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    Clinical Trial Results:
    GAP - Grazax Asthma Prevention

    Summary
    EudraCT number
    		 2009-011235-12
    Trial protocol
    		 FR   DE   FI   DK   GB   SE   AT   ES  
    Global end of trial date
    30 Sep 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Jul 2016
    First version publication date
    05 Jun 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    correction of data

    Trial information

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    Trial identification
    Sponsor protocol code
    GT-21
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALK
    Sponsor organisation address
    Bøge Alle 1, Hørsholm, Denmark, 2970
    Public contact
    Global Clinical Development, ALK, 45 45747576, clinicaltrials@alk.net
    Scientific contact
    Global Clinical Development, ALK, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of Grazax compared to placebo on the risk of developing asthma during 3 treatment years and 2 post-treatment years
    Protection of trial subjects
    Safety surveillance Access to symptomatic pharmacotherapy if needed.
    Background therapy
    		 Allergic rhinoconjunctivitis pharmacotherapy: At the winter visits, the subjects were provided with one standard panel box of ARC pharmacotherapy for use on a voluntarily basis: •Loratadine tablets, 10 mg or desloratadine syrup 0.5 mg/ml •Olopatadine eye drops, 1 mg/ml •Budesonide nasal spray, 32 or 64 μg/dose or fluticasone propionate nasal spray 50 μg/dose (in UK) Any other use of ARC medication was allowed but not provided by the sponsor. Asthma pharmacotherapy: A standard panel of asthma pharmacotherapy was at the investigators disposal. The asthma pharmacotherapy provided was: •Salbutamol for inhalation, 100 μg/dose •Fluticasone for inhalation, 100 μg/dose •Prednisolone tablets, 5 mg It was at the discretion of the investigator’s to prescribe asthma pharmacotherapy to the subjects. Any other use of asthma medication was acceptable, except for medication listed as prohibited concomitant medication.
    Evidence for comparator
    		 Placebo comparator
    Actual start date of recruitment
    24 Nov 2009
    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: 36
    Country: Number of subjects enrolled
    Poland: 103
    Country: Number of subjects enrolled
    Spain: 106
    Country: Number of subjects enrolled
    Sweden: 119
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    Austria: 25
    Country: Number of subjects enrolled
    Denmark: 117
    Country: Number of subjects enrolled
    Finland: 44
    Country: Number of subjects enrolled
    France: 112
    Country: Number of subjects enrolled
    Germany: 110
    Country: Number of subjects enrolled
    Switzerland: 16
    Worldwide total number of subjects
    812
    EEA total number of subjects
    796
    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)
    754
    Adolescents (12-17 years)
    58
    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
    		 Subjects were recruited from 101 sites in 11 countries (AT, CH, DE, DK, ES, FI, FR, GB, NO, PL, SE) First subject first visit  24 November 2009 Last subject last visit  30 September 2015

    Pre-assignment
    Screening details
    		 Selection criteria Females or males 5-12 years of age at time of randomisation, clinically relevant history of grass pollen ARC requiring symptomatic treatment for 2 years, positive SPT response and specific IgE to Phleum pratense, no other relevant allergies overlapping the grass pollen season, no signs or symptoms of asthma

    Period 1
    Period 1 title
    Trial period (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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Grazax
    Arm description
    		 Active treatment group: Grazax 75,000 SQ-T
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral lyophilisate
    Routes of administration
    Sublingual use
    Dosage and administration details
    The daily dose of IMP was one lyophilisate [tablet], preferably taken in the morning. The tablet was placed under the tongue, and swallowing was to be avoided for one minute. In addition, eating and drinking was not allowed within 5 minutes after intake of IMP.

    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 was one lyophilisate [tablet], preferably taken in the morning. The tablet was placed under the tongue, and swallowing was to be avoided for one minute. In addition, eating and drinking was not allowed within 5 minutes after intake of IMP.

