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    Clinical Trial Results:
    Randomised placebo-controlled study of grass pollen allergen immunotherapy tablet (AIT) for seasonal rhinitis: time course of nasal, cutaneous and immunological outcomes

    Summary
    EudraCT number
    		 2013-003732-72
    Trial protocol
    		 GB  
    Global end of trial date
    01 Mar 2017

    Results information
    Results version number
    		 v1
    This version publication date
    23 Aug 2019
    First version publication date
    23 Aug 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    13IC0847
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02005627
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Norfolk Place, London, United Kingdom, W2 1PG
    Public contact
    Nabila Youssouf , Imperial College London, +44 (0)2033110206, nabila.youssouf08@imperial.ac.uk
    Scientific contact
    Nabila Youssouf , Imperial College London, +44 (0)2033110206, nabila.youssouf08@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
    07 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To understand the time course of clinical and immunological actions of grass pollen allergen immunotherapy tablets in the treatment of seasonal allergic rhinitis.
    Protection of trial subjects
    This trial was conducted in compliance with the protocol, current Good Clinical Practice (GCP) guidelines and all applicable regulatory requirements. All participants read, signed, and dated the consent form before participating in the study. Participant’s privacy and confidentiality were preserved by assigning a sequential identification number used to collect, store, and report participant information. Grazax sublingual immunotherapy is commonly associated with local side effects of itching and swelling in the mouth that may last up to 30 minutes after taking each tablet. Systemic side effects after Grazax are very rare and generally of mild intensity. The first Grazax® or Grazax® placebo was administered under the supervision of a trial physician and the participant observed for one hour thereafter before discharge from the clinic.
    Background therapy
    		 All atopic participants were provided with anti-allergic rescue medications (antihistamine tablets, topical intranasal corticosteroids, and eye-drops) throughout the pollen season.
    Evidence for comparator
    		 Sublingual immunotherapy tablet is a fast-dissolving tablet that is registered throughout Europe for sublingual use in patients aged 5–65 years (18–65 years in UK). The tablet is administered daily for a minimum of 2 months before and during the grass pollen season to be taken for at least 3 years. In a double-blind trial of Grazax® that included a withdrawal phase, efficacy was maintained for 2–3 years with continuous treatment and at 1 year following withdrawal.
    Actual start date of recruitment
    01 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    46
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants who were having severe allergic rhinoconjunctivitis were recruited during out of pollen season from January 2014. All participants were recruited from United Kingdom.

    Pre-assignment
    Screening details
    		 Individuals with severe grass pollen hay fever, with or without associated seasonal asthma were recruited after the 2013 grass pollen season, between December 2013 and April 2014. Screening of 94 participants was completed before 46 eligible atopic participants were randomized to one of the following two treatment arms in a 1:1 ratio.

    Period 1
    Period 1 title
    September 2014 to March 2015 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Placebo controlled trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active
    Arm description
    		 Grazax active tablet
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Grazax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    75,000 SQ fast dissolving sublingual tablet.

    Arm title
    		 Placebo arm
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Grazax placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Placebo sublingual tablet without active ingredient

    Number of subjects in period 1
    		Active Placebo arm
    Started
    23
    23
    Completed
    21
    19
    Not completed
    2
    4
         Consent withdrawn by subject
    1
    2
         Lost to follow-up
    1
    2

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Grazax active tablet

    Reporting group title
    Placebo arm
    Reporting group description
    		 -

    Subject analysis set title
    Active SLIT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Allergic rhinitis were randomised to 12 months treatment with grass pollen allergen tablet immunotherapy or matched placebo and clinical, surrogate clinical and immunological outcomes monitored. The primary outcome was total nasal symptom score at 0-1 hour after nasal allergen challenge with grass pollen allergen extract. Secondary endpoints included peak nasal inspiratory flow after nasal allergen challenge, seasonal symptom visual analogue scale and skin test sensitivity to allergen.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Hay fever participants

    Primary: The area under the curve (AUC) of the early phase response (total nasal symptom score, TNSS, 0-60 minutes)

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    End point title
    		 The area under the curve (AUC) of the early phase response (total nasal symptom score, TNSS, 0-60 minutes)
    End point description
    End point type
    Primary
    End point timeframe
    The area under the curve (AUC) of the early phase response (total nasal symptom score, TNSS, 0-60 minutes) following grass pollen nasal allergen challenge in active versus placebo treated participants at 12 months.
    End point values
    		 Active Placebo arm Active SLIT Placebo
    Number of subjects analysed
    23 [1]
    23
    23
    23
    Units: 0- 12 points
    23
    23
    23
    23
    Notes
    [1] - active group hay fever
    Statistical analysis title
    		 non-parametric statistics
    Comparison groups
    Active SLIT v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.05
    Method
    		 Kruskal-wallis
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [2] - Intent-to-treat (ITT) samples are all randomized participants, regardless of the medication actually received. Per-protocol (PP) sample will be defined as ITT sample participants who remain in the study for 12 months and in whom the primary endpoints were assessed. Safety sample (SS) will be defined as all randomized participants who received at least one dose of study medication.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse and severe adverse events (SAEs) were recorded on the appropriate case report forms and the specific serious adverse events were to report as soon as possible and within 24 hours. Data were entered into MHRA approved clinical trial database.
    Adverse event reporting additional description
    Systemic reactions related to either AIT tablet treatment were graded according to the WAO SCIT Systemic Reaction Grading System. Reference: Cox L, Larenas-Linnemann D, Lockey RF, et al. Editors speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System J Allergy Clin Immunol 2010;125:569-
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 World allergy organi
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Active group
    Reporting group description
    		 Active SLIT group-Grazax

    Reporting group title
    Placebo group
    Reporting group description
    		 PLacebo non-active treated group

    Serious adverse events
    		 Active group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 23 (86.96%)
    18 / 23 (78.26%)
    Gastrointestinal disorders
    Local reaction
    Additional description: In the SLIT-tablet group more adverse events were present especially gastrointestinal system such as dyspepsia and vomiting after taking SLIT.
    alternative dictionary used: CTCAE 5
         subjects affected / exposed
    20 / 23 (86.96%)
    18 / 23 (78.26%)
         occurrences all number
    33
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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