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    Clinical Trial Results:
    Phase IIb Study of the Efficacy of FLU-v, a Broad Spectrum Influenza Vaccine in an H1N1 Influenza Healthy Human Challenge Model.

    Summary
    EudraCT number
    		 2016-002134-74
    Trial protocol
    		 GB  
    Global end of trial date
    25 May 2017

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    FLU-v-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03180801
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PepTcell Ltd (t/a SEEK)
    Sponsor organisation address
    Central Point, 45 Beech Street, London, United Kingdom, EC2Y 8AD
    Public contact
    Gregory Stoloff, PepTcell Ltd (t/a SEEK), +44 207 153 6575, gregory.stoloff@seekacure.com
    Scientific contact
    Dr Olga Pleguezuelos, PepTcell Ltd (t/a 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
    24 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    25 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect of FLU-v on reducing the incidence of Mild to Moderate Influenza Disease (MMID) defined as detectable viral shedding plus at least one symptom of influenza.
    Protection of trial subjects
    Subjects were submitted to two subcutaneous injections with vaccine or placebo, blood samplings, intranasal inoculation with influenza virus and nasal swabs. There were minimal risks to these procedures as they 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. Subjects were closely monitored under quarantine after inoculation with influenza virus. The virus was GMP manufactured, dosage was optimised in previous clinical trials approved by the FDA sponsored by NIAID-NIH, US.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 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
    United Kingdom: 153
    Worldwide total number of subjects
    153
    EEA total number of subjects
    153
    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)
    153
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment took place at two UK sites, London and Manchester, during Q3 and Q4 of 2017.

    Pre-assignment
    Screening details
    		 Only subjects with an HAI<40 for the influenza challenge strain at the time of screening were allowed to enrol the study.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Only pharmacy staff responsible for vaccine formulation were unblinded. The randomisation codes were kept locked in the pharmacy and only unblinded staff had access to them. The placebo and active doses were identical in appearance, thus there was no need for masking the contents of the syringe.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adjuvanted Placebo
    Arm description
    		 Received two doses of adjuvanted placebo 21 days apart and 21 days after the last vaccination were inoculated with influenza.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Adjuvanted placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5ml of water in oil emulsion composed of 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection.

    Arm title
    		 1x adjuvanted FLU-v
    Arm description
    		 Subjects received one dose of adjuvanted FLU-v and 21 days later a dose of adjuvanted placebo, followed by intranasal influenza inoculation 21 days after that.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adjuvanted placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5ml of water in oil emulsion composed of 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection.

    Investigational medicinal product name
    Adjuvanted FLU-v
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    500 micrograms of FLU-v reconstituted in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and emulsified with 0.25ml of water for injection.

    Arm title
    		 2x Adjuvanted FLU-v
    Arm description
    		 Subjects received two doses of adjuvanted FLU-v 21 days apart, and 21 days after the last dose were intranasally inoculated with influenza.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adjuvanted placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5ml of water in oil emulsion composed of 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection.

    Investigational medicinal product name
    Adjuvanted FLU-v
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    500 micrograms of FLU-v reconstituted in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and emulsified with 0.25ml of water for injection.

    Number of subjects in period 1
    		Adjuvanted Placebo 1x adjuvanted FLU-v 2x Adjuvanted FLU-v
    Started
    50
    52
    51
    Vaccinated
    50
    48
    48
    Completed
    42
    40
    41
    Not completed
    8
    12
    10
         Consent withdrawn by subject
    2
    2
    1
         Physician decision
    3
    3
    1
         Adverse event, non-fatal
    1
    -
    2
         Non-compliance
    1
    4
    -
         Lost to follow-up
    -
    2
    3
         inoculation target reached
    1
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adjuvanted Placebo
    Reporting group description
    		 Received two doses of adjuvanted placebo 21 days apart and 21 days after the last vaccination were inoculated with influenza.

    Reporting group title
    1x adjuvanted FLU-v
    Reporting group description
    		 Subjects received one dose of adjuvanted FLU-v and 21 days later a dose of adjuvanted placebo, followed by intranasal influenza inoculation 21 days after that.

