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    Clinical Trial Results:
    A dose-response evaluation of ALK tree AIT

    Summary
    EudraCT number
    		 2012-000031-59
    Trial protocol
    		 LT   FI   NO   SE   NL   PL   DK  
    Global end of trial date
    05 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Feb 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TT-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALK-Abelló
    Sponsor organisation address
    Bøge Allé 1, Hørsholm, Denmark, 2970
    Public contact
    Global Clinical Development, ALK-Abelló A/S, +45 45747576, ClinicalTrials@alk.net
    Scientific contact
    Global Clinical Development, ALK-Abelló A/S, +45 45747576, ClinicalTrials@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
    05 Jul 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To identify an optimal dose interval with respect to efficacy and safety for the ALK tree AIT in adults and adolescents with moderate to severe birch pollen induced allergic rhinoconjunctivitis.
    Protection of trial subjects
    Rescue medication for residual sypmtoms allowed Ongoing safety surveillance
    Background therapy
    		 Subjects received open-labelled pharmacotherapy for rhinoconjunctivitis symptoms. In case of asthma symptoms, subjects were free to use their regular controller and reliever medications.
    Evidence for comparator
    		 Placebo comparator
    Actual start date of recruitment
    20 Aug 2012
    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
    Norway: 24
    Country: Number of subjects enrolled
    Netherlands: 60
    Country: Number of subjects enrolled
    Poland: 100
    Country: Number of subjects enrolled
    Sweden: 120
    Country: Number of subjects enrolled
    Denmark: 100
    Country: Number of subjects enrolled
    Finland: 100
    Country: Number of subjects enrolled
    Lithuania: 133
    Worldwide total number of subjects
    637
    EEA total number of subjects
    637
    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)
    57
    Adults (18-64 years)
    577
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial included 65 sites in 7 European countries: Denmark, Finland, Lithuania, The Netherlands, Norway, Poland, Sweden. 773 subjects were screened and 637 subjects were randomised.

    Pre-assignment
    Screening details
    		 136 subjects were screening failures. Common reasons for screening failures were negative SPT to Betula verrucosa, specific IgE <class 2, or clinically relevant perennial allergic rhinitis or asthma.

    Period 1
    Period 1 title
    Overall trial (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
    The placebo tablets were similar to the active IMP in appearance, smell and taste. The randomisation code was not broken for any subject during the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP in this trial was 1 tablet, which should be taken at the same time each day; preferably in the morning. Instructions were to carefully remove the foil from the back of tablet blister card, to take out the tablet with dry fingers and to place the tablet under the tongue. Swallowing was to be avoided for 1 minute and eating and drinking was not allowed within 5 minutes after intake of the tablet.

    Arm title
    		 Tree SLIT-tablet 0.5 DU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tree SLIT-tablet 0.5 DU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP in this trial was 1 tablet, which should be taken at the same time each day; preferably in the morning. Instructions were to carefully remove the foil from the back of tablet blister card, to take out the tablet with dry fingers and to place the tablet under the tongue. Swallowing was to be avoided for 1 minute and eating and drinking was not allowed within 5 minutes after intake of the tablet.

    Arm title
    		 Tree SLIT-tablet 1 DU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tree SLIT-tablet 1 DU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP in this trial was 1 tablet, which should be taken at the same time each day; preferably in the morning. Instructions were to carefully remove the foil from the back of tablet blister card, to take out the tablet with dry fingers and to place the tablet under the tongue. Swallowing was to be avoided for 1 minute and eating and drinking was not allowed within 5 minutes after intake of the tablet.

    Arm title
    		 Tree SLIT tablet 2 DU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tree SLIT-tablet 2 DU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP in this trial was 1 tablet, which should be taken at the same time each day; preferably in the morning. Instructions were to carefully remove the foil from the back of tablet blister card, to take out the tablet with dry fingers and to place the tablet under the tongue. Swallowing was to be avoided for 1 minute and eating and drinking was not allowed within 5 minutes after intake of the tablet.

