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    Clinical Trial Results:
    Safety of Nasal Influenza Immunisation in Children with Asthma: The SNIFFLE 4 study

    Summary
    EudraCT number
    		 2016-002352-24
    Trial protocol
    		 GB  
    Global end of trial date
    31 Mar 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    16SM3348
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02866942
    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
    24 Jul 2018
    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
    31 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess changes in asthma symptoms / symptom control following LAIV in children with asthma / recurrent wheezing, including children with difficult/severe asthma
    Protection of trial subjects
    Participants were recruited through local asthma clinics and informed consent obtained. Participants were immunised in the hospital environment, by personnel qualified in the recognition and treatment of anaphylaxis, and observed for at least 20 minutes following a dose. Families were then contacted at 72 hours after immunisation to establish the occurrence of any delayed effects, and also contacted 4 weeks later to complete a validated questionnaire to re-assess asthma control. Participating families had contact details for their local paediatric respiratory/research team during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Sep 2016
    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: 478
    Worldwide total number of subjects
    478
    EEA total number of subjects
    478
    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)
    320
    Adolescents (12-17 years)
    154
    Adults (18-64 years)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited through 2 routes: existing specialist paediatric asthma/allegy outpatient services or from prior participation in SNIFFLE studies at t 14 hospitals with paediatric services in England.

    Pre-assignment
    Screening details
    		 Inclusion criteria: age 2-18 years; physician diagnosis of asthma and prescribed regular inhaled corticosteroids (ICS) OR if <5yrs, 2+ exacerbations in previous 12 mths requiring oral steroids or hospitalisation. Exclusion criteria: invasive ventilation due to a respiratory illness in the preceding 2 years; acute wheeze not an exclusion criteria

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

    Arms
    Arm title
    		 LAIV
    Arm description
    		 Participant received at least 1 dose of LAIV for 2016/17 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)

    Number of subjects in period 1
    		LAIV
    Started
    478
    Completed
    478

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 478 478
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 154 154
        Adults (18-64 years)
    		 4 4
        Children (2-4 years)
    		 85 85
        Children (5-11 years)
    		 235 235
    Gender categorical
    Units: Subjects
        Female
    		 190 190
        Male
    		 288 288
    Asthma control
    “Persistent poor control” defined as: • Age 2-4yrs: ICS>200µg + LRTA or ≥2 exacerbations in past year requiring oral steroids/hospitalisation • Age 5-11yr: ICS>400µg/day • Age 12+yr: ICS>800µg/day (BTS criteria, 2014)
    Units: Subjects
        Persistent poor asthma control
    		 229 229
        Not persistent
    		 249 249
    Treatment with high dose ICS
    High dose inhaled corticosteroids (ICS), defined as • Age 2-4yrs: ICS≥400µg/day • Age 5+yrs: ICS>800µg/day
    Units: Subjects
        High dose ICS
    		 208 208
        Not high dose ICS
    		 270 270
    Difficult asthma
    “Difficult asthma” defined as persistence of asthma symptoms despite treatment with high-dose therapies (BTS definition)
    Units: Subjects
        Difficult asthma
    		 142 142
        Not difficult asthma
    		 336 336

    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 2016/17 influenza season

    Subject analysis set title
    Full dataset for subjects age >5yrs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    For participants aged 5+ years only

    Primary: Change in asthma control

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    End point title
    		 Change in asthma control
    End point description
    No. of participants with a significant change in TRACK or (c-)ACT score comparing pre to 4 weeks post LAIV. The minimum important difference (MID) for the ACT score is around 2 points in children and 3 points in adults, and 10 points for TRACK. For the purpose of this analysis, a change in ACT of at least 3 points, or 10 points for TRACK will be determined to be a significant change, where this results in an ACT score changing to < / >= 20 or TRACK score to </ >= 80 points.
    End point type
    Primary
    End point timeframe
    4 weeks post LAIV administration
    End point values
    		 LAIV Full dataset for subjects age >5yrs
    Number of subjects analysed
    319 [1]
    259 [2]
    Units: No. cases
        Improvement >= MID
    28
    25
        No change
    254
    205
        Deterioration >= MID
    37
    29
    Notes
    [1] - 4 week follow-up data available in 319/478 participants
    [2] - Follow-up data available for 259 participants aged 5+ years
    Statistical analysis title
    		 Change in asthma control
    Statistical analysis description
    For the primary outcome, the change in TRACK or ACT score pre- and 4 weeks post LAIV is assessed by McNemar’s test for paired data for combined ages for TRACK/ACT.
    Comparison groups
    LAIV v Full dataset for subjects age >5yrs
    Number of subjects included in analysis
    578
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.26 [3]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [3] - Overall the proportion with a significant deterioration was 37/319 (11.6%, 95% CI 8.3% - 15.6%). But this did not significantly differ to the proportion that improved of 28/319 (8.8%), p=0.26, so there is no evidence this is due to LAIV.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 72hr of LAIV administration for AEs and SAEs unrelated to asthma symptoms Within 4 weeks of LAIV for SAEs related or possibly related to asthma symptoms
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Internal PHE categor
    Dictionary version
    1
    Reporting groups
    Reporting group title
    LAIV
    Reporting group description
    		 Participant received at least 1 dose of LAIV for 2016/17 influenza season

    Serious adverse events
    		 LAIV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 478 (0.84%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Wheezing
    Additional description: Asthma exacerbation
         subjects affected / exposed
    4 / 478 (0.84%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LAIV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    150 / 478 (31.38%)
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    42 / 478 (8.79%)
         occurrences all number
    42
    Rhinitis
         subjects affected / exposed
    54 / 478 (11.30%)
         occurrences all number
    54
    Infections and infestations
    Cough
         subjects affected / exposed
    27 / 478 (5.65%)
         occurrences all number
    27
    Wheezing
         subjects affected / exposed
    27 / 478 (5.65%)
         occurrences all number
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2016
    Subsitution of "surveillance nasal swabs" during influenza season with nasal swabs to be taken during the 7 days post vaccination to assess for viral shedding.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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