    Reporting group title
    2x Adjuvanted FLU-v
    Reporting group description
    		 Subjects received two doses of adjuvanted FLU-v 21 days apart, and 21 days after the last dose were intranasally inoculated with influenza.

    Reporting group values
    		 Adjuvanted Placebo 1x adjuvanted FLU-v 2x Adjuvanted FLU-v Total
    Number of subjects
    		 50 52 51 153
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 50 52 51 153
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.9 ( 7.6 ) 30.2 ( 9.3 ) 27.6 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 19 14 50
        Male
    		 33 33 37 103
    Subject analysis sets

    Subject analysis set title
    Placebo Efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT includes those participants in the adjuvanted placebo group who received both vaccination and challenge with an influenza virus.

    Subject analysis set title
    1xFLU-v Efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all subjects in the 1 dose adjuvanted FLU-v group who completed the vaccinations and were challenge with influenza.

    Subject analysis set title
    2xFLU-v efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all subjects in the 2 dose adjuvanted FLU-v who completed all vaccinations and were challenged with influenza.

    Subject analysis sets values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects
    42
    40
    41
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    42
    40
    41
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    28.8 ( 7.5 )
    29.9 ( 8.9 )
    27.4 ( 9.2 )
    Gender categorical
    Units: Subjects
        Female
    13
    12
    11
        Male
    29
    28
    30

    End points

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    End points reporting groups
    Reporting group title
    Adjuvanted Placebo
    Reporting group description
    		 Received two doses of adjuvanted placebo 21 days apart and 21 days after the last vaccination were inoculated with influenza.

    Reporting group title
    1x adjuvanted FLU-v
    Reporting group description
    		 Subjects received one dose of adjuvanted FLU-v and 21 days later a dose of adjuvanted placebo, followed by intranasal influenza inoculation 21 days after that.

    Reporting group title
    2x Adjuvanted FLU-v
    Reporting group description
    		 Subjects received two doses of adjuvanted FLU-v 21 days apart, and 21 days after the last dose were intranasally inoculated with influenza.

    Subject analysis set title
    Placebo Efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT includes those participants in the adjuvanted placebo group who received both vaccination and challenge with an influenza virus.

    Subject analysis set title
    1xFLU-v Efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all subjects in the 1 dose adjuvanted FLU-v group who completed the vaccinations and were challenge with influenza.

    Subject analysis set title
    2xFLU-v efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all subjects in the 2 dose adjuvanted FLU-v who completed all vaccinations and were challenged with influenza.

    Primary: Incidence of MMID

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    End point title
    		 Incidence of MMID
    End point description
    To determine the effect of FLU-v on reducing the incidence of Mild to Moderate Influenza Disease (MMID) defined as detectable viral shedding plus at least one symptom of influenza. This analysis was done in the ITT population which included all subjects that completed vaccination and inoculation milestones.
    End point type
    Primary
    End point timeframe
    From 24h post-viral inoculation (Day 1) until the end of the quarantine phase on Day 7
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: Number of subjects
        Positive for MMID
    23
    13
    15
        Negative for MMID
    19
    27
    26
    Statistical analysis title
    		 1xFLU-v vs Placebo: incidence MMID
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower MMID rate.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0349 [1]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - P-value<0.05 was considered significant, therefore the difference in the incidence of MMID in the 1xFLU-v group compared to placebo is significant.
    Statistical analysis title
    		 2xFLU-v vs Placebo: Incidence of MMID
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower MMID rate.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0745 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - P-value<0.05 was considered significant. The p-value obtained shows that difference in incidence of MMID between the 2xFLU-v and Placebo is not quite significant.