    Number of subjects in period 1
    		Grazax Placebo
    Started
    398
    414
    Completed
    300
    308
    Not completed
    98
    106
         Consent withdrawn by subject
    14
    22
         Adverse event, non-fatal
    39
    13
         Lost to follow-up
    14
    22
         Protocol deviation
    20
    24
         not specified
    11
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Grazax
    Reporting group description
    		 Active treatment group: Grazax 75,000 SQ-T

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Grazax Placebo Total
    Number of subjects
    		 398 414 812
    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)
    		 372 382 754
        Adolescents (12-17 years)
    		 26 32 58
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.5 ± 2.1 8.7 ± 2.1 -
    Gender categorical
    Units: Subjects
        Female
    		 143 158 301
        Male
    		 255 256 511
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was used for efficacy analyses. The safety analysis set and FAS were identical and comprised a total of 812 subjects; 398 subjects in the Grazax group, and 414 subjects in the placebo group

    Subject analysis sets values
    		 FAS
    Number of subjects
    812
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    754
        Adolescents (12-17 years)
    58
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.6 ± 2.1
    Gender categorical
    Units: Subjects
        Female
    301
        Male
    511

    End points

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    End points reporting groups
    Reporting group title
    Grazax
    Reporting group description
    		 Active treatment group: Grazax 75,000 SQ-T

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was used for efficacy analyses. The safety analysis set and FAS were identical and comprised a total of 812 subjects; 398 subjects in the Grazax group, and 414 subjects in the placebo group

    Primary: time to onset of asthma according to protocol definition

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    End point title
    		 time to onset of asthma according to protocol definition
    End point description
    The primary endpoint was the time to onset of asthma according to protocol definition measured in days from randomisation
    End point type
    Primary
    End point timeframe
    from randomisation to end of trial
    End point values
    		 Grazax Placebo
    Number of subjects analysed
    398
    414
    Units: number of subject with dagnosis
    34
    39
    Statistical analysis title
    		 Time to onset of asthma by protocol criteria
    Statistical analysis description
    The primary endpoint was the time to onset of asthma by protocol criteria measured in days from randomisation (largely based on reversible impairment of lung function). For subjects with not fulfilling the asthma criteria, the time was right-censored at the end of trial visit . Subjects who discontinued were right-censored at the date of discontinuation.
    Comparison groups
    Grazax v Placebo
    Number of subjects included in analysis
    812
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.43

    Secondary: Asthma status at end of trial

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    End point title
    		 Asthma status at end of trial
    End point description
    Number of subjects Odds-ratio for not experiencing asthma symptoms or using asthma medication
    End point type
    Secondary
    End point timeframe
    the last 'between visits' period trial of the trial - roughly from January 2015- August 2015, with observations carried forward for subjects not compleeting the trial
    End point values
    		 Grazax Placebo
    Number of subjects analysed
    377
    398
    Units: number of subjects without symptoms/med
    318
    317
    Statistical analysis title
    		 Asthma symptom and medication status
    Statistical analysis description
    Asthma symptom and medication status since last visit at end of trial; the analysis of the odds for not having any asthma symptoms and any asthma medication use was performed with a generalised logistic regression analysis. The adjusted OR for having an asthma symptom and asthma medication free period at the end of trial visit was estimated with the two-sided 95% CI. For subjects discontinuing prematurely, last observation was carried forward
    Comparison groups
    Grazax v Placebo
    Number of subjects included in analysis
    775
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 2.22

    Secondary: Allergic rhinoconjunctivitis VAS score

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    End point title
    		 Allergic rhinoconjunctivitis VAS score
    End point description
    The allergic rhinoconjunctivitis symptoms were evaluated yearly at the GPS visits by answering 'How has your hay fever been the last week?' on a VAS. The VAS score was evaluated on a scale from 0 (no symptoms) to 100 mm (severe symptoms).
    End point type
    Secondary
    End point timeframe
    Measured for each of the 5 grass pollen seasons in the trial - reported here for year 5 (2015) - the second treatment-free follow year of the trial
    End point values
    		 Grazax Placebo
    Number of subjects analysed
    300 [1]
    309 [2]
    Units: VAS score
        arithmetic mean (confidence interval 95%)
    19.6 (16 to 23.3)
    25.5 (21.7 to 29.3)
    Notes
    [1] - Subjects reporting VAS score during the 2015 grass pollen season
    [2] - Subjects reporting VAS score during the 2015 grass pollen season
    Statistical analysis title
    		 VAS scoring of rhinoconjunctivitis symptoms
    Statistical analysis description
    The yearly VAS scoring of ARC symptoms at the GPS visits was evaluated with a repeated measures analysis. Treatment, visit and treatment by visit were included as fixed effects, baseline VAS as covariate and country as random effect. Data included here is for the fifth year of the trial (2015) - the second treatment-free follow-up year.
    Comparison groups
    Grazax v Placebo
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.18
         upper limit
    		 9.43

