepTcell Limited (trading as SEEK), 44 207 153 6570, olga.pleguezuelos@seekacure.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 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    (1) Cellular Immunogenicity - To evaluate the cellular immune responses based on multi-parametric FACS analysis in all subjects at 0 and 42 and 180 days following FLU-v vaccination. - To evaluate the cellular immune responses based on IFN-γ ELISA assays in all subjects at 0 and 42 and 180 days following FLU-v vaccination. (2) Safety - To evaluate the solicited AEs in all subjects until 21 days after the last dosing of the study vaccine (FLU-v). - To evaluate the unsolicited AEs and SAEs in all subjects during the whole study period.
    Protection of trial subjects
    Subjects were submitted to two subcutaneous injections and three blood samplings. If subjects showed influenza symptoms a nasopharyngeal swab was taken. There were minimal risks to these procedures who were performed by trained personnel. Doctors and nurses were always available if subjects had any concerns or suffered any discomfort. Subjects were allowed to take over the counter anti-inflammatories to alleviate any adverse events post-vaccination. Subjects remained under observation for 30min post-vaccination.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Aug 2016
    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
    Netherlands: 175
    Worldwide total number of subjects
    175
    EEA total number of subjects
    175
    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)
    175
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Healthy volunteers 18-60 years old were recruited from the Zwolle city of the Netherlands during the summer of 2016. Interested subjects were screened over the phone before being invited for the screening visit on Site.

    Pre-assignment
    Screening details
    195 subjects were screened, 3 were lost to follow up, 9 withdrew consent and 8 failed inclusion/exclusion criteria. 175 subjects were randomised. 1 subject in 1x adjuvanted FLU-v arm received the wrong treatment and could not be included in any arm for analysis leaving the total number as 174 subjects.

    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, Monitor
    Blinding implementation details
    The only personnel unblinded were those formulating the vaccine ready for administration and there were not involved in other trial-related activities. The appearance of the placebo and active treatments were the same and therefore no masking of the syringes was required. The randomisation codes remained in the pharmacy under locked key only accessible to unblinded personnel.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    2x Non-adjuvanted FLU-v
    Arm description
    FLU-v on Day 0 and Day 21 FLU-v: Subcutaneous injection in the upper arm with 500 ug of FLU-v as 0.5ml suspension in 0.01M HCl and 0.01M NaOH
    Arm type
    Experimental

    Investigational medicinal product name
    FLU-v
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    500micrograms in 0.5ml

    Arm title
    1x Adjuvanted FLU-v
    Arm description
    adjuvanted FLU-v on Day 0, saline (0.5mL) on Day 21 adjuvanted FLU-v: Subcutaneous injection in the upper arm with 500ug of FLU-v emulsified in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection Saline: Subcutaneous injection in the upper arm with 0.5ml of saline
    Arm type
    Experimental

    Investigational medicinal product name
    FLU-v
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    500ug in 0.5ml

    Arm title
    Non-adjuvanted Placebo
    Arm description
    saline solution (0.5ml) on Day 0 and Day 21 Saline: Subcutaneous injection in the upper arm with 0.5ml of saline
    Arm type
    Non-adjuvanted Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Adjuvanted Placebo
    Arm description
    Adjuvanted placebo on Day 0, saline (0.5mL) on Day 21 Adjuvanted placebo: Subcutaneous injection in the upper arm with an emulsion made with 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection Saline: Subcutaneous injection in the upper arm with 0.5ml of saline
    Arm type
    Adjuvanted Placebo