    Primary: Incidence of Treatment Emergent AEs

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    End point title
    		 Incidence of Treatment Emergent AEs
    End point description
    To determine the safety and tolerability of FLU-v by means of recording the incidence of TEAEs.
    End point type
    Primary
    End point timeframe
    From the first administration of treatment to the end of the study.
    End point values
    		 Adjuvanted Placebo 1x adjuvanted FLU-v 2x Adjuvanted FLU-v
    Number of subjects analysed
    50
    52
    51
    Units: number of TEAEs
    arithmetic mean (standard error)
        Overall
    1.86 ( 0.26 )
    1.38 ( 0.24 )
    2.35 ( 0.27 )
        Pre-inoculation
    1.00 ( 0.21 )
    0.81 ( 0.13 )
    1.51 ( 0.19 )
        Post-inoculation
    0.86 ( 0.16 )
    0.58 ( 0.15 )
    0.84 ( 0.16 )
    Statistical analysis title
    		 Comparison of TEAEs pre-inoculation
    Statistical analysis description
    One sided Fisher’s exact test is used to test if AE rates of vaccine group is higher than the placebo group.
    Comparison groups
    Adjuvanted Placebo v 1x adjuvanted FLU-v
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6474 [3]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - The difference in pre-inoculation TEAEs is not significant.
    Statistical analysis title
    		 Comparison of TEAEs pre-inoculation
    Statistical analysis description
    One sided Fisher’s exact test is used to test if AE rates of vaccine group is higher than the placebo group.
    Comparison groups
    Adjuvanted Placebo v 2x Adjuvanted FLU-v
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9995 [4]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [4] - The difference in pre-inoculation TEAEs is not significant.
    Statistical analysis title
    		 Comparison of TEAEs post-inoculation
    Statistical analysis description
    One sided Fisher’s exact test is used to test if AE rates of vaccine group is higher than the placebo group.
    Comparison groups
    Adjuvanted Placebo v 1x adjuvanted FLU-v
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.024 [5]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [5] - The lower rate of post-inoculation TEAEs in the 1xFLU-v group compared to placebo is significant.
    Statistical analysis title
    		 Comparison of TEAEs post-inoculation
    Statistical analysis description
    One sided Fisher’s exact test is used to test if AE rates of vaccine group is higher than the placebo group.
    Comparison groups
    Adjuvanted Placebo v 2x Adjuvanted FLU-v
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.186 [6]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [6] - The difference in post-inoculation TEAEs in the 2xFLU-v group compared to placebo is not significant.

    Primary: TEAEs relatedness and severity

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    End point title
    		 TEAEs relatedness and severity [7]
    End point description
    Number of subjects with one or more AE are reported by severity and relatedness to vaccine or challenge virus inoculation.
    End point type
    Primary
    End point timeframe
    From the day the first treatment was administered until the ned of the study.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were performed only summary numeration of the TEAEs in the different categories of relatedness and severity.
    End point values
    		 Adjuvanted Placebo 1x adjuvanted FLU-v 2x Adjuvanted FLU-v
    Number of subjects analysed
    50
    52
    51
    Units: Number of subjects
        Subjects with TEAEs definately related to vaccine
    7
    24
    29
        Subjects with TEAEs probably related to vaccine
    1
    0
    6
        Subjects with TEAEs possibly related to vaccine
    3
    2
    3
        Subjects with TEAEs definately related to virus
    1
    0
    0
        Subjects with TEAEs probably related to virus
    3
    1
    1
        Subjects with TEAEs possibly related to virus
    4
    3
    6
        Subjects with mild TEAEs
    37
    33
    42
        Subjects with moderate TEAEs
    13
    4
    11
        Subjects with severe TEAEs
    0
    1
    3
    No statistical analyses for this end point

