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    Clinical Trial Results:
    Efficacy & Safety of Nasal Influenza Immunisation in Children - The SNIFFLE-3 study

    Summary
    EudraCT number
    		 2015-003019-39
    Trial protocol
    		 GB  
    Global end of trial date
    27 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2018
    First version publication date
    14 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15SM2801
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02549365
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Norfolk Place, London, United Kingdom,
    Public contact
    Dr Paul Turner, Imperial College London, 44 02033127754, p.turner@imperial.ac.uk
    Scientific contact
    Dr Paul Turner, Imperial College London, 44 02033127754, p.turner@imperial.ac.uk
    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
    21 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of LAIV in children and their siblings in the 2015/16 influenza season, through documentation of the incidence of laboratory confirmed influenza and other respiratory viruses, in children receiving LAIV (recruited to both the intervention and surveillance phases of the study), compared to their household sibling controls (recruited to only the surveillance phase).
    Protection of trial subjects
    Study undertaken by research team on paediatric research unit. Partipants who were consented to provide blood samples were offered local anaesthetic cream prior to venepuncture.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 276
    Worldwide total number of subjects
    276
    EEA total number of subjects
    276
    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)
    13
    Children (2-11 years)
    195
    Adolescents (12-17 years)
    68
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 164 Index cases (who received LAIV) and 122 siblings (household controls) were recruited.

    Pre-assignment
    Screening details
    		 Subjects were recruited through 2 routes: existing paediatric outpatient services at St Mary’s Hospital or from prior participation in SNIFFLE studies.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LAIV
    Arm description
    		 Participant received at least 1 dose of LAIV for 2015/16 influenza season
    Arm type
    		 Experimental

    Investigational medicinal product name
    Live Attenuated Influenza Vaccine
    Investigational medicinal product code
    EU/1/13/887/001
    Other name
    Fluenz Tetra
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    0.2ml (administered as 0.1ml per nostril)

    Arm title
    		 Household control
    Arm description
    		 Household sibling of index case
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		LAIV Household control
    Started
    164
    112
    Completed
    164
    112
    Period 2
    Period 2 title
    Surveillance
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LAIV
    Arm description
    		 Participant received at least 1 dose of LAIV for 2015/16 influenza season
    Arm type
    		 Experimental

    Investigational medicinal product name
    Live Attenuated Influenza Vaccine
    Investigational medicinal product code
    EU/1/13/887/001
    Other name
    Fluenz Tetra
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    0.2ml (administered as 0.1ml per nostril)

    Arm title
    		 Household control
    Arm description
    		 Household sibling of index case
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		LAIV Household control
    Started
    164
    112
    Completed
    164
    112

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LAIV
    Reporting group description
    		 Participant received at least 1 dose of LAIV for 2015/16 influenza season

    Reporting group title
    Household control
    Reporting group description
    		 Household sibling of index case

    Reporting group values
    		 LAIV Household control Total
    Number of subjects
    		 164 112 276
    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 13 13
        Children (2-11 years)
    		 32 75 107
        Adolescents (12-17 years)
    		 132 24 156
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 65 48 113
        Male
    		 99 64 163
    Prior influenza vaccination in previous 3 years
    Units: Subjects
        No prior vaccination
    		 96 107 203
        1 vaccine
    		 37 4 41
        2 vaccines
    		 22 1 23
        3 vaccines
    		 9 0 9

    End points

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    End points reporting groups
    Reporting group title
    LAIV
    Reporting group description
    		 Participant received at least 1 dose of LAIV for 2015/16 influenza season

    Reporting group title
    Household control
    Reporting group description
    		 Household sibling of index case
    Reporting group title
    LAIV
    Reporting group description
    		 Participant received at least 1 dose of LAIV for 2015/16 influenza season

    Reporting group title
    Household control
    Reporting group description
    		 Household sibling of index case

    Primary: Laboratory positive infuenza infection

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    End point title
    		 Laboratory positive infuenza infection
    End point description
    End point type
    Primary
    End point timeframe
    Influenza season 2015/2016
    End point values
    		 LAIV Household control
    Number of subjects analysed
    164 [1]
    112 [2]
    Units: Number of cases
    number (not applicable)
        Positive for H1N1
    4
    2
        Positive for 'flu B
    4
    0
    Attachments
    		 Vaccine Efficacy
    Notes
    [1] - 39 swabs collected in 29 children
    [2] - 19 swabs in 17 children
    Statistical analysis title
    		 Efficacy
    Statistical analysis description
    Incidence of laboratory confirmed influenza is compared between those vaccinated and household controls. VE will be calculated as 1 – RR with 95% confidence intervals using Poisson regression. Adjustment for age will be included and the influence of prior vaccinations.
    Comparison groups
    LAIV v Household control
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 13.9
    Variability estimate
    Standard deviation
    Notes
    [3] - Incidence of laboratory confirmed influenza is compared between those vaccinated and household controls. VE will be calculated as 1 – RR with 95% confidence intervals using Poisson regression. Adjustment for age will be included and the influence of prior vaccinations.

    Secondary: Immunogenicity pre/post LAIV

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    End point title
    		 Immunogenicity pre/post LAIV [4]
    End point description
    End point type
    Secondary
    End point timeframe
    3-6 weeks post LAIV
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Household controls did not undergo venepuncture in this protocol (since no intervention was administered)
    End point values
    		 LAIV
    Number of subjects analysed
    41 [5]
    Units: antibody titre
        geometric mean (confidence interval 95%)
    1.06 (0.95 to 1.19)
    Attachments
    		 Untitled (Filename: Sniffle 3 Immunogenicity.docx)
    Notes
    [5] - 41 participants consented to venepuncture
    No statistical analyses for this end point

    Secondary: Safety - serious adverse events

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    End point title
    		 Safety - serious adverse events [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks post LAIV
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: AE data was not collected in the household controls (since no intervention was administered)
    End point values
    		 LAIV
    Number of subjects analysed
    164
    Units: No. cases
    0
    No statistical analyses for this end point

    Secondary: Safety - adverse events

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    End point title
    		 Safety - adverse events [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Up 72 hours post LAIV
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: AE data was not collected in the household controls (since no intervention was administered)
    End point values
    		 LAIV
    Number of subjects analysed
    164
    Units: No. cases
    63
    Attachments
    		 Safety
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 72 hours following LAIV for non-serious AEs Up to 4 weeks following LAIV for SAEs
    Adverse event reporting additional description
    Questionnaire after 72 hours Asthma control questionnaire 4 weeks following LAIV.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Internal PHE categor
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Atopic status: positive
    Reporting group description
    		 Existing atopic disease e.g. asthma, food allergy, eczema

    Reporting group title
    Non-atopic participants
    Reporting group description
    		 -

    Serious adverse events
    		 Atopic status: positive Non-atopic participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atopic status: positive Non-atopic participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 116 (39.66%)
    12 / 48 (25.00%)
    General disorders and administration site conditions
    Rhinitis
         subjects affected / exposed
    23 / 116 (19.83%)
    5 / 48 (10.42%)
         occurrences all number
    19
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    13 / 116 (11.21%)
    3 / 48 (6.25%)
         occurrences all number
    13
    3
    Fever
         subjects affected / exposed
    4 / 116 (3.45%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    Malaise
         subjects affected / exposed
    3 / 116 (2.59%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1

    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.
    Sniffle 3 was unable to demonstrate a protective effect of LAIV in 2015/16 when comparing vaccinated children with siblings. In fact there were more positive flu swabs in those vaccinated, perhaps indicating a reporting bias.
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    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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