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo
    Started
    58
    58
    32
    27
    vaccination completed
    58
    54
    32
    26
    day 42 sample collected
    58
    51
    32
    26
    day 180 sample collected
    58
    50
    32
    24
    Completed
    58
    50
    32
    24
    Not completed
    0
    8
    0
    3
         Protocol deviation
    -
    1
    -
    -
         Physician decision
    -
    1
    -
    -
         Consent withdrawn by subject
    -
    3
    -
    2
         Lost to follow-up
    -
    3
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2x Non-adjuvanted FLU-v
    Reporting group description
    FLU-v on Day 0 and Day 21 FLU-v: Subcutaneous injection in the upper arm with 500 ug of FLU-v as 0.5ml suspension in 0.01M HCl and 0.01M NaOH

    Reporting group title
    1x Adjuvanted FLU-v
    Reporting group description
    adjuvanted FLU-v on Day 0, saline (0.5mL) on Day 21 adjuvanted FLU-v: Subcutaneous injection in the upper arm with 500ug of FLU-v emulsified in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Reporting group title
    Non-adjuvanted Placebo
    Reporting group description
    saline solution (0.5ml) on Day 0 and Day 21 Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Reporting group title
    Adjuvanted Placebo
    Reporting group description
    Adjuvanted placebo on Day 0, saline (0.5mL) on Day 21 Adjuvanted placebo: Subcutaneous injection in the upper arm with an emulsion made with 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Reporting group values
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo Total
    Number of subjects
    58 58 32 27 175
    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)
    58 58 32 27 175
        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)
    40.02 ± 13.691 40.12 ± 12.221 41.19 ± 12.458 39.07 ± 13.074 -
    Gender categorical
    Units: Subjects
        Female
    36 31 18 13 98
        Male
    22 27 14 14 77
    Subject analysis sets

    Subject analysis set title
    Full analysis data set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The safety population includes all subjects that received at least one influenza injection

    Subject analysis sets values
    Full analysis data set
    Number of subjects
    167
    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)
    167
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.11 ± 12.847
    Gender categorical
    Units: Subjects
        Female
    95
        Male
    72

    End points

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    End points reporting groups
    Reporting group title
    2x Non-adjuvanted FLU-v
    Reporting group description
    FLU-v on Day 0 and Day 21 FLU-v: Subcutaneous injection in the upper arm with 500 ug of FLU-v as 0.5ml suspension in 0.01M HCl and 0.01M NaOH

    Reporting group title
    1x Adjuvanted FLU-v
    Reporting group description
    adjuvanted FLU-v on Day 0, saline (0.5mL) on Day 21 adjuvanted FLU-v: Subcutaneous injection in the upper arm with 500ug of FLU-v emulsified in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Reporting group title
    Non-adjuvanted Placebo
    Reporting group description
    saline solution (0.5ml) on Day 0 and Day 21 Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Reporting group title
    Adjuvanted Placebo
    Reporting group description
    Adjuvanted placebo on Day 0, saline (0.5mL) on Day 21 Adjuvanted placebo: Subcutaneous injection in the upper arm with an emulsion made with 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Subject analysis set title
    Full analysis data set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The safety population includes all subjects that received at least one influenza injection