    Secondary: Number of symptomatic and asymptomatic subjects

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    End point title
    		 Number of symptomatic and asymptomatic subjects
    End point description
    Number of subjects experiencing no symptoms, at least one influenza symptom and at least two influenza symptoms.
    End point type
    Secondary
    End point timeframe
    Quarantine period from day 1 to day 7
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: Number of subjects
        no symptoms
    5
    6
    11
        at least one symptom
    37
    34
    30
        at least two symptoms
    27
    16
    23
    Statistical analysis title
    		 At least one symptom
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of "at least one symptom" than placebo.
    Comparison groups
    1xFLU-v Efficacy analysis v Placebo Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4648 [8]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [8] - Differences with a P-value<0.05 were considered significant. The results of this analysis are not significant.
    Statistical analysis title
    		 At least one symptom
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of "at least one symptom" than placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0736 [9]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [9] - Differences with a P-value<0.05 were considered significant. The results of this analysis are not quite significant.
    Statistical analysis title
    		 At least two symptoms
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of "at least two symptoms" than placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0235 [10]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [10] - Differences with a P-value<0.05 were considered significant. The results of this analysis are significant.
    Statistical analysis title
    		 At least two symptoms
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of "at least two symptoms" than placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2955 [11]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [11] - Differences with a P-value<0.05 were considered significant. The results of this analysis are not significant.
    Statistical analysis title
    		 No symptoms
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of "no symptoms" than placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05 [12]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [12] - Differences were considered significant if P-value<0.05. The results show that the differences in this analysis are not significant.
    Statistical analysis title
    		 No symptoms
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of "no symptoms" than placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05 [13]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [13] - Differences were considered significant if P-value<0.05. The results show that the differences in this analysis are not significant.

    Secondary: Number of subjects with detectable viral shedding

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    End point title
    		 Number of subjects with detectable viral shedding
    End point description
    Subjects were swabbed intranasally daily in the morning and evening. Swabs were tested for the presence of virus using a Respiratory Pathogen Panel (RPP) Luminex test. If influenza virus was detected then the subject was positive for shedding.
    End point type
    Secondary
    End point timeframe
    Quarantine period from day 1 to day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: Number of subjects
    23
    15
    18
    Statistical analysis title
    		 incidence of viral shedding
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of shedding compared to placebo.
    Comparison groups
    1xFLU-v Efficacy analysis v Placebo Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0891 [14]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [14] - Differences were considered significant if the p-value<0.05. In this analysis the difference is not quite significant.
    Statistical analysis title
    		 incidence of viral shedding
    Statistical analysis description
    One-sided Fisher exact test is used to test if vaccine group has lower rate of shedding compared to placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2208 [15]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [15] - Differences were considered significant if the p-value<0.05. In this analysis the difference is not significant.

    Secondary: Shedding duration

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    End point title
    		 Shedding duration
    End point description
    Number of days from day 1 with a positive test for viral shedding in nasal swabs tested by Luminex RPP assay.
    End point type
    Secondary
    End point timeframe
    Starting from evening of Day 1 post-inoculation up to Day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: days
        arithmetic mean (standard error)
    1.95 ( 0.3574 )
    1.20 ( 0.3084 )
    1.90 ( 0.3917 )
    Statistical analysis title
    		 Shedding duration
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has shorter shedding duration than placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0501 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - Differences are considered significant if the p-value<0.05. This analysis indicates that the difference is almost significant.
    Statistical analysis title
    		 Shedding duration
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has shorter shedding duration than placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3139 [17]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [17] - Differences are considered significant if the p-value<0.05. This analysis indicates that the difference is not significant.

    Secondary: Total viral shedding

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    End point title
    		 Total viral shedding
    End point description
    Subjects were swabbed daily (morning and evening) whilst under quarantine. The swabs were tested by RT-PCR to measure the number of copies of viral genetic material.
    End point type
    Secondary
    End point timeframe
    Starting from evening of Day 1 post-inoculation up to Day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    40
    Units: hours*log10 copy number/ml
        arithmetic mean (standard error)
    153.67 ( 33.39 )
    98.47 ( 27.39 )
    138.79 ( 31.73 )
    Statistical analysis title
    		 Total viral shedding (AUC)
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has smaller shedding AUC than the placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1018 [18]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [18] - Differences were considered significant if p-value<0.05. The difference in this analysis is not quite significant.
    Statistical analysis title
    		 Total viral shedding (AUC)
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has smaller shedding AUC than the placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4808 [19]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - Differences were considered significant if p-value<0.05. The difference in this analysis is not significant.

