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    Clinical Trial Results:
    A phase III trial investigating the efficacy and safety of Grazax in children aged 5-16 years with grass pollen induced rhinoconjunctivitis with or without asthma

    Summary
    EudraCT number
    		 2006-003415-46
    Trial protocol
    		 DE  
    Global end of trial date
    21 Sep 2007

    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
    GT-12
    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
    Clinical Development, ALK-Abelló, +45 4574 7576, ClinicalTrials@alk.net
    Scientific contact
    Clinical Development, ALK-Abelló, +45 4574 7576, 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
    21 Sep 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of specific immunotherapy with Grazax compared to placebo, in children with grass pollen induced allergic rhinoconjunctivitis.
    Protection of trial subjects
    Safety surveillance Use of symptomatic medications allowed
    Background therapy
    		 Rescue Medication Rhinoconjunctivitis: Loratadine tablets (10 mg), levocabastine eye drops (0.5 mg/ml), budesonide nasal spray (50 μg), prednisolone tablets (5 mg). Asthma: Salbutamol inhaler or spray (0.10%), fluticasone inhaler or spray (125 or 250 μg), prednisolone tablets (5 mg).
    Evidence for comparator
    		 Placebo comparator
    Actual start date of recruitment
    22 Nov 2006
    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
    Germany: 253
    Worldwide total number of subjects
    253
    EEA total number of subjects
    253
    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)
    140
    Adolescents (12-17 years)
    113
    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
    		 253 subjects were recruited by 26 investigators in Germany

    Pre-assignment
    Screening details
    		 307 subjects were screened, 54 were screening failures

    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
    Placebo tablets were similar to the Grazax tablets as regards appearance, smell and taste.

    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
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    1 fast-disolving tablet per day

    Arm title
    		 Grazax
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazax
    Investigational medicinal product code
    Other name
    SQ grass SLIT-tablet
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    1 fast-disolving tablet per day

    Number of subjects in period 1
    		Placebo Grazax
    Started
    127
    126
    Completed
    120
    114
    Not completed
    7
    12
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    2
    4
         Lost to follow-up
    -
    2
         Protocol deviation
    2
    3
         not specified
    2
    3

    Baseline characteristics

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

    Reporting group title
    Grazax
    Reporting group description
    		 Active treatment

    Reporting group values
    		 Placebo Grazax Total
    Number of subjects
    		 127 126 253
    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)
    		 81 86 167
        Adolescents (12-17 years)
    		 46 40 86
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Children 5-16 years
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.1 ( 3.1 ) 10.1 ( 2.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 44 43 87
        Male
    		 83 83 166

    End points

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

    Reporting group title
    Grazax
    Reporting group description
    		 Active treatment

    Primary: Rhinoconjunctivitis Symptom Score

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    End point title
    		 Rhinoconjunctivitis Symptom Score
    End point description
    A total of 6 rhinoconjunctivitis symptoms were evaluated on a scale of 0 to 3, as follows: 0 No symptoms 1 Mild symptoms 2 Moderate symptoms 3 Severe symptoms Nose symptoms: Runny nose, Blocked nose, Sneezing, Itchy nose Eye symptoms: Gritty feeling / red/itchy eyes, Watery eyes
    End point type
    Primary
    End point timeframe
    during the grass pollen season
    End point values
    		 Placebo Grazax
    Number of subjects analysed
    121 [1]
    117 [2]
    Units: score unit
        arithmetic mean (standard deviation)
    3.2 ( 2.1 )
    2.7 ( 2.4 )
    Notes
    [1] - all who provided diary data during the grass pollen season
    [2] - all who provided diary data during the grass pollen season
    Statistical analysis title
    		 Analysis of average rhinoconjunctivitis symptom sc
    Statistical analysis description
    Parametric analysis: ANOVA, square-root-transformed data, adjusted means with 95% confidence intervals backtransformed by squaring
    Comparison groups
    Placebo v Grazax
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0215
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1.15
    Variability estimate
    Standard deviation

    Secondary: Rhinoconjunctivitis medication score

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    End point title
    		 Rhinoconjunctivitis medication score
    End point description
    The average daily rhinoconjunctivitis medication scores over the entire grass pollen season
    End point type
    Secondary
    End point timeframe
    During the entire grass pollen season
    End point values
    		 Placebo Grazax
    Number of subjects analysed
    121 [3]
    117 [4]
    Units: score units
        median (confidence interval 95%)
    1.19 (0.74 to 2.64)
    0.78 (0.43 to 1.3)
    Notes
    [3] - Subjects with diary data during the grass pollen season
    [4] - Subjects with diary data during the grass pollen season
    Statistical analysis title
    		 Analysis of average rhinoconjunctivitis medication
    Statistical analysis description
    Analysis of average rhinoconjunctivitis medication score, entire grass pollen season (FAS)
    Comparison groups
    Placebo v Grazax
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0156
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.68
    Variability estimate
    Standard deviation
    Notes
    [5] - A parametric ANOVA could not be performed for the average rhinoconjunctivitis medication score, since neither the untransformed data, nor transformed data fulfilled the assumption of normal distribution. A non-parametric analysis was performed using the Wilcoxon rank sum test.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent to end of trial
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    6.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Grazax
    Reporting group description
    		 Active treatment

    Serious adverse events
    		 Placebo Grazax
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 127 (1.57%)
    2 / 126 (1.59%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Grazax
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 127 (83.46%)
    109 / 126 (86.51%)
    Gastrointestinal disorders
    Oral pruritus
         subjects affected / exposed
    3 / 127 (2.36%)
    39 / 126 (30.95%)
         occurrences all number
    3
    49
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    12 / 127 (9.45%)
    6 / 126 (4.76%)
         occurrences all number
    15
    6
    Cough
         subjects affected / exposed
    14 / 127 (11.02%)
    8 / 126 (6.35%)
         occurrences all number
    17
    9
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 127 (8.66%)
    12 / 126 (9.52%)
         occurrences all number
    18
    14
    Viral infection
         subjects affected / exposed
    13 / 127 (10.24%)
    23 / 126 (18.25%)
         occurrences all number
    14
    25

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Oct 2006
    pre-trial - incorporation of comments given by competent authorities

    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.
    Not applicable

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/19130937
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