    Secondary: Allergic rhinoconjunctivitis medication score

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    End point title
    		 Allergic rhinoconjunctivitis medication score
    End point description
    The use of allergic rhinoconjunctivitis medication was recorded daily during the 14 days prior to the grass pollen visit in 2015. The total daily allergic rhinoconjunctivitis medication score was calculated as the sum of the total daily scores for each medication (Antihistamine tablet: 6 points per tablets, eye drops: 1.5 points per drop, nasal spray: 1 point per puff). The average allergic rhinoconjunctivitis medication score was calculated as the average of total daily allergic rhinoconjunctivitis medication score based on observed data during the 14 days of recording.
    End point type
    Secondary
    End point timeframe
    14 days prior to the grass pollen visit in 2015
    End point values
    		 Grazax Placebo
    Number of subjects analysed
    241 [3]
    263 [4]
    Units: Medication score
        arithmetic mean (confidence interval 95%)
    15.17 (12.71 to 17.85)
    19.54 (16.9 to 22.38)
    Notes
    [3] - Subjects reporting daily medication for 14 days prior to the grass pollen season visit 2015
    [4] - Subjects reporting daily medication for 14 days prior to the grass pollen season visit 2015
    Statistical analysis title
    		 Allergic rhinoconjunctivitis medication score
    Statistical analysis description
    The average daily allergic rhinoconjunctivitis medication score prior to the 2015 GPS visit was evaluated with a LME model. The average allergic rhinoconjunctivitis medication score was the response variable, treatment was a fixed class effect and country was a random class variable.
    Comparison groups
    Grazax v Placebo
    Number of subjects included in analysis
    504
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.35
         upper limit
    		 7.41