    Secondary: Peak viral shedding

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    End point title
    		 Peak viral shedding
    End point description
    The highest RT-qPCR (log10 copy number/ml) recorded for each subject under quarantine.
    End point type
    Secondary
    End point timeframe
    Starting from evening of Day 1 post-inoculation up to Day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: log10 copy number/ml
        arithmetic mean (standard error)
    2.24 ( 0.40 )
    1.54 ( 0.39 )
    2.28 ( 0.42 )
    Statistical analysis title
    		 Peak viral shedding
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has lower peak viral shedding than the placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.128 [20]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [20] - Differences are considered significant if p-value<0.05. The difference in this analysis is not quite significant.
    Statistical analysis title
    		 Peak viral shedding
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has lower peak viral shedding than the placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6007 [21]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [21] - Differences are considered significant if p-value<0.05. The difference in this analysis is not significant.

    Secondary: Symptom duration

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    End point title
    		 Symptom duration
    End point description
    Number of symptomatic days as per physician's assessment.
    End point type
    Secondary
    End point timeframe
    Starting from evening of Day 1 post-inoculation up to Day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: days
        arithmetic mean (standard error)
    3.26 ( 0.37 )
    2.67 ( 0.35 )
    2.76 ( 0.37 )
    Statistical analysis title
    		 Duration of symptoms
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has shorter duration of symptoms than the placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1416 [22]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [22] - Differences are considered significant when p-value<0.05. The difference in this analysis is not quite significant.
    Statistical analysis title
    		 Duration of symptoms
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has shorter duration of symptoms than the placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1469 [23]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [23] - Differences are considered significant when p-value<0.05. The difference in this analysis is not quite significant.

    Secondary: Average number of symptoms experienced

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    End point title
    		 Average number of symptoms experienced
    End point description
    Sum of symptoms experienced divided by the number of days in which symptoms were collected.
    End point type
    Secondary
    End point timeframe
    Starting from evening of Day 1 post-inoculation up to Day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: number of symptoms
        arithmetic mean (standard error)
    2.57 ( 0.33 )
    2.08 ( 0.32 )
    2.51 ( 0.41 )
    Statistical analysis title
    		 Total average symptoms experienced
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has fewer number of symptoms than placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0795 [24]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [24] - Differences are considered significant if p-value<0.05. The difference in this analysis is not quite significant.
    Statistical analysis title
    		 Total average symptoms experienced
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has fewer number of symptoms than placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.271 [25]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [25] - Differences are considered significant if p-value<0.05. The difference in this analysis is not significant.

    Secondary: Peak number of symptoms

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    End point title
    		 Peak number of symptoms
    End point description
    The highest number of symptoms recorded in a time point as per physician's assessment.
    End point type
    Secondary
    End point timeframe
    Starting from evening of Day 1 post-inoculation up to Day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: number of symptoms
        arithmetic mean (standard error)
    2.12 ( 0.26 )
    1.68 ( 0.22 )
    1.88 ( 0.28 )
    Statistical analysis title
    		 Peak number of symptoms
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has fewer peak number of symptoms than placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0985 [26]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [26] - Differences are considered significant if p-value<0.05. The difference in this analysis is not quite significant.
    Statistical analysis title
    		 Peak number of symptoms
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has fewer peak number of symptoms than placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.178 [27]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [27] - Differences are considered significant if p-value<0.05. The difference in this analysis is not significant.

    Secondary: Self-assessed symptom severity score (FLU-PRO)