    Primary: Percentage of CD4+ TH1 Cytokine Responders

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    End point title
    Percentage of CD4+ TH1 Cytokine Responders
    End point description
    To compare the number of subjects that showed at least a two-fold increase on day 42 and day 180 following vaccination in the number of CD4+T-cells secreting TH1 cytokines in all groups.
    End point type
    Primary
    End point timeframe
    prevaccination, day 42 (21 days after last vaccination) and day 180.
    End point values
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo
    Number of subjects analysed
    58
    51
    32
    26
    Units: Percentage of subjects responders
    number (not applicable)
        IFN gamma CD4+ day 42
    12.96
    76
    3.33
    8.70
        TNF alpha CD4+ day 42
    5.46
    44
    3.33
    0
        IL-2 CD4+ day 42
    1.82
    56
    3.33
    0
        IFN gamm CD4+ day 180
    14.29
    63.27
    6.67
    4.76
        TNF alpha CD4+ day 180
    3.57
    24.49
    3.33
    0
        IL-2 CD4+ day 180
    1.79
    57.14
    3.33
    0
    Statistical analysis title
    IFNg day 42 nonadjuvanted FLUv vs nonadj placebo
    Statistical analysis description
    Comparison of IFNgamma responders on day 42. Differences considered significant if p-value <0.05.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.249
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    IFNg Adj-FLU-v vs AdjPlacebo day 42
    Statistical analysis description
    Comparison of IFNgamma responders on day 42. Differences considered significant if pvalue <0.05.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    TNF day 42 nonadjuvanted FLUv vs non-adj placebo
    Statistical analysis description
    Comparison of TNF alpha responders on day 42. Differences considered significant if pvalue <0.05.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    TNF day 42adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of TNF alpha responders on day 42. Differences considered significant if pvalue <0.05.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    IL-2 day 42 nonadjuvanted FLUv vs nonadj placebo
    Statistical analysis description
    Comparison of IL-2 responders on day 42. Differences considered significant if p-value <0.05.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    IL-2 day 42adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of IL-2 responders on day 42. Differences considered significant if p-value <0.05.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    IFNg day 180 nonadjuvanted FLUv vs nonadj placebo
    Statistical analysis description
    Comparison of IFNgamma responders on day 180.Differences considered significant if pvalue <0.05.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.483
    Method
    Fisher exact
    Parameter type
    Cox proportional hazard
    Confidence interval
    Statistical analysis title
    IFNg day 180 adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of IFNgamma responders on day 180.Differences considered significant if p-value <0.05.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    TNF day 180 nonadjuvanted FLUv vs non-adj placebo
    Statistical analysis description
    Comparison of TNF alpha responders on day 180. Differences considered significant if p-value <0.05.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    TNF day 180 adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of TNF alpha responders on day 180. Differences considered significant if p-value <0.05.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.013
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    IL-2 day 180 nonadjuvanted FLUv vs non-adj placebo
    Statistical analysis description
    Comparison of IL-2 responders on day 180. Differences considered significant if p-value <0.05.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 1
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    IL-2 day 180 adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of IL-2 responders on day 180. Differences considered significant if p-value <0.05.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Chi-squared
    Confidence interval

    Primary: Percentage of Responders on Day 42 and Day 180 for IFNgamma Secretion by PBMCs

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    End point title
    Percentage of Responders on Day 42 and Day 180 for IFNgamma Secretion by PBMCs
    End point description
    Responders were defined as subjects having at least a two-fold increase in the amount of IFNg secreted on day 42 and day 180 compared the amount secreted on day 0. IFNg was measured by ELISA
    End point type
    Primary
    End point timeframe
    prevaccination (day 0) to postvaccination (day 42 and day 180)
    End point values
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo
    Number of subjects analysed
    58
    51
    32
    26
    Units: percentage of responder subjects
    number (not applicable)
        day 42
    59.57
    95.46
    40.00
    45.00
        day 180
    45.83
    93.02
    56.52
    55.00
    Statistical analysis title
    day 42 non-adj FLU-v vs Non-Adj placebo
    Statistical analysis description
    Comparison of number of responders on day 42. A subject was considered a "responder" if an increase of secreted IFNgamma of at least two fold was observed from day 0 to day 42.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.113
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    day 42 adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of number of responders on day 42. A subject was considered a "responder" if an increase of secreted IFNgamma of at least two fold was observed from day 0 to day 42.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    day 180 non-adj FLU-v vs Non-Adj placebo
    Statistical analysis description
    Comparison of number of responders on day 180. A subject was considered a "responder" if an increase of secreted IFNgamma of at least two fold was observed from day 0 to day 180.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.399
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    day 180 adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of number of responders on day 180. A subject was considered a "responder" if an increase of secreted IFNgamma of at least two fold was observed from day 0 to day 180.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Fisher exact
    Confidence interval