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the entire trial
    Adverse event reporting additional description
    All events meeting the definition of an AE were collected and reported from the first trial-related activity after the subject signed the informed consent and until the end of trial. Adverse events were defined according to ICH Harmonised Tripartite Guideline E2A, Step 5
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    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
    30 / 414 (7.25%)
    43 / 398 (10.80%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign salivary gland neoplasm
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Tympanoplasty
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (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
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 398 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord disorder
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Somatisation disorder
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    2 / 414 (0.48%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hereditary haemochromatosis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningomyelocele
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 398 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 414 (0.00%)
    3 / 398 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 414 (0.24%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 398 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland cyst
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver injury
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral meatus stenosis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee deformity
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 414 (0.48%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    4 / 414 (0.97%)
    6 / 398 (1.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    2 / 414 (0.48%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Borrelia infection
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchopneumonia
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 414 (0.48%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 414 (0.00%)
    2 / 398 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 414 (0.48%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal osteomyelitis
         subjects affected / exposed
    1 / 414 (0.24%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 414 (0.00%)
    1 / 398 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    2 / 414 (0.48%)
    0 / 398 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    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
    385 / 414 (93.00%)
    380 / 398 (95.48%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    37 / 414 (8.94%)
    45 / 398 (11.31%)
         occurrences all number
    82
    74
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    29 / 414 (7.00%)
    16 / 398 (4.02%)
         occurrences all number
    37
    17
    Pyrexia
         subjects affected / exposed
    30 / 414 (7.25%)
    28 / 398 (7.04%)
         occurrences all number
    39
    35
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    13 / 414 (3.14%)
    22 / 398 (5.53%)
         occurrences all number
    16
    28
    Seasonal allergy
         subjects affected / exposed
    22 / 414 (5.31%)
    22 / 398 (5.53%)
         occurrences all number
    29
    29
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    224 / 414 (54.11%)
    145 / 398 (36.43%)
         occurrences all number
    393
    248
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    19 / 414 (4.59%)
    21 / 398 (5.28%)
         occurrences all number
    21
    25
    Oral pruritus
         subjects affected / exposed
    7 / 414 (1.69%)
    131 / 398 (32.91%)
         occurrences all number
    7
    164
    Tongue pruritus
         subjects affected / exposed
    1 / 414 (0.24%)
    22 / 398 (5.53%)
         occurrences all number
    6
    23
    Vomiting
         subjects affected / exposed
    20 / 414 (4.83%)
    26 / 398 (6.53%)
         occurrences all number
    23
    36
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    50 / 414 (12.08%)
    28 / 398 (7.04%)
         occurrences all number
    74
    42
    Cough
         subjects affected / exposed
    83 / 414 (20.05%)
    68 / 398 (17.09%)
         occurrences all number
    129
    106
    Dyspnoea
         subjects affected / exposed
    41 / 414 (9.90%)
    30 / 398 (7.54%)
         occurrences all number
    62
    40
    Dyspnoea exertional
         subjects affected / exposed
    22 / 414 (5.31%)
    10 / 398 (2.51%)
         occurrences all number
    32
    18
    Oropharyngeal pain
         subjects affected / exposed
    21 / 414 (5.07%)
    26 / 398 (6.53%)
         occurrences all number
    24
    36
    Rhinitis allergic
         subjects affected / exposed
    23 / 414 (5.56%)
    17 / 398 (4.27%)
         occurrences all number
    29
    23
    Throat irritation
         subjects affected / exposed
    5 / 414 (1.21%)
    52 / 398 (13.07%)
         occurrences all number
    5
    61
    Wheezing
         subjects affected / exposed
    32 / 414 (7.73%)
    19 / 398 (4.77%)
         occurrences all number
    48
    28
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    27 / 414 (6.52%)
    24 / 398 (6.03%)
         occurrences all number
    31
    27
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    248 / 414 (59.90%)
    211 / 398 (53.02%)
         occurrences all number
    781
    655
    Bronchitis
         subjects affected / exposed
    29 / 414 (7.00%)
    29 / 398 (7.29%)
         occurrences all number
    44
    47
    Conjunctivitis
         subjects affected / exposed
    24 / 414 (5.80%)
    26 / 398 (6.53%)
         occurrences all number
    30
    34
    Ear infection
         subjects affected / exposed
    15 / 414 (3.62%)
    22 / 398 (5.53%)
         occurrences all number
    22
    23
    Gastroenteritis
         subjects affected / exposed
    71 / 414 (17.15%)
    65 / 398 (16.33%)
         occurrences all number
    104
    89
    Influenza
         subjects affected / exposed
    54 / 414 (13.04%)
    49 / 398 (12.31%)
         occurrences all number
    67
    63
    Otitis media
         subjects affected / exposed
    13 / 414 (3.14%)
    22 / 398 (5.53%)
         occurrences all number
    16
    26
    Pharyngitis
         subjects affected / exposed
    53 / 414 (12.80%)
    43 / 398 (10.80%)
         occurrences all number
    78
    76
    Respiratory tract infection
         subjects affected / exposed
    15 / 414 (3.62%)
    22 / 398 (5.53%)
         occurrences all number
    26
    48
    Rhinitis
         subjects affected / exposed
    29 / 414 (7.00%)
    26 / 398 (6.53%)
         occurrences all number
    36
    32
    Tonsillitis
         subjects affected / exposed
    43 / 414 (10.39%)
    41 / 398 (10.30%)
         occurrences all number
    61
    70
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 414 (5.07%)
    23 / 398 (5.78%)
         occurrences all number
    29
    34
    Viral infection
         subjects affected / exposed
    56 / 414 (13.53%)
    60 / 398 (15.08%)
         occurrences all number
    85
    89

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Apr 2010
    Changes to pharmacotherapy and asthma diagnosis criteria (after PEI scientific advice)
    04 Feb 2011
    Update to the master patient/parent/guardian information sheet and informed consent (all subjects were asked to re-consent)
    30 Jun 2011
    Change in discontinuation criteria (deletion of requirement of less than 100 days of IMP interruption)
    27 Feb 2012
    Change of timing of primary analyses from year 3 (after end of treatment) to year 5 (end of trial)
    28 Jan 2015
    Addition of allergic rhinoconjunctivitis pamphlet for GPS 2015 Addition of blood sample for future pharmacogenetic analyses Specification of immunological analyses Clarify that worst case severity of AEs should be kept throughout the trial Clarify that the authorship policy listed in the Vancouver Declaration will be followed for the primary publication

    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.
    No objective asthma diagnosis exists. The diagnosis used was based on advice from experts and regulators; it relied on symptoms and reversible impairment of lung function. However, lung function tests in this population turned out to lack sensitivity

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21999887
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