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    End point title
    		 Self-assessed symptom severity score (FLU-PRO)
    End point description
    The mean of self-assessed daily symptom score over all study quarantine days.
    End point type
    Secondary
    End point timeframe
    Starting from evening of Day 1 post-inoculation up to Day 7.
    End point values
    		 Placebo Efficacy analysis 1xFLU-v Efficacy analysis 2xFLU-v efficacy analysis
    Number of subjects analysed
    42
    40
    41
    Units: symptom score
        arithmetic mean (standard error)
    0.05 ( 0.01 )
    0.03 ( 0.01 )
    0.04 ( 0.01 )
    Statistical analysis title
    		 Total symptom score (FLU-PRO)
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has lower FluPro scores than placebo.
    Comparison groups
    Placebo Efficacy analysis v 1xFLU-v Efficacy analysis
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0638 [28]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [28] - Differences are considered significant if p-value<0.05. The difference in this analysis is not quite significant.
    Statistical analysis title
    		 Total symptom score (FLU-PRO)
    Statistical analysis description
    One-sided Wilcoxon test is used to test if vaccine group has lower FluPro scores than placebo.
    Comparison groups
    Placebo Efficacy analysis v 2xFLU-v efficacy analysis
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2009 [29]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [29] - Differences are considered significant if p-value<0.05. The difference in this analysis is not significant.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of first administration of vaccine to the date of inoculation with the challenge virus.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Adjuvanted Placebo
    Reporting group description
    		 Received two doses of adjuvanted placebo 21 days apart and 21 days after the last vaccination were inoculated with influenza.

    Reporting group title
    1x adjuvanted FLU-v
    Reporting group description
    		 Subjects received one dose of adjuvanted FLU-v and 21 days later a dose of adjuvanted placebo, followed by intranasal influenza inoculation 21 days after that.

    Reporting group title
    2x Adjuvanted FLU-v
    Reporting group description
    		 Subjects received two doses of adjuvanted FLU-v 21 days apart, and 21 days after the last dose were intranasally inoculated with influenza.

    Serious adverse events
    		 Adjuvanted Placebo 1x adjuvanted FLU-v 2x Adjuvanted FLU-v
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Adjuvanted Placebo 1x adjuvanted FLU-v 2x Adjuvanted FLU-v
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 50 (80.00%)
    33 / 52 (63.46%)
    45 / 51 (88.24%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    3
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    3
    0
    2
    Neutrophil count decreased
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 52 (3.85%)
    2 / 51 (3.92%)
         occurrences all number
    4
    2
    2
    Headache
         subjects affected / exposed
    11 / 50 (22.00%)
    5 / 52 (9.62%)
    13 / 51 (25.49%)
         occurrences all number
    11
    5
    13
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    3
    General disorders and administration site conditions
    Injection site induration
         subjects affected / exposed
    9 / 50 (18.00%)
    24 / 52 (46.15%)
    31 / 51 (60.78%)
         occurrences all number
    9
    24
    31
    Injection site pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    0
    1
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    1
    Nausea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    1
    0
    3
    Toothache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    3
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
         occurrences all number
    3
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
         occurrences all number
    0
    3
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    6 / 50 (12.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    6
    0
    3
    Oral herpes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
         occurrences all number
    1
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 50 (28.00%)
    9 / 52 (17.31%)
    8 / 51 (15.69%)
         occurrences all number
    14
    9
    8
    Laceration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2016
    Section 7.2; Inclusion Criteria 9: Clarification to participant asthma history prior to entry into study.  Section 7.2; Inclusion Criteria 11: Clarification on the time-point for acquiring a subject’s medical history from their GP.  Section 18.7.1; Informed consent procedure: Amended to include Investigator or delegate to conduct participant consenting.  Section 18.7.3; Information for General Practitioners: Amendment to the requirement for participant’s medical history from their GP.
    18 Apr 2017
    Pages 1, 6 and 12 updated to reflect change in PI.  Section 6.3.1 and throughout updated to reflect exploratory endpoints may be reported separately from CSR.  Section 9.3.1 correction for consistency that subjects will be admitted to the Quarantine unit with a minimum 20 days not 21 days post second vaccination.  Section 9.3.1 and throughout a clarification that serology test and result must be available within 90 days of Day 0 inoculation  Section 13.1.2 inspection of the eyes removed from mandatory list in directed physical examination.  Section 13.2.2 language inserted to state how missing Flu-PRO data will be handled.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/17668898
    http://www.ncbi.nlm.nih.gov/pubmed/2257516
    http://www.ncbi.nlm.nih.gov/pubmed/25994549
    http://www.ncbi.nlm.nih.gov/pubmed/26084515
    http://www.ncbi.nlm.nih.gov/pubmed/25416753
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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