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    Clinical Trial Results:
    Molecular and cellular mechanism in rhinitis allergic patients treated with GRAZAX®

    Summary
    EudraCT number
    		 2009-011453-41
    Trial protocol
    		 ES  
    Global end of trial date
    04 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Nov 2016
    First version publication date
    23 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GT-20
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02437786
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALK-Abelló S.A.
    Sponsor organisation address
    Miguel Fleta, 19, Madrid, Spain, 28037
    Public contact
    Pilar Rico, ALK-Abelló, +34 913276100, prnes@alk.net
    Scientific contact
    Pilar Rico, ALK-Abelló, +34 913276100, prnes@alk.net
    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
    04 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine biomarkers which can be related to the tolerability and the clinical response to GRAZAX® treatment. A full array of specific immunoglobulins, cytokines, molecular diagnostics, poblational analyses, lymphoproliferative response to allergens and activation of basophile will be studied and related to the outcome of three-year treatment of GRAZAX® in terms of tolerance and clinical benefit, followed by a two years period without treatment. The tolerance will be evaluated according to the recording of adverse events and the efficacy will be based in a global subjective evaluation of rhinoconjunctivitis symptoms
    Protection of trial subjects
    Informed Consent Form. Internal clinical Safety Group, to evaluate from time to time the adverse events ocurred during the trial period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Sep 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 58
    Worldwide total number of subjects
    58
    EEA total number of subjects
    58
    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)
    58
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment start period was from 14 Sep 2009 until 23 Nov 2009 in 1 investigational site in Spain

    Pre-assignment
    Screening details
    		 Adult patients suffering from rhinoconjuctivitis with/without asthma due to sensitization to grass pollen. 60 patients will be included

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No randomisation and blinding will be made as this trial is non-controlled. Patients which fulfil with all selection criteria will be assigned to treatment and a subject number

    Arms
    Arm title
    		 Experimental
    Arm description
    		 All of trial subjects will receive GRAZAX® as a daily treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GRAZAX
    Investigational medicinal product code
    68398
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    75000SQ-T/tablet The daily dose of trial medication is one tablet, which should preferably be taken in the morning. The tablet is placed under the tongue and swallowing should be avoided for one minute. Eating and drinking is not allowed within five minutes after trial medication intake.

    Number of subjects in period 1
    		Experimental
    Started
    58
    Completed
    37
    Not completed
    21
         Adverse event, serious fatal
    2
         Adverse event, non-fatal
    4
         Breast feeding
    1
         Lost to follow-up
    13
         Protocol deviation
    1
    Period 2
    Period 2 title
    Follow up period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No randomisation and blinding was made as this trial was non-controlled. This period was without treatment.

    Arms
    Arm title
    		 Follow up
    Arm description
    		 2 year follow up
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Follow up
    Started
    37
    Completed
    30
    Not completed
    7
         Consent withdrawn by subject
    2
         Move out of Spain
    3
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 Experimental

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 58 58
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 58 58
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 29 29
        Male
    		 29 29
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    comprised all subjects who received at least one dose of IMP according to the International Conference on Harmonisation (ICH) intent-to-treat principle.The safety analysis set was identical to the FAS.

    Subject analysis set title
    3 year treatment
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Comprising all Per Protocol subjects from Visit 1 to Visit 10 (complete data until end of treatment)

    Subject analysis set title
    3 year treatment + 2 year follow up
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Visit 1 to visit 15

    Subject analysis sets values
    		 FAS 3 year treatment 3 year treatment + 2 year follow up
    Number of subjects
    58
    37
    30
    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)
    58
    37
    30
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    29
    21
    16
        Male
    29
    16
    14

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 All of trial subjects will receive GRAZAX® as a daily treatment.
    Reporting group title
    Follow up
    Reporting group description
    		 2 year follow up

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    comprised all subjects who received at least one dose of IMP according to the International Conference on Harmonisation (ICH) intent-to-treat principle.The safety analysis set was identical to the FAS.