    Secondary: Antibody Responses to FLU-v

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    End point title
    Antibody Responses to FLU-v
    End point description
    To evaluate the humoral immune responses specific to FLU-v from baseline in all groups 42 and 180 days following FLU-v vaccination. Specific FLU-v IgG antibodies were measured by ELISA. The geometric mean for each treatment group was provided.
    End point type
    Secondary
    End point timeframe
    prevaccination, day 42 (21 days after last vaccination) and day 180. Analysis Population
    End point values
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo
    Number of subjects analysed
    58
    51
    32
    26
    Units: IgG ng/ml
    geometric mean (standard error)
        day 0
    499.11 ± 103.19
    362.86 ± 82.93
    331.16 ± 59.00
    371.89 ± 67.47
        day 42
    2593.02 ± 1652.34
    8740.48 ± 2432.9
    336.37 ± 58.92
    381.17 ± 61.18
        day 180
    1276.34 ± 344.52
    4769.16 ± 1131.67
    344.88 ± 66.57
    387.26 ± 61.48
    Statistical analysis title
    day 42 non-adj FLU-v vs Non-Adj placebo
    Statistical analysis description
    Comparison of geometric mean IgG titers specific to FLU-v antigens on day 42 postvaccination.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    day 42 adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of geometric mean IgG titers specific to FLU-v antigens on day 42 postvaccination.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    day 180 non-adj FLU-v vs Non-Adj placebo
    Statistical analysis description
    Comparison of geometric mean IgG titers specific to FLU-v antigens on day 180 postvaccination.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Cox proportional hazard
    Confidence interval
    Statistical analysis title
    day 180 adjuvanted FLUv vs adj placebo
    Statistical analysis description
    Comparison of geometric mean IgG titers specific to FLU-v antigens on day 180 postvaccination.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Other pre-specified: Percentage of subjects positive for influenza infection

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    End point title
    Percentage of subjects positive for influenza infection
    End point description
    During the influenza season (Dec 2016 to March 2017), fully vaccinated subjects will contact the trial center immediately if they feel unwell for 24h, with a sudden onset of flu-like symptoms. The medical staff will arrange for a nasopharyngeal swab to be performed if the subject has at least one respiratory (cough, sore throat, shortness of breath, runny nose, stuffy nose, sneezing and earache) and one systemic symptom (fever, malaise, headache and myalgia (muscle and joint pain). Swabs should be taken from the reported subjects within 3 days from the trial center being contacted or within 4 days of the onset of symptoms, whatever time is shorter.
    End point type
    Other pre-specified
    End point timeframe
    For up to 4 months during the influenza season
    End point values
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo Full analysis data set
    Number of subjects analysed
    58
    51
    32
    26
    167
    Units: Percentage of subjects
    number (not applicable)
        positive for influenza A
    5.2
    7.8
    6.3
    19.2
    8.4
        positive for influenza B
    0
    2.0
    3.1
    3.8
    1.8
        positive for influenza H1
    0
    0
    0
    0
    0
        positive for influenza H3
    5.2
    7.8
    6.3
    19.2
    8.4
        positive for any influenza
    5.2
    9.8
    9.4
    23.1
    10.2
    Statistical analysis title
    Subjects tested positive for any influenza
    Statistical analysis description
    Differences in the infection rates against any of the strains tested between treatment group and corresponding placebo.
    Comparison groups
    2x Non-adjuvanted FLU-v v Non-adjuvanted Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.662
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    subjects who tested positive for influenza
    Statistical analysis description
    Differences in the infection rates against any of the strains tested between treatment group and corresponding placebo.
    Comparison groups
    1x Adjuvanted FLU-v v Adjuvanted Placebo
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.168
    Method
    Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From vaccination to the end of the study
    Adverse event reporting additional description
    Solicited Adverse Events were collected for 21 days after each vaccination. Subjects had to fill in the AEs diary card daily and return to the clinic on the next scheduled visit. Unsolicited Adverse Events and Severe Adverse Events were collected at any time during the study directly to the PI or study doctor.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    2x Non-adjuvanted FLU-v
    Reporting group description
    FLU-v on Day 0 and Day 21 FLU-v: Subcutaneous injection in the upper arm with 500 ug of FLU-v as 0.5ml suspension in 0.01M HCl and 0.01M NaOH