    Arm title
    		 Tree SLIT-tablet 4 DU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tree SLIT-tablet 4 DU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP in this trial was 1 tablet, which should be taken at the same time each day; preferably in the morning. Instructions were to carefully remove the foil from the back of tablet blister card, to take out the tablet with dry fingers and to place the tablet under the tongue. Swallowing was to be avoided for 1 minute and eating and drinking was not allowed within 5 minutes after intake of the tablet.

    Arm title
    		 Tree SLIT-tablet 7 DU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tree SLIT-tablet 7 DU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP in this trial was 1 tablet, which should be taken at the same time each day; preferably in the morning. Instructions were to carefully remove the foil from the back of tablet blister card, to take out the tablet with dry fingers and to place the tablet under the tongue. Swallowing was to be avoided for 1 minute and eating and drinking was not allowed within 5 minutes after intake of the tablet.

    Arm title
    		 Tree SLIT-tablet 12 DU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tree SLIT-tablet 12 DU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP in this trial was 1 tablet, which should be taken at the same time each day; preferably in the morning. Instructions were to carefully remove the foil from the back of tablet blister card, to take out the tablet with dry fingers and to place the tablet under the tongue. Swallowing was to be avoided for 1 minute and eating and drinking was not allowed within 5 minutes after intake of the tablet.

    Number of subjects in period 1
    		Placebo Tree SLIT-tablet 0.5 DU Tree SLIT-tablet 1 DU Tree SLIT tablet 2 DU Tree SLIT-tablet 4 DU Tree SLIT-tablet 7 DU Tree SLIT-tablet 12 DU
    Started
    88
    93
    90
    89
    92
    88
    97
    Completed
    76
    83
    82
    83
    83
    77
    84
    Not completed
    12
    10
    8
    6
    9
    11
    13
         Consent withdrawn by subject
    5
    -
    1
    -
    2
    1
    3
         Adverse event, non-fatal
    3
    7
    7
    3
    4
    9
    7
         Not specified
    1
    2
    -
    1
    1
    -
    2
         Lost to follow-up
    2
    -
    -
    -
    -
    1
    -
         Lack of efficacy
    1
    -
    -
    -
    -
    -
    -
         Protocol deviation
    -
    1
    -
    2
    2
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 0.5 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 1 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT tablet 2 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 4 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 7 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 12 DU
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Tree SLIT-tablet 0.5 DU Tree SLIT-tablet 1 DU Tree SLIT tablet 2 DU Tree SLIT-tablet 4 DU Tree SLIT-tablet 7 DU Tree SLIT-tablet 12 DU Total
    Number of subjects
    		 88 93 90 89 92 88 97 637
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 5 7 8 12 9 9 7 57
        Adults (18-64 years)
    		 83 86 81 76 83 78 90 577
        From 65-84 years
    		 0 0 1 1 0 1 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.6 ( 12.6 ) 34.7 ( 13.1 ) 35.4 ( 13.3 ) 36.2 ( 13.5 ) 35.5 ( 13.4 ) 36.6 ( 13.5 ) 37.5 ( 12.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 40 44 45 48 46 38 48 309
        Male
    		 48 49 45 41 46 50 49 328

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 0.5 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 1 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT tablet 2 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 4 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 7 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 12 DU
    Reporting group description
    		 -