    Subject analysis set title
    3 year treatment
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Comprising all Per Protocol subjects from Visit 1 to Visit 10 (complete data until end of treatment)

    Subject analysis set title
    3 year treatment + 2 year follow up
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Visit 1 to visit 15

    Primary: IgE to Phl p 1 + Phl p 5

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    End point title
    		 IgE to Phl p 1 + Phl p 5 [1]
    End point description
    The present trial is an exploratory trial of immunological changes after 3 year of treatment with GRAZAX and 2 year follow up without treatment. As an example the analysis of IgE to Phl p 1 + Phl p 5 is presented. Other analyses are a full array of specific immunoglobulins and cellular analyses.
    End point type
    Primary
    End point timeframe
    Visit 1 to visit 15
    Notes
    [1] - 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: The trial is an exploratory trial. Endpoints are described by their median values during the three year treatment period at baseline and after 1 week, 1 month, four month, and after peak of grass pollen season and autumn visits. No inferential analyses have been performed.
    End point values
    		 Experimental Follow up 3 year treatment + 2 year follow up
    Number of subjects analysed
    58
    37
    30
    Units: ku/L
        median (standard deviation)
    18.27 ( 35.28 )
    26.92 ( 67.4 )
    13.59 ( 44.92 )
    No statistical analyses for this end point

    Secondary: Global evalutation of rhinoconjunctivitis

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    End point title
    		 Global evalutation of rhinoconjunctivitis
    End point description
    Subject global evaluation of rhinoconjuctivitis in a semiquantitative scale (much better, better, same, worse, much worse) comparing the actual grass pollen season to the previous
    End point type
    Secondary
    End point timeframe
    Yearly (visit 7, 9, 11, 13 and 15) after peak of grass pollen season during 3 years of treatment and 2 years of follow up.
    End point values
    		 FAS
    Number of subjects analysed
    58 [2]
    Units: Subjects
    58
    Attachments
    		 Untitled (Filename: Efficacy Results_160707.pdf)
    Notes
    [2] - Efficacy results are presented in the attached file
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Sep 2009 until December 2014
    Adverse event reporting additional description
    From the first trial related activity after the subject signed the informed consent until the follow- up telephone contact
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 58 (15.52%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abortion late
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Device extrusion
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 58 (100.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 58 (15.52%)
         occurrences all number
    20
    Migraine
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    4
    Immune system disorders
    Oral allergy syndrome
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    5
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    42 / 58 (72.41%)
         occurrences all number
    197
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    13
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    18 / 58 (31.03%)
         occurrences all number
    53
    Throat irritation
         subjects affected / exposed
    38 / 58 (65.52%)
         occurrences all number
    79
    Cough
         subjects affected / exposed
    21 / 58 (36.21%)
         occurrences all number
    46
    Dyspnoea
         subjects affected / exposed
    16 / 58 (27.59%)
         occurrences all number
    29
    Sneezing
         subjects affected / exposed
    14 / 58 (24.14%)
         occurrences all number
    24
    Rhinitis allergic
         subjects affected / exposed
    10 / 58 (17.24%)
         occurrences all number
    12
    Wheezing
         subjects affected / exposed
    10 / 58 (17.24%)
         occurrences all number
    15
    nasal discomfort
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    13
    Nasal congestion
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    8
    Rhinorrhoea
         subjects affected / exposed
    6 / 58 (10.34%)
         occurrences all number
    9
    Dry throat
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    8
    Oropharyngeal pain
         subjects affected / exposed
    6 / 58 (10.34%)
         occurrences all number
    8
    Pharyngeal oedema
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    6
    Dysphonia
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jan 2010
    This amendment is prepared to include new in vitro evaluations in the serum samples and to plan an interim analysis to evaluate the in vitro parameters corresponding to the first month of treatment
    08 Feb 2012
    This amendment was prepared to add a period without IMP treatment (Grazax – Phleum allergy immunotherapy tablet) to determine which of the changes related to the immune system are sustained in the absence of Grazax treatment (sustained effect). Patients will, after the last visit during 2012 pollen season sign for a follow up period of 2 year without Grazax treatment. During the follow up, 5 visits are scheduled to draw samples for immunological assays.

    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/24290282
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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
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