    Reporting group title
    1x Adjuvanted FLU-v
    Reporting group description
    adjuvanted FLU-v on Day 0, saline (0.5mL) on Day 21 adjuvanted FLU-v: Subcutaneous injection in the upper arm with 500ug of FLU-v emulsified in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Reporting group title
    Non-adjuvanted Placebo
    Reporting group description
    saline solution (0.5ml) on Day 0 and Day 21 Saline: Subcutaneous injection in the upper arm with 0.5ml of saline

    Reporting group title
    Adjuvanted Placebo
    Reporting group description
    Adjuvanted placebo on Day 0, saline (0.5mL) on Day 21 Saline: Subcutaneous injection in the upper arm with 0.5ml of saline Adjuvanted placebo: Subcutaneous injection in the upper arm with an emulsion made with 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection

    Serious adverse events
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 57 (3.51%)
    0 / 32 (0.00%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    upper lim
    Additional description: mild/ treatment unrelated, 16 day duration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 32 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominal hernia repair
    Additional description: mild/ treatment unrelated, 1 day duration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    0 / 32 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
    Additional description: severe/ unlikely related to treatment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 57 (0.00%)
    0 / 32 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
    Additional description: moderate/ treatment unrelated
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 32 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol abuse
    Additional description: moderate/ treatment unrelated
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 57 (1.75%)
    0 / 32 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    2x Non-adjuvanted FLU-v 1x Adjuvanted FLU-v Non-adjuvanted Placebo Adjuvanted Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 58 (84.48%)
    54 / 57 (94.74%)
    28 / 32 (87.50%)
    27 / 27 (100.00%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 58 (27.59%)
    17 / 57 (29.82%)
    8 / 32 (25.00%)
    3 / 27 (11.11%)
         occurrences all number
    18
    20
    9
    5
    Nasal congestion
         subjects affected / exposed
    15 / 58 (25.86%)
    11 / 57 (19.30%)
    9 / 32 (28.13%)
    8 / 27 (29.63%)
         occurrences all number
    16
    12
    12
    9
    Pharyngitis
         subjects affected / exposed
    21 / 58 (36.21%)
    15 / 57 (26.32%)
    14 / 32 (43.75%)
    7 / 27 (25.93%)
         occurrences all number
    24
    19
    17
    8
    Rhinorrhoea
         subjects affected / exposed
    20 / 58 (34.48%)
    17 / 57 (29.82%)
    14 / 32 (43.75%)
    6 / 27 (22.22%)
         occurrences all number
    25
    19
    20
    7
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    7 / 58 (12.07%)
    4 / 57 (7.02%)
    3 / 32 (9.38%)
    4 / 27 (14.81%)
         occurrences all number
    8
    4
    4
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 58 (22.41%)
    19 / 57 (33.33%)
    14 / 32 (43.75%)
    10 / 27 (37.04%)
         occurrences all number
    20
    30
    18
    13
    Presyncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 57 (5.26%)
    1 / 32 (3.13%)
    1 / 27 (3.70%)
         occurrences all number
    2
    4
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 58 (24.14%)
    17 / 57 (29.82%)
    11 / 32 (34.38%)
    6 / 27 (22.22%)
         occurrences all number
    16
    25
    12
    6
    Injection site haematoma
         subjects affected / exposed
    5 / 58 (8.62%)
    19 / 57 (33.33%)
    0 / 32 (0.00%)
    5 / 27 (18.52%)
         occurrences all number