    Primary: average rhinoconjunctivitis daily symptom score

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    End point title
    		 average rhinoconjunctivitis daily symptom score
    End point description
    The average rhinoconjunctivitis daily symptom score during the birch pollen season (calculated for each subject as the sum of the rhinoconjunctivitis individual daily symptom score during the birch pollen season divided by the number of days with diary records in the birch pollen season)
    End point type
    Primary
    End point timeframe
    During the birch pollen season (defined by limits of 10 grains/m3)
    End point values
    		 Placebo Tree SLIT-tablet 0.5 DU Tree SLIT-tablet 1 DU Tree SLIT tablet 2 DU Tree SLIT-tablet 4 DU Tree SLIT-tablet 7 DU Tree SLIT-tablet 12 DU
    Number of subjects analysed
    58 [1]
    71 [2]
    68 [3]
    71 [4]
    65 [5]
    62 [6]
    58 [7]
    Units: symptom score units
        arithmetic mean (confidence interval 95%)
    3.4 (2.7 to 4.3)
    3.1 (2.4 to 3.9)
    3.8 (3 to 4.6)
    3.5 (2.7 to 4.4)
    3.4 (2.7 to 4.2)
    2.3 (1.7 to 3)
    2.9 (2.2 to 3.7)
    Notes
    [1] - subjects with no major protocol deviations that might influence the primary endpoint
    [2] - subjects with no major protocol deviations that might influence the primary endpoint
    [3] - subjects with no major protocol deviations that might influence the primary endpoint
    [4] - subjects with no major protocol deviations that might influence the primary endpoint
    [5] - subjects with no major protocol deviations that might influence the primary endpoint
    [6] - subjects with no major protocol deviations that might influence the primary endpoint
    [7] - subjects with no major protocol deviations that might influence the primary endpoint
    Statistical analysis title
    		 daily symptom score, 12 DU vs placebo
    Comparison groups
    Tree SLIT-tablet 12 DU v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.2992
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 1.6
    Notes
    [8] - The primary endpoint, the average rhinoconjunctivitis daily symptom score, was planned to be analysed by fitting appropriate dose response curves. However, as the daily symptom score did not display a dose response relationship (due to modest pollen exposure), none of the planned models for fitting the data were appropriate to execute and the data was instead presented as pairwise comparisons.
    Statistical analysis title
    		 daily symptom score, 7 DU vs placebo
    Comparison groups
    Placebo v Tree SLIT-tablet 7 DU
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0189
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 2.1
    Notes
    [9] - The primary endpoint, the average rhinoconjunctivitis daily symptom score, was planned to be analysed by fitting appropriate dose response curves. However, as the daily symptom score did not display a dose response relationship (due to modest pollen exposure), none of the planned models for fitting the data were appropriate to execute and the data was instead presented as pairwise comparisons.
    Statistical analysis title
    		 daily symptom score, 4 DU vs placebo
    Comparison groups
    Placebo v Tree SLIT-tablet 4 DU
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.907
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1
    Notes
    [10] - The primary endpoint, the average rhinoconjunctivitis daily symptom score, was planned to be analysed by fitting appropriate dose response curves. However, as the daily symptom score did not display a dose response relationship (due to modest pollen exposure), none of the planned models for fitting the data were appropriate to execute and the data was instead presented as pairwise comparisons.
    Statistical analysis title
    		 daily symptom score, 2 DU vs placebo
    Comparison groups
    Placebo v Tree SLIT tablet 2 DU
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.9571
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 1
    Notes
    [11] - The primary endpoint, the average rhinoconjunctivitis daily symptom score, was planned to be analysed by fitting appropriate dose response curves. However, as the daily symptom score did not display a dose response relationship (due to modest pollen exposure), none of the planned models for fitting the data were appropriate to execute and the data was instead presented as pairwise comparisons.
    Statistical analysis title
    		 daily symptom score, 1 DU vs placebo
    Comparison groups
    Placebo v Tree SLIT-tablet 1 DU
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.5132
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.7
    Notes
    [12] - The primary endpoint, the average rhinoconjunctivitis daily symptom score, was planned to be analysed by fitting appropriate dose response curves. However, as the daily symptom score did not display a dose response relationship (due to modest pollen exposure), none of the planned models for fitting the data were appropriate to execute and the data was instead presented as pairwise comparisons.
    Statistical analysis title
    		 daily symptom score, 0.5 DU vs placebo
    Comparison groups
    Placebo v Tree SLIT-tablet 0.5 DU
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.5277
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1.3
    Notes
    [13] - The primary endpoint, the average rhinoconjunctivitis daily symptom score, was planned to be analysed by fitting appropriate dose response curves. However, as the daily symptom score did not display a dose response relationship (due to modest pollen exposure), none of the planned models for fitting the data were appropriate to execute and the data was instead presented as pairwise comparisons.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from signing the informed consent form until end of trial
    Adverse event reporting additional description
    Pre-planned procedures and pre-existing conditions found as a result of screening procedures were not considered adverse events. Common signs and symptoms of rhinoconjunctivitis should also not be recorded as adverse events unless there was a clear temporal relationship to IMP administration or the event meet the definition of a serious event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 0.5 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 1 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT tablet 2 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 4 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 7 DU
    Reporting group description
    		 -