    6
    19
    0
    5
    Influenza like illness
         subjects affected / exposed
    11 / 58 (18.97%)
    18 / 57 (31.58%)
    10 / 32 (31.25%)
    9 / 27 (33.33%)
         occurrences all number
    12
    19
    11
    12
    Injection site erythema
         subjects affected / exposed
    13 / 58 (22.41%)
    38 / 57 (66.67%)
    0 / 32 (0.00%)
    6 / 27 (22.22%)
         occurrences all number
    15
    40
    0
    6
    Injection site induration
         subjects affected / exposed
    16 / 58 (27.59%)
    49 / 57 (85.96%)
    0 / 32 (0.00%)
    10 / 27 (37.04%)
         occurrences all number
    18
    49
    0
    11
    Injection site pain
         subjects affected / exposed
    4 / 58 (6.90%)
    39 / 57 (68.42%)
    4 / 32 (12.50%)
    11 / 27 (40.74%)
         occurrences all number
    6
    46
    4
    12
    Injection site pruritus
         subjects affected / exposed
    9 / 58 (15.52%)
    22 / 57 (38.60%)
    0 / 32 (0.00%)
    10 / 27 (37.04%)
         occurrences all number
    10
    23
    0
    14
    Injection site swelling
         subjects affected / exposed
    6 / 58 (10.34%)
    38 / 57 (66.67%)
    0 / 32 (0.00%)
    7 / 27 (25.93%)
         occurrences all number
    7
    39
    0
    7
    Injection site warmth
         subjects affected / exposed
    7 / 58 (12.07%)
    29 / 57 (50.88%)
    1 / 32 (3.13%)
    6 / 27 (22.22%)
         occurrences all number
    9
    30
    1
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 58 (12.07%)
    7 / 57 (12.28%)
    1 / 32 (3.13%)
    2 / 27 (7.41%)
         occurrences all number
    7
    8
    2
    2
    Vomiting
         subjects affected / exposed
    3 / 58 (5.17%)
    5 / 57 (8.77%)
    2 / 32 (6.25%)
    0 / 27 (0.00%)
         occurrences all number
    3
    6
    2
    0
    Diarrhoea
         subjects affected / exposed
    6 / 58 (10.34%)
    8 / 57 (14.04%)
    4 / 32 (12.50%)
    2 / 27 (7.41%)
         occurrences all number
    8
    9
    4
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 57 (5.26%)
    3 / 32 (9.38%)
    1 / 27 (3.70%)
         occurrences all number
    3
    3
    3
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 58 (8.62%)
    5 / 57 (8.77%)
    6 / 32 (18.75%)
    2 / 27 (7.41%)
         occurrences all number
    5
    7
    7
    2
    Myalgia
         subjects affected / exposed
    11 / 58 (18.97%)
    9 / 57 (15.79%)
    6 / 32 (18.75%)
    4 / 27 (14.81%)
         occurrences all number
    12
    12
    6
    5
    Pain in extremity
         subjects affected / exposed
    2 / 58 (3.45%)
    6 / 57 (10.53%)
    0 / 32 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    6
    0
    2
    Arthralgia
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 57 (8.77%)
    1 / 32 (3.13%)
    0 / 27 (0.00%)
         occurrences all number
    5
    6
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    11 / 57 (19.30%)
    0 / 32 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    12
    0
    1
    Infections and infestations
    Herpes simplex
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 57 (3.51%)
    3 / 32 (9.38%)
    1 / 27 (3.70%)
         occurrences all number
    2
    2
    3
    1
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 58 (24.14%)
    14 / 57 (24.56%)
    13 / 32 (40.63%)
    6 / 27 (22.22%)
         occurrences all number
    15
    15
    14
    6

    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.
    Recruitment stopped early at 175 subjects instead of 222. Dropout rate was lower than anticipated (4% vs 20%). The number of participants recruited was considered to be sufficient to provide statistically significant data in the primary endpoints.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28376743
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