    Reporting group title
    Tree SLIT-tablet 12 DU
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Tree SLIT-tablet 0.5 DU Tree SLIT-tablet 1 DU Tree SLIT tablet 2 DU Tree SLIT-tablet 4 DU Tree SLIT-tablet 7 DU Tree SLIT-tablet 12 DU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    1 / 90 (1.11%)
    2 / 89 (2.25%)
    1 / 92 (1.09%)
    0 / 88 (0.00%)
    5 / 97 (5.15%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid adenoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
    0 / 88 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
    0 / 88 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
    0 / 88 (0.00%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal growth restriction
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
    0 / 88 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
    0 / 88 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 92 (0.00%)
    0 / 88 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 92 (0.00%)
    0 / 88 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 93 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 92 (1.09%)
    0 / 88 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tree SLIT-tablet 0.5 DU Tree SLIT-tablet 1 DU Tree SLIT tablet 2 DU Tree SLIT-tablet 4 DU Tree SLIT-tablet 7 DU Tree SLIT-tablet 12 DU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 88 (80.68%)
    85 / 93 (91.40%)
    78 / 90 (86.67%)
    83 / 89 (93.26%)
    86 / 92 (93.48%)
    82 / 88 (93.18%)
    89 / 97 (91.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 88 (15.91%)
    14 / 93 (15.05%)
    12 / 90 (13.33%)
    13 / 89 (14.61%)
    14 / 92 (15.22%)
    11 / 88 (12.50%)
    9 / 97 (9.28%)
         occurrences all number
    22
    25
    19
    22
    16
    27
    19
    Gastrointestinal disorders
    Oedema mouth
         subjects affected / exposed
    0 / 88 (0.00%)
    8 / 93 (8.60%)
    14 / 90 (15.56%)
    12 / 89 (13.48%)
    20 / 92 (21.74%)
    21 / 88 (23.86%)
    14 / 97 (14.43%)
         occurrences all number
    0
    11
    21
    12
    30
    31
    29
    Oral pruritus
         subjects affected / exposed
    13 / 88 (14.77%)
    48 / 93 (51.61%)
    46 / 90 (51.11%)
    47 / 89 (52.81%)
    57 / 92 (61.96%)
    56 / 88 (63.64%)
    60 / 97 (61.86%)
         occurrences all number
    16
    71
    73
    79
    116
    75
    104
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    6 / 88 (6.82%)
    21 / 93 (22.58%)
    14 / 90 (15.56%)
    27 / 89 (30.34%)
    31 / 92 (33.70%)
    28 / 88 (31.82%)
    28 / 97 (28.87%)
         occurrences all number
    6
    27
    15
    34
    42
    33
    39
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 88 (20.45%)
    17 / 93 (18.28%)
    15 / 90 (16.67%)
    17 / 89 (19.10%)
    20 / 92 (21.74%)
    12 / 88 (13.64%)
    17 / 97 (17.53%)
         occurrences all number
    31
    27
    19
    23
    37
    20
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2012
    Before FSFV - minor general corrections and change of inclusion criterion i8.d (relating to breast-feeding) to an exclusion criterion (e24)
    06 Mar 2013
    An error in the protocol was corrected regarding the use of other antihistamines than those provided as pharmacotherapy

    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.
    The trial was carried out in a pollen season that was unusually low for birch as well as alder and hazel pollen counts. The low pollen exposure is a likely explanation for the inability to identify a dose response for the primary efficacy endpoint.
